U.S. patent application number 17/088718 was filed with the patent office on 2021-02-25 for 9-aminomethyl minocycline compounds and use thereof in treating community-acquired bacterial pneumonia (cabp).
This patent application is currently assigned to Paratek Pharmaceuticals, Inc.. The applicant listed for this patent is Paratek Pharmaceuticals, Inc.. Invention is credited to Lynne Garrity-Ryan, Amy L. Manley, Paul McGovern, S. Ken Tanaka, Evangelos L. Tzanis.
Application Number | 20210052609 17/088718 |
Document ID | / |
Family ID | 1000005199066 |
Filed Date | 2021-02-25 |
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United States Patent
Application |
20210052609 |
Kind Code |
A1 |
Tzanis; Evangelos L. ; et
al. |
February 25, 2021 |
9-Aminomethyl Minocycline Compounds And Use Thereof In Treating
Community-Acquired Bacterial Pneumonia (CABP)
Abstract
The invention disclosed herein provides a method for treating
Community-Acquired Bacterial Pneumonia (CABP) using
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt
thereof, in either oral or IV doses or a combination of both.
Inventors: |
Tzanis; Evangelos L.;
(Newtown Square, PA) ; McGovern; Paul; (Berwyn,
PA) ; Manley; Amy L.; (Phoenixville, PA) ;
Garrity-Ryan; Lynne; (Melrose, MA) ; Tanaka; S.
Ken; (Bellevue, WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Paratek Pharmaceuticals, Inc. |
Boston |
MA |
US |
|
|
Assignee: |
Paratek Pharmaceuticals,
Inc.
Boston
MA
Paratek Pharmaceuticals, Inc.
Boston
MA
|
Family ID: |
1000005199066 |
Appl. No.: |
17/088718 |
Filed: |
November 4, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16507410 |
Jul 10, 2019 |
10835542 |
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17088718 |
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15798573 |
Oct 31, 2017 |
10383884 |
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16507410 |
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62514415 |
Jun 2, 2017 |
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62500611 |
May 3, 2017 |
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62480516 |
Apr 2, 2017 |
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62422843 |
Nov 16, 2016 |
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62416010 |
Nov 1, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0053 20130101;
A61P 11/00 20180101; A61P 31/04 20180101; A61K 31/65 20130101; Y02A
50/30 20180101; A61K 9/0019 20130101 |
International
Class: |
A61K 31/65 20060101
A61K031/65; A61K 9/00 20060101 A61K009/00; A61P 11/00 20060101
A61P011/00; A61P 31/04 20060101 A61P031/04 |
Claims
1. A method of treating Community-Acquired Bacterial Pneumonia
(CABP) in a subject in need of treatment thereof, comprising
administering to said subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) three intravenous doses of about 100
mg each, administered 12 hours apart, followed by, (2) one or more
intravenous doses of about 100 mg each, each administered 24 hours
following the immediate preceding intravenous dose, followed by,
(3) optionally, one oral dose of about 300 mg, administered in the
morning and 12-24 hrs after the immediate preceding intravenous
dose, followed by, (4) optionally, one or more oral doses of about
300 mg each, each administered 24 hours following the immediate
preceding oral dose, such that said subject is treated.
2. A method of treating Community-Acquired Bacterial Pneumonia
(CABP) in a subject in need of treatment thereof, comprising
administering to said subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) three intravenous doses of about 100
mg each, administered 12 hours apart, followed by, (2) optionally,
one or more intravenous doses of about 100 mg each, each
administered 24 hours following the immediate preceding intravenous
dose, followed by, (3) optionally, one oral dose of about 300 mg,
administered in the morning and 12-24 hrs after the immediate
preceding intravenous dose, followed by, (4) optionally, one or
more oral doses of about 300 mg each, each administered 24 hours
following the immediate preceding oral dose, such that said subject
is treated.
3. A method of treating Community-Acquired Bacterial Pneumonia
(CABP) in a subject in need of treatment thereof, comprising
administering to said subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) three intravenous doses of about 100
mg each, administered 12 hours apart, followed by, (2) one or more
intravenous doses of about 100 mg each, each administered 24 hours
following the immediate preceding intravenous dose, followed by,
(3) one or more oral doses of about 300 mg each, each administered
24 hours following the immediate preceding dose, such that said
subject is treated.
4. A method of treating Community-Acquired Bacterial Pneumonia
(CABP) in a subject in need of treatment thereof, comprising
administering to said subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) three intravenous doses of about 100
mg each, administered 12 hours apart, followed by, (2) optionally,
one or more intravenous doses of about 100 mg each, each
administered 24 hours following the immediate preceding intravenous
dose, followed by, (3) one or more oral doses of about 300 mg each,
each administered 24 hours following the immediate preceding dose,
such that said subject is treated.
5. The method of claim 3 or 4, wherein step (2) consists of one
intravenous dose of about 100 mg of said subject
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt
thereof.
6. A method of treating Community-Acquired Bacterial Pneumonia
(CABP) in a subject in need of treatment thereof, comprising
administering to said subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) three intravenous doses of about 100
mg each, administered 12 hours apart, followed by, (2) one or more
intravenous doses of about 100 mg each, each administered 24 hours
following the immediate preceding intravenous dose, such that said
subject is treated.
7. The method of any one of claims 1-6, wherein the steps are
completed within 7 days, 8 days, 9 days, 10 days, 11 days, 12 days,
13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, or
20 days.
8. The method of any one of claims 1-6, wherein the steps are
completed within 7-14 days.
9. The method of claim 8, wherein the steps are completed within
7-10 days.
10. The method of claim 8, wherein the steps are completed within
11-14 days.
11. The method of claim 8, wherein the steps are completed within
10 days.
12. The method of any one of claims 1-11, wherein the number of
days of IV dosing is 3-10 days.
13. The method of claim 12, wherein the number of days of IV dosing
is 3-6 days.
14. The method of claim 12, wherein the number of days of IV dosing
is 7-10 days.
15. The method of claim 12, wherein the number of days of IV dosing
is 5 days.
16. The method of any one of claims 1-15, comprising one or more
oral doses, and wherein the number of days of IV dosing is 4-7
days.
17. The method of claim 16, wherein the number of days of IV dosing
is 4-5 days.
18. The method of claim 16, wherein the number of days of IV dosing
is 6-7 days.
19. The method of claim 16, wherein the number of days of IV dosing
is 5 days.
20. The method of any one of claims 16-19, wherein the number of
days of oral dosing is 1-7 days.
21. The method of claim 20, wherein the number of days of oral
dosing is 1-4 days.
22. The method of claim 20, wherein the number of days of oral
dosing is 5-7 days.
23. The method of claim 20, wherein the number of days of oral
dosing is 5 days.
24. The method of claim 16, wherein the number of days of IV dosing
is 5 days, and the number of days of oral dosing is 5 days.
25. A method of treating Community-Acquired Bacterial Pneumonia
(CABP) in a subject in need of treatment thereof, comprising
administering to said subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) three oral doses of about 300-450 mg
each, administered 12 hours apart, followed by, (2) optionally, one
or more oral doses of about 300-600 mg each, each administered 24
hours following the immediate preceding oral dose, such that said
subject is treated.
26. The method of claim 25, wherein each oral dose is about 300
mg.
27. The method of claim 25, wherein each oral dose is about 450
mg.
28. The method of claim 25, wherein each oral dose in step (1) is
about 300 mg.
29. The method of claim 25, wherein each oral dose in step (1) is
about 450 mg.
30. The method of claim 25, 28, or 29, wherein each oral dose in
step (2) is about 300 mg.
31. The method of claim 25, 28, or 29, wherein each oral dose in
step (2) is about 450 mg.
32. The method of claim 25, 28, or 29, wherein each oral dose in
step (2) is about 600 mg.
33. The method of claim 25, wherein the first two oral doses of
step (1) are each 300 mg, and the last oral dose of step (1) is
about 300, 450, or 600 mg.
34. The method of claim 25, wherein the first two oral doses of
step (1) are each 450 mg, and the last oral dose of step (1) is
about 300, 450, or 600 mg.
35. A method of treating Community-Acquired Bacterial Pneumonia
(CABP) in a subject in need of treatment thereof, comprising
administering to said subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) one or two once-daily oral dose(s) of
about 450-600 mg (administered 24 hrs apart for two once-daily oral
doses), followed by, (2) one or more oral doses of about 300-600 mg
each, each administered 24 hours following the immediate preceding
oral dose, such that said subject is treated.
36. The method of claim 35, wherein said dosing regimen is: (1) one
or two once-daily oral dose(s) of about 450 or 600 mg (administered
24 hrs apart for two once-daily oral doses), followed by, (2) one
or more oral doses of about 300 mg each, each administered 24 hours
following the immediate preceding oral dose.
37. The method of claim 35, wherein said dosing regimen is: (1) two
once-daily oral doses of about 450 mg, administered 24 hrs apart,
followed by, (2) one or more oral doses of about 300 mg each, each
administered 24 hours following the immediate preceding oral
dose.
38. The method of any one of claims 25-37, wherein the steps are
completed within 7 days, 8 days, 9 days, 10 days, 11 days, 12 days,
13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20
days, or 21 days.
39. The method of any one of claims 25-37, wherein the steps are
completed within 7-14 days, within 7-10 days, within 11-14 days, or
within 10 days.
40. The method of any one of claims 1-39, wherein said CABP is
caused by Staphylococcus aureus including methicillin-resistant
Staphylococcus aureus (MRSA), Streptococcus pneumoniae including
penicillin-resistant Streptococcus pneumoniae (PRSP), Haemophilus
influenzae, Moraxella catarrhalis, Klebsiella pneumoniae,
Legionella pneumophila, Chlamydophila pneumoniae, Mycoplasma
pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Escherichia
coli, or a combination thereof.
41. The method of claim 40, wherein said Streptococcus pneumoniae
is penicillin-resistant Streptococcus pneumoniae (PRSP),
macrolide-resistant Streptococcus pneumoniae,
cephalosporin-resistant Streptococcus pneumoniae, or
multidrug-resistant Streptococcus pneumoniae (MDRSP).
42. The method of any one of claims 1-39, wherein said CABP is
caused by intracellular pathogens, such as Legionella pneumophila,
Mycoplasma pneumoniae, Chlamydophila pneumoniae, Chlamydophila
psittaci, Coxiella burnetii, or a combination thereof.
43. The method of any one of claims 1-39, wherein said CABP is
caused by Haemophilus parainfluenzae.
44. The method of any one of claims 1-43, wherein said subject is a
human.
45. The method of any one of claims 1-44, wherein each of said oral
dose is administered independently as two 150-mg tablets.
46. The method of any one of claims 1-45, wherein each of said
intravenous dose is administered continuously over about 30 minutes
(e.g., at least 30 minutes and not more than 45 minutes).
47. The method of any one of claims 1-46, wherein said dosing
regimen has a clinical success rate that is within 10% (or 12.5%)
margin of non-inferiority compared to moxifloxacin administered as
400 mg intravenous dose once every 24 hours for three or more days,
followed by one or more doses of 400 mg oral doses of moxifloxacin
once every 24 hours.
48. The method of any one of claims 1-47, wherein said subject
experience improvement, at day 3 to day 5 after step (1), in at
least two symptoms selected from: chest pain, frequency or severity
of cough, amount of productive sputum, and difficulty breathing,
wherein said symptoms are evaluated on a four-point scale of
absent, mild, moderate, and severe, and wherein improvement is at
least a one-point improvement from baseline to the assessment at
said day 3 to day 5 (e.g., from severe to moderate, from moderate
to absent, or from mild to absent).
49. The method of any one of claims 1-47, wherein said subject, at
day 3 to day 5 after step (1), experience improvement in at least
two symptoms and no worsening in any of the symptoms selected from:
chest pain, frequency or severity of cough, amount of productive
sputum, and difficulty breathing, and improvement in at least one
vital sign selected from: body temperature, blood pressure, heart
rate, and respiratory rate.
50. The method of any one of claims 1-49, wherein the subject
undergoes fasting overnight, with no food or drink except water for
at least 6 hours, just before step (3) dosing (if present), and
wherein the subject continues fasting after step (3) dosing, with
no food for 2 hours, and no dairy products for 4 hours.
51. The method of any one of claims 1-50, wherein said salt is a
tosylate salt.
52. The method of any one of claims 1-51, which method has a
clinical success rate of about 70%-100%.
53. The method of claim 52, wherein said clinical success rate is
about 75-95%, about 80-95%, about 75-90%, about 80-90%, about
75-85%, about 80-85%, about 85-90%, about 90-95%, about 80-82%, or
about 81%.
54. The method of claim 53, wherein said clinical success rate is
about 75-85%, observed at about 72-120 hours after the
administration of the first intravenous dose.
55. The method of claim 54, wherein said clinical success rate is
about 80-82%, or 80% or 81%.
56. The method of claim 53, wherein said clinical success rate is
observed at about 5-10 days after the last dose of treatment (e.g.,
equivalent to a time for post treatment evaluation in clinically
evaluable population, or CE-PTE; or in ITT population).
57. The method of claim 56, wherein said clinical success rate is
about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%, 93%, 94%, 95%, 96%, or 97%.
58. The method of any one of claims 1-57, wherein said subject has
CABP categorized as PORT Risk Class II.
59. The method of claim 58, wherein said method has a clinical
success rate of about 70-100%, about 75-96%, about 75-90%, about
80-83%, about 82%, about 80-96%, about 90-96%, or about 95%.
60. The method of claim 59, wherein said clinical success rate is
about 75-85%, or about 90-100%, observed at about 5-10 days after
the last dose of treatment.
61. The method of claim 60, wherein said clinical success rate is
about 82%, or about 95%.
62. The method of any one of claims 1-57, wherein said subject has
CABP categorized as PORT Risk Class III.
63. The method of claim 62, wherein said method has a clinical
success rate of about 80-100%, about 85-95%, about 90-95%, about
90-91%, or about 93-94%.
64. The method of claim 63, wherein said clinical success rate is
about 85-100%, observed at about 5-10 days after the last dose of
treatment.
65. The method of claim 64, wherein said clinical success rate is
about 90-91%, or about 93-94%.
66. The method of any one of claims 1-57, wherein said subject has
CABP categorized as PORT Risk Class IV.
67. The method of claim 66, wherein said method has a clinical
success rate of about 70-100%, about 75-95%, about 80-95%, about
83-85%, or about 90-91%.
68. The method of claim 67, wherein said clinical success rate is
about 80-95%, observed at about 5-10 days after the last dose of
treatment.
69. The method of claim 68, wherein said clinical success rate is
about 83-85%, or about 90-91%.
70. The method of any one of claims 1-57, wherein said subject has
CABP categorized as PORT Risk Class III or IV.
71. The method of claim 70, wherein said method has a clinical
success rate of about 75-100%, about 85-95%, about 85-90%, about
88-89%, about 90-95%, or about 92-93%.
72. The method of claim 71, wherein said clinical success rate is
about 85-95%, observed at about 5-10 days after the last dose of
treatment.
73. The method of claim 72, wherein said clinical success rate is
about 88-89%, or about 92-93%.
74. The method of any one of claims 1-73, wherein gastrointestinal
(GI) adverse events (AEs) associated with treatment of said subject
are mild.
75. The method of any one of claims 1-73, wherein GI adverse events
(AEs) associated with treatment of said subject do not result in
discontinuation of therapy with said method.
76. The method of any one of claims 1-75, wherein treatment of said
subject (1) does not result in increased risk of C. difficile
(e.g., C. difficile colitis and Pseudomembranous colitis) infection
in said subject, or (2) does not substantially disrupting gut
microbiome in said subject.
77. The method of claim 76, wherein said subject is at risk of, or
is predisposed to, developing a C. difficile infection.
78. The method of claim 77, wherein said subject has recently been
treated with one or more antibiotics (such as broad spectrum
antibiotics), has had surgery of the gastrointestinal tract, has a
disease of the colon (such as an inflammatory bowel disease or
colorectal cancer), has a kidney disease, has a weakened immune
system; is on chemotherapy, has previously had C. difficile
infection, is 65 years or older, takes proton-pump inhibitors, or
is living in an environment that predisposes said subject to
developing C. difficile infection (such as in a hospital, a nursing
home, or an assisted living facility).
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/507,410, filed on Jul. 10, 2019, which is a
continuation of U.S. patent application Ser. No. 15/798,573, filed
on Oct. 31, 2017, now U.S. Pat. No. 10,383,884, issued Aug. 20,
2019, which claims the benefit of the filing dates under 35 U.S.C.
.sctn. 119(e) of U.S. Provisional Application No. 62/416,010, filed
on Nov. 1, 2016; 62/422,843, filed on Nov. 16, 2016; 62/480,516,
filed on Apr. 2, 2017; 62/500,611, filed on May 3, 2017; and
62/514,415, filed on Jun. 2, 2017, the entire contents of each of
which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The development of the tetracycline antibiotics was the
direct result of a systematic screening of soil specimens collected
from many parts of the world for evidence of microorganisms capable
of producing bactericidal and/or bacteriostatic compositions. The
first of these novel compounds was introduced in 1948 under the
name chlortetracycline. Two years later, oxytetracycline became
available. The elucidation of the chemical structure of these
compounds confirmed their similarity and furnished the analytical
basis for the production of a third member of this group in 1952,
tetracycline. A new family of minocycline compounds, without the
ring-attached methyl group present in earlier tetracyclines, was
prepared in 1957 and became publicly available in 1967; and
minocycline was in use by 1972.
[0003] Recently, research efforts have focused on developing new
tetracycline antibiotic compositions effective under varying
therapeutic conditions and routes of administration. New
tetracycline analogues have also been investigated which may prove
to be equal to or more effective than the originally introduced
minocycline compounds. Examples include U.S. Pat. Nos. 2,980,584;
2,990,331; 3,062,717; 3,165,531; 3,454,697; 3,557,280; 3,674,859;
3,957,980; 4,018,889; 4,024,272; and 4,126,680. These patents are
representative of the range of pharmaceutically active tetracycline
and tetracycline analogue compositions.
[0004] Historically, soon after their initial development and
introduction, the tetracyclines were found to be highly effective
pharmacologically against rickettsia; a number of gram-positive and
gram-negative bacteria; and the agents responsible for
lymphogranuloma venereum, inclusion conjunctivitis, and
psittacosis. Hence, tetracyclines became known as "broad spectrum"
antibiotics. With the subsequent establishment of their in vitro
antimicrobial activity, effectiveness in experimental infections,
and pharmacological properties, the tetracyclines as a class
rapidly became widely used for therapeutic purposes. However, this
widespread use of tetracyclines for both major and minor illnesses
and diseases led directly to the emergence of resistance to these
antibiotics even among highly susceptible bacterial species both
commensal and pathogenic (e.g., Pneumococci and Salmonella). The
rise of tetracycline-resistant organisms has resulted in a general
decline in use of tetracyclines and tetracycline analogue
compositions as antibiotics of choice. In addition, other
antibacterial agents have also been over used creating strains of
multiple drug resistant bacteria. Therefore, there is a need for
effective antibacterial agents for the treatment of bacterial
infections in general, particularly antibacterial agents with no or
less severe resistance by disease-responsible pathogens.
[0005] Community Acquired Bacterial Pneumonia (CABP), also known as
Community Acquired Pneumonia (CAP) (which terms can be used
interchangeably), is defined as an acute bacterial infection of the
pulmonary parenchyma associated with chest pain, cough, sputum
production, difficulty breathing, chills, rigors, fever, or
hypotension, and is accompanied by the presence of a new lobar or
multilobar infiltrate on a chest radiograph. Common typical
bacterial pathogens that cause CABP include Streptococcus
pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and
Moraxella catarrhalis. Atypical bacterial pathogens such as
Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella
pneumophila also cause CABP.
[0006] CABP is a leading cause of morbidity and mortality in the
United States (US) and throughout the world (Mandell et al., Clin.
Infect. Dis. 44:S27-S72, 2007). Four to 6 million cases of CABP
occur per year in the US, resulting in 10 million physician visits,
600,000 hospitalizations, and tens of thousands of deaths. The
total cost of CABP to the annual US health care budget exceeds $10
billion (in 2007-adjusted dollars) (Niederman et al., Clin. Ther.
20(4): 820-37, 1998). Furthermore, there is increasing resistance
to antibiotics among common pathogens, with a resulting critical
need for new antibiotics (Spellberg et al., Clin. Infect. Dis.
46(2):155-164, 2008). Bacterial resistance to the most frequently
prescribed, currently available antibiotics has limited their
potential to treat infections, which prevents their use as a
first-line empiric monotherapy. Methicillin-resistant
Staphylococcus aureus (MRSA) and multi-drug resistant Streptococcus
pneumoniae (MDR-SP) in the community have posed treatment
challenges because of resistance to penicillins (resistance rate
100% for both), cephalosporins (100% and 11%, respectively, for
ceftriaxone), macrolides (83% and 86%, respectively, for
azithromycin/erythromycin), and quinolones (73% and 2%,
respectively, for levofloxacin), in CABP. In addition, the growing
concern about, "collateral damage" associated with use of quinolone
and beta-lactam class antibiotics further underscores the need for
new antibiotic treatment options for CABP (Paterson, Clin Infect
Dis. 38 Suppl 4: S341-345, 2004). Failure of therapy due to
resistance will continue to contribute to the morbidity and
mortality of CABP and treatment failures of mild disease will
result in increased hospitalizations and contribute to increased
healthcare costs.
SUMMARY OF THE INVENTION
[0007] The invention described herein provides 9-aminomethyl
minocyclines, such as 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline (Omadacycline, or "Compound 1"), for use
in the treatment of CABP.
[0008] The invention is also partly based on the discovery that
9-aminomethyl minocyclines, such as Compound 1, can be provided as
IV dosage form for the treatment of CABP, either alone or in
combination with oral dosage form (such as an oral step down after
initial IV doses). In certain embodiments, the invention provides
the use of 9-aminomethyl minocyclines, such as Compound 1, as IV
dosage form for the treatment of CABP.
[0009] The invention is further based on the discovery that
9-aminomethyl minocyclines, such as Compound 1, has a relatively
broad spectrum against a wide variety of pathogens associated with
CABP, including intracellular CABP pathogens. The finding that
Compound 1 has in vitro activity against common typical and
atypical pathogens, and the sustained epithelial lining fluid (ELF)
and alveolar cell (AC) including alveolar macrophages (AM)
concentrations for 24 hours suggest that Compound 1 has utility as
antibacterial agent for the treatment of lower respiratory tract
bacterial infections caused by susceptible pathogens, such as
intracellular CABP pathogens including Legionella pneumophila,
Mycoplasma pneumoniae, Chlamydophila pneumoniae, Chlamydophila
psittaci, and/or Coxiella burnetii.
[0010] The invention is further based on the discovery that
9-aminomethyl minocyclines, such as Compound 1, has a relatively
broad spectrum against a wide variety of pathogens associated with
CABP as further described below.
[0011] 9-aminomethyl minocyclines, such as Compound 1, are also
advantageous for treatment of CABP associated antibiotic-resistant
pathogens, such as MRSA and penicillin-resistant Streptococcus
pneumoniae (PRSP). Due to its efficacy against resistant pathogens,
9-aminomethyl minocyclines, such as Compound 1, can also be used as
a front-line therapeutic agent in cases in which known or suspected
drug-resistant bacteria may be the causative pathogen. On the other
hand, 9-aminomethyl minocyclines, such as Compound 1, can also be
used as a therapeutic agent in patients who have previously been
treated by other antibiotics, but have had inadequate response or
have developed/exhibited unacceptable or undesirable adverse events
(AEs), such as gastrointestinal tracts AEs (GI tract AEs) and/or C.
difficile infection.
[0012] Thus one aspect of the invention provides a method of
treating Community-Acquired Bacterial Pneumonia (CABP) in a subject
in need of treatment thereof, comprising administering to the
subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a
salt thereof according to the following dosing regimen: (1) three
intravenous doses of about 100 mg each, administered 12 hours
apart, followed by, (2) one or more intravenous doses of about 100
mg each, each administered 24 hours following the immediate
preceding intravenous dose, followed by, (3) one oral dose of about
300 mg, administered in the morning and 12-24 hrs after the
immediate preceding intravenous dose, followed by, (4) one or more
oral doses of about 300 mg each, each administered 24 hours
following the immediate preceding oral dose, such that the subject
is treated.
[0013] A related aspect of the invention provides a method of
treating Community-Acquired Bacterial Pneumonia (CABP) in a subject
in need of treatment thereof, comprising administering to the
subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a
salt thereof according to the following dosing regimen: (1) three
intravenous doses of about 100 mg each, administered 12 hours
apart, followed by, (2) optionally, one or more intravenous doses
of about 100 mg each, each administered 24 hours following the
immediate preceding intravenous dose, followed by, (3) optionally,
one oral dose of about 300 mg, administered in the morning and
12-24 hrs after the immediate preceding intravenous dose, followed
by, (4) optionally, one or more oral doses of about 300 mg each,
each administered 24 hours following the immediate preceding oral
dose, such that the subject is treated.
[0014] A related aspect of the invention provides a method of
treating Community-Acquired Bacterial Pneumonia (CABP) in a subject
in need of treatment thereof, comprising administering to the
subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a
salt thereof according to the following dosing regimen: (1) three
intravenous doses of about 100 mg each, administered 12 hours
apart, followed by, (2) one or more intravenous doses of about 100
mg each, each administered 24 hours following the immediate
preceding intravenous dose, followed by, (3) one or more oral doses
of about 300 mg each, each administered 24 hours following the
immediate preceding dose, such that said subject is treated.
[0015] Another related aspect of the invention provides a method of
treating Community-Acquired Bacterial Pneumonia (CABP) in a subject
in need of treatment thereof, comprising administering to the
subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a
salt thereof according to the following dosing regimen: (1) three
intravenous doses of about 100 mg each, administered 12 hours
apart, followed by, (2) optionally, one or more intravenous doses
of about 100 mg each, each administered 24 hours following the
immediate preceding intravenous dose, followed by, (3) one or more
oral doses of about 300 mg each, each administered 24 hours
following the immediate preceding dose, such that the subject is
treated.
[0016] In certain embodiments, step (2) consists of one intravenous
dose of about 100 mg of the subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or salt thereof.
[0017] Yes another related aspect of the invention provides a
method of treating Community-Acquired Bacterial Pneumonia (CABP) in
a subject in need of treatment thereof, comprising administering to
the subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a
salt thereof according to the following dosing regimen: (1) three
intravenous doses of about 100 mg each, administered 12 hours
apart, followed by, (2) one or more intravenous doses of about 100
mg each, each administered 24 hours following the immediate
preceding intravenous dose, such that the subject is treated.
[0018] In certain embodiments, the method steps are completed
within 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12
days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19
days, 20 days, or 21 days.
[0019] In certain embodiments, the steps are completed within 7-14
days, such as 7-10 days, 11-14 days, or 10 days.
[0020] In certain embodiments, the number of days of IV dosing is
3-10 days, such as 3-6 days, 7-10 days, or 5 days.
[0021] In certain embodiments, the method comprises one or more
oral doses, and wherein the number of days of IV dosing is 4-7
days, such as 4-5 days, 6-7 days, or 5 days.
[0022] In certain embodiments, the number of days of oral dosing is
1-7 days, such as 1-4 days, 5-7 days, or 5 days.
[0023] In certain embodiments, the number of days of IV dosing is 5
days, and the number of days of oral dosing is 5 days.
[0024] Another related aspect of the invention provides a method of
treating Community-Acquired Bacterial Pneumonia (CABP) in a subject
in need of treatment thereof, comprising administering to the
subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a
salt thereof according to the following dosing regimen: (1) three
oral doses of about 300-450 mg each, administered 12 hours apart,
followed by, (2) optionally, one or more oral doses of about
300-600 mg each, each administered 24 hours following the immediate
preceding oral dose, such that the subject is treated.
[0025] In certain embodiments, each oral dose is about 300 mg.
[0026] In certain embodiments, each oral dose is about 450 mg.
[0027] In certain embodiments, each oral dose in step (1) is about
300 mg.
[0028] In certain embodiments, each oral dose in step (1) is about
450 mg.
[0029] In certain embodiments, each oral dose in step (2) is about
300 mg.
[0030] In certain embodiments, each oral dose in step (2) is about
450 mg.
[0031] In certain embodiments, each oral dose in step (2) is about
600 mg.
[0032] In certain embodiments, the first two oral doses of step (1)
are each 300 mg, and the last oral dose of step (1) is about 300,
450, or 600 mg.
[0033] In certain embodiments, the first two oral doses of step (1)
are each 450 mg, and the last oral dose of step (1) is about 300,
450, or 600 mg.
[0034] Another related aspect of the invention provides a method of
treating Community-Acquired Bacterial Pneumonia (CABP) in a subject
in need of treatment thereof, comprising administering to the
subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a
salt thereof, such that the subject is treated, wherein the
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline is administered
as once-daily oral dose of 300 mg, for 5, 6, 7, or 8 consecutive
days.
[0035] Another related aspect of the invention provides a method of
treating Community-Acquired Bacterial Pneumonia (CABP) in a subject
in need of treatment thereof, comprising administering to the
subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a
salt thereof according to the following dosing regimen: (1) one or
two once-daily oral dose(s) of about 450-600 mg (administered 24
hrs apart for two once-daily oral doses), followed by, (2) one or
more oral doses of about 300-600 mg each, each administered 24
hours following the immediate preceding oral dose, such that the
subject is treated.
[0036] In certain embodiments, the dosing regimen is: (1) one or
two once-daily oral dose(s) of about 450 or 600 mg (administered 24
hrs apart for two once-daily oral doses), followed by, (2) one or
more oral doses of about 300 mg each, each administered 24 hours
following the immediate preceding oral dose.
[0037] In certain embodiments, the dosing regimen is: (1) two
once-daily oral doses of about 450 mg, administered 24 hrs apart,
followed by, (2) one or more oral doses of about 300 mg each, each
administered 24 hours following the immediate preceding oral
dose.
[0038] In certain embodiments, the steps are completed within 7
days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days,
15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21
days.
[0039] In certain embodiments, the steps are completed within 7-14
days, within 7-10 days, within 11-14 days, or within 10 days.
[0040] In certain embodiments, the CABP is caused by Staphylococcus
aureus including methicillin-resistant Staphylococcus aureus
(MRSA), Streptococcus pneumoniae including penicillin-resistant
Streptococcus pneumoniae (PRSP), Haemophilus influenzae, Moraxella
catarrhalis, Klebsiella pneumoniae, Legionella pneumophila,
Chlamydophila pneumoniae, Mycoplasma pneumoniae, Chlamydophila
psittaci, Coxiella burnetii, Escherichia coli, or a combination
thereof.
[0041] In certain embodiments, the Streptococcus pneumoniae is
penicillin-resistant Streptococcus pneumoniae (PRSP),
macrolide-resistant Streptococcus pneumoniae,
cephalosporin-resistant Streptococcus pneumoniae, or
multidrug-resistant Streptococcus pneumoniae (MDRSP).
[0042] In certain embodiments, the CABP is caused by intracellular
pathogens, such as Legionella pneumophila, Mycoplasma pneumoniae,
Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella
burnetii, or a combination thereof.
[0043] In certain embodiments, the CABP is caused by Haemophilus
parainfluenzae.
[0044] In certain embodiments, the subject is a human.
[0045] In certain embodiments, each of said oral dose is
administered independently as two 150-mg tablets.
[0046] In certain embodiments, each of said intravenous dose is
administered continuously over about 30 minutes (e.g., at least 30
minutes and not more than 45 minutes).
[0047] In certain embodiments, the dosing regimen has a clinical
success rate that is (1) greater than that of moxifloxacin, or (2)
within 10% (or 12.5%) margin of non-inferiority compared to
moxifloxacin, wherein the moxifloxacin is administered as 400 mg
intravenous dose once every 24 hours for three or more days,
followed by one or more doses of 400 mg oral doses of moxifloxacin
once every 24 hours.
[0048] In certain embodiments, the subject experiences improvement,
at day 3 to day 5 after step (1), in at least two symptoms selected
from: chest pain, frequency or severity of cough, amount of
productive sputum, and difficulty breathing, wherein said symptoms
are evaluated on a four-point scale of absent, mild, moderate, and
severe, and wherein improvement is at least a one-point improvement
from baseline to the assessment at said day 3 to day 5 (e.g., from
severe to moderate, from moderate to absent, or from mild to
absent).
[0049] In certain embodiments, the subject, at day 3 to day 5 after
step (1), experiences improvement in at least two symptoms and no
worsening in any of the symptoms selected from: chest pain,
frequency or severity of cough, amount of productive sputum, and
difficulty breathing, and improvement in at least one vital sign
selected from: body temperature, blood pressure, heart rate, and
respiratory rate.
[0050] In certain embodiments, the subject undergoes fasting
overnight, with no food or drink except water for at least 6 hours,
just before step (3) dosing, and wherein the subject continues
fasting after step (3) dosing, with no food for 2 hours, and no
dairy products for 4 hours.
[0051] In certain embodiments, the salt is a tosylate salt.
[0052] In certain embodiments, the method has a clinical success
rate of about 70%-100%.
[0053] In certain embodiments, the clinical success rate is about
75-95%, about 80-95%, about 75-90%, about 80-90%, about 75-85%,
about 80-85%, about 85-90%, about 90-95%, about 80-82%, or about
81%.
[0054] In certain embodiments, the clinical success rate is about
75-85%, observed at about 72-120 hours after the administration of
the first intravenous dose.
[0055] In certain embodiments, the clinical success rate is about
80-82%, or 80% or 81%.
[0056] In certain embodiments, the clinical success rate is
observed at about 5-10 days after the last dose of treatment (e.g.,
equivalent to a time for post treatment evaluation in clinically
evaluable population, or CE-PTE; or in ITT population).
[0057] In certain embodiments, the clinical success rate is about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,
93%, 94%, 95%, 96%, or 97%.
[0058] In certain embodiments, the subject has CABP categorized as
PORT Risk Class II.
[0059] In certain embodiments, the method has a clinical success
rate of about 70-100%, about 75-96%, about 75-90%, about 80-83%,
about 82%, about 80-96%, about 90-96%, or about 95%.
[0060] In certain embodiments, the clinical success rate is about
75-85%, or about 90-100%, observed at about 5-10 days after the
last dose of treatment.
[0061] In certain embodiments, the clinical success rate is about
82%, or about 95%.
[0062] In certain embodiments, the subject has CABP categorized as
PORT Risk Class III.
[0063] In certain embodiments, the method has a clinical success
rate of about 80-100%, about 85-95%, about 90-95%, about 90-91%, or
about 93-94%.
[0064] In certain embodiments, the clinical success rate is about
85-100%, observed at about 5-10 days after the last dose of
treatment.
[0065] In certain embodiments, the clinical success rate is about
90-91%, or about 93-94%.
[0066] In certain embodiments, subject has CABP categorized as PORT
Risk Class IV.
[0067] In certain embodiments, the method has a clinical success
rate of about 70-100%, about 75-95%, about 80-95%, about 83-85%, or
about 90-91%.
[0068] In certain embodiments, the clinical success rate is about
80-95%, observed at about 5-10 days after the last dose of
treatment.
[0069] In certain embodiments, the clinical success rate is about
83-85%, or about 90-91%.
[0070] In certain embodiments, the subject has CABP categorized as
PORT Risk Class III or IV.
[0071] In certain embodiments, the method has a clinical success
rate of about 75-100%, about 85-95%, about 85-90%, about 88-89%,
about 90-95%, or about 92-93%.
[0072] In certain embodiments, the clinical success rate is about
85-95%, observed at about 5-10 days after the last dose of
treatment.
[0073] In certain embodiments, the clinical success rate is about
88-89%, or about 92-93%.
[0074] In certain embodiments, gastrointestinal (GI) adverse events
(AEs) associated with treatment of said subject are mild.
[0075] In certain embodiments, GI adverse events (AEs) associated
with treatment of said subject do not result in discontinuation of
therapy with the method.
[0076] In certain embodiments, treatment of the subject (1) does
not result in increased risk of C. difficile (also known as C.
difficile colitis and Pseudomembranous colitis) infection in the
subject, or (2) does not substantially disrupting gut microbiome in
the subject.
[0077] In certain embodiments, the subject is at risk of, or is
predisposed to, developing a C. difficile infection.
[0078] In certain embodiments, the subject has recently been
treated with one or more antibiotics (such as broad spectrum
antibiotics), has had surgery of the gastrointestinal tract, has a
disease of the colon (such as an inflammatory bowel disease or
colorectal cancer), has a kidney disease, has a weakened immune
system; is on chemotherapy, has previously had C. difficile
infection, is 65 years or older, takes proton-pump inhibitors, or
is living in an environment that predisposes said subject to
developing C. difficile infection (such as in a hospital, a nursing
home, or an assisted living facility).
[0079] It should be understood that any one embodiment can be
combined with any other embodiment unless explicitly disclaimed or
improper.
BRIEF DESCRIPTION OF THE DRAWING
[0080] FIG. 1 shows the result of mean Compound 1 (Omadacycline)
concentration vs. time profile in AC (Alveolar Cells), plasma, and
ELF.
[0081] FIG. 2 shows that Compound 1 ("Omadacycline") demonstrated
statistical non-inferiority (10% margin) relative to moxifloxacin,
for early clinical response (ECR) in the ITT (Intent To Treat)
population (see the pair of bars on the left) (FDA Primary
Endpoint); and for clinical success at the PTE (Post
Treatment/Therapy Evaluation), in both the ITT population (see the
middle pair of bars) and the CE-PTE (Clinically Evaluable
population at the PTE) population (see the right pair of bars) (FDA
Secondary Endpoints).
[0082] FIG. 3 shows that Compound 1 ("Omadacycline") demonstrated
statistical non-inferiority (10% margin) relative to moxifloxacin,
based on clinical success at the PTE in both the ITT population
limited to patients with CABP categorized as PORT Risk Class III/IV
(see the left pair of bars) and the CE-PTE population limited to
patients with CABP categorized as PORT Risk Class III/IV (see the
right pair of bars) (EMA co-Primary Endpoints).
[0083] FIG. 4 shows clinical success rate at PTE for both Compound
1 (Omadacycline) and Moxifloxacin, by baseline pathogen in the
Compound 1 treatment arm with 10 or more isolates. N1=Number of
subjects with the specific baseline pathogen. n=Number of subjects
in the specific category. Percentages are based on the number of
subjects with the specific baseline pathogen.
[0084] FIG. 5 shows plasma concentration versus time curves of
omadacycline after oral administration. Mean (.+-.SD) plasma
concentrations of omadacycline versus time are shown by
omadacycline dose (300, 450, or 600 mg) for the pharmacokinetic
population. Oral omadacycline doses were administered at time 0 on
each of 5 consecutive days of dosing in each of 3 periods. Blood
samples were collected for PK analysis on Day 1 (left panel) and
Day 5 (right panel). Data was pooled by omadacycline dose for all
subjects regardless of the period in which they received a
particular dose.
DETAILED DESCRIPTION OF THE INVENTION
[0085] The invention pertains, at least in part, to the discovery
that 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline (Compound
1/Omadacycline) is effective to treat certain bacterial infections,
such as CABP, based on a specific dosage and administration
regimen.
[0086] The invention is further based on the discovery that
9-aminomethyl minocyclines, such as Compound 1, has a relatively
broad spectrum against a wide variety of pathogens associated with
CABP as further described below.
[0087] In addition, 9-aminomethyl minocyclines, such as Compound 1,
also has a relatively broad spectrum against intracellular CABP
pathogens. The finding that Compound 1 has in vitro activity
against common typical and atypical pathogens, and the sustained
epithelial lining fluid (ELF) and alveolar cell (AC) including
alveolar macrophages (AM) concentrations for 24 hours suggest that
Compound 1 has utility as antibacterial agent for the treatment of
lower respiratory tract bacterial infections caused by susceptible
pathogens, such as intracellular CABP pathogens including
Legionella pneumophila, Mycoplasma pneumoniae, Chlamydophila
pneumoniae, Chlamydophila psittaci, and/or Coxiella burnetii.
[0088] Thus in one aspect, the invention provides a method of
treating CABP in a subject in need of treatment thereof.
[0089] In a 1.sup.st embodiment, the method comprises administering
to the subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline
(e.g., as a tosylate salt) according to the following dosing
regimen: (1) three intravenous (IV) doses of about 100 mg each,
administered 12 hours apart, followed by, (2) one or more IV doses
of about 100 mg each, each administered 24 hours following the
immediate preceding IV dose, followed by, (3) one oral dose of
about 300 mg, administered in the morning and 12-24 hrs after the
immediate preceding intravenous dose, followed by, (4) one or more
oral doses of about 300 mg each, each administered 24 hours
following the immediate preceding oral dose, such that the subject
is treated.
[0090] In a related, 2.sup.nd embodiment, the method comprises
administering to the subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) three intravenous doses of about 100
mg each, administered 12 hours apart, followed by, (2) optionally,
one or more intravenous doses of about 100 mg each, each
administered 24 hours following the immediate preceding intravenous
dose, followed by, (3) optionally, one oral dose of about 300 mg,
administered in the morning and 12-24 hrs after the immediate
preceding intravenous dose, followed by, (4) optionally, one or
more oral doses of about 300 mg each, each administered 24 hours
following the immediate preceding oral dose, such that the subject
is treated.
[0091] In a related, 3.sup.rd embodiment, the method comprises
administering to the subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) three intravenous doses of about
100-125 mg each, administered 12 hours apart, followed by, (2)
optionally, one or more intravenous doses of about 100-125 mg each,
each administered 24 hours following the immediate preceding
intravenous dose, followed by, (3) optionally, one oral dose of
about 300-475 mg (i.e., 3 times of the IV dose administered in oral
dose), administered in the morning and 12-24 hrs after the
immediate preceding intravenous dose, followed by, (4) optionally,
one or more oral doses of about 300-475 mg each (i.e., 3 times of
the IV dose administered in oral dose), each administered 24 hours
following the immediate preceding oral dose, such that the subject
is treated. In certain embodiments, the 100-125 mg IV dose is about
100-120 mg, about 100-115 mg, about 100-110 mg, and about 100-105
mg; and the 300-475 mg oral dose is 3 times of the corresponding IV
dose (i.e., the 300-475 mg oral dose is about 300-360 mg, about
300-345 mg, about 300-330 mg, and about 300-315 mg,
respectively).
[0092] In a 4.sup.th embodiment, the method comprises administering
to the subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline
(e.g., as a tosylate salt) according to the following dosing
regimen: (1) one intravenous (IV) dose of about 200 mg, followed
by, (2) optionally, one or more IV doses of about 100 mg each, each
administered 24 hours following the immediate preceding IV dose,
followed by, (3) optionally, one oral dose of about 300 mg,
administered in the morning and 12-24 hrs after the immediate
preceding intravenous dose, followed by, (4) one or more oral doses
of about 300 mg each, each administered 24 hours following the
immediate preceding oral dose, such that the subject is
treated.
[0093] In a 5.sup.th embodiment, the method comprises administering
to the subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline
or a salt thereof according to the following dosing regimen: (1)
three intravenous doses of about 100 mg each, administered 12 hours
apart, followed by, (2) one or more intravenous doses of about 100
mg each, each administered 24 hours following the immediate
preceding intravenous dose, followed by, (3) one or more oral doses
of about 300 mg each, each administered 24 hours following the
immediate preceding dose, such that the subject is treated.
[0094] In a related 6.sup.th embodiment, the method comprises
administering to the subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) three intravenous doses of about 100
mg each, administered 12 hours apart, followed by, (2) optionally,
one or more intravenous doses of about 100 mg each, each
administered 24 hours following the immediate preceding intravenous
dose, followed by, (3) one or more oral doses of about 300 mg each,
each administered 24 hours following the immediate preceding dose,
such that the subject is treated.
[0095] In a related 7.sup.th embodiment, the method comprises
administering to the subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) three intravenous doses of about
100-125 mg each, administered 12 hours apart, followed by, (2)
optionally, one or more intravenous doses of about 100-125 mg each,
each administered 24 hours following the immediate preceding
intravenous dose, followed by, (3) one or more oral doses of about
300-475 mg (i.e., 3 times of the IV dose administered in oral dose)
each, each administered 24 hours following the immediate preceding
dose, such that the subject is treated. In certain embodiments, the
100-125 mg IV dose is about 100-120 mg, about 100-115 mg, about
100-110 mg, and about 100-105 mg; and the 300-475 mg oral dose is 3
times of the corresponding IV dose (i.e., the 300-475 mg oral dose
is about 300-360 mg, about 300-345 mg, about 300-330 mg, and about
300-315 mg, respectively).
[0096] In an 8.sup.th embodiment, the method comprises
administering to the subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) one intravenous dose of about 200 mg,
followed by, (2) optionally, one or more intravenous doses of about
100 mg each, each administered 24 hours following the immediate
preceding intravenous dose, followed by, (3) optionally, one or
more oral doses of about 300 mg each, each administered 24 hours
following the immediate preceding dose, such that the subject is
treated.
[0097] In a 9.sup.th embodiment, step (2) in the method of any one
of the 5.sup.th to the 8.sup.th embodiments consists of one
intravenous dose of about 100 mg of the subject
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt
thereof.
[0098] In a 10.sup.th embodiment, the method comprises
administering to the subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) three intravenous doses of about 100
mg each, administered 12 hours apart, followed by, (2) one or more
intravenous doses of about 100 mg each, each administered 24 hours
following the immediate preceding intravenous dose, such that said
subject is treated.
[0099] In a related 11.sup.th embodiment, the method comprises
administering to the subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) three intravenous doses of about
100-125 mg each, administered 12 hours apart, followed by, (2) one
or more intravenous doses of about 100-125 mg each, each
administered 24 hours following the immediate preceding intravenous
dose, such that said subject is treated. In certain embodiments,
the 100-125 mg IV dose is about 100-120 mg, about 100-115 mg, about
100-110 mg, and about 100-105 mg.
[0100] In a related 12.sup.th embodiment, the method comprises
administering to the subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof according to the
following dosing regimen: (1) one intravenous dose of about 200 mg,
followed by, (2) one or more intravenous doses of about 100 mg
each, each administered 24 hours following the immediate preceding
intravenous dose, such that said subject is treated.
[0101] In a 13.sup.th embodiment, the method steps of any one of
the 1.sup.st-12.sup.th embodiments are completed within 5 days, 6
days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days,
14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or
21 days. In certain related embodiments, the method steps are
completed within 7 days, 8 days, 9 days, 10 days, 11 days, 12 days,
13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, or
20 days. In yet another embodiment, the method steps are completed
within 5 days, 6 days, or 21 days. In certain related embodiments,
the method steps are completed within 5 or 6 days. In certain
related embodiments, the method steps are completed within 7-14
days.
[0102] In a 14.sup.th embodiment, the method steps of any one of
the 1.sup.st-12.sup.th embodiments are completed within 7-14 days,
such as 7-10 days, 11-14 days, or 10 days.
[0103] In a 15.sup.th embodiment, the number of days of IV dosing
in the 14.sup.th embodiment is 3-10 days, such as 3-6 days, 7-10
days, or 5 days.
[0104] In a 16.sup.th embodiment, the method of any one of the
1.sup.st-15.sup.th embodiments comprise one or more oral doses, and
wherein the number of days of IV dosing is 4-7 days, such as 4-5
days, 6-7 days, or 5 days.
[0105] In a 17.sup.th embodiment, the number of days of oral dosing
in the 16.sup.th embodiment is 1-7 days, such as 1-4 days, 5-7
days, or 5 days.
[0106] In an 18.sup.th embodiment, the number of days of IV dosing
in any one of the 1.sup.st-17.sup.th embodiments is 5 days, and the
number of days of oral dosing is 5 days.
[0107] In a 19.sup.th embodiment, the method comprises
administering to the subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline (e.g., as a tosylate salt) according to
the following dosing regimen: (1) three oral doses of about 300-450
mg (such as 300 mg or 450 mg) each, administered 12 hours apart,
followed by, (2) optionally, one or more oral doses of about
300-600 mg (such as 300 mg, 450 mg, or 600 mg) each, each
administered 24 hours following the immediate preceding oral dose,
such that the subject is treated.
[0108] In a 20.sup.th embodiment, each oral dose of the 19.sup.th
embodiment is about 300 mg.
[0109] In a 21.sup.st embodiment, each oral dose of the 19.sup.th
embodiment is about 450 mg.
[0110] In a 22.sup.nd embodiment, each oral dose in step (1) of the
19.sup.th embodiment is about 300 mg.
[0111] In a 23.sup.rd embodiment, each oral dose in step (1) of the
19.sup.th embodiment is about 450 mg.
[0112] In a 24.sup.th embodiment, each oral dose in step (2) of the
19.sup.th, 22.sup.nd, or 23.sup.rd embodiment is about 300 mg.
[0113] In a 25.sup.th embodiment, each oral dose in step (2) of the
19.sup.th, 22.sup.nd, or 23.sup.rd embodiment is about 450 mg.
[0114] In a 26.sup.th embodiment, each oral dose in step (2) of the
19.sup.th, 22.sup.nd, or 23.sup.rd embodiment is about 600 mg.
[0115] In a 27.sup.th embodiment, the first two oral doses of step
(1) of the 19.sup.th embodiment are each 300 mg, and the last oral
dose of step (1) is about 300, 450, or 600 mg.
[0116] In a 28.sup.th embodiment, the first two oral doses of step
(1) of the 19.sup.th embodiment are each 450 mg, and the last oral
dose of step (1) is about 300, 450, or 600 mg.
[0117] In a 29.sup.th embodiment, the method comprises
administering to the subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline (e.g., as a tosylate salt) according to
the following dosing regimen: (1) one or two once-daily oral
dose(s) of about 450-600 mg (such as 450 mg, or 600 mg)
(administered 24 hrs apart for two once-daily oral doses), followed
by, (2) one or more oral doses of about 300-600 mg (such as 300 mg,
450 mg, or 600 mg) each, each administered 24 hours following the
immediate preceding oral dose, such that the subject is
treated.
[0118] In a 30.sup.th embodiment, the method comprises
administering to the subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline (e.g., as a tosylate salt) according to
the following dosing regimen: (1) one or two once-daily oral
dose(s) of about 300-600 mg (such as 300 mg, 450 mg, or 600 mg)
(administered 24 hrs apart for two once-daily oral doses), followed
by, (2) one or more oral doses of about 300-600 mg (such as 300 mg,
450 mg, or 600 mg) each, each administered 24 hours following the
immediate preceding oral dose, such that the subject is
treated.
[0119] In a 31.sup.st embodiment, the method comprises
administering to the subject 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof, such that the subject
is treated, wherein the 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline is administered as once-daily oral dose
of 300 mg, for 5, 6, 7, or 8 consecutive days.
[0120] In a 32.sup.nd embodiment, the dosing regimen of the
29.sup.th embodiment is: (1) one or two once-daily oral dose(s) of
about 450-600 mg, such as 450 mg or 600 mg, (administered 24 hrs
apart for two once-daily oral doses), followed by, (2) one or more
oral doses of about 300 mg each, each administered 24 hours
following the immediate preceding oral dose.
[0121] In a 33.sup.rd embodiment, the dosing regimen of the
29.sup.th embodiment is: (1) two once-daily oral doses of about 450
mg, administered 24 hrs apart, followed by, (2) one or more oral
doses of about 300 mg each, each administered 24 hours following
the immediate preceding oral dose.
[0122] In a 34.sup.th embodiment, the dosing regimen of the
29.sup.th embodiment is: (1) two once-daily oral doses of about 600
mg, administered 24 hrs apart, followed by, (2) one or more oral
doses of about 300 mg each, each administered 24 hours following
the immediate preceding oral dose.
[0123] In a 35.sup.th embodiment, the steps of any one of the
25.sup.th-34.sup.th embodiments are completed within 7 days, 8
days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days,
16 days, 17 days, 18 days, 19 days, 20 days, or 21 days.
[0124] In a 36.sup.th embodiment, the steps of any one of the
25.sup.th-34.sup.th embodiments are completed within 7-14 days,
within 7-10 days, within 11-14 days, or within 10 days.
[0125] In a 37.sup.th embodiment, the CABP of any one of the
1.sup.st-36.sup.th embodiments is caused by Staphylococcus aureus
including methicillin-resistant Staphylococcus aureus (MRSA),
Streptococcus pneumoniae including penicillin-resistant
Streptococcus pneumoniae (PRSP), Haemophilus influenzae, Moraxella
catarrhalis, Klebsiella pneumoniae, Legionella pneumophila,
Chlamydophila pneumoniae, Mycoplasma pneumoniae, Chlamydophila
psittaci, Coxiella burnetii, Escherichia coli, or a combination
thereof.
[0126] In a 38.sup.th embodiment, the Streptococcus pneumoniae of
the 37.sup.th embodiment is penicillin-resistant Streptococcus
pneumoniae (PRSP), macrolide-resistant Streptococcus pneumoniae,
cephalosporin-resistant Streptococcus pneumoniae, or
multidrug-resistant Streptococcus pneumoniae (MDRSP).
[0127] In a 39.sup.th embodiment, the CABP of any one of the
1.sup.st-36.sup.th embodiments is caused by intracellular
pathogens, such as Legionella pneumophila, Mycoplasma pneumoniae,
Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella
burnetii, or a combination thereof.
[0128] In a 40.sup.th embodiment, the CABP of any one of the
1.sup.st-36.sup.th embodiments is caused by Haemophilus
parainfluenzae.
[0129] In a 41.sup.st embodiment, the subject of any of the
1.sup.st-40.sup.th embodiments is a human.
[0130] In a 42.sup.nd embodiment, each of the oral dose of any of
the 1.sup.st-41.sup.st embodiments is administered independently as
two 150-mg tablets.
[0131] In a 43.sup.rd embodiment, each of the intravenous dose of
any of the 1.sup.st-42.sup.nd embodiments is administered
continuously over about 30 minutes (e.g., at least 30 minutes and
not more than 45 minutes).
[0132] In a 44.sup.th embodiment, the dosing regimen of any of the
1.sup.st-43.sup.rd embodiments has a clinical success rate that is
within 10% (or 12.5%) margin of non-inferiority compared to
moxifloxacin administered as 400 mg intravenous dose once every 24
hours for three or more days, followed by one or more doses of 400
mg oral doses of moxifloxacin once every 24 hours.
[0133] In a 45.sup.th embodiment, the subject of any of the
1.sup.st-44.sup.th embodiments: (1) has at least 3 of the symptoms
selected from: cough, production of purulent sputum, dyspnea
(shortness of breath), and pleuritic chest pain; (2) has at least
two abnormal vital signs selected from: fever or hypothermia
(temperature >38.0.degree. C. [100.4.degree. F.] or
<36.0.degree. C. [95.5.degree. F.]), hypotension with systolic
blood pressure (SBP)<90 mm Hg, tachycardia (heart rate >90
beats per minute (bpm)), and tachypnea (respiratory rate (RR)>20
breaths/minute); (3) has at least one clinical sign or laboratory
finding associated with CABP: hypoxemia (partial pressure of
arterial oxygen [PaO.sub.2] <60 mm Hg by arterial blood gas
[ABG] or oxygen saturation <90% by pulse oximetry), clinical
evidence (e.g., by physical examination findings) of pulmonary
consolidation (e.g., dullness on percussion, bronchial breath
sounds, or egophony), and an elevated total white blood cell (WBC)
count (>12,000 cells/mm.sup.3) or leucopenia (WBC<4,000
cells/mm.sup.3) or elevated immature neutrophils (>15% band
forms, regardless of total peripheral WBC count); (4) has
radiographically-confirmed pneumonia (i.e., new or progressive
pulmonary infiltrate(s) in a lobar or a multilobar distribution on
chest X-ray (CXR) or chest computed tomography (CT) scan consistent
with acute bacterial pneumonia within 24 or 48 hours prior to step
(1)); and (5) has disease categorized as being PORT Risk Class II,
III, or IV, or has appropriate sputum specimen characterized by
fewer than 10 squamous epithelial cells and more than 25
polymorphonuclear cells per low power field.
[0134] In a 46.sup.th embodiment, the subject of any of the
1.sup.st-44.sup.th embodiments experience improvement, at day 3 to
day 5 after step (1), in at least two symptoms selected from: chest
pain, frequency or severity of cough, amount of productive sputum,
and difficulty breathing, wherein the symptoms are evaluated on a
four-point scale of absent, mild, moderate, and severe, and wherein
improvement is at least a one-point improvement from baseline to
the assessment at the day 3 to day 5 (e.g., from severe to
moderate, from moderate to absent, or from mild to absent).
[0135] In a 47.sup.th embodiment, the subject of any of the
1.sup.st-46.sup.th embodiments, at day 3 to day 5 after step (1),
experience improvement in at least two symptoms and no worsening in
any of the symptoms selected from: chest pain, frequency or
severity of cough, amount of productive sputum, and difficulty
breathing, and improvement in at least one vital sign selected
from: body temperature, blood pressure, heart rate, and respiratory
rate.
[0136] Compound 1 was found to have a significant food effect, in
that food consumption has a significant impact on the oral
bioavailability of orally administered 300 mg dose of Compound 1.
See Example 3. A PK study in healthy volunteers showed that,
compared with a fasted dose, bioavailability was reduced by 15% to
17% for a nondairy meal 4 hours before dosing, 40% to 42% for a
nondairy meal 2 hours before dosing, and 59% to 63% for a dairy
meal 2 hours before dosing. Thus, the effect of food was more
pronounced when a high-fat meal was consumed closer to dosing and
when dairy was included in the meal. Based on this result, oral
Compound 1 should be administered at least 6 hours following a meal
in order to achieve maximum bioavailability for the oral dose
designed to achieve therapeutic efficacy.
[0137] Thus in a 48.sup.th embodiment, the subject of any one of
the first-47.sup.th embodiments undergoes fasting overnight, with
no food or drink except water for at least 6 hours, just before
step (3) dosing, and wherein the subject continues fasting after
step (3) dosing, with no food for 2 hours, and no dairy products
for 4 hours.
[0138] In a 49.sup.th embodiment, the salt of any one of the
1.sup.st-48.sup.th embodiments is a tosylate salt.
[0139] In a 50.sup.th embodiment, the method of any one of the
1.sup.st-49.sup.th embodiments has a clinical success rate of about
70%-100%.
[0140] In a 51.sup.st embodiment, the clinical success rate of the
50.sup.th embodiment is about 75-95%, about 80-95%, about 75-90%,
about 80-90%, about 75-85%, about 80-85%, about 85-90%, about
90-95%, about 80-82%, or about 81%.
[0141] In a 52.sup.nd embodiment, the clinical success rate of the
51.sup.st embodiment is about 75-85%, observed at about 72-120
hours after the administration of the first intravenous dose.
[0142] In a 53.sup.rd embodiment, the clinical success rate of the
52.sup.nd embodiment is about 80-82%, or 80% or 81%.
[0143] In a 54.sup.th embodiment, the clinical success rate of the
51.sup.st embodiment is observed at about 5-10 days after the last
dose of treatment (e.g., equivalent to a time for post treatment
evaluation in clinically evaluable population, or CE-PTE; or in ITT
population).
[0144] In a 55.sup.th embodiment, the clinical success rate of the
54.sup.th embodiment is about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, or 97%.
[0145] In a 56.sup.th embodiment, the subject of any one of the
1.sup.st-55.sup.th embodiments has CABP categorized as PORT Risk
Class II.
[0146] In a 57.sup.th embodiment, the method of the 56.sup.th
embodiment has a clinical success rate of about 70-100%, about
75-96%, about 75-90%, about 80-83%, about 82%, about 80-96%, about
90-96%, or about 95%.
[0147] In a 58.sup.th embodiment, the clinical success rate of the
57.sup.th embodiment is about 75-85%, or about 90-100%, observed at
about 5-10 days after the last dose of treatment.
[0148] In a 59.sup.th embodiment, the clinical success rate of the
58.sup.th embodiment is about 82%, or about 95%.
[0149] In a 60.sup.th embodiment, the subject of and one of the
1.sup.st-55.sup.th embodiments has CABP categorized as PORT Risk
Class III.
[0150] In a 61.sup.st embodiment, the method of any one of the
1.sup.st-60.sup.th embodiments has a clinical success rate of about
80-100%, about 85-95%, about 90-95%, about 90-91%, or about
93-94%.
[0151] In a 62.sup.nd embodiment, the clinical success rate of the
61.sup.st embodiment is about 85-100%, observed at about 5-10 days
after the last dose of treatment.
[0152] In a 63.sup.rd embodiment, the clinical success rate of the
62.sup.nd embodiment is about 90-91%, or about 93-94%.
[0153] In a 64.sup.th embodiment, the subject of any one of the
1.sup.st-55.sup.th embodiments has CABP categorized as PORT Risk
Class IV.
[0154] In a 65.sup.th embodiment, the method of the 64.sup.th
embodiment has a clinical success rate of about 70-100%, about
75-95%, about 80-95%, about 83-85%, or about 90-91%.
[0155] In a 66.sup.th embodiment, the clinical success rate of the
65.sup.th embodiment is about 80-95%, observed at about 5-10 days
after the last dose of treatment.
[0156] In a 67.sup.th embodiment, the clinical success rate of the
66.sup.th embodiment is about 83-85%, or about 90-91%.
[0157] In a 68.sup.th embodiment, the subject of any one of the
1.sup.st-55.sup.th embodiments has CABP categorized as PORT Risk
Class III or IV.
[0158] In a 69.sup.th embodiment, the method of the 68.sup.th
embodiment has a clinical success rate of about 75-100%, about
85-95%, about 85-90%, about 88-89%, about 90-95%, or about
92-93%.
[0159] In a 70.sup.th embodiment, the clinical success rate of the
69.sup.th embodiment is about 85-95%, observed at about 5-10 days
after the last dose of treatment.
[0160] In a 71.sup.st embodiment, the clinical success rate of the
70.sup.th embodiment is about 88-89%, or about 92-93%.
[0161] In a 72.sup.nd embodiment, gastrointestinal (GI) adverse
events (AEs) associated with treatment of the subject in method of
any one of the 1.sup.st-71.sup.st embodiments are mild.
[0162] In a 73.sup.rd embodiment, GI adverse events (AEs)
associated with treatment of the subject in method of any one of
the 1.sup.st-71.sup.st embodiments do not result in discontinuation
of therapy with the method.
[0163] In a 74.sup.th embodiment, treatment of the subject in the
method of any one of the 1.sup.st-73.sup.rd embodiments (1) does
not result in increased risk of C. difficile (also known as C.
difficile colitis and Pseudomembranous colitis) infection in the
subject, or (2) does not substantially disrupting gut microbiome in
the subject.
[0164] In a 75.sup.th embodiment, the subject of the 74.sup.th
embodiment is at risk of, or is predisposed to, developing a C.
difficile infection.
[0165] In a 76.sup.th embodiment, the subject of the 75.sup.th
embodiment has recently been treated with one or more antibiotics
(such as broad spectrum antibiotics), has had surgery of the
gastrointestinal tract, has a disease of the colon (such as an
inflammatory bowel disease or colorectal cancer), has a kidney
disease, has a weakened immune system; is on chemotherapy, has
previously had C. difficile infection, is 65 years or older, takes
proton-pump inhibitors, or is living in an environment that
predisposes the subject to developing C. difficile infection (such
as in a hospital, a nursing home, or an assisted living
facility).
[0166] In a 77.sup.th embodiment, in any of the preceding methods,
GI adverse events (AEs) associated with treatment of the subject do
not result in discontinuation of therapy with the method, and
treatment of the subject (1) does not result in increased risk of
C. difficile (e.g., C. difficile colitis and Pseudomembranous
colitis) infection in the subject or (2) does not substantially
disrupting gut microbiome in the subject.
[0167] As used herein, the term "subject" may include animals
(e.g., non-human mammal) capable of suffering from a bacterial
infection. Examples of subjects include animals such as farm
animals (e.g., cows, pigs, horses, goats, rabbits, sheep, etc.),
lab animals (mice, rats, etc.), pets (e.g., dogs, cats, ferrets,
etc.), and primates (e.g., humans and non-human primates such as
monkeys, gorillas, chimpanzees, etc.).
[0168] In any of the above embodiments, the subject may be a human,
a non-human primate, or a non-human mammal.
[0169] The term "treating" or "treatment" refers to the
amelioration, eradication, or diminishment of one or more symptoms
of the disorder, e.g., a bacterial infection, to be treated. In
certain embodiments, the disorder term includes the eradication of
bacteria associated with the infection to be treated.
[0170] The term "prophylaxis" means to prevent or reduce the risk
of bacterial infection.
[0171] The term "resistance" or "resistant" refers to the
antibiotic/organism standards as defined by the Clinical and
Laboratories Standards Institute (CLSI) and/or the Food and Drug
Administration (FDA).
[0172] In certain embodiments, the infection may be resistant to
other antibiotics, such as penicillin or tetracycline.
[0173] The term "effective amount" includes the amount of the
tetracycline compound (e.g., Compound 1) needed to treat a
bacterial infection (e.g., CABP). For example, an effective amount
describes an efficacious level sufficient to achieve the desired
therapeutic effect through the killing of bacteria and/or
inhibition of bacterial growth. Preferably, the bacterial infection
is treated when the pathogen (e.g., bacteria) is eradicated. The
bacterial infection is also treated when at least one symptom of
infection is reduced, alleviated, or eliminated.
[0174] The term "evaluable clinical success" refers to a clinical
trial participant who: (1) did not meet any criteria for evaluable
clinical failure; (2) did not receive potentially effective
non-study antibiotics for any other reason; and (3) the blinded
evaluator indicated at the test of cure evaluation that the
infection had sufficiently resolved such that antibiotics were not
needed.
[0175] The term "evaluable clinical failure" refers to a clinical
trial participant who met any one of the following criteria: the
blinded evaluator discontinued study drug and indicated that the
infection had responded inadequately such that alternative
antibiotic(s) were needed; the blinded evaluator discontinued study
drug because of an adverse event that was assessed as probably or
possibly drug-related; the primary site of infection was surgically
removed; or the subject had no evaluation after the end of
intravenous or oral treatment.
[0176] The term "clinical success rate" refers to the number of
evaluable clinical successes divided by the total number of
population in the trial.
[0177] The term "microbiologically evaluable clinical success rate"
refers to those who met the definition of evaluable clinical
success and had an infecting pathogen at baseline.
[0178] In one embodiment, the effective amount of the tetracycline
compound, e.g. 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline,
when administered orally is from about 150 to about 600 mg, about
150 to about 450 mg, from about 150 to about 300 mg, or about 300
mg.
[0179] In certain embodiments, each oral dose is administered as
multiples of 150 mg doses (e.g., 150 mg, 2.times.150 mg,
3.times.150 mg, or 4.times.150 mg). For example, a 300 mg oral dose
may consists of two 150 mg tablets/pills/capsules/gels, etc.
[0180] In another embodiment, the effective amount of the
tetracycline compound, e.g., 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline, when administered intravenously (IV) is
from about 50 to about 200 mg, from about 50 to about 150 mg, from
about 50 to about 100 mg, or about 100 mg, or about 200 mg.
[0181] The compound, either in IV formulation or in oral
formulation, may be administered as a salt (e.g., tosylate salt or
hydrochloride salt) or as a free base. For example, any salt or a
polymorph of a salt, such as a tosylate salt of Compound 1, as
described in U.S. Pat. No. 8,383,610 (incorporated herein by
reference), may be used in the instant invention. In addition, any
formulation, such as oral formulation in tablet form, as described
in U.S. Pat. No. 9,314,475 (incorporated herein by reference), may
be used in the instant invention.
[0182] It is to be understood that wherever values and ranges are
provided herein, e.g., in ages of subject populations, dosages, and
blood levels, all values and ranges encompassed by these values and
ranges, including recited upper and/or lower limits of the ranges,
are meant to be encompassed within the scope of the present
invention. Moreover, all values in these values and ranges may also
be the upper or lower limits of a range.
[0183] In another embodiment, the tetracycline compound (e.g.,
Compound 1) may be administered once or twice per day, either
intravenously or orally. In certain embodiments, twice per day
administration has two equal doses.
[0184] In certain embodiments, the 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline has a microbiologically evaluable
clinical success rate of greater than about 60%. In certain
embodiments, the compound of the invention has a clinical success
rate of greater than about 60%, 65%, 70%, 75%, 76%, 77%, 78%, 79%,
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,
93%, 93.7%, 94%, 95%, 96%, 97%, 97.5%, 98%, 99% or more, either in
the intent to treat (ITT) patient population or in the clinically
evaluable (CE) patient population.
[0185] As used herein, an "Intent-to-Treat (or ITT)" population
refers to all enrolled clinical trial subjects. In certain
embodiments, the ITT population is further limited to all enrolled
clinical trial subjects who have received at least one dose of the
study drug (e.g., Compound 1). A "Clinically Evaluable (or CE)"
population refers to all ITT subjects who had a qualifying
infection as defined by the relevant clinical protocol, e.g., those
with CABP. "Clinical success" refers to the continued improvement
or complete resolution of baseline symptoms in the ITT or CE
populations, assessed by the clinical investigator, at a set period
(e.g., 10 to 17 days) after the last dose of the study drug.
[0186] In one example, a subject is treated intravenously followed
by an oral step down. In certain embodiments, the subject is
treated directly by oral dose without any preceding IV dose.
[0187] In certain embodiments, the present invention provides a
method of treating a subject for an infection (e.g., CABP),
comprising administering to the subject an effective amount of
Compound 1 or a salt thereof wherein the subject is initially
treated about 1, 2, 3, 4, or 5 days intravenously, followed by
about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days of
oral treatment, such that the subject is treated. In certain
embodiments, the first day of IV treatment consists of a higher
loading dose (e.g., 2.times. dose, or 2.times.100 mg doses). In
certain embodiments, each IV dose from day 2 and beyond is
administered about 24 hrs from the immediate preceding IV dose. In
certain embodiments, the total treatment period is about 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In certain embodiments,
one (e.g., the 2.sup.nd IV loading dose) or both of the IV loading
doses is replaced by a 300 mg or 450 mg oral dose.
[0188] In another embodiment, the present invention provides a
method of treating a subject for an infection (e.g., CABP),
comprising administering to said subject an effective amount of
Compound 1 or a salt thereof wherein the subject initially treated
intravenously has elevated compound 1 blood levels followed by
reduced Compound 1 blood levels with oral treatment, such that the
subject is treated. In certain embodiments, the initially elevated
compound 1 blood level is achieved by a higher (e.g., 2.times.)
loading dose(s), such as 2 IV loading doses of about 100 mg
each.
[0189] Pharmaceutical Compositions of the Invention
[0190] The invention also utilizes or pertains to pharmaceutical
compositions comprising a therapeutically effective amount of a
tetracycline compound (e.g., a 9-aminomethyl tetracycline compound,
e.g., 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline) or a salt
thereof and, optionally, a pharmaceutically acceptable carrier.
[0191] In a further embodiment, the invention pertains to a
pharmaceutical composition comprising from about 100 to about 700
mg (e.g., about 300, 450, or 600 mg) of 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline or a salt thereof and a pharmaceutically
acceptable carrier. In a further embodiment, the pharmaceutically
acceptable carrier is acceptable for oral administration. In
another further embodiment, the tetracycline compound is a free
base or a tosylate salt.
[0192] In yet another further embodiment, the composition comprises
from about 110 to about 490 mg, from about 120 to about 480 mg,
from about 130 to about 470 mg, from about 140 to about 460 mg,
from about 150 to about 450 mg, from about 160 to about 440 mg,
from about 170 mg to about 430 mg, from about 180 mg to about 420
mg, from about 190 mg to about 410 mg, from about 200 mg to about
400 mg, from about 210 mg to about 390 mg, from about 220 mg to
about 380 mg, from about 230 mg to about 370 mg, from about 240 mg
to about 360 mg, from about 250 mg to about 350 mg, from about 260
mg to about 340 mg, from about 270 mg to about 330 mg, from about
280 mg to about 320 mg, from about 290 mg to about 310 mg, or about
300 mg of 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline.
Optionally, the pharmaceutically acceptable carrier is suitable for
oral administration.
[0193] In another embodiment, the invention also pertains to a
pharmaceutical composition comprising from about 50 to about 250 mg
(e.g., about 100 mg) of
9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof
(e.g., a hydrochloride salt) and a pharmaceutically acceptable
carrier suitable for intravenous administration.
[0194] In yet another further embodiment, the composition comprises
from about 100 to about 300 mg, from about 125 to about 275 mg,
from about 150 mg to about 250 mg, from about 100 mg to about 200
mg, about 100 mg, or about 200 mg of IV or oral
9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline.
[0195] The language "pharmaceutically acceptable carrier" includes
substances capable of being co-administered with the tetracycline
compound of the invention, e.g., 9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline, and which allow the tetracycline
compound to perform its intended function, e.g., treat or prevent a
bacterial infection. Suitable pharmaceutically acceptable carriers
include but are not limited to water, salt solutions, alcohol,
vegetable oils, polyethylene glycols, gelatin, lactose, amylose,
magnesium stearate, talc, silicic acid, viscous paraffin, perfume
oil, fatty acid monoglycerides and diglycerides, petroethral fatty
acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.
The pharmaceutical preparations can be sterilized and if desired
mixed with auxiliary agents, e.g., lubricants, preservatives,
stabilizers, wetting agents, emulsifiers, salts for influencing
osmotic pressure, buffers, colorings, flavorings and/or aromatic
substances and the like which do not deleteriously react with the
active compounds of the invention.
[0196] The tetracycline compounds of the invention (e.g., Compound
1) that are basic in nature are capable of forming a wide variety
of salts with various inorganic and organic acids. The acids that
may be used to prepare pharmaceutically acceptable acid addition
salts of the minocycline compounds of the invention that are basic
in nature are those that form nontoxic acid addition salts, i.e.,
salts containing pharmaceutically acceptable anions, such as the
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, isonicotinate, acetate,
lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,
bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,
gluconate, glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate and palmoate [i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts. Although such
salts must be pharmaceutically acceptable for administration to a
subject, e.g., a mammal, it is often desirable in practice to
initially isolate a minocycline compound of the invention from the
reaction mixture as a pharmaceutically unacceptable salt and then
simply convert the latter back to the free base compound by
treatment with an alkaline reagent and subsequently convert the
latter free base to a pharmaceutically acceptable acid addition
salt. The acid addition salts of the base compounds of this
invention are readily prepared by treating the base compound with a
substantially equivalent amount of the chosen mineral or organic
acid in an aqueous solvent medium or in a suitable organic solvent,
such as methanol or ethanol. Upon careful evaporation of the
solvent, the desired solid salt is readily obtained. Preferably,
the tetracycline compound of the invention is administered as a
tosylate (e.g., p-toluenesulfonate) salt or as a freebase orally or
as a hydrochloride salt intravenously.
[0197] The tetracycline compounds of the invention (e.g., Compound
1) and pharmaceutically acceptable salts thereof can be
administered via either the oral, parenteral or topical routes. In
general, these compounds are most desirably administered in
effective dosages, depending upon the weight and condition of the
subject being treated and the particular route of administration
chosen. Variations may occur depending upon the species of the
subject being treated and its individual response to said
medicament, as well as on the type of pharmaceutical formulation
chosen and the time period and interval at which such
administration is carried out.
[0198] The pharmaceutical compositions of the invention may be
administered alone or in combination with other known compositions
for treating tetracycline responsive states in a subject, e.g., a
mammal. Mammals include pets (e.g., cats, dogs, ferrets, etc.),
farm animals (cows, sheep, pigs, horses, goats, etc.), lab animals
(rats, mice, monkeys, etc.), and primates (chimpanzees, humans,
gorillas). The language "in combination with" a known composition
is intended to include simultaneous administration of the
composition of the invention and the known composition,
administration of the composition of the invention first, followed
by the known composition and administration of the known
composition first, followed by the composition of the invention.
Any of the therapeutic compositions known in the art for treating
tetracycline responsive states can be used in the methods of the
invention.
[0199] The compounds of the invention may be administered alone or
in combination with pharmaceutically acceptable carriers or
diluents by any of the routes previously mentioned, and the
administration may be carried out in single or multiple doses. For
example, the novel therapeutic agents of this invention can be
administered advantageously in a wide variety of different dosage
forms, i.e., they may be combined with various pharmaceutically
acceptable inert carriers in the form of tablets, capsules,
lozenges, troches, hard candies, powders, sprays, creams, salves,
suppositories, jellies, gels, pastes, lotions, ointments, aqueous
suspensions, injectable solutions, elixirs, syrups, and the like.
Such carriers include solid diluents or fillers, sterile aqueous
media and various non-toxic organic solvents, etc. Moreover, oral
pharmaceutical compositions can be suitably sweetened and/or
flavored. In general, the therapeutically-effective tetracycline
compounds of this invention are present in such dosage forms at
concentration levels ranging from about 5.0% to about 70% by
weight.
[0200] For oral administration, tablets containing various
excipients such as microcrystalline cellulose, sodium citrate,
calcium carbonate, dicalcium phosphate and glycine may be employed
along with various disintegrants such as starch (and preferably
corn, potato or tapioca starch), alginic acid and certain complex
silicates, together with granulation binders like
polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often very useful for tableting purposes.
Solid compositions of a similar type may also be employed as
fillers in gelatin capsules; preferred materials in this connection
also include lactose or milk sugar as well as high molecular weight
polyethylene glycols.
[0201] When aqueous suspensions and/or elixirs are desired for oral
administration, the active ingredient may be combined with various
sweetening or flavoring agents, coloring matter or dyes, and, if so
desired, emulsifying and/or suspending agents as well, together
with such diluents as water, ethanol, propylene glycol, glycerin
and various like combinations thereof.
[0202] For parenteral administration (including intraperitoneal,
subcutaneous, intravenous, intradermal or intramuscular injection),
solutions of a therapeutic compound of the present invention in
either sesame or peanut oil or in aqueous propylene glycol may be
employed. The aqueous solutions should be suitably buffered
(preferably pH greater than 8) if necessary and the liquid diluent
first rendered isotonic.
[0203] These aqueous solutions are suitable for intravenous
injection purposes. The oily solutions are suitable for
intraarticular, intramuscular and subcutaneous injection purposes.
The preparation of all these solutions under sterile conditions is
readily accomplished by standard pharmaceutical techniques well
known to those skilled in the art. For parenteral application,
examples of suitable preparations include solutions, preferably
oily or aqueous solutions as well as suspensions, emulsions, or
implants, including suppositories. Therapeutic compounds may be
formulated in sterile form in multiple or single dose formats such
as being dispersed in a fluid carrier such as sterile physiological
saline or 5% saline dextrose solutions commonly used with
injectables.
[0204] For enteral application, particularly suitable are tablets,
dragees or capsules having talc and/or carbohydrate carrier binder
or the like, the carrier preferably being lactose and/or corn
starch and/or potato starch. A syrup, elixir or the like can be
used wherein a sweetened vehicle is employed. Sustained release
compositions can be formulated including those wherein the active
component is protected with differentially degradable coatings,
e.g., by microencapsulation, multiple coatings, etc.
[0205] In addition to treatment of human subjects, the therapeutic
methods of the invention also will have significant veterinary
applications, e.g. for treatment of livestock such as cattle,
sheep, goats, cows, swine and the like; poultry such as chickens,
ducks, geese, turkeys and the like; horses; and pets such as dogs
and cats. Also, the compounds of the invention may be used to treat
non-animal subjects, such as plants.
EXEMPLIFICATION OF THE INVENTION
Example 1 An Open-Label, Parallel Group, Multiple IV Dose Study to
Assess Intra-Pulmonary Steady-State Concentrations of Compound 1
and Tigecycline in Healthy Adult Subjects
[0206] To be effective in lower respiratory tract infections (RTI),
an antibiotic must attain adequate concentrations in respiratory
tissue to affect respiratory pathogens. Both extracellular and
intracellular pathogens may cause infection, and therefore
extracellular and intracellular concentrations of antibiotics must
be adequate to cover all of the pathogens. The concentration of
antibiotic in bronchial mucosa provides a reliable guide to
bronchial penetration of the drug and may be a better predictor of
clinical efficacy than serum levels for treatment of bronchitis and
bronchopneumonia.
[0207] Epithelial lining fluid (ELF) and alveolar cells (AC),
including mostly alveolar macrophages (AM), have been advocated as
important infection sites for common extracellular and
intracellular pathogens, respectively. Direct measurement of the
concentration of antimicrobial agents in the ELF allows for a more
informed approach to appropriate dosing of the agent for RTI, and
to evaluate the pharmacokinetic (PK) and exposure-response targets
of the drug for respiratory tract infections. Bronchoalveolar
lavage (BAL) to collect respiratory tract fluid and tissue has
become a standard method of ascertaining both extracellular and
intracellular antibiotic concentrations after systemic
administration of the antibiotic. Extracellular concentrations are
calculated from fluid reflecting ELF, and intracellular
concentrations are measured in ACs, including macrophages.
[0208] This study was designed to determine intra-pulmonary PK of
Compound 1 in healthy subjects; currently there is no information
on the concentration of Compound 1 in pulmonary compartments in
humans.
[0209] Compound 1 has been shown to have in vitro activity against
the most common typical and atypical causes of community-acquired
bacterial pneumonia (CABP) and is being developed for the treatment
of CABP. It is very active in vitro against most Gram-positive
pathogens. It also exhibits activity against atypical pathogens
(e.g., Legionella species (spp.), Chlamydophila spp.), and some
anaerobic and Gram-negative pathogens. The drug is active against
strains expressing both mechanisms of tetracycline resistance, as
well as strains that are resistant to currently available
antibiotics, including methicillin, vancomycin, erythromycin, and
ciprofloxacin. The in vitro activity of Compound 1 was not affected
by serum or lung surfactant, an important characteristic that is
consistent with potential utility in infections involving the lower
respiratory tract. Further, it has been shown to be effective in
mouse models of lower respiratory tract infections caused by
Streptococcus pneumoniae and Haemophilus influenzae. In mice,
Compound 1 concentrations in lung tissue exceed plasma
concentrations by 3.7 to 4.4 fold. In vitro results against
intracellular bacteria and tissue culture experiments indicate that
Compound 1 concentrates within mammalian cells.
[0210] Tigecycline has a similar PK profile to Compound 1, and with
its documented concentration levels achieved in human ELF, the
inclusion of tigecycline is intended to provide assay sensitivity
in the study.
[0211] Compound 1 has been developed for both iv and oral
administration and has been well characterized in 16 Phase 1
studies including 536 subjects exposed to Compound 1. In addition,
Compound 1 was evaluated in a Phase 2 study of 219 subjects with
complicated skin and skin structure infection (cSSSI) and a
sponsor-terminated Phase 3 study that enrolled 143 subjects with
cSSSI. Compound 1 was well-tolerated and demonstrated efficacy
similar to an established comparator (linezolid).
[0212] The purpose of the study was to determine the concentration
of Compound 1 in pulmonary compartments (ELF and in pulmonary ACs,
including AMs) and define time course of pulmonary distribution in
comparison with the plasma pharmacokinetic (PK) profile. Compound 1
was administered intravenously to healthy subjects for 4 days (5
doses) to steady-state systemic concentrations. Subjects were
grouped to have BAL at set times after the last dose of drug.
Concomitant blood samples were taken to compare tissue with serum
antibiotic concentrations.
[0213] The data obtained in this study, namely the in vitro
activity against common typical and atypical pathogens and the
sustained ELF and AC (mostly AM) concentrations for 24 hours
suggest that Compound 1 has the potential to be a useful
antibacterial agent for the treatment of lower respiratory tract
bacterial infections caused by susceptible pathogens.
[0214] Tigecycline has a similar PK profile to Compound 1, and with
its ability to achieve concentrations in ELF, the inclusion of
tigecycline provided assay sensitivity in the study.
[0215] Thus the primary objective of this study was to determine
concentrations of Compound 1 in ELF and AC (mostly AM) and define
the time course of pulmonary distribution with concurrent plasma PK
sampling of Compound 1 in healthy adult subjects.
[0216] The secondary objective was to evaluate the PK of Compound 1
in pulmonary and plasma compartments in healthy adult subjects.
[0217] The exploratory objective was to determine the PK of
Compound 1 in pulmonary and plasma compartments compared to
tigecycline PK in pulmonary and plasma compartments in healthy
adult subjects.
[0218] This study was designed as a single-center, multiple-dose,
open-label study to determine concentrations of Compound 1 and
tigecycline in pulmonary compartments (ELF and AC) in healthy adult
subjects after administration of Compound 1 and tigecycline to
steady state levels of dosing. Enrollment of approximately 62
subjects was planned to ensure approximately 42 subjects receive
Compound 1 and to have a bronchoalveolar lavage (BAL) performed and
approximately 20 subjects received tigecycline and had a BAL
performed. Additional subjects were to be enrolled to replace
subjects who discontinued or were screen failures.
[0219] Approximately 42 subjects received 5 doses of Compound 1 100
mg intravenously (30 minute infusions at t=0, 12, 24, 48, and 72
hours); Compound 1 subjects were assigned equally to 1 of 7 BAL
sampling time points (approximately 6 subjects per BAL time point
group) for collection of ELF and AC samples.
[0220] Upon completion of the study, 42 enrolled subjects received
Compound 1 (69% male, median age 36 y, median BMI 27 kg/m.sup.2).
Six subjects had BAL at each of the 7 time points. One subject had
a BAL sampling error and was not included in BAL analyses.
[0221] Compound 1 concentrations in ELF and AC were measured at
only 1 observation time for each subject, and data from all
subjects were pooled for a PK analysis of the mean intrapulmonary
concentrations. The concentration of Compound 1 in BAL fluid was
normalized by the dilution factor in respect to urea levels
detected in plasma and BAL.
[0222] One standard bronchoscopy was performed for each subject.
Within 1 BAL timepoint group, all subjects were assessed at the
same timepoint, either at 0.5, 1, 2, 4, 8, 12, and 24 hours after
the last dose administration on Day 4. A blood sample was taken at
the time of bronschoscopy for plasma urea measurement.
Additionally, blood samples were collected for plasma PK assessment
at 0, 0.5 (end of infusion), 1, 1.5, 2, 3, 4, 6, 8, 12, and 24
hours post-dose for all subjects on Day 4.
[0223] Blood samples were taken and BAL performed in Compound
1-treated subjects according to the schedule below:
TABLE-US-00001 Day 1 Day 2 Day 3 Day 4 Compound 1 Dose 1 Dose 2
Dose 3 Dose 4 Dose 5 100 mg iv t = 0 h t = 12 h t = 24 h t = 48 h t
= 72 h Blood sample for Pre-dose N/A N/A N/A Predose, 0.5 (end of
infusion), plasma PK (baseline) 1, 1.5, 2, 3, 4, 6, 8, 12, and (all
subjects) 24 h Taken right before BAL (.+-.3 min), from the arm
contralateral to the infusion site BAL sample N/A N/A N/A N/A
Subjects assigned to either 0.5 (approximately (end of infusion),
1, 2, 4, 8, 6 subjects for each time 12, or 24 h point) Blood
sample for N/A N/A N/A N/A 0.5 (end of infusion) 1, 2, 4, 8, plasma
urea 12, or 24 h, taken right before measurement (same BAL (.+-.3
min) time point as BAL; 1 sample per subject) BAL = bronchoalveolar
lavage; h = hour; N/A = not applicable; PK = pharmacokinetic; t =
time.
[0224] For the patients receiving Compound 1, Mean (.+-.SD) plasma
pharmacokinetic parameters after the fifth Compound 1 dose included
maximum concentration of 2.26.+-.0.76 .mu.g/mL, volume of
distribution of 165.+-.58 L, clearance of 8.03.+-.1.43 L/h, and
elimination half-life of 14.7.+-.4.2 h. Mean (.+-.SD) Compound 1
concentrations (.mu.g/mL) at time of bronchoscopy and BAL were:
TABLE-US-00002 Sampling Time Plasma ELF AM 0.5 h 1.80 .+-. 0.13
1.73 .+-. 1.01 14.26 .+-. 9.30 1 h 0.89 .+-. 0.19 2.25 .+-. 0.72
12.80 .+-. 8.48 2 h 0.93 .+-. 0.33 1.51 .+-. 0.94 10.77 .+-. 7.59 4
h 0.59 .+-. 0.15 0.95 .+-. 0.33 17.99 .+-. 7.17 8 h 0.56 .+-. 0.12
0.58 .+-. 0.19 12.27 .+-. 4.70 12 h 0.42 .+-. 0.07 0.61 .+-. 0.29
12.29 .+-. 4.61 24 h 0.27 .+-. 0.05 0.41 .+-. 0.13 10.36 .+-.
4.04
[0225] Penetration ratios based on AUC.sub.0-24 values of mean and
median ELF and plasma concentrations were 1.47 and 1.42, whereas
ratios of AC (Alveolar Cell, mostly AM) to plasma concentrations
were 25.8 and 24.8.
[0226] Approximately 20 subjects received 1 dose of 100 mg
tigecycline intravenously (30 minute infusion at t=0) followed by 6
doses of 50 mg tigecycline intravenously (30 minute infusions at
t=12, 24, 36, 48, 60, and 72 hours). Tigecycline subjects were
assigned equally to 1 of 4 BAL sampling timepoints (approximately 5
subjects per BAL timepoint group) for collection of ELF and AC
samples. Tigecycline concentrations in ELF and AC were measured at
only 1 observation time for each subject, and data from all
subjects were pooled for a PK analysis of the mean intrapulmonary
concentrations. The concentration of tigecycline in BAL fluid was
normalized by the dilution factor in respect to urea levels
detected in plasma and BAL.
[0227] Blood samples were taken and BAL performed in
tigecycline-treated subjects according to the schedule below:
TABLE-US-00003 Day 1 Day 2 Day 3 Day 4 Tigecycline Dose 1 Dose 2
Dose 3 Dose 4 Dose 5 Dose 6 Dose 7 iv 100 mg 50 mg 50 mg 50 mg 50
mg 50 mg 50 mg t = 0 h t= 12 h t = 24 h t = 36 h t = 48 h t = 60 h
t = 72 h Blood sample for Pre-dose N/A N/A N/A N/A N/A Predose, 0.5
(end of plasma PK (base line) infusion), 1, 1.5, 2, (all subjects)
3, 4, 6, 8, and 12 h Taken right before BAL (.+-.3 min), from the
arm contralateral to the infusion site BAL sample N/A N/A N/A N/A
N/A N/A Subjects assigned to (approximately 5 either 2, 4, 6, or 12
h subjects for each timepoint) Blood sample for N/A N/A N/A N/A N/A
N/A 2, 4, 6, or 12 h, plasma urea taken right before measurement
(same BAL (.+-.3 min) timepoint as BAL; 1 sample per subject) BAL =
bronchoalveolar lavage; h = hour; N/A = not applicable; PK =
pharmacokinetic; t = time.
[0228] Safety assessments included physical examinations,
electrocardiograms (ECG), vital signs, standard clinical laboratory
evaluations (blood chemistry, hematology), pregnancy testing, and
adverse event (AE) and serious adverse event (SAE) monitoring.
[0229] Treatment-emergent adverse events (TEAEs) were reported in
29%. The most common TEAE was headache (12%). There were no severe
or serious TEAEs, and no discontinuations due to TEAEs in Compound
1 treated subjects. There were no clinically significant changes in
vital signs, laboratory or ECG parameters.
[0230] The duration of treatment was designed to ensure that both
treatment arms were at steady state at the time of BAL.
[0231] During the bronchoscopy 4 aliquots of 50 mL each of sterile
saline solution were instilled into the right lobe of the lungs,
immediately aspirated, and placed on ice. The first bronchoalveolar
lavage aliquot instilled (BALX) fraction was prepared and analyzed
separately from subsequent instillations. The aspirate from the
second through the fourth instillation, once pooled, represented
the BAL fraction. An aliquot of BAL was removed and used to
determine the cell count and differential cell composition
including pulmonary macrophages. The remaining supernatant was
centrifuged and the supernatant and cell pellet were immediately
frozen pending analysis. An aliquot of the BAL supernatant was
frozen separately for urea assay. The amount of test article
detected in the cell pellet was normalized by the corresponding
fraction of macrophages. Fraction BALX was analyzed in a similar
manner, except the cell pellet was not assessed or assayed. A blood
sample to determine urea concentration was obtained at the time of
the second instillation (.+-.3 minutes). The concentration of test
article detected in the BALX and BAL fluid was normalized by the
dilution factor with respect to urea levels detected in the BALX
and BAL fractions respectively.
[0232] Subjects participated in the study for approximately 34
days. Following screening, eligible subjects were randomly assigned
to Compound 1 or tigecycline treatment and assigned to a BAL lavage
sample timepoint. Subjects had Baseline evaluations on Day -1 and
then received test article treatment for 4 days followed by BAL at
their assigned timepoint. A Study Completion visit was conducted on
the day following the final test article dose. There was a Final
Follow-up assessment 7 to 14 days following the subject's last dose
of test article which may be completed by telephone contact or
other interactive technology unless an examination was needed to
evaluate AEs or abnormalities noted at the Study Completion
visit.
[0233] Safety assessments included physical examinations,
electrocardiograms (ECG), vital signs, standard clinical laboratory
evaluations (blood chemistry, hematology), pregnancy testing, and
AE and SAE monitoring.
[0234] Dosing Regimen:
[0235] The current intended therapeutic dose of Compound 1 for the
treatment of CABP is 100 mg iv every 12 hours (q12h) for 2 doses
followed by every 24 hours (q24h), with the option to switch to 300
mg orally q24h.
[0236] The approved therapeutic dose of tigecycline (TYGACIL.RTM.)
for the treatment of CABP is 100 mg iv for 1 dose followed by 50 mg
iv q12h.
[0237] Patient Inclusion/Exclusion Criteria
[0238] Enrolled patients were male or female subjects age 18 to 55
years of age, in good health as determined by past medical history,
physical examination, vital signs, ECG, and laboratory tests (no
clinically significant abnormalities in the opinion of the
investigator). Vital signs (oral body temperature, systolic and
diastolic blood pressure (BP), and pulse rate) were assessed in a
sitting position after the subject had rested for at least 3
minutes. Sitting vital signs should be within the following ranges:
oral body temperature, 35.0.degree. C. to 37.5.degree. C.
(95.0.degree. F. to 99.5.degree. F.); systolic BP, 90 to 140 mm Hg;
diastolic BP, 50 to 90 mm Hg; pulse rate, 40 to 90 bpm; Blood
pressure and pulse were assessed again after 3 minutes in a
standing position at the Screening visit. There were no more than a
20 mm Hg drop in systolic or 10 mm Hg drop in diastolic BP and
increase in heart rate (>20 bpm) associated with clinical
manifestation of postural hypotension. Out-of-range vital signs may
be repeated once at the discretion of the investigator, if
necessary.
[0239] Subjects weighed at least 50 kg, and had a body mass index
(BMI) within the range of .gtoreq.18.0 to .ltoreq.30.0 kg/m.sup.2.
Females had a negative serum pregnancy test at the Screening and
Baseline visits and agreed to comply with using an acceptable form
of birth control from Screening through the final follow-up
assessment. Males agreed to use an acceptable method of birth
control with female partner(s) and did not donate sperm from
Screening through the Final Follow-up assessment.
[0240] Patients were excluded from the study if one or more of the
following was present: [0241] Use of other investigational drugs
within 5 half-lives or 30 days prior to Screening, whichever is
longer. [0242] Had a history of hypersensitivity or allergic
reaction (e.g., anaphylaxis, urticaria, other significant reaction)
to any tetracycline (e.g., minocycline, doxycycline, or
tigecycline). [0243] Had a history of clinically significant ECG
abnormalities, or any of the following ECG abnormalities at the
Screening or Baseline visit: PR>220 msec, QRS complex >120
msec, Long QT syndrome, QTc Fridericia's Correction Formula (QTcF)
>450 msec (males), and QTcF >470 msec (females) [0244]
Pregnant or nursing (breastfeeding) women. [0245] History of
malignancy of any organ system (other than localized basal cell
carcinoma of the skin), treated or untreated, within the past 5
years, regardless of whether there is evidence of local recurrence
or metastases. [0246] Use of tobacco products in the 3 months prior
to Screening. [0247] A positive urine cotinine test at Screening or
Baseline. [0248] Use of any prescription drugs or herbal
supplements within 4 weeks prior to the Baseline visit, and/or
over-the-counter (OTC) medications including dietary and
fitness/body-building supplements (vitamins included) within 2
weeks prior to the Baseline visit. [0249] Donation or loss of 400
mL or more of blood or plasma within 8 weeks prior to the Baseline
visit, or longer if required by local regulation. [0250] Hemoglobin
levels <12.5 g/dL for males, <11.5 g/dL for females at
Screening/Baseline visit. [0251] Significant illness within 2 weeks
prior to Baseline visit. [0252] History of autonomic dysfunction
(e.g., recurrent episodes of fainting, palpitations, etc) within 3
years prior to Screening. [0253] History of acute or chronic
bronchospastic disease (including asthma and chronic obstructive
pulmonary disease (COPD), treated or not treated) within 3 years
prior to Screening. [0254] Any surgical or medical condition which,
in the opinion of the investigator, might significantly alter the
absorption, distribution, metabolism, or excretion of drugs, or
which may jeopardize the subject in case of participation in the
study. [0255] History of, or active, inflammatory bowel disease,
ulcers, GI or rectal bleeding, or pancreatitis. [0256] Liver
disease or liver injury as indicated by abnormal LFTs such as
aspartate aminotransferase (AST), ALT, gamma-glutamyl
transpeptidase (GGT), CK, alkaline phosphatase (ALP), or serum
bilirubin. The investigator should be guided by the following
criteria: Serum bilirubin may not exceed 1.2 times the upper limit
of normal (ULN); Any other single parameter listed above may not
exceed 1.5 times ULN; any elevation of more than 1 parameter
excludes a subject from participation in the study. Testing may be
repeated once more as soon as possible to rule out lab error.
Recheck results must not meet the criteria above in order for
subject to qualify. [0257] History or presence of impaired renal
function as indicated by clinically significant abnormal creatinine
or blood urea nitrogen (BUN) and/or urea values, or abnormal
urinary constituents (e.g., albuminuria). [0258] Evidence of
urinary obstruction or difficulty in voiding at Screening. [0259]
Was known to be human immunodeficiency virus (HIV)-positive. [0260]
Had known chronic hepatitis B or chronic hepatitis C infection.
[0261] Positive alcohol test or positive drug screen at the
Screening or Baseline visit. [0262] Had previously been treated
with Compound 1 or previously enrolled in this study. [0263] Any
concomitant condition that, in the opinion of the investigator, is
likely to interfere with the determination of AEs or completion of
the study procedures.
[0264] Procedures
[0265] There were 3 protocol-defined phases of the study:
Screening, Treatment and Follow-up. The study had the following
protocol-defined evaluations: [0266] Screening visit [0267]
Baseline visit [0268] Visits on Days 1, 2, and 3 (test article
dosing) Visit on Day 4 (test article dosing and BAL) [0269] Study
Completion visit on Day 5 [0270] Final Follow-up assessment: Study
Day 11-18 (7-14 days after the last dose of test article)
[0271] Subjects who discontinued study treatment prematurely had
the Study Completion procedures performed prior to clinic discharge
and a Final Follow-up assessment.
[0272] Screening was used to establish subject eligibility and
Baseline characteristics for each subject. The following
information was collected: review of inclusion/exclusion criteria;
relevant medical/surgical history and current medical conditions
(predisposing factors that may affect lung function (e.g., prior
lung infection, mild to moderate COPD, asthma, history of smoking,
chronic cough, etc); demographics; physical examination; urine
alcohol test, drug screen, cotinine test; vital signs; 12-lead ECG;
laboratory tests (hematology, chemistry, coagulation, pregnancy
test (women only)); and AEs since the signing of the ICF
Concomitant medications (past 4 weeks).
[0273] The treatment period was 5 days in duration. Subjects who
met inclusion criteria and did not meet exclusion criteria received
their first dose of test article. The following assessments were
done: Vital signs; AEs; Concomitant treatments; and Test article
administration and accountability.
[0274] During the Intravenous Treatment Phase (Test Article),
infusions of Compound 1 were administered continuously over
approximately 30 minutes (at least 30 minutes and not more than 45
minutes) according to the schedule in Table 1-3 below. Infusions of
tigecycline were administered continuously over approximately 30
minutes (at least 30 minutes and not more than 45 minutes)
according the schedule in Table 1-4. All infusion start and stop
times and compliance (delivery of .gtoreq.90% of the dose) were
recorded in source documents and on the eCRF.
TABLE-US-00004 TABLE 1-1 Treatment Regimen for IV Compound 1
Time.sup.a Dose.sup.b t = 0 h Compound 1 100 mg in 100 mL NS t = 12
h Compound 1 100 mg in 100 mL NS t = 24 h Compound 1 100 mg in 100
mL NS t = 48 h Compound 1 100 mg in 100 mL NS t = 72 h Compound 1
100 mg in 100 mL NS t = time; NS = normal saline (0.9% sodium
chloride) for injection .sup.aThe start time of the start of the
first infusion was designated time 0 (t = 0 h). Subsequent
infusions were administered within .+-.1 hour of the target
infusion times listed. .sup.bAll 100 mL infusions of Compound 1
were administered continuously over 30 min (at least 30 min and not
more than 45 min).
TABLE-US-00005 TABLE 1-2 Treatment Regimen for IV Tigecycline
Time.sup.a Dose.sup.b
TABLE-US-00006 TABLE 1-1 Treatment Regimen for IV Compound 1
Time.sup.a Dose.sup.b t = 0 h tigecycline 100 mg in 100 mL NS t =
12 h tigecycline 50 mg in 100 mL NS t = 24 h tigecycline 50 mg in
100 mL NS t = 36 h tigecycline 50 mg in 100 mL NS t = 48 h
tigecycline 50 mg in 100 mL NS t = 60 h tigecycline 50 mg in 100 mL
NS t = 72 h tigecycline 50 mg in 100 mL NS t = time; NS = normal
saline (0.9% sodium chloride) for injection. .sup.aThe start time
of the start of the first infusion was designated time 0 (t = 0 h).
Subsequent infusions were administered within .+-.1 hour of the
target infusion times listed. .sup.bAll 100 mL infusions of
tigecycline were administered continuously over 30 min (at least 30
min and not more than 45 min).
[0275] During the Follow-up Phase, subjects were evaluated at 2
visits after the completion of treatment: at the Study Completion
visit on Day 5 and at a Final Follow-up assessment on Study Days 11
to 18 (7 to 14 days after subject's last dose of test article). The
Final Follow-up Assessment was conducted by telephone contact
unless an examination was needed to evaluate AEs or abnormalities
noted at Study Completion.
[0276] For IV injection, Compound 1 was supplied as 100 mg (plus 4%
overfill) sterile, lyophilized powder for reconstitution packaged
in a clear, glass vial with a rubber stopper and aluminum overseal.
Excipients included tosylate acid counter ion, sucrose,
hydrochloric acid and sodium hydroxide to adjust the pH. Each vial
was reconstituted into a clear solution by adding 5 mL Sterile
Water for Injection. The vial was swirled gently to ensure complete
dissolution prior to use. Excessive shaking was avoided to prevent
foaming. Reconstituted vials were used immediately to prepare the
infusion solution. The infusion solution was prepared by
withdrawing 5 mL of reconstituted solution from the vial and slowly
injecting into a 100 mL normal saline (NS) for injection (0.9%
sodium chloride) infusion bag. The prepared infusion solution was
used within 8 h or stored at up to 24 h at 2.degree. C. to
8.degree. C. (35.6.degree. F. to 46.4.degree. F.). The 100 mL
infusion solution was administered at room temperature continuously
over 30 minutes (at least 30 minutes and not more than 45
minutes).
[0277] Reconstituted Compound 1 was injected as 100 mg iv q12h for
first 2 doses followed by 100 mg iv q24h (starting 24 h after first
dose) for 2-3 doses. Total treatment consisted of 5 doses, and a
duration of 5 days.
[0278] The comparator test article Tigecycline was injected as 100
mg iv first dose followed by 50 mg iv q12h for 6 doses. Total
treatment consisted of 7 doses, for a duration of 5 days.
[0279] Safety
[0280] Any subject who received at least 1 dose of test article was
included in the evaluation for safety. Safety was assessed by the
following measures: Physical exams; AEs and SAEs; Vital signs;
Laboratory assessments (Blood samples for hematology, chemistry,
and coagulation (prothrombin time only)); ECG; and Pregnancy
assessments.
[0281] Data Analysis
[0282] All analyses of data for this study complied with
International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH-E9) and the
sponsor's guidance documents and standards. Statistical analyses
were performed using Statistical Analysis Software (SAS).
[0283] a) Analysis Populations
[0284] Subject populations have been defined for the various
analyses of PKs and safety, as follows: [0285] The PK population
consisted of all subjects who received test article and had at
least 1 evaluable PK parameter. [0286] The Safety population
consisted of all subjects who received at least 1 dose of test
article.
[0287] b) Subject Demographics and Baseline Characteristics
[0288] Descriptive statistics, by treatment arm, was provided for
the following: Subject disposition (completed test article,
discontinued test article by reason for discontinuation, completed
study, discontinued study by reason for discontinuation); Protocol
deviations; Medical histories and continuing medical
conditions.
[0289] Baseline demographic and medical variables were analyzed
using a 2-sided Fisher's exact test (for categorical variables) or
a 2-sided Wilcoxon Rank Sum test (for ordinal and continuous
variables).
[0290] c) Safety Outcome Measures
[0291] Safety variables included the incidence rate of AEs, change
in vital signs, ECG parameters, and laboratory test results
obtained during the course of the study. Subjects were analyzed
according to the treatment actually received.
[0292] d) PK
[0293] All completed subjects with evaluable plasma PK parameter
data were included in the PK data analysis. The following Compound
1 and tigecycline plasma PK parameters were determined: [0294] Area
under the curve (AUC) from time 0 to 24 hours after dosing
(AUC.sub.0-24) for Compound 1, and AUC from time 0 to 12 hours
after dosing (AUC.sub.0-12) for tigecycline, [0295] Maximum plasma
concentration (C.sub.max), [0296] Time to maximum plasma
concentration (T.sub.max) and [0297] Terminal elimination half-life
(T.sub.1/2) associated with the terminal slope of the
semilogarithmic concentration-time curve.
[0298] All the biofluid concentrations were expressed in ng/mL. All
concentrations below the limit of quantification (BLQ) or missing
data were labeled as such in the concentration data listings.
Concentrations BLQ were treated as zero in summary statistics for
concentration data only. They were not considered for calculation
of PK Parameters (with the exception of the predose samples). PK
parameters were determined using non-compartmental method(s) using
WinNonlin Pro.
[0299] The primary objective of the study was to assess the
concentration of Compound 1 in lung ELF and AC (mostly AM). The
concentration of Compound 1 and tigecycline in lung ELF and AC were
calculated as area under the (concentration/time) curve in
epithelial lung fluid (AUC.sub.ELF)/area under the
(concentration/time) curve in plasma (AUC.sub.plasma) and area
under the (concentration/time) curve in alveolar cells
(AUC.sub.AC)/AUC.sub.plasma, respectively. These were obtained from
the above plasma PK parameter calculations (AUC.sub.0-24 and
AUC.sub.0-12). The tigecycline concentration information was serve
as an internal validation for assay sensitivity purposes.
[0300] To determine the AUC.sub.ELF parameters for Compound 1 and
tigecycline, their concentration data were used by deriving from
the corresponding BAL concentrations. The concentration of Compound
1 or tigecycline in the lung ELF (C.sub.ELF) was calculated as:
C.sub.ELF=C.sub.BAL*(V.sub.BAL/V.sub.ELF), where C.sub.BAL is the
concentration in the BAL fluid, V.sub.BAL is the volume of the
aspirated BAL fluid, and V.sub.ELF is the volume of lung ELF.
[0301] The volume of the lung ELF within the BAL fluid was
estimated by (urea.sub.BAL/urea.sub.plasma), where urea.sub.BAL and
urea.sub.plasma represented the concentrations of urea in the BAL
fluid and plasma, respectively.
[0302] Compound 1 and tigecycline concentration data from ELF, AC,
and AM were presented in a listing. AUC.sub.ELF and AUC.sub.AC were
determined from pooled pulmonary concentration data and were
summarized by treatment group. For the Compound 1 cohort there were
at least 6 ELF and AC concentrations for each of the 7 timepoints
over the 24 hour dosing interval. For the tigecycline cohort there
were 5 ELF and AC concentrations for each of the 4 timepoints over
the 12 hour dosing interval.
[0303] The calculated concentration of Compound 1 and tigecycline
in lung ELF and AC as the ratios of AUC.sub.ELF/AUC.sub.plasma and
AUC.sub.AC/AUC.sub.plasma, were summarized by treatment group. BALX
was assessed separately and in an identical fashion. The impact of
"BALX" on the PK understanding of Compound 1 and tigecycline was
assessed.
[0304] PK Samples for Compound 1 or Tigecycline Concentration
[0305] The permitted windows for PK sample collection were as
follows:
TABLE-US-00007 Window PK blood collection- scheduled time relative
to test article dose Predose within 10 min before test article
administration 0.5 to 1 h .+-.2 min 1.5 h to 6 h .+-.5 min 8 h to
24 h .+-.15 min Sample collected at the bronchoscopy .+-.3 min of
the second BAL instillation scheduled time Bronchoscopy - BAL and
AC collection Scheduled time .+-.15 min Blood sample for plasma
urea testing Sample collected at the bronchoscopy .+-.3 min of the
second scheduled time BAL instillation
[0306] For PK blood collection and processing, all blood samples
were taken by either direct venipuncture or an indwelling cannula
inserted in a forearm vein (on the arm contralateral to the
infusion site) at the timepoints specified in the Study Flowchart.
The PK blood sample collected at the bronchoscopy scheduled time
was obtained at the time of the second BAL instillation (.+-.3
minutes) from the arm contralateral to the infusion site.
[0307] Blood samples were collected into labeled 4 mL tubes
containing sodium heparin. Immediately after the sample was
collected, the tube was gently inverted 5 to 8 times to thoroughly
mix the anticoagulant and then placed upright in a cryoblock or
test tube rack surrounded by ice until centrifugation. Samples were
centrifuged at 1500.times.g (gravity) for 10 minutes at
approximately 4.degree. C. within 30 minutes of collection. The
resultant plasma was divided into 2 equal aliquots, placed in
individual cryovials, and immediately frozen at -70.degree. C. or
colder within 1 hour of collection. The tubes were kept frozen at
-70.degree. C. or colder pending shipment to the bioanalytical
laboratory.
[0308] For BAL and AC sample collection and handling, one standard
bronchoscopy was performed in each subject following the last
administration of test article at the timepoints specified in the
Study Flowchart. Subjects were continuously monitored during
bronchoscopy. Blood pressure, heart rate, and respiratory rate were
recorded just prior to (within 30 minutes) the bronchoscopy
procedure scheduled time, 30 minutes after, and 60 minutes after of
the bronchoscopy procedure scheduled time. Topical lidocaine, 4%
solution for the oropharynx, and 2% solution for the nasopharynx,
were applied to the upper airways to prepare subjects for
bronchoscopy. If needed, a 1% lidocaine solution was used in the
lower airways. A fiberoptic bronchoscope was inserted into the
middle lobe of the right lung. Four-50 mL aliquots of sterile 0.9%
saline solution were instilled into the right lobe and immediately
aspirated, and placed on ice. The first 50 mL instilled (fraction
BALX) was collected (2 aliquots of 4 mL), immediately placed on
ice, the volume recorded, stored, prepared, and analyzed separately
from subsequent instillations. The aspirate from the second through
the fourth instillation was collected immediately, placed on ice,
and the volume recorded. The collective aspirates (second through
fourth), once pooled, represented the BAL fraction.
[0309] An aliquot of BAL was removed and used to determine the cell
count and differential cell composition. The fraction of pulmonary
macrophages was determined during cell count and differentiation.
An aliquot of the BALX and BAL supernatants were reserved for a
urea assay. The remaining supernatant was centrifuged immediately
at 400.times.g for 5 minutes in a refrigerated centrifuge.
Supernatant, fractionated into 5 mL aliquots, and the cell pellet
were immediately frozen at -70.degree. C. or colder pending
analysis. Fraction BALX was analyzed in a similar manner, with the
exception that the cell pellet was not assessed or assayed.
[0310] For urea assay in BAL fluid and plasma, a blood sample to
determine urea concentration was obtained at the time of the second
BAL instillation (.+-.3 minutes). Urea blood samples were taken by
either direct venipuncture or an indwelling cannula inserted in a
forearm vein (on the arm contralateral to the infusion site).
Plasma was prepared from the urea blood sample in the same manner
as plasma samples for PK analysis.
[0311] Plasma samples, BAL supernatant samples and BALX supernatant
samples were analyzed for urea concentration by the bioanalytical
laboratory.
[0312] After all of the PK samples from a single subject had been
collected and frozen at -70.degree. C. or colder, the primary
samples from each timepoint were batched together with
corresponding primary samples from other subjects and be carefully
packaged and shipped frozen at -70.degree. C. or colder to the
bioanalytical laboratory designated by the sponsor. Samples were
shipped with sufficient dry ice to remain frozen during overnight
transit. For each subject and timepoint, the remaining stored
aliquots were retained on-site at -70.degree. C. or colder until
released or requested by the sponsor.
[0313] The bioanalytical laboratory assayed the samples for
Compound 1 or tigecycline using a specific, sensitive, and
validated liquid chromatography/tandem mass spectrometry (LC/MS/MS)
method approved by the sponsor.
[0314] To determine ELF volume and concentrations of Compound 1 or
Tigecycline in ELF, urea measured in the BALX and BAL supernatant
and in plasma was used to calculate the volume of ELF using the
conventional urea dilution method. The volume of ELF was determined
by the following equation:
V.sub.ELF=V.sub.BAL*(urea.sub.BAL/urea.sub.plasma),
where V.sub.ELF=volume of ELF in the BAL sample, V.sub.BAL=volume
of aspirated BAL fluid, urea.sub.BAL=concentration of urea in BAL
supernatant, and urea.sub.plasma=concentration of urea in
plasma.
[0315] The concentration of Compound 1 or tigecycline in ELF
(C.sub.ELE) was calculated as:
C.sub.ELF=C.sub.BAL*(V.sub.BAL/V.sub.ELF),
where C.sub.ELF=concentration of Compound 1 or tigecycline in ELF,
C.sub.BAL=measured concentration of Compound 1 or tigecycline in
BAL supernatant, V.sub.ELF=volume of ELF in the BAL sample, and
V.sub.BAL=volume of aspirated BAL fluid.
[0316] To determine AC volume and concentration of Compound 1 or
Tigecycline in AC and AM, the volume of AC collected in the BAL
cell pellet suspension was determined from the BAL fluid cell
count. The volume of cells was calculated by multiplication of cell
counts in ELF with the known volume of ACs. The volume of cells was
determined by multiplying the cell count with the mean macrophage
cell volume of 2.42 .mu.L/10.sup.6 cell.
[0317] The measured concentration of Compound 1 or tigecycline in
AC (CAC) was determined by the following equation:
CAC=(C.sub.pellet suspension/V.sub.AC),
where C.sub.pellet suspension is the Compound 1 or tigecycline
concentration in 1 mL cell suspension and V.sub.AC is the volume of
AC in 1 mL cell suspension.
[0318] The measured concentration of Compound 1 or tigecycline in
AMs (C.sub.AM) was derived from CAC by adjusting for the percentage
of macrophages and monocytes in the AC as determined by a
differential cell count of the BAL fluid.
[0319] FIG. 1 shows the result of mean Compound 1 concentration vs.
time profile in AC, plasma, and ELF. It is apparent that the mean
Compound 1 concentration in AC (mostly AM) is at least an order of
magnitude higher (about 25 fold) than that in plasma, while the
mean Compound 1 concentration in ELF is at least about 40% higher
than that in plasma. See tables.
TABLE-US-00008 Sampling Time ELF to Plasma (Mean, SD) AM to Plasma
(Mean, SD) 0.5-hour.sup.a 0.95 .+-. 0.56 8.12 .+-. 5.95
1-hour.sup.a 2.72 .+-. 1.26 13.85 .+-. 7.38 2-hour.sup.b 1.50 .+-.
0.61 12.29 .+-. 6.57 4-hour.sup.a 1.79 .+-. 0.49 34.72 .+-. 15.14
8-hour.sup.a 1.07 .+-. 0.45 23.12 .+-. 11.17 12-hour.sup.a 1.44
.+-. 0.57 28.97 .+-. 8.78 24-hour.sup.a 1.65 .+-. 0.86 40.33 .+-.
10.29 .sup.a6 reported plasma, ELF, and AM concentrations at this
sampling time .sup.b5 samples plasma, ELF, and AM concentrations at
this sampling time
Compound 1 Demonstrated Higher Epithelial Lining Fluid (ELF) and
Alveolar Cellular (AC) Concentrations
TABLE-US-00009 [0320] Plasma ELF AC (.mu.g*h/ (.mu.g*h/ Ratio
(.mu.g*h/ Ratio mL) mL) ELF:Plasma mL) AC:Plasma AUC.sub.mean 11.73
17.23 1.47 302.5 25.8 AUC.sub.median 11.80 16.74 1.42 292.3 24.8
AUC.sub.mean = Area-under-the-curve based on mean concentration at
each BAL sampling time AUC.sub.median = Area-under-the-curve based
on median concentration at each BAL sampling time
[0321] This data provides important information on the time course
and magnitude of extracellular and intracellular concentrations of
Compound 1 in the lung. Intravenous administration of Compound 1 at
100 mg as a 30-minute infusion produced concentrations that were
higher in epithelial lining fluid (ELF) and alveolar cellular (AC,
including AM) than simultaneous plasma concentrations throughout
the 24-hour period after five doses. The in vitro activity against
common typical and atypical pathogens and the sustained ELF and
AC/AM concentrations for 24 hours suggest that Compound 1 can be a
useful antibacterial agent for the treatment of lower respiratory
tract bacterial infections caused by susceptible pathogens.
[0322] Safety Monitoring
[0323] An AE is any untoward, undesired, or unplanned event in the
form of signs, symptoms, disease, or laboratory or physiologic
observations occurring in a person given a test article or in a
clinical study. The event does not need to be causally related to
the test article or clinical study. An AE includes, but is not
limited to, the following: any clinically significant worsening of
a preexisting condition; an AE occurring from overdose of a test
article, whether accidental or intentional (overdose is a dose
greater than that specified in the protocol); an AE occurring from
abuse (e.g., use for nonclinical reasons) of a test article; and an
AE that has been associated with the discontinuation of the use of
a test article.
[0324] A SAE is an AE that: results in death; is life-threatening;
requires hospitalization or prolongation of an existing
hospitalization; results in a persistent or significant disability
or incapacity; results in a congenital anomaly or birth defect; or
additionally, important medical events that may not result in
death, be life-threatening, or require hospitalization may be
considered SAEs when, based on appropriate medical judgment, they
may jeopardize the subject and may require medical or surgical
intervention to prevent 1 of the outcomes listed in this
definition. Examples of such events include allergic bronchospasm
requiring intensive treatment in an emergency room or at home,
blood dyscrasias or convulsions that do not result in
hospitalization, or development of drug dependency or drug
abuse.
[0325] If there was any doubt about whether the information
constitutes an SAE, the information was treated as an SAE.
[0326] A protocol-related AE is an AE occurring during a clinical
study that is not related to the test article, but is considered by
the investigator or the Medical Monitor (or designee) to be related
to the research conditions, i.e., related to the fact that a
subject is participating in the study. For example, a
protocol-related AE may be an untoward event related to a medical
procedure required by the protocol.
Example 2 Effect of Food on the Bioavailability of Omadacycline in
Healthy Volunteers
[0327] Compound 1 (9-[(2,2-dimethyl-propyl
amino)-methyl]-minocycline) is a first-in-class aminomethylcycline
antibiotic that is characterized by improved in vitro antimicrobial
activity (Honeyman et al, Antimicrob Agents Chemother.
59:7044-7053, 2015).
[0328] Phase 3 studies have concluded with Compound 1 as oral and
intravenous (IV) monotherapy in patients with acute bacterial skin
and skin structure infection (ABSSSI). During the development
process, oral Compound 1 formulations have evolved from free-base
in a capsule through a series of tablet and salt formulations in
order to optimize oral bioavailability while improving
tolerability. The current phase 3 tablet formulation is the
tosylate salt of Compound 1, which has been shown to have an
absolute bioavailability of 34.5% when administered under fasting
conditions. The primary objective of this study was to evaluate the
relative bioavailability of a single oral 300 mg dose of Compound 1
(administered as the phase 3 tablet formulation) at various times
after the consumption of food in healthy adult subjects.
[0329] The result of this study showed that food consumption has an
effect on the oral bioavailability of a single 300 mg Compound 1
dose.
[0330] Briefly, the study was a phase 1, randomized, open-label
4-period, crossover study. Before dosing on Day 1 of Period 1,
subjects were randomized to one of four treatment sequences (see
Table 2-1). On Day 1 of each period, subjects received a single
oral dose of 300 mg Compound 1 (2.times.150 mg tablets) at various
times after the consumption of food. There was a washout period of
at least 5 days between each dosing period. A final study
completion visit occurred 6 to 10 days after the last dose of
Compound 1.
TABLE-US-00010 TABLE 2-1 Treatment Sequences Sequence Period 1
Period 2 Period 3 Period 4 ADBC A D B C BACD B A C D CBDA C B D A
DCAB D C A B A: subjects fasted overnight (no food or drink except
for water for at least 6 hours before dosing); a standard high-fat
(nondairy) meal was served 3 hours after dosing B: a standard
high-fat (nondairy) meal completed at 4 hours before dosing C: a
standard high-fat (nondairy) meal completed at 2 hours before
dosing D: a standard high-fat meal including dairy completed at 2
hours before dosing
[0331] The high-fat (approximately 50% of total caloric content of
the meal) and high-calorie (approximately 800 to 1000 calories)
meal followed Food and Drug Administration guidance
recommendations, and provided approximately 150, 250, and 500 to
600 calories from protein, carbohydrate, and fat, respectively (FDA
Guidance, 2002). These meals were to be consumed within 20 minutes.
Dose administration for Treatments B, C, and D was based off of the
end time of the meal. During all 4 treatment periods, subjects
received no food or drink except water for at least 3 hours after
dosing and no dairy products, antacids or multivitamins for 4 hours
after dosing.
[0332] A total of 32 subjects were enrolled and dosed in at least
one treatment period. Overall mean age was 32.3 years, with a range
of 21 to 50 years; 47% were male (Table 2-2). One subject was
discontinued from the study because of a positive alcohol screen at
baseline of period 3 and did not receive Treatments A and D. One
subject requested withdrawal and did not receive Treatments B and
C. PK data were available for 31 subjects for each treatment
condition.
TABLE-US-00011 TABLE 2-2 Baseline Demographics Subjects (n = 32)
Age, years.sup.a 32.2 (8.0) Age range, years 21-50 Male, n (%) 15
(46.9) Race, n (%) white 24 (75) black/African American 8 (25)
Hispanic/Latino 12 (37.5) Height, cm.sup.a 168.0 (9.5) Weight,
kg.sup.a 71.5 (13.4) BMI (body Mass Index), kg/m.sup.2a 25.2 (3.2)
.sup.aMean (Standard Deviation)
[0333] Blood samples for pharmacokinetic (PK) assessments of
Compound 1 were collected before dosing (predose) and at 0.5, 1,
1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours after dosing in each
period. PK parameters included: Area under the plasma
concentration-time curve (AUC) from time 0 to 24 hours after dosing
(AUC.sub.0-24); AUC from time 0 to the last quantifiable
concentration (AUC.sub.0-t); AUC time 0 extrapolated to infinity
(AUC.sub.0-inf); Maximum (peak) observed plasma concentration
(C.sub.max); Time to reach C.sub.max (T.sub.max); Terminal
elimination half-life (T.sub.1/2); Terminal phase rate constant
(.lamda.z).
[0334] Safety and tolerability was assessed by: Adverse events
(AEs); vital sign measurements at multiple time-points within 24
hours post-dose in each treatment period; and clinical laboratory
tests 24 hours post-dose in each treatment period.
[0335] For statistical analysis, individual PK parameters for
Compound 1 were summarized with descriptive statistics. Geometric
means were determined for AUC and C.sub.max. PK parameters were
evaluated using noncompartmental analysis using Phoenix.RTM.
WinNonlin.RTM. (Pharsight Corp, St. Louis, Mo.), Version 6.2.1.
Confidence intervals (CI) for test treatments (fed states:
Treatments B, C, and D) compared with the reference treatment
(fasted state: Treatment A) were constructed for AUC.sub.0-24,
AUC.sub.0-t, AUC.sub.0-inf, and C.sub.max. Absence of the effect of
food was concluded if the 90% CI for the test-to-reference ratios
(B/A, C/A, or D/A) of geometric means were contained within the
criterion interval of 80% to 125% for AUC.sub.0-24, AUC.sub.0-t,
AUC.sub.0-inf, and C.sub.max. For T.sub.max, the Wilcoxon signed
rank test was performed. p.ltoreq.0.05 was considered statistically
significant.
[0336] A linear mixed-effect model with treatment condition,
sequence, and period as fixed effects and subject nested within
sequence as a random effect was fitted to the natural
log-transformed PK parameters for estimation of effects and 90%
confidence intervals (CIs) for the fed states compared with the
fasted state.
TABLE-US-00012 TABLE 2-3 Plasma PK Parameters for Compound 1 after
a Single 300 mg Oral Dose Mean (Coefficient of Variation) Treatment
A Treatment B Treatment C Treatment D Parameter N = 31 N = 31 N =
31 N = 31 AUC.sub.0-24, mcg*h/mL 7.2 (28.1) 6.1 (26.3) 4.2 (23.4)
2.8 (44.3) AUC.sub.0-t, mcg*h/mL 7.2 (28.1) 6.1 (26.3) 4.2 (23.4)
2.8 (44.3) AUC.sub.0-inf, mcg*h/mL 10.2 (27.0).sup.b 8.8 (29.2) 6.0
(25.4) 4.0 (44.1) C.sub.max, mcg/mL 0.6 (25.3) 0.6 (25.0) 0.4
(22.4) 0.3 (42.6) T.sub.max, h.sup.a 2.5 (1.5, 4.1) 2.9 (1.0, 6.9)
2.9 (1.0, 6.0) 2.9 (1.0, 6.0) T.sub.1/2, h 13.8 (10.3).sup.b 13.6
(12.7) 13.6 (12.2) 13.5 (14.7) PK analysis showed that, for the 31
subjects included in the PK analysis, fasted AUC.sub.0-inf,
AUC.sub.0-t, and AUC.sub.0-24 were 10.2, 7.2, and 7.2 mcg*h/mL,
respectively, and C.sub.max was 0.6 mcg/mL. Across all treatment
periods, mean T.sub.1/2 ranged from 13.5 to 13.8 hours, and median
T.sub.max ranged from 2.5 to 2.9 hours. No treatment-related
adverse events or clinically relevant changes in laboratory values,
or vital signs occurred. See Table 2-3.
[0337] A significant reduction in systemic exposure to omadacycline
was observed for all three treatments (Treatments B, C, and D) vs.
Treatment A (FIG. 1 and Table 2-4).
TABLE-US-00013 TABLE 2-4 Effect of Food on Plasma PK Parameters of
Compound 1 (N = 31) Treat- ment Ratio of Treat- Geometric Compar-
Geometric 90% CI of Parameter ment LS Mean ison LS Mean (%) Ratio
(%) AUC.sub.0-24, A 7.4 mcg*h/L B 6.2 B/A 83.4 74.9, 92.7 C 4.3 C/A
57.7 51.9, 64.2 D 2.8 D/A 37.3 33.6, 41.5 AUC.sub.0-t, A 7.4
mcg*h/L B 6.2 B/A 83.3 74.9, 92.7 C 4.3 C/A 57.7 51.9, 64.1 D 2.8
D/A 37.9 33.5, 41.4 AUC.sub.0-inf, A* 10.6 mcg*h/L B 9.0 B/A 84.7
75.8, 94.6 C 6.2 C/A 58.4 52.3, 65.3 D 4.0 D/A 37.9 34.0, 42.3
C.sub.max, A 0.66 mcg/L B 0.56 B/A 84.5 75.9, 94.1 C 0.39 C/A 60.1
54.0, 66.9 D 0.27 D/A 40.7 36.5, 45.2 *N = 30, a terminal
mono-exponential phase could not be identified for one subject. CI,
confidence interval; LS, least squares
[0338] The effect of food was more pronounced when a high-fat meal
was consumed closer to dosing and when dairy was included in the
meal. Compared with a fasted dose, Compound 1 exposure (C.sub.max
and AUC) was Reduced by 15% to 17% for a nondairy meal 4 hours
before dosing; reduced by 40% to 42% for a nondairy meal 2 hours
before dosing; and reduced by 59% to 63% for a dairy meal 2 hours
before dosing. The between-subject variability in systemic exposure
to omadacycline was similar for Treatments A, B and C (CV
22.4-29.2%) for C.sub.max and AUC. By contrast, for Treatment D the
CV was 42.6-44.4% for these parameters.
[0339] Concerning safety and tolerability, two subjects experienced
treatment emergent AEs (one reported nausea, one reported
somnolence); both events were of mild intensity and considered
unrelated to study drug. No subject discontinued the study for an
AE, and no subject experienced a serious AE (SAE). A slight
increase from baseline in heart rate (median 8 to 10 bpm at 4 to 6
hours post dose) was observed for Treatment A (i.e., the group with
highest omadacycline exposure). In all other treatment groups, the
median change from baseline in heart rate was .ltoreq.3 bpm at all
measured time points. No notable changes in blood pressure were
observed. There were no clinically significant changes in clinical
laboratory tests.
[0340] The results showed that a single oral dose of Compound 1 was
well tolerated. Administration of a 300 mg dose within 2 to 4 hours
of food reduced the bioavailability compared with the fasted state.
Thus preferably, once daily oral Compound 1 should be administered
at least 6 hours following a meal.
Example 3 A Phase 3 Randomized, Double-Blind, Multi-Center Study to
Compare the Safety and Efficacy of Compound 1 IV/PO to Moxifloxacin
IV/PO for Treating Adult Subjects with Community-Acquired Bacterial
Pneumonia (CABP)
[0341] This study evaluates the safety and efficacy of intravenous
(iv) and oral (po) Compound 1 as compared to iv and po moxifloxacin
in the treatment of adults with CABP.
[0342] More specifically, the primary objective of this study is to
demonstrate that Compound 1 100 mg iv every 12 hours (q12h) for 2
doses, followed by 100 mg iv/300 mg po once every 24 hours (q24h)
is non-inferior to moxifloxacin 400 mg iv/po q24h in the treatment
of adults with CABP. The secondary objectives are: to evaluate the
safety of Compound 1 in the treatment of adult subjects with CABP
in the Safety population; to evaluate the Clinical Response
according to the identified causative pathogen; and to evaluate the
pharmacokinetics (PK) of Compound 1 in adult subjects with
CABP.
[0343] According to the study design, a randomized (1:1), active
comparator-controlled, double-blind, Phase 3 study was conducted to
compare Compound 1 and moxifloxacin in the treatment of adults with
CABP (Pneumonia Outcomes Research Team [PORT] Risk Class II, III,
or IV). PORT Risk Class Calculation was adapted from Fine et al.,
N. Engl. J. Med. 336:243-250, 1997 (incorporated by reference).
About 750 patients were enrolled. Both iv and po phases of the
study were double-blind. Enrollment of subjects with disease
characterized as PORT Risk Class II were limited to no more than
15% of randomized subjects. Enrollment of subjects who have
received a single dose of an allowed short-acting antibiotic within
the 72 hours prior to the first dose of test article were limited
to no more than 25% of randomized subjects. Enrolled subjects
participated in the study for approximately 30 days.
[0344] The study consists of 3 phases: Screening, Double-Blind
Treatment, and Follow-up. Screening evaluations, with the exception
of the blood culture sample collection and radiographic
confirmation of pneumonia, were completed within the 24 hours prior
to randomization. The blood culture sample collection and
radiographic confirmation of pneumonia were completed within the 24
hours prior to the first dose of test article. Following Screening,
eligible subjects who meet inclusion criteria, and do not meet
exclusion criteria were randomly assigned to a treatment group to
receive 7 to 14 days of treatment with either Compound 1 or
moxifloxacin. The randomized subjects received their first dose of
test article within 4 hours after randomization.
[0345] The comparator drug for this study is selected to be
moxifloxacin (400 mg iv q24h with the option to transition to 400
mg po q24h), given the wide acceptance of fluoroquinolone
monotherapy as a safe, first-line option for treating subjects with
CABP. Moxifloxacin provides a broad spectrum of activity against
respiratory pathogens that are causative agents of CABP, including
typical (e.g., Streptococcus pneumoniae) and atypical (e.g.,
Legionella, Chlamydophila, and Mycoplasma spp.) pathogens, with a
similar spectrum of activity to that of Compound 1. Like Compound
1, moxifloxacin has both iv and po formulation options and was
administered once daily.
[0346] A post therapy evaluation visit occurred approximately 5 to
10 days after the last dose of test article and a follow-up
telephone contact occurred approximately 30 to 37 days after the
first dose of test article. Details of the study are further
described below.
[0347] As used herein, "post therapy evaluation," "post treatment
evaluation," and "PTE," are used interchangeably herein throughout
the application without distinction in meaning.
[0348] Dosing Regimen:
[0349] Compound 1 was administered as 100 mg iv q12h for 2 doses,
followed by 100 mg iv q24h (starting 24 h after first dose), with
the option to switch to 300 mg po q24h after a minimum of 3 days (4
doses) of iv treatment.
[0350] The comparator drug Moxifloxacin was administered as 400 mg
iv q24h (with a single placebo infusion to match the Compound 1
dosing regimen 12 hours after the first dose on Day 1), with the
option to switch to 400 mg po q24h after a minimum of 3 days (4
doses) of iv treatment.
[0351] Patient Inclusion/Exclusion Criteria
[0352] Patients were male or female 18-years or older. Patients had
fulfilled ALL of the following criteria: had at least 3 of the
following symptoms: cough, production of purulent sputum, dyspnea
(shortness of breath), and pleuritic chest pain; had at least two
of the following abnormal vital signs: fever or hypothermia
documented by the investigator (temperature >38.0.degree. C.
[100.4.degree. F.] or <36.0.degree. C. [95.5.degree. F.]),
hypotension with systolic blood pressure (SBP)<90 mm Hg, heart
rate >90 beats per minute (bpm), and respiratory rate (RR)
>20 breaths/minute; had at least 1 clinical sign or laboratory
finding associated with CABP: hypoxemia (partial pressure of
arterial oxygen [PaO.sub.2]<60 mm Hg by arterial blood gas [ABG]
or oxygen saturation <90% by pulse oximetry), physical
examination findings of pulmonary consolidation (e.g., dullness on
percussion, bronchial breath sounds, or egophony), and an elevated
total white blood cell (WBC) count (>12,000 cells/mm.sup.3) or
leucopenia (WBC <4,000 cells/mm.sup.3) or elevated immature
neutrophils (>15% band forms, regardless of total peripheral WBC
count); had radiographically-confirmed pneumonia, i.e., new or
progressive pulmonary infiltrate(s) on chest X-ray (CXR) or chest
computed tomography (CT) scan consistent with acute bacterial
pneumonia within 24 or 48 hours prior to the first dose of test
article; and had disease categorized as being PORT Risk Class II,
III, or IV at Screening, and were expected to require a minimum of
at least 3 days of iv therapy for the initial treatment of
CABP.
[0353] Females patients had a negative urine pregnancy test at
Screening and agreed to comply with using an acceptable method of
birth control as per local requirements from Screening through post
therapy evaluation (PTE). Males agreed to use an acceptable method
of birth control with female partner(s) and did not donate sperm
from Screening through PTE.
[0354] Patients with any of the following conditions were not
allowed in the trial: had received one or more dose(s) of a
potentially effective systemic antibacterial treatment within the
72 hours prior to the first dose of test article (a subject was
considered to have received a potentially effective systemic
antibacterial treatment if the pathogen identified as causing
infection was shown to be susceptible to the antibacterial given
or, in the circumstance where a pathogen was not identified, if the
antibacterial agent was approved for treatment of pneumonia or was
known to have activity against any of the leading causes of CABP
(e.g., Streptococcus pneumoniae, Haemophilus influenzae, Moraxella
catarrhalis, Staphylococcus aureus, Legionella pneumophila). One
exception was that subjects may be eligible despite prior
antibacterial therapy if they had been treated with a single dose
of a short-acting antibacterial (i.e., an antibacterial whose
standard dosing regimen was more frequent than once per day); was
known or suspected to have CABP caused by a pathogen that may be
resistant to either test article (e.g., Klebsiella pneumoniae,
Pseudomonas aeruginosa, Pneumocystis jiroveci, obligate anaerobes,
mycobacteria, fungal pathogens); suspected or confirmed empyema (a
parapneumonic pleural effusion was not an exclusion criteria) or
lung abscess; subjects with known or suspected hospital-acquired
pneumonia (HAP) or healthcare-associated pneumonia (HCAP). HAP was
defined as pneumonia with onset of clinical signs and symptoms
.gtoreq.48 hours after hospitalization in an acute in-subject
health care facility. HCAP was defined as pneumonia acquired in a
long-term care or subacute/intermediate healthcare facility (e.g.,
nursing home) or in a subject admitted with pneumonia following a
recent hospitalization (discharged within 90 days of current
admission and previously hospitalized for .gtoreq.48 hours); had
known or was clinically suspected to have 1 or more of the
following prior to randomization: alanine aminotransferase (ALT) or
aspartate aminotransferase (AST) .gtoreq.2.times.Upper Limit of
Normal (ULN), total bilirubin >1.5.times.ULN, or evidence of
end-stage liver disease (e.g., ascites, hepatic encephalopathy);
had a known history of having experienced unstable cardiac disease
(e.g., unstable angina, myocardial infarction, acute congestive
heart failure, unstable cardiac arrhythmia, etc.) within the 3
months prior to Screening; had a QT interval corrected for heart
rate using Fridericia's formula (QTcF) >450 msec (males) or
>470 msec (females), were known to have long QT syndrome, used
drugs of potential proarrhythmic or QT prolonging effect, and/or
presented with tachyarrhythmia; required any form of dialysis
(e.g., hemodialysis, peritoneal dialysis); history or evidence of
severe renal disease or had a calculated creatinine clearance
(CrCl) of <30 mL/minute, using the Cockcroft-Gault equation;
evidence of significant immunological disease determined by any of
the following: current or anticipated neutropenia defined as
<500 neutrophils/mm.sup.3, known infection with Human
Immunodeficiency Virus (HIV) and a cluster of differentiation 4
(CD4) count that was unknown or documented to be <200
cells/mm.sup.3 within the last year, or an Acquired Immune
Deficiency Syndrome (AIDS)-defining illness; the receipt of cancer
chemotherapy, radiotherapy, or potent, non-corticosteroid
immunosuppressant drugs (e.g., cyclosporine, azathioprine,
tacrolimus, immune-modulating monoclonal antibody therapy, etc.)
within the past 3 months, or the receipt of corticosteroids
equivalent to or greater than 40 mg of prednisone per day or for
more than 14 days in the prior 30 days; required acute
pharmacologic intervention to stabilize blood pressure (BP) and/or
adequate tissue perfusion, OR had evidence of septic shock defined
by ALL of the following: fever or hypothermia documented by the
investigator (temperature >38.0.degree. C. [100.4.degree. F.] or
<36.0.degree. C. [95.5.degree. F.]), heart rate >90
beats/minute, RR>20 breaths/minute, WBC>12,000 cells/mm.sup.3
or <4,000 cells/mm.sup.3 or >10% immature (band) forms,
regardless of the total peripheral WBC count, hypotension with
SBP<90 mm Hg despite an iv fluid challenge of 20-30 cc/kg over a
30 minute period, and perfusion abnormalities that may included,
but were not limited to, lactic acidosis (blood lactate
concentration .gtoreq.4 mmol/L), oliguria, or acute alteration in
mental status; known or suspected primary or metastatic neoplastic
lung disease, aspiration pneumonia, active tuberculosis, cystic
fibrosis, bronchiectasis, bronchial obstruction (e.g.,
post-obstructive pneumonia), chronic neurological disorder
preventing clearance of pulmonary secretions, or severe chronic
obstructive pulmonary disease (COPD); pregnant or nursing
(breastfeeding) women; had a history of hypersensitivity or
allergic reaction (e.g., anaphylaxis, urticaria, other significant
reaction) to any tetracycline (e.g., minocycline, doxycycline or
tigecycline) or to any fluoroquinolone antibiotic; had a history of
pseudotumor cerebri, or prior (within 2 weeks prior to Screening)
or planned concomitant use of isotretinoin; had a history of
systemic lupus erythematosus or lupus-like syndrome; had current
evidence of pancreatitis; had a history of a central nervous system
disorder that may predispose to seizures or lower the seizure
threshold; use of other investigational drugs within 5 half-lives
or 30 days prior to Screening, whichever was longer; had previously
been treated with Compound 1 or previously enrolled in this study;
any planned medical intervention that might interfere with the
ability to comply with the study requirements; and had a life
expectancy of less than or equal to 3 months or any concomitant
condition that, in the opinion of the investigator, was likely to
interfere with evaluation of the response of the infection under
study, determination of adverse events (AEs), or completion of the
expected course of treatment.
[0355] In addition, no systemic prior or concomitant antibacterial
therapy was allowed, other than a single dose of a short-acting
antibacterial, within the 72 hours prior to the first dose of test
article. All other medications not prohibited by the protocol and
considered necessary for the subject's welfare may be administered
and/or continued under the supervision of the investigator.
[0356] Dosing Regimens
[0357] The double-blind treatment period was up to 14 days in
duration. Subjects who met inclusion criteria and did not meet
exclusion criteria were randomly assigned to a treatment group, and
received their first dose of test article within 4 hours after
randomization.
[0358] The following assessments were done: vital signs, physical
examinations (worsening of observations since the Screening
examination was recorded as AEs), AEs and SAEs, concomitant
treatments, CABP symptom severity scale, microbiological
assessments, 12-lead ECG (performed just prior [within 30 minutes]
and 30-90 minutes after the start of the first infusion of the
first and third doses of test article, at the Day 7 visit, at the
EOT visit, and as otherwise clinically indicated), blood for
Central Laboratory assessments: hematology, chemistry, pregnancy
(for women only), test article administration and accountability,
assessment for po switch or need to continue therapy, and
investigator's assessment of clinical response.
[0359] Subjects were randomized (1:1) to 1 of the following 2
treatment arms:
[0360] a. Investigational therapy: Compound 1 (supplied with
tosylate acid counter ion, sucrose, hydrochloric acid and sodium
hydroxide to adjust the pH), 100 mg iv q12 h (first 2 doses),
followed by 100 mg iv q24h (starting 24 hours after first dose),
with the option to switch to 300 mg (two 150 mg Compound 1 tablets
and 1 over-encapsulated placebo tablet matching moxifloxacin) po
q24h after at least 3 days (4 doses) of iv treatment.
[0361] b. Reference therapy: moxifloxacin, 400 mg iv q24h (with a
single placebo infusion to match the Compound 1 dosing regimen 12
hours after the first dose on Day 1) with the option to switch to
400 mg (one 400 mg moxifloxacin over-encapsulated tablet and 2
placebo tablets matching Compound 1 tablets) po q24h after at least
3 days (4 doses) of iv treatment.
[0362] The iv treatment phase (minimum of 3 days, 4 doses) followed
a double-dummy design with placebo infusions matched to active
Compound 1 and moxifloxacin infusions as shown in Table 3-1 below.
Infusions of Compound 1 and matched placebo were administered
continuously over approximately 30 minutes. During the first 24
hours of iv treatment, subjects on the moxifloxacin treatment arm
received a placebo infusion to match the t=12 h infusion in the
Compound 1 arm as shown in the table.
[0363] Infusions of moxifloxacin and matched placebo were
administered continuously over approximately 60 minutes. All
infusion start and stop times were recorded.
TABLE-US-00014 Table 3-1 Treatment Regimens for IV Test Article
Infusion Regimen.sup.a Compound 1 Arm.sup.b,c Moxifloxacin
Arm.sup.b,c t = 0 h.sup.d Compound 1 100 mg in 100 mL NS 100 mL NS
placebo 250 mL NS placebo moxifloxacin 400 mg in 250 mL 0.8% saline
t= 12 h Compound 1 100 mg in 100 mL NS 100 mL NS placebo t = 24
h.sup.d Compound 1 100 mg in 100 mL NS 100 mL NS placebo 250 mL NS
placebo moxifloxacin 400 mg in 250 mL 0.8% saline t = 48 h.sup.d
Compound 1 100 mg in 100 mL NS 100 mL NS placebo 250 mL NS placebo
moxifloxacin 400 mg in 250 mL 0.8% saline t = 72 h.sup.e, Compound
1 100 mg in 100 mL NS 100 mL NS placebo then q24 h.sup.d 250 mL NS
placebo moxifloxacin 400 mg in 250 mL 0.8% saline t = time; NS =
Normal saline (0.9% sodium chloride) for injection; q12 h = every
12 hours; q24 h = every 24 hours. .sup.aThe start time of the first
infusion was designated time 0 (t = 0 h), followed by 2 q12 h doses
(t = 12 h, t = 24 h), and then all subsequent doses were q24 h for
a minimum of 3 days, 4 doses of iv treatment (through t = 48 h).
.sup.bAll 100 mL infusions of Compound 1 or 100 mL NS placebo were
administered continuously over 30 minutes (at least 30 minutes and
not more than 45 minutes). .sup.cAll 250 mL infusions of
moxifloxacin or 250 mL NS placebo were administered continuously
over approximately 60 minutes. .sup.dAt these time points a 100 mL
infusion was administered first, followed by a 250 mL infusion.
.sup.eBeginning with the fifth dose (t = 72 h), based on the
investigator decision the therapy could be iv or was switched to po
therapy. Note, the first po dose should be administered in the
morning, 12-24 hours after the last iv dose, therefore the first po
dose might have occurred as early as t = 60 h.
[0364] A representative (but none limiting) illustration of the
above treatment regimen for Compound 1 is provided below:
TABLE-US-00015 Day 1 Day 2 Day 3 Day 4 and Beyond 0 hr 12 hr 24 hr
48 hr 72 hr - Com- 100 100 100 100 After Day 3, either pound 1 mg
IV mg IV mg IV mg IV 100 mg IV or 300 mg oral q24 h Total duration
of treatment (IV + oral (if present)) is typically 7-14 days.
[0365] While the subject was receiving iv therapy, the investigator
assessed the subject daily and chose ONE of the following based on
the overall clinical assessment of the subject:
[0366] (1) continue iv test article;
[0367] (2) switch to po test article (after a minimum of 3 days [4
doses] of iv therapy) Note, the first po dose was administered in
the morning, 12-24 h after the last iv dose, therefore the first po
dose may occur as early as t=60 h;
[0368] (3) discontinue test article--this decision prompted the EOT
evaluation.
[0369] Each daily decision was recorded.
[0370] At all times during the study the decision to continue iv,
switch to po, or discontinue test article was made based on the
clinical judgment of the investigator. The investigator may have
used the culture and susceptibility results from the local
microbiology laboratory to help guide therapy; however, decisions
to continue or discontinue test article was based on clinical
response rather than susceptibility results (as Compound 1
susceptibility testing was not available at the local site). If the
CABP was caused by a microorganism that was not susceptible to
moxifloxacin in vitro, the decision to continue or discontinue
study treatment was based on the subject's clinical course and the
investigator's clinical judgment. The rationale for this decision
was recorded.
[0371] The decision to switch to po treatment was made by the
investigator. For a subject to be considered clinically stable and
meet criteria for transition to a po regimen, they must have had
the following findings noted and recorded:
[0372] a. Temperature .ltoreq.37.8.degree. C. (100.degree. F.)
[0373] b. Heart rate .ltoreq.100 beats/minute
[0374] c. RR.ltoreq.24 breaths/minute
[0375] d. SBP .gtoreq.95 mm Hg
[0376] e. Oxygen saturation .gtoreq.90% as measured by pulse
oximetry or PaO.sub.2.gtoreq.60 mm Hg by ABG
[0377] f. No worsening of CABP symptoms (cough, sputum production,
pleuritic chest pain, dyspnea) compared to Screening
[0378] g. Normal mental status ("absence of confusion" or
pre-illness Baseline for subjects who did not have normal mental
status before onset of pneumonia)
[0379] h. Ability to maintain po intake.
[0380] Switch to po was not permitted until after the subject had
completed at least the first 3 days of iv treatment (after 4 iv
doses).
[0381] The date and time the investigator confirmed the criteria
for the subject's eligibility for po treatment were met and made
the decision to switch to po treatment was recorded. For subjects
that had been switched to po test article and discharged from the
hospital prior to study Day 6, visits were conducted on study Days
4 and 5, while a study Day 6 visit was optional.
[0382] Treatment regimens for po dosing were shown in Table 3-2.
When switching from iv to po test article the recommended interval
between doses was maintained. The first po dose, for both Compound
1 and moxifloxacin treatment arms, was given in the morning 12 to
24 hours after the last iv dose. The po treatment phase also
employed a double-blind, double-dummy design using Compound 1
placebo comparator tablets of matching size and shape to active
Compound 1 tablets and matching over-encapsulated placebo and
active moxifloxacin tablets.
[0383] The tablets had excipients including lactose monohydrate,
microcrystalline cellulose, sodium stearyl fumarate, crospovidone,
colloidal silicone dioxide, sodium bisulfite, polyvinyl alcohol,
titanium dioxide, talc, soya lecithin, xanthan gum, FD&C Yellow
#6 and FD&C #2. The Compound 1 tablets were taken with water in
a fasting state (no food, antacids or multivitamins containing
multivalent cations (e.g., aluminum, magnesium, calcium, bismuth,
iron, or zinc) or drink except water for at least 6 hours). After
dosing, no food was to be consumed for 2 hours; no dairy products,
antacids or multivitamins containing multivalent cations (e.g.,
aluminum, magnesium, calcium, bismuth, iron, or zinc) for 4
hours.
TABLE-US-00016 TABLE 3-2 Treatment Regimens for Oral Test Article
a) Time b) Compound 1 c) Moxifloxacin d) Dosing of Dosing Arm Arm
Condition.sup.a, b Morning Two 150 mg One 400 mg Fasting overnight
(no tablets and 1 over-encapsulated food or drink except
over-encapsulated tablet and 2 water for at least 6 placebo tablet
placebo tablets hours) before dosing; resembling resembling after
dosing, no food moxifloxacin Compound 1 for 2 hours, no dairy
tablets products for 4 hours .sup.aAll doses of po test article
were taken with water. .sup.b All subjects were instructed to avoid
taking antacids and multivitamins containing multivalent cations
(e.g., aluminum, magnesium, calcium, bismuth, iron, or zinc) while
taking po test article.
[0384] While the subject was receiving po therapy, the investigator
assessed the subject on study Day 7, 10 and 14 and choose 1 of the
following actions:
[0385] a. continue po test article;
[0386] b. discontinue test article--this decision prompted the EOT
evaluation.
[0387] The investigator may have used the culture and
susceptibility results from the local microbiology laboratory to
help guide therapy; however, decisions to continue or discontinue
test article was based on clinical response rather than
susceptibility results (as Compound 1 susceptibility testing was
not available at the local site). If the CABP was caused by a
microorganism that was not susceptible to moxifloxacin in vitro,
the decision to continue or discontinue study treatment was based
on the subject's clinical course and the investigator's clinical
judgment.
[0388] No dose adjustments and interruptions of test article were
permitted.
[0389] Subjects were evaluated at 2 visits after the completion of
treatment: at the PTE 5 to 10 days after the last treatment day,
and at a Final Follow-up assessment 30 to 37 days after the first
dose of treatment.
[0390] The following table summarizes the study drug exposure in
the safety population.
TABLE-US-00017 Compound 1 Moxifloxacin All Subjects Characteristics
(N = 382) (N = 388) (N = 770) Duration of exposure on therapy
(days) n 382 388 770 Mean (SD) 9.6 (2.88) 9.6 (2.94) 9.6 (2.91)
Medium 10.0 10.0 10.0 Min, Max 1, 14 1, 17 1, 17 Duration of
exposure on therapy (days), n (%) 382 388 770 0 0 0 0 1-3 17 (4.5)
17 (4.4) 34 (4.4) 4-6 10 (2.6) 17 (4.4) 27 (3.5) 7-10 238 (62.3)
218 (56.2) 456 (59.2) 11-14 117 (30.6) 134 (34.5) 251 (32.6) >14
0 2 (0.5) 2 (0.3) Number of days of IV therapy n 382 388 770 Mean
(SD) 5.7 (2.51) 5.7 (2.54) 5.7 (2.52) Medium 5.0 5.0 5.0 Min, Max
1, 14 1, 14 1, 14 Number of days of IV therapy, n (%) 382 388 770 0
0 0 0 1-2 15 (3.9) 13 (3.4) 28 (3.6) 3-6 222 (58.1) 232 (59.8) 454
(59.0) 7-10 134 (35.1) 130 (33.5) 264 (34.3) 11-14 11 (2.9) 13
(3.4) 24 (3.1) >14 0 0 0 Number of days of IV therapy prior to
oral switch n 295 294 589 Mean (SD) 5.0 (2.02) 5.0 (2.08) 5.0
(2.04) Medium 4.7 4.7 4.7 Min, Max 2, 13 2, 11 2, 13 Subjects
switching to oral therapy, n (%) 295 (77.2) 294 (75.8) 589 (76.5)
Day of oral switch, n (%) 295 294 589 1-3 1 (0.3) 1 (0.3) 2 (0.3)
4-5 130 (44.1) 132 (44.9) 262 (44.5) 6-7 80 (27.1) 81 (27.6) 161
(27.3) .gtoreq.8 84 (28.5) 80 (27.2) 164 (27.8) Number of days of
oral therapy n 295 294 589 Mean (SD) 5.1 (1.93) 5.2 (2.04) 5.2
(1.98) Medium 5.0 5.0 5.0 Min, Max 1, 11 1, 14 1, 14 Number of days
of oral therapy, n (%) 295 294 589 0 0 0 0 1-4 132 (44.7) 132
(44.9) 264 (44.8) 5-7 152 (51.5) 147 (50.0) 299 (50.8) 8-11 11
(3.7) 14 (4.8) 25 (4.2) >11 0 1 (0.3) 1 (0.2) Note: Both active
test article and placebo are included.
[0391] Percentages for IV summaries are based on subjects receiving
at least one IV dose. Percentages for oral summaries are based on
subjects receiving at least one oral dose. Percentages for subjects
who switched from IV to oral are based on the number who switched
(e.g., 295 for Compound 1).
[0392] Note: Duration of study drug exposure in days=Date of last
IV or oral dose-Date of first IV dose+1. Number of days of IV
therapy (IV dosing) prior to oral switch=Date of last IV dose-Date
of first IV dose+1.
[0393] Criteria for switching from IV to oral treatment include:
Temperature .ltoreq.37.8.degree. C. (100.degree. F.); Heart rate
.ltoreq.100 beats/minute; Respiratory Rate <=24 breaths/minute;
Systolic Blood Pressure .gtoreq.95 mmHg; Oxygen saturation
.gtoreq.90% by pulse oximetry or PaO.sub.2.gtoreq.60 mmHg by ABG;
No worsening of CABP symptoms compared to screening; Normal Mental
Status; and Ability to maintain PO intake. For patients
administered Compound 1, 100% of the 295 patients who switched from
IV dose to oral dose satisfied each of the above criteria.
[0394] Safety Evaluation
[0395] Any subject who received test article were included in the
evaluation for safety. Safety evaluations of the enrolled subjects
included physical exams, vital signs (blood pressure, pulse rate,
body temperature), AEs and SAEs, laboratory assessments
(hematology, serum chemistry, urinalysis), 12-lead
electrocardiogram (ECG) evaluations, and pregnancy assessments.
[0396] After Screening, a physical examination was conducted on the
study days and at the EOT and PTE visits. Any new clinically
significant finding occurs (i.e., not noted at Screening) after the
Screening exam was captured as an AE.
[0397] Vital signs including body temperature, BP, pulse/heart
rate, and RR were recorded prior to each dose while the subject was
on iv treatment.
[0398] Blood samples for hematology, chemistry and coagulation
(prothrombin time only) were drawn at Screening, Day 4, Day 7, Day
10, EOT, and PTE.
[0399] Safety studies included a standard 12-lead ECG at the
following times: screening, just prior (within 30 minutes) to the
start of the first infusion of the first dose of test article (t=0
h), 30-90 minutes after the start of the first infusion of the
first dose of test article, just prior (within 30 minutes) to the
start of the first infusion of the third dose of test article (t=24
h), 30-90 minutes after the start of the first infusion of the
third dose of test article, at the Day 7 visit, at the EOT visit,
and in any case in which a subject developed an AE of non-pleuritic
cardiac chest pain, palpitations, tachyarrhythmia or as otherwise
clinically indicated.
[0400] Safety studies also included pregnancy and assessments of
fertility. All women had a urine pregnancy test at the site at the
Screening visit. No one was enrolled if a positive urine pregnancy
test result was obtained. A serum sample for .beta.-hCG testing was
also collected at the Screening visit and sent to the Central
Laboratory for confirmation of the urine pregnancy results. Serum
samples for .beta.-hCG testing at the Central Laboratory were also
collected at EOT and PTE. Test article administration was
discontinued if a positive .beta.-hCG result was reported by the
Central Laboratory after a woman was enrolled.
[0401] Safety studies also included two sets of blood cultures
collected within the 24 hours prior to the first dose of test
article. Each set of blood cultures were collected by direct
venipuncture from independent body sites 15-30 minutes apart. If
bacteria were isolated from baseline blood cultures, repeat blood
cultures were collected on the day that the positive blood culture
is detected. If subsequent blood cultures were also positive, the
blood cultures were repeated as necessary until negative blood
cultures were obtained.
[0402] Efficacy Evaluation
[0403] In order to satisfy different health authority requirements,
the primary variables were tested with 2 response endpoints: [0404]
Successful Early Clinical Response or ECR (72-120 hours after first
dose) was determined programmatically and defined as survival with
improvement in at least 2 of 4 subject symptoms (cough, sputum
production, pleuritic chest pain, dyspnea), as assessed by the
investigator, without deterioration in any of these 4 symptoms (FDA
primary efficacy point). One such evaluation was done in the ITT
population. [0405] Successful Investigator's Assessment of Clinical
Response at the PTE visit, defined as survival after completion of
a test article regimen, with resolution of signs and symptoms of
the infection to the extent that further antibacterial therapy was
not necessary (EMA primary efficacy point). One of such evaluation
was done in both the ITT and CE populations, limited to PORT Risk
Class III/IV subjects. In addition, 97.5% CI was used in addition
to the 95% CI level for 10% non-inferiority assessment.
[0406] The Early Clinical Response endpoint was tested in the
intent-to-treat (ITT) analysis population. The Investigator's
Assessment of Clinical Response at PTE endpoint was tested in the
ITT and clinically evaluable (CE) populations (co-primary
endpoints).
[0407] Secondary efficacy variables included: [0408] Response
category for Early Clinical Response [0409] Clinical Response
category for Investigator's Assessment of Clinical Response at EOT
and PTE [0410] Clinical Response category according to the
identified causative pathogen
[0411] The following is a list of key assessments that was
performed: [0412] Assessment of signs and symptoms of CABP by the
investigator [0413] Microbiological assessment of the infection
[0414] Assessment of clinical response
[0415] Each of the key assessments is described in further detail
below.
[0416] a) Assessment of CABP Symptom Severity
[0417] The assessment of CABP symptoms observed by the investigator
was conducted at every scheduled evaluation with the exception of
the Final Follow-up assessment. The investigator specifically
assessed the severity level of the subject's symptoms of cough,
sputum production, pleuritic chest pain and dyspnea on a 4 point
scale (absent, mild, moderate, or severe) based upon the Community
Acquired Bacterial Pneumonia Subject Symptom Severity Guidance
Framework for Investigator Assessment (see below) and entered the
symptom severity scores into the eCRF. For subjects that had been
switched to po test article and discharged from the hospital prior
to study Day 6, visits were conducted on study Days 4 and 5, while
a study Day 6 visit was optional.
CABP Subject Symptom Severity Guidance Framework for Investigator
Assessment
TABLE-US-00018 [0418] Absent Mild Moderate Severe COUGH? No cough
or Cough present but Cough present, Cough is present resolution (to
pre- it does not interfere frequent and it does throughout the day
CABP Baseline) with subject's usual interfere with some and night;
it limits daily activities of the subject's most of the usual daily
subjects' usual activities daily activities and sleep patterns
PLEURITIC No chest pain or Chest pain present Chest pain is Chest
pain is CHEST PAIN? resolution of chest occasionally with present
with normal present at rest pain related to deep breathing but
breaths and it does and/or with shallow CABP it does not interfere
interfere with the breathing; it limits with subject's usual
subject's usual most of the daily activities daily activities
subject's usual daily activities SHORTNESS OF No shortness of
Shortness of breath Shortness of breath Shortness of breath BREATH?
breath or resolution with strenuous with usual activities with
minimal (to pre-CABP activities only but it and it does interfere
exertion or at rest; Baseline) does not interfere with the
subject's it limits most of the with subject's usual usual daily
subject's usual daily activities activities daily activities
PHLEGM/ No coughing up of Subject coughs up Subject coughs up
Subject coughs up SPUTUM phlegm/sputum or a small amount of a
moderate amount a large amount of PRODUCTION? resolution (to pre-
phlegm/sputum of phlegm/sputum phlegm/sputum CABP Baseline)
[0419] b) Microbiological Assessments
[0420] Microbiological assessments included respiratory culture and
Gram stain, urine test for Legionella pneumophila and Streptococcus
pneumoniae antigen screening, and serology test for Legionella
pneumophila, Mycoplasma pneumoniae and Chlamydophila pneumoniae
titers.
[0421] For respiratory culture and Gram stain, at the Screening
visit collection of an adequate quality expectorated or induced
sputum or other respiratory specimen reflecting fluid from the
lower respiratory tract (e.g., respiratory fluid obtained by
bronchoalveolar lavage or bronchoscopy; pleural fluid obtained by
thoracentesis; or expectorated or induced sputum meeting adequacy
criteria) was attempted from all subjects and submitted to the
local microbiology laboratory for Gram stain and culture. The date,
time and type of specimen submitted were recorded. An adequate
quality sputum specimen was defined as having the following 2
findings as reported by the local laboratory:
[0422] 1. <10 Squamous epithelial cells/low power field (lpf)
(i.e., 100.times.)
[0423] 2. >25 Polymorphonuclear cells/lpf (i.e., 100.times.)
[0424] Adequate quality sputum specimens and other Screening
respiratory specimens for culture were obtained prior to first dose
of test article. At the EOT and/or PTE visit, respiratory specimen
cultures and Gram stains were obtained only for subjects who were
Clinical Failures and required alternative antibacterial treatment
for CABP.
[0425] Laboratory reports on Gram stains included a
semi-quantitative description of the number of polymorphonuclear
leukocytes per low power field (i.e., 100.times.) and a description
of bacteria seen. For Gram stains of respiratory specimens a
semi-quantitative description of the number of squamous epithelial
cells per low power field (i.e., 100.times.) was included.
[0426] Culture results included identification of all pathogens to
the level of genus and species. Susceptibility testing for
moxifloxacin (or other fluoroquinolones) was performed using a
standard method.
[0427] All isolates identified from expectorated or induced sputum
specimens meeting the 2 criteria that define the specimen as being
of adequate quality and/or that were isolated from respiratory
specimens or blood and were potential pathogens were submitted to
the Central Laboratory for verification of genus and species and
for standardized minimum inhibitory concentration (MIC) testing
performed for Compound 1, moxifloxacin and a panel of currently
approved antibiotics.
[0428] Regarding urine tests for Legionella pneumophila and
Streptococcus pneumoniae antigen screening, urine was collected at
the Screening visit to test for the presence of Legionella
pneumophila and Streptococcus pneumoniae antigens.
[0429] Regarding serology test for Legionella pneumophila,
Mycoplasma pneumoniae and Chlamydophila pneumoniae titers, blood
samples were collected to conduct serology for Legionella
pneumophila, Mycoplasma pneumoniae and Chlamydophila pneumoniae by
the Central Laboratory at the Screening visit, and at the PTE
visit.
[0430] c) Assessment of Clinical Outcome
[0431] Assessment of clinical outcome occurred at Early Clinical
Response assessment (programmatically), EOT, and PTE as described
below.
[0432] 1. Evaluation of the Infection Under Study at the Early
Clinical Response Assessment
[0433] The formal determination of the response to therapy at the
Early Clinical Response assessment (72 to 120 hours after
administration of the first dose of test article) was done
programmatically using the investigator's assessment of the
subject's symptoms associated with CABP entered into the eCRF. The
investigator was not responsible for categorizing subjects as
Clinical Success, Failure, or Indeterminate at the Early Clinical
Response assessment. The severity of the subject CABP symptoms of
cough, sputum production, pleuritic chest pain and dyspnea was
evaluated on a 4-point scale (absent, mild, moderate, or severe)
based upon the Community Acquired Bacterial Pneumonia Subject
Symptom Severity Guidance Framework for Investigator Assessment. A
CABP subject symptom severity assessment was completed at every
scheduled evaluation with the exception of the Final Follow-up
assessment. For subjects that had been switched to po test article
and discharged from the hospital prior to study Day 6, visits was
conducted on study Days 4 and 5, while a study Day 6 visit was
optional.
[0434] Clinical Success: at the Early Clinical Response assessment
was defined as survival with improvement of at least 1 level (i.e.,
severe to moderate, moderate to mild, mild to absent) compared to
Screening in 2 CABP symptoms (cough, sputum production, pleuritic
chest pain and dyspnea) with no worsening by at least 1 level in
the other inclusion CABP symptoms. In order for the subject to be
considered a Clinical Success, the subject may not meet any
criteria for Clinical Failure or Indeterminate Early Clinical
Response.
[0435] Clinical Failure: defined as meeting any of the following
criteria: [0436] There was no improvement by at least 1 level
(i.e., severe to moderate, moderate to mild, mild to absent)
compared to Screening in 2 CABP symptoms. [0437] Any of the 4 CABP
symptoms was worse (by at least 1 level) compared to Screening.
[0438] The subject required alternative (rescue) antibacterial
treatment for CABP prior to the Early Clinical Response assessment
related to either (a) progression or development of new symptoms
attributable to CABP or (b) development of infectious complications
of CABP (e.g., empyema, lung abscess). [0439] The subject was
receiving antibacterial therapy that may be effective for the
infection under study for a different infection from the 1 under
study. [0440] Discontinued study therapy due to an AE and received
alternative antibacterial treatment for CABP prior to the Early
Clinical Response assessment. [0441] Death prior to the Early
Clinical Response assessment.
[0442] Indeterminate: the clinical response to test article can not
be adequately inferred due to: [0443] Subject was not seen for the
evaluation because they withdrew consent, were lost to follow-up,
other reason (specify). [0444] Other specified reason.
[0445] 2. Clinical Evaluation of the Infection Under Study at
EOT
[0446] EOT assessments were performed on the calendar day of, or
within 2 days following the last dose of any test article. If a
subject withdrew prematurely or terminated participation in the
study prior to completion of the planned antibiotic therapy, the
EOT visit was conducted.
[0447] The investigator determined whether or not the subject met
the criteria of 1 of the following clinical outcomes:
[0448] Clinical Success: the subject was alive and the infection
was sufficiently resolved such that further antibacterial therapy
was not needed. These subjects may have some residual findings
related to infection (i.e., cough) requiring ancillary (i.e.,
non-antibiotic) treatment (e.g., expectorant). In order for the
subject to be considered a Clinical Success at EOT, the subject may
not meet any criteria for Clinical Failure or Indeterminate at
EOT.
[0449] Clinical Failure: the subject required alternative
antibacterial treatment for CABP prior to EOT related to either (a)
progression or development of new symptoms of CABP or (b)
development of infectious complications of CABP (e.g., empyema,
lung abscess) or (c) subject developed an AE that required
discontinuation of study therapy. Other reasons for Clinical
Failure are: [0450] Subject was receiving antibacterial therapy
that may be effective for the infection under study for a different
infection from the 1 under study. [0451] Death prior to EOT
visit.
[0452] Indeterminate: the clinical response to test article could
not be adequately inferred due to: [0453] Subjects were not seen
for EOT evaluation because they withdrew consent, were lost to
follow-up, other reason (specify). [0454] Other specified
reason.
[0455] 3. Clinical Evaluation of the Infection Under Study at
PTE
[0456] The PTE assessment was performed 5 to 10 days after the
subject's last day of therapy. The investigator determined whether
or not the subject met the criteria of 1 of the following clinical
outcomes:
[0457] Clinical Success: survival after completion of a test
article regimen without receiving any systemic antibacterial
therapy other than test article, resolution of signs and symptoms
of the infection present at Screening with no new symptoms or
complications attributable to CABP and no need for further
antibacterial therapy.
[0458] Clinical Failure: the subject required alternative
antibacterial treatment for CABP prior to PTE related to either (a)
progression or development of new symptoms of CABP or (b)
development of infectious complications of CABP (e.g., empyema,
lung abscess). [0459] The subject was receiving antibiotics that
may be effective for the infection under study for a different
infection from the 1 under study. [0460] Death prior to PTE.
[0461] Indeterminate: the clinical response to test article could
not be adequately inferred due to: [0462] Subjects were not seen
for PTE evaluation because they withdrew consent, were lost to
follow-up, other (specify). [0463] Other specified reason.
[0464] d) Pharmacokinetic Plasma Samples for Compound 1
Concentration
[0465] PK data was analyzed using a population PK model. PK samples
were collected using a sparse sampling method for the population PK
model. The number of samples and collection schedule varied for
individual subjects. Up to 4 samples were collected per subject
between study Days 1 to 7. Blood was collected either by fresh
venipuncture or via a cannula used SOLEY for that purpose (PK
samples were NOT drawn through the same iv access used for
administration of test article). The dates and times for all doses
of test article and PK sample collections were recorded. For
intravenously administered doses of test article, the start and
stop times for each infusion were recorded. The sample tube were
centrifuged at 1500.times.g for 10 minutes and the separated plasma
transferred in 2 equal aliquots into pre-labeled tubes; and the
tubes frozen at -70.degree. C. within 60 minutes of collection. The
time the sample was frozen was recorded to the nearest minute. All
of the PK samples from a single subject were collected and frozen
at -70.degree. C. and shipped frozen at -70.degree. C. to the
Central Laboratory. The samples were assayed at Analytical
Laboratory for Compound 1 using a specific, sensitive and validated
Liquid Chromatography/Tandem Mass Spectrometry (LC/MS/MS)
method.
[0466] e) Safety Monitoring--Adverse Events
[0467] An AE was defined as any untoward, undesired, or unplanned
event in the form of signs, symptoms, disease, or laboratory or
physiologic observations occurring in a person given a test article
or in a clinical study. The event does not need to be causally
related to the test article or clinical study. An AE included, but
was not limited to, the following: [0468] Any clinically
significant worsening of a preexisting condition. [0469] An AE
occurring from overdose of a test article, whether accidental or
intentional. Overdose is a dose greater than that specified in the
protocol. [0470] An AE occurring from abuse (e.g., use for
nonclinical reasons) of a test article. [0471] An AE that had been
associated with the discontinuation of the use of a test article. A
SAE is an AE that: [0472] Resulted in death. [0473] Was
life-threatening (see below). [0474] Required hospitalization or
prolongation of an existing hospitalization (see below). [0475]
Resulted in a persistent or significant disability or incapacity
(see below). [0476] Resulted in cancer. [0477] Resulted in a
congenital anomaly or birth defect. [0478] Additionally, important
medical events that may not result in death, be life-threatening,
or require hospitalization may be considered SAEs when, based on
appropriate medical judgment, they may jeopardize the subject and
may require medical or surgical intervention to prevent 1 of the
outcomes listed in this definition. Examples of such events
included allergic broncho spasm requiring intensive treatment in an
emergency room or at home, blood dyscrasias or convulsions that did
not result in hospitalization, or development of drug dependency or
drug abuse.
[0479] A protocol-related AE was defined as an AE occurring during
a clinical study that was not related to the test article, but was
considered by the investigator or the Medical Monitor (or designee)
to be related to the research conditions, i.e., related to the fact
that a subject was participating in the study. For example, a
protocol-related AE may be an untoward event related to a medical
procedure required by the protocol.
[0480] Certain information, although not considered an SAE, must be
recorded, reported, and followed up as indicated for an SAE. This
included: pregnancy exposure to a test article, lactation exposure
to a test article with or without an AE, overdose of a test article
as specified in this protocol with or without an AE, and
inadvertent or accidental exposure to a test article with or
without an AE.
[0481] Data Analysis
[0482] All analyses of data for this study complied with
International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH-E9) and the
sponsor's guidance documents and standards. Statistical analyses
were performed using Statistical Analysis Software (SAS).
[0483] a) Analysis Populations
[0484] A number of subject populations had been defined for the
various analyses of efficacy and safety, as follows: [0485] The ITT
population consisted of all randomized subjects. [0486] The
microbiological intent-to-treat (microlTT) population consisted of
subjects in the ITT population who had at least 1 causative
pathogen identified at Screening from culture of a respiratory
specimen (e.g., respiratory fluid obtained by bronchoalveolar
lavage or bronchoscopy; pleural fluid obtained by thoracentesis; or
expectorated or induced sputum meeting adequacy criteria), culture
of blood, or from a culture-independent method (e.g., positive
urinary antigen test for Streptococcus pneumoniae or Legionella
pneumophila, or positive serology for Legionella pneumophila,
Mycoplasma pneumoniae or Chlamydophila pneumoniae). [0487] Expanded
microlTT population was defined using the same criteria as for the
microlTT population, except that an adequate Gram stain was defined
as >10 PMNs/LPF and <10 SECs/LPF for determination of whether
an isolate from a sputum culture is a pathogen or not. Here,
PMN=Polymorphonuclear; SEC=Squamous Epithelial Cells; LPF=Low Power
Field. [0488] The CE population consisted of all ITT subjects who
received test article, had a qualifying CABP, an assessment of
outcome, and met all other evaluability criteria detailed in the
SAP. [0489] The CE-EOT/PTE population consisted of all randomized
safety subjects who received any amount of active test article, had
completed the investigator's assessment of clinical response at the
EOT/PTE visit, with no indeterminate clinical response and met
specific criteria related to the required assessments. Here,
CE=Clinically Evaluable; EOT=End of treatment; PTE=Post Therapy
Evaluation. [0490] The microbiologically evaluable (ME) population
included subjects in the CE population who have at least 1
causative pathogen at Screening. [0491] The ME-EOT/PTE consisted of
all subjects in both microlTT and the CE-EOT/PTE populations.
[0492] The Safety population consists of all randomized subjects
who receive test article.
[0493] The various study populations enrolled in the study, as
defined above, are listed below.
TABLE-US-00019 Compound 1 Moxifloxacin All Subjects Population n
(%) n (%) n (%) ITT 386 388 774 Safety 382 (99.0) 388 (100.0) 770
(99.5) microITT 204 (52.8) 182 (46.9) 386 (49.9) Expanded microITT
218 (56.5) 198 (51.0) 416 (53.7) CE-EOT 357 (92.5) 357 (92.0) 714
(92.2) CE-PTE 340 (88.1) 345 (88.9) 685 (88.5) ME-EOT 193 (50.0)
172 (44.3) 365 (47.2) ME-PTE 188 (48.7) 169 (43.6) 357 (46.1)
[0494] b) Subject Demographics and Baseline Characteristics
[0495] Descriptive statistics, by treatment arm, was provided for
the following: Subject disposition (completed test article,
discontinued test article by reason for discontinuation, completed
study, and discontinued study by reason for discontinuation);
Protocol deviations; CABP background information (subject
demographics: age (years), gender, race, height (cm), weight (kg),
Body Mass Index (BMI) (kg/m.sup.2)); PORT Risk Class; and Medical
histories and continuing medical conditions.
[0496] Baseline demographic and medical variables were analyzed
using a 2-sided Fisher's exact test (for categorical variables) or
a 2-sided Wilcoxon Rank Sum test (for ordinal and continuous
variables).
[0497] Selected results of these analysis were compiled in the
tables below.
TABLE-US-00020 Subject Disposition - ITT Population Compound 1
Moxifloxacin All Subjects (N = 386) (N = 388) (N = 774)
Parameter/Category n (%) n (%) n (%) p-value Randomized 386 (100.0)
388 (100.0) 774 (100.0) Completed Study Treatment.sup.[1] 352
(91.2) 346 (89.2) 698 (90.2) Prematurely Discontinued from Study 34
(8.8) 42 (10.8) 76 (9.8) 0.3981 Treatment Reason For Premature
Discontinuation from Study Treatment Adverse Event 17 (4.4) 28
(7.2) 45 (5.8) Lost to Follow-up 0 1 (0.3) 1 (0.1) Withdrawal by
Subject 4 (1.0) 3 (0.8) 7 (0.9) Physician Decision 3 (0.8) 9 (2.3)
12 (1.6) Death 4 (1.0) 1 (0.3) 5 (0.6) Other 6 (1.6) 0 6 (0.8)
Completed Study.sup.[2] 356 (92.2) 362 (93.3) 718 (92.8)
Prematurely Discontinued from Study 30 (7.8) 26 (6.7) 56 (7.2)
0.5819 Reason For Premature Discontinuation from Study Adverse
Event 7 (1.8) 9 (2.3) 16 (2.1) Lost to Follow-up 0 3 (0.8) 3 (0.4)
Withdrawal by Subject 7 (1.8) 8 (2.1) 15 (1.9) Physician Decision 0
1 (0.3) 1 (0.1) Death 6 (1.6) 3 (0.8) 9 (1.2) Other 10 (2.6) 2
(0.5) 12 (1.6) .sup.[1]Summary of subjects that completed the study
treatment. .sup.[2]Summary of subjects that completed the study
(i.e., received at least one dose of test article and completed
EOT, PTE and Follow-up).
[0498] Percentages are based on the ITT population. P-values for
differences between treatment groups are from Fisher's exact test.
Number of subjects prematurely discontinuing study treatment due to
an adverse event may not match counts in adverse events tables as
some reasons for discontinuations are coded as death rather than
adverse event. Subjects randomized but not treated (total n=4) are
counted in the Other category. Total number of deaths are 12 (8
omadacycline and 4 moxifloxacin). EOT=End of Treatment; PTE=Post
Treatment Evaluation.
TABLE-US-00021 Subject Disposition - CE-PTE Population Compound 1
Moxifloxacin All Subjects (N = 340) (N = 345) (N = 685)
Parameter/Category n (%) n (%) n (%) p-value Randomized 340 (100.0)
345 (100.0) 685 (100.0) Completed Study Treatment.sup.[1] 322
(94.7) 317 (91.9) 639 (93.3) Prematurely Discontinued from Study 18
(5.3) 28 (8.1) 46 (6.7) 0.1694 Treatment Reason For Premature
Discontinuation from Study Treatment Adverse Event 12 (3.5) 19
(5.5) 31 (4.5) Lost to Follow-up 0 0 0 Withdrawal by Subject 0 0 0
Physician Decision 3 (0.9) 8 (2.3) 11 (1.6) Death 3 (0.9) 1 (0.3) 4
(0.6) Other 0 0 0 Completed Study.sup.[2] 330 (97.1) 339 (98.3) 669
(97.7) Prematurely Discontinued from Study 10 (2.9) 6 (1.7) 16
(2.3) 0.3234 Reason For Premature Discontinuation from Study
Adverse Event 4 (1.2) 2 (0.6) 6 (0.9) Lost to Follow-up 0 0 0
Withdrawal by Subject 1 (0.3) 0 1 (0.1) Physician Decision 0 1
(0.3) 1 (0.1) Death 5 (1.5) 3 (0.9) 8 (1.2) Other 0 0 0
.sup.[1]Summary of subjects that completed the study treatment.
.sup.[2]Summary of subjects that completed the study (i.e.,
received at least one dose of test article and completed EOT, PTE
and Follow-up).
[0499] Percentages in the table above are based on the CE-PTE
population. p-values for differences between treatment groups were
from Fisher's exact test. The number of subjects prematurely
discontinuing study treatment due to an adverse event may not match
counts in adverse events tables as some reasons for
discontinuations were coded as death rather than adverse event.
TABLE-US-00022 Demographic and Baseline Characteristics - Safety
Population Compound 1 Moxifloxacin All Subjects Characteristics (N
= 382) (N = 388) (N = 770) p-value Gender, n (%) n 382 388 770
Female 177 (46.3) 169 (43.6) 346 (44.9) Male 205 (53.7) 219 (56.4)
424 (55.1) 0.4689 Race, n (%) n 382 388 770 White 353 (92.4) 355
(91.5) 708 (91.9) Black or African 11 (2.9) 7 (1.8) 18 (2.3)
American Asian 17 (4.5) 18 (4.6) 35 (4.5) American Indian or 0 2
(0.5) 2 (0.3) Alaska Native Native Hawaiian or 0 0 0 Other Pacific
Islander Other 1 (0.3) 6 (1.5) 7 (0.9) 0.1762 Ethnicity, n (%) n
382 388 770 Hispanic or Latino 8 (2.1) 14 (3.6) 22 (2.9) Not
Hispanic or Latino 370 (96.9) 370 (95.4) 740 (96.1) Not
Reported/Unknown 4 (1.0) 4 (1.0) 8 (1.0) 0.4465 Age (years) n 382
388 770 Mean (SD) 60.9 (15.18) 62.1 (15.21) 61.5 (15.20) Median
61.0 63.0 62.0 Min, Max 19, 97 19, 94 19, 97 0.1394 Categorical Age
(years), n (%) n 382 388 770 18-45 61 (16.0) 61 (15.7) 122 (15.8)
>45-65 171 (44.8) 155 (39.9) 326 (42.3) >65 150 (39.3) 172
(44.3) 322 (41.8) 0.3303 >75 74 (19.4) 83 (21.4) 157 (20.4)
Height (cm) n 382 388 770 Mean (SD) 168.6 (9.90) 168.5 (9.84) 168.6
(9.87) Median 169.0 168.0 169.0 Min, Max 137, 196 135, 198 135, 198
0.8528 Weight (kg) n 382 388 770 Mean (SD) 77.67 (18.018) 78.00
(17.861) 77.83 (17.928) Median 76.00 77.50 77.00 Min, Max 36.0,
147.0 28.0, 145.2 28.0, 147.0 0.9687 BMI (kg/m.sup.2) n 382 388 770
Mean (SD) 27.26 (5.763) 27.42 (5.791) 27.34 (5.774) Median 26.28
26.50 26.36 Min, Max 16.0, 50.6 12.6, 54.7 12.6, 54.7 0.6103 Renal
Function (Local Lab), n (%) n 382 388 770 Normal renal function 186
(48.7) 207 (53.4) 393 (51.0) [CrCl >80 mL/min] Mild renal
impairment 127 (33.2) 119 (30.7) 246 (31.9) [CrCl >50-80 mL/min]
Mod. renal impairment 69 (18.1) 62 (16.0) 131 (17.0) [CrCl 30-50
mL/min] Severe renal impairment 0 0 0 0.4245 [CrCl <30 mL/min]
PORT Score (actual) n 382 388 770 Mean (SD) 83.1 (16.25) 84.0
(15.99) 83.5 (16.12) Median 80.0 82.0 81.0 Min, Max 48, 130 36, 136
36, 136 0.1571 PORT Risk Class (actual) n 382 388 770 I (0 .ltoreq.
Port Score .ltoreq. 50) 2 (0.5) 2 (0.5) 4 (0.5) II (51 .ltoreq.
PortScore .ltoreq. 70) 54 (14.1) 54 (13.9) 108 (14.0) III (71
.ltoreq. Port Score .ltoreq. 90) 226 (59.2) 216 (55.7) 442 (57.4)
IV (91 .ltoreq. Port Score .ltoreq. 130) 100 (26.2) 115 (29.6) 215
(27.9) V (Port Score .gtoreq. 131) 0 1 (0.3) 1 (0.1) 0.7341
[0500] In the table above, Age is calculated from the date of birth
to the informed consent date. p-values for differences between
treatment groups are from Fisher's exact test (for categorical
variables) or Wilcoxon Rank Sum test (for continuous variables).
For each categorical parameter, the denominator for the percentage
is the number of subjects who had that parameter assessed. PORT
Score (actual) and PORT Risk Class (actual) are based on PORT score
(derived/corrected) from CRF.
TABLE-US-00023 Demographic and Baseline Characteristics - CE-PTE
Population Omadacycline Moxifloxacin All Subjects Characteristics
(N = 340) (N = 345) (N = 685) p-value Gender, n (%) n 340 345 685
Female 154 (45.3) 152 (44.1) 306 (44.7) Male 186 (54.7) 193 (55.9)
379 (55.3) 0.7590 Race, n (%) n 340 345 685 White 312 (91.8) 316
(91.6) 628 (91.7) Black or African American 11 (3.2) 6 (1.7) 17
(2.5) Asian 16 (4.7) 17 (4.9) 33 (4.8) American Indian or 0 2 (0.6)
2 (0.3) Alaska Native Native Hawaiian or 0 0 0 Other Pacific
Islander Other 1 (0.3) 4 (1.2) 5 (0.7) 0.3022 Ethnicity, n (%) n
340 345 685 Hispanic or Latino 8 (2.4) 8 (2.3) 16 (2.3) Not
Hispanic or Latino 328 (96.5) 335 (97.1) 663 (96.8) Not
Reported/Unknown 4 (1.2) 2 (0.6) 6 (0.9) 0.9061 Age (years) n 340
345 685 Mean (SD) 61.3 (15.34) 62.2 (15.12) 61.8 (15.23) Median
61.0 63.0 63.0 Min, Max 19, 97 19, 94 19, 97 0.3188 Categorical Age
(years), n (%) n 340 345 685 18-45 55 (16.2) 52 (15.1) 107 (15.6)
>45-65 145 (42.6) 141 (40.9) 286 (41.8) >65 140 (41.2) 152
(44.1) 292 (42.6) 0.7574 >75 70 (20.6) 75 (21.7) 145 (21.2)
Height (cm) n 340 345 685 Mean (SD) 168.8 (9.84) 168.5 (9.82) 168.7
(9.82) Median 169.0 168.0 169.0 Min, Max 137, 196 135, 198 135, 198
0.7520 Weight (kg) n 340 345 685 Mean (SD) 77.70 (17.203) 78.20
(18.029) 77.95 (17.613) Median 75.80 78.00 77.00 Min, Max 38.7,
136.0 28.0, 145.2 28.0, 145.2 0.8760 BMI (kg/m.sup.2) n 340 345 685
Mean (SD) 27.25 (5.623) 27.48 (5.821) 27.37 (5.721) Median 26.23
26.57 26.37 Min, Max 16.5, 50.6 12.6, 54.7 12.6, 54.7 0.5139 Renal
Function (Local Lab), n (%) n 340 345 685 Normal renal function 164
(48.2) 180 (52.2) 344 (50.2) [CrCl >80 mL/min] Mild renal
impairment 119 (35.0) 112 (32.5) 231 (33.7) [CrCl >50-80 mL/min]
Moderate renal impairment 57 (16.8) 53 (15.4) 110 (16.1) [CrCl
30-50 mL/min] Severe renal impairment 0 0 0 0.5897 [CrCl <30
mL/min] PORT Score (actual) n 340 345 685 Mean (SD) 83.5 (15.98)
83.6 (15.19) 83.6 (15.57) Median 80.0 82.0 81.0 Min, Max 51, 130
53, 123 51, 130 0.5004 PORT Risk Class (actual) n 340 345 685 I (0
.ltoreq. Port Score .ltoreq. 50) 0 0 0 II (51 .ltoreq. Port Score
.ltoreq. 70) 45 (13.2) 49 (14.2) 94 (13.7) III (71 .ltoreq. Port
Score .ltoreq. 90) 204 (60.0) 202 (58.6) 406 (59.3) IV (91 .ltoreq.
PortScore .ltoreq. 130) 91 (26.8) 94 (27.2) 185 (27.0) V (Port
Score .gtoreq. 131) 0 0 0 0.9048
[0501] In the table above, Age is calculated from the date of birth
to the informed consent date. p-values for differences between
treatment groups are from Fisher's exact test (for categorical
variables) or Wilcoxon Rank Sum test (for continuous variables).
For each categorical parameter, the denominator for the percentage
is the number of subjects who had that parameter assessed. PORT
Score (actual) and PORT Risk Class (actual) are based on PORT score
(derived/corrected) from CRF.
[0502] c) Efficacy Analysis
[0503] For all efficacy analyses, subject data was analyzed in the
group to which the subject was randomized.
[0504] The following table summarizes the primary analysis results
for early clinical response determined 72-120 hours after the first
infusion of test article in the ITT population.
TABLE-US-00024 Compound 1 Moxifloxacin (N = 386) (N = 388)
Difference Efficacy Outcome n (%) n (%) (95% CI) Clinical Success
313 (81.1) 321 (82.7) -1.6 (-7.1, 3.8) Clinical Failure or 73
(18.9) 67 (17.3) Indeterminate Clinical Failure 49 (12.7) 47 (12.1)
Indeterminate 24 (6.2) 20 (5.2) CI = Confidence Interval.
Difference was observed difference in Early Clinical Success rate
between the Compound 1 and moxifloxacin groups. 95% CI was
constructed based on the Miettinen and Nurminen method without
stratification. Percentages were based on the number of subjects in
each treatment group.
[0505] The early clinical success rates (at 72-120 hr) in the ITT
population, for both Compound 1 and Moxifloxacin, are depicted in
FIG. 2. See the left most pair of bars. The data shows that the
observed -1.6% difference in clinical success rate is well within
the 10% margin of statistical non-inferiority between -7.1% and
3.8%, at 95% CI (Confidence Interval), and thus the primary
efficacy point (for FDA approval) is met.
[0506] For Early Clinical Response Efficacy Variable (Clinical
Success, Clinical Failure or Indeterminate), an Indeterminate
Response was included in the denominator for the calculation of the
percentage of subjects with a Clinical Success in the ITT
population and thus, was essentially considered as a Clinical
Failure for the purpose of the primary analysis.
[0507] The following table summarizes the overall clinical response
at PTE visit based on investigator assessment of the ITT and CE-PTE
populations.
TABLE-US-00025 Popula- Efficacy Compound 1 Moxifloxacin Difference
tion Outcome n (%) n (%) (95% CI) .sup.[1] ITT (N = 386) (N = 388)
Clinical 338 (87.6) 330 (85.1) 2.5 (-2.4, Success 7.4) Clinical
Failure 48 (12.4) 58 (14.9) or Indeterminate Clinical Failure 32
(8.3) 42 (10.8) Indeterminate 16 (4.1) 16 (4.1) CE-PTE (N = 340) (N
= 345) Clinical 316 (92.9) 312 (90.4) 2.5 (-1.7, Success 6.8)
Clinical Failure 24 (7.1) 33 (9.6) .sup.[1] 95% CI was constructed
based on the Miettinen and Nurminen method without stratification.
CI = Confidence Interval; Difference was observed difference in
Overall Clinical Success rate at PTE between the Compound 1 and
Moxifloxacin groups. Overall Clinical Response at PTE was based on
the Investigator Assessment at the EOT and PTE visits. Percentages
were based on the number of subjects in each treatment group. EOT =
End of Treatment; PTE = Post Treatment Evaluation.
[0508] The overall clinical response rates at PTE visit based on
investigator assessment of the ITT population and the CE-PTE
population, for both Compound 1 and Moxifloxacin, are also depicted
in FIG. 2. See the middle (ITT) and the right most (CE-PTE) pairs
of bars. The data shows that the observed 2.5% difference in
overall clinical response rate in the ITT population is within the
10% margin of statistical non-inferiority between -2.4% and 7.4%,
at 95% CI (Confidence Interval); and that the observed 2.5%
difference in overall clinical response rate in the CE-PTE
population is within the 10% margin of statistical non-inferiority
between -1.7% and 6.8%, at 95% CI (Confidence Interval). Thus the
secondary efficacy point (for FDA approval) is also met.
[0509] For Investigator's Assessment of Clinical Response at PTE
Efficacy Variable (Clinical Success, Clinical Failure or
Indeterminate in the ITT population and Clinical Success and
Clinical Failure in the CE population), an Indeterminate Response
was included in the denominator for the calculation of the
percentage of subjects with a Clinical Success in the ITT
population and thus, was essentially considered a Clinical Failure
for the purpose of the primary analysis for the EMA.
[0510] To demonstrate the efficacy of Compound 1 was non-inferior
to moxifloxacin in the treatment of adults with CABP, the following
hypothesis were evaluated by analysis of the Clinical Success
rates.
[0511] The null hypothesis and alternate hypothesis for the Early
Clinical Response endpoint was assessed in the ITT population as
follows:
H.sub.o: .theta..sub.T-.theta..sub.C.ltoreq.-.DELTA. H.sub.ai:
.theta..sub.T-.theta..sub.C>-.DELTA.
[0512] Where the clinical success rate for the Compound 1 regimen
was .theta..sub.T and for moxifloxacin is .theta..sub.C. A was the
non-inferiority (NI) margin and was 0.10 (or 10%).
[0513] Similar null and alternative hypotheses can be set up with
.DELTA. of 0.10 for the PTE endpoint. For the Early Clinical
Response (FDA) endpoint, a 2-sided 95% confidence interval (CI)
approach for the difference of clinical success rates (using the
point estimate of the difference: Compound 1 response proportion
minus moxifloxacin response proportion) was used to test for the NI
of the Compound 1 arm compared to the moxifloxacin arm in the ITT
population. The 95% CI was calculated using the unstratified method
proposed by Miettinen and Nurminen (Statistics in Medicine
4:213-226, 1985). Compound 1 is considered non-inferior to
moxifloxacin if the lower bound of the CI is greater than -0.10 (or
-10%). This concept is expressed herein as "within 10% margin of
non-inferiority."
[0514] For Investigator's Assessment of Clinical Response at PTE
(EMA) primary efficacy analyses in both the ITT and CE populations,
a 2-sided 97.5% CI approach for the difference of clinical success
rates (using the point estimate of the difference: Compound 1
response proportion minus moxifloxacin response proportion) was
used to test for the NI of the Compound 1 arm compared to the
moxifloxacin arm in those subjects with a PORT Risk Class of III or
higher. The 97.5% CI was calculated using the stratified (for the
randomization stratification factors) method proposed by Miettinen
and Nurminen. Compound 1 is considered non-inferior to moxifloxacin
if the lower bound of the CI is greater than -0.10 (or -10%).
[0515] Early Clinical Response and Investigator's Assessment of
Clinical Response at PTE was tested separately and were not
co-primary endpoints. The probability for approving an ineffective
drug based on PTE efficacy was 1.25%, regardless of the result for
the Early Clinical Response endpoint and vice versa. An adjustment
would only be required if winning on at least 1 endpoint would
result in global approval which was not the case here. In addition,
no alpha adjustment was needed for the co-primary efficacy
endpoints for the EMA (ITT and CE populations) since NI must be
shown in both populations to conclude NI. Hence there was no
adjustment for multiple endpoints.
[0516] Additional and sensitivity analyses of the primary efficacy
outcomes (Early Clinical Response and Investigator's Assessment of
Clinical Response at PTE) were performed. If the null hypothesis of
inferiority is rejected for the Early Clinical Response in the ITT
population and the observed success response proportion for
Compound 1 is larger than the observed proportion for moxifloxacin,
a formal statistical analysis of superiority would be conducted. If
the lower limit of the 2-sided CI for the treatment difference is
greater than 0%, Compound 1 will be considered superior to
moxifloxacin.
[0517] The primary efficacy outcome was also assessed separately
across the stratification factors of PORT Risk Class, receipt of
allowed antibacterial therapy in the 72 hours prior to study
treatment and geographic region stratum by treatment group. For
each PORT Risk Class stratum, each prior antibacterial therapy
stratum and each geographic region stratum, a 2-sided 95% CI for
the observed difference in Early Clinical Response rates were
calculated for the ITT population. Additional subgroup analyses of
the primary efficacy outcome might have been conducted as
descriptive analyses.
[0518] The following two tables summarize the overall clinical
response at PTE visit based on investigator assessment by PORT Risk
Class in the ITT population and the CE-PTE population,
respectively.
TABLE-US-00026 Overall Clinical Response at PTE Visit based on
Investigator Assessment by PORT Risk Class in the ITT Population
PORT Risk Class as Randomized Actual PORT Risk Class.sup.[1]
Compound 1 Moxifloxacin Compound 1 Moxifloxacin PORT Risk Class (N
= 386) (N = 388) Difference (N = 386) (N = 388) Difference Efficacy
Outcome n (%) n (%) (CI) n (%) n (%) (CI) PORT Risk Class
II.sup.[2] 56 56 57 56 Clinical Success 45 (80.4) 47 (83.9) -3.6
(-18.2, 11.0).sup.[4] 47 (82.5) 47 (83.9) -1.5 (-15.7,
12.8).sup.[4] Clinical Failure or Indeterminate 11 (19.6) 9 (16.1)
10 (17.5) 9 (16.1) Clinical Failure 6 (10.7) 7 (12.5) 5 (8.8) 7
(12.5) Indeterminate 5 (8.9) 2 (3.6) 5 (8.8) 2 (3.6) PORT Risk
Class III/IV 330 332 329 331 Clinical Success 293 (88.8) 283 (85.2)
3.5 (-1.6, 8.7).sup.[4] 291 (88.4) 282 (85.2) 3.3 (-1.9,
8.5).sup.[4] (-2.7, 9.3).sup.[5] Clinical Failure or Indeterminate
37 (11.2) 49 (14.8) 38 (11.6) 49 (14.8) Clinical Failure 26 (7.9)
35 (10.5) 27 (8.2) 35 (10.6) Indeterminate 11 (3.3) 14 (4.2) 11
(3.3) 14 (4.2) PORT Risk Class III 241 232 227 216 Clinical Success
217 (90.0) 201 (86.6) 3.4 (-2.4, 9.4).sup.[4] 206 (90.7) 190 (88.0)
2.8 (-3.0, 8.7).sup.[4] Clinical Failure or Indeterminate 24 (10.0)
31 (13.4) 21 (9.3) 26 (12.0) Clinical Failure 17 (7.1) 21 (9.1) 16
(7.0) 18 (8.3) Indeterminate 7 (2.9) 10 (4.3) 5 (2.2) 8 (3.7) PORT
Risk Class IV.sup.[3] 89 100 102 116 Clinical Success 76 (85.4) 82
(82.0) 3.4 (-7.5, 14.0).sup.[4] 85 (83.3) 93 (80.2) 3.2 (-7.4,
13.4).sup.[4] Clinical Failure or Indeterminate 13 (14.6) 18 (18.0)
17 (16.7) 23 (19.8) Clinical Failure 9 (10.1) 14 (14.0) 11 (10.8)
17 (14.7) Indeterminate 4 (4.5) 4 (4.0) 6 (5.9) 6 (5.2) The overall
clinical response rates at PTE visit based on investigator
assessment of the ITT population limited to actual PORT Risk Class
III/IV subjects, for both Compound 1 and Moxifloxacin, are depicted
in FIG. 3. See the left pairs of bars. The data shows that the
observed 3.3% difference in overall clinical response rate is
within the 10% margin of statistical non-inferiority between -2.7%
and 9.3%, at 97.5% CI (Confidence Interval). Thus one of the
co-primary efficacy point (for EMA approval) is met.
TABLE-US-00027 Overall Clinical Response at PTE Visit based on
Investigator Assessment by PORT Risk Class in the CE-PTE Population
PORT Risk Class as Randomized Actual PORT Risk Class.sup.[1]
Compound 1 Moxifloxacin Compound 1 Moxifloxacin PORT Risk Class (N
= 340) (N = 345) Difference (N = 340) (N = 345) Difference Efficacy
Outcome n (%) n (%) (CI) n (%) n (%) (CI) PORT Risk Class II 44 48
45 49 Clinical Success 41 (93.2) 44 (91.7) 1.5 (-11.2,
13.9).sup.[4] 43 (95.6) 44 (89.8) 5.8 (-6.1, 18.1).sup.[4] Clinical
Failure 3 (6.8) 4 (8.3) 2 (4.4) 5 (10.2) PORT Risk Class III/IV 296
297 295 296 Clinical Success 275 (92.9) 268 (90.2) 2.7 (-1.9,
7.3).sup.[4] 273 (92.5) 268 (90.5) 2.0 (-2.6, 6.6).sup.[4] (-3.2,
7.4).sup.[5] Clinical Failure 21 (7.1) 29 (9.8) 22 (7.5) 28 (9.5)
PORT Risk Class III 216 212 204 202 Clinical Success 202 (93.5) 193
(91.0) 2.5 (-2.7, 7.8).sup.[4] 191 (93.6) 186 (92.1) 1.5 (-3.6,
6.9).sup.[4] Clinical Failure 14 (6.5) 19 (9.0) 13 (6.4) 16 (7.9)
PORT Risk Class IV 80 85 91 94 Clinical Success 73 (91.3) 75 (88.2)
3.0 (-6.8, 12.8).sup.[4] 82 (90.1) 82 (87.2) 2.9 (-6.7,
12.5).sup.[4] Clinical Failure 7 (8.8) 10 (11.8) 9 (9.9) 12 (12.8)
.sup.[1]Actual PORT Risk Class was based on PORT score
(derived/corrected) from CRF. .sup.[2]Also includes 4 subjects with
an actual PORT Risk Class of I. .sup.[3]Also includes 1 subject
with an actual PORT Risk Class of V. .sup.[4]Unstratified 95% CI
was constructed based on the Miettinen and Nurminen method without
stratification. .sup.[5]Stratified 97.5% CI was adjusted for prior
antibiotics use (yes and no) constructed based on the Miettinen and
Nurminen method with stratification, using Cochran-Mantel-Haenszel
weights as stratum weights. CI = Confidence Interval; PTE = Post
Treatment Evaluation. Difference was observed difference in Overall
Clinical Success rate at PTE between the Compound 1 and
Moxifloxacin groups. Percentages were based on the number of
subjects in each treatment group within each PORT Risk Class. The
overall clinical response rates at PTE visit based on investigator
assessment of the CE-PTE population, limited to patients with PORT
III/IV CABP, for both Compound 1 and Moxifloxacin, are also
depicted in FIG. 3. See the right pairs of bars. The data shows
that the observed 2.0% difference in overall clinical response rate
is within the 10% margin of non-inferiority between -3.2% and 7.4%,
at 97.5% CI (Confidence Interval). Thus another of the co-primary
efficacy point (for EMA approval) is also met.
[0519] Sensitivity analyses include: conducting an adjusted
analysis of the primary efficacy outcome based on the randomized
stratum and separately, based on the stratum the subject actually
belongs, and conducting an analysis where all subjects with an
Indeterminate response are considered Clinical Successes.
[0520] d) Analysis of Secondary Variables
[0521] The number and percentage of subjects classified as a
Clinical Success, Clinical Failure and Indeterminate by the
Investigator's Assessment at PTE in the ITT and CE populations (by
definition subjects with an Indeterminate response were excluded
from the CE population) were calculated for each treatment group. A
2-sided unadjusted 95% CI was constructed for the observed
difference in the clinical success rate using the method of
Miettinen and Nurminen. For Investigator's Assessment of Clinical
Response at PTE in the ITT and CE populations the 95% CI was for
descriptive purposes only and no conclusion of NI was made. The
number and percentage of subjects in each treatment group in each
response category for Early Clinical Response was presented for the
microlTT population. The number and percentage of subjects who were
classified as a Clinical Success and Clinical Failure by the
investigator at the PTE visit in ME population were calculated.
Two-sided unadjusted 95% CI was constructed for the observed
difference in the clinical success rates using the method of
Miettinen and Nurminen.
[0522] The number and percentage of subjects with an Early Clinical
Response of success and an Investigator's Assessment of Clinical
Response at PTE of Clinical Success by pathogen was provided in the
microlTT and ME populations. All-cause mortality (ACM) at 15 and 30
days after the first dose of test article was summarized in the ITT
population. Subjects who were lost to follow-up were considered
deceased for this analysis. A 2-sided unadjusted 95% CI for the
observed difference in mortality rates was calculated for ACM.
[0523] e) Analysis of Additional Efficacy Variables
[0524] Additional efficacy analyses were conducted to support the
efficacy findings of the primary and secondary outcomes. CIs were
determined for descriptive purposes, but no conclusions of NI were
made. The number and percentage of subjects classified as a
Clinical Success, Clinical Failure and Indeterminate by the
Investigator's Assessment at EOT in the ITT and CE populations (by
definition subjects with an Indeterminate response were excluded
from the CE population) were calculated. A 2-sided unadjusted 95%
CI was constructed for the observed difference in the Clinical
Success rate using the method of Miettinen and Nurminen. The number
and percentage of subjects with stabilization of vital signs and
clinical signs/laboratory findings associated with CABP at 72-120
hours post first dose of test article were presented by treatment
group in the ITT population. These include body temperature (no
fever or hypothermia), SBP (>90 mm Hg), heart rate (<90 bpm),
RR (<20 breaths/minute), PaO.sub.2 (.gtoreq.60 mm Hg by ABG or
oxygen saturation .gtoreq.90% by pulse oximetry), physical exam
findings (no findings of pulmonary consolidation), WBC count
(<12,000 cells/mm.sup.3 or .gtoreq.4,000 cells/mm.sup.3) or
immature neutrophils (<15%). A summary (number and percentage of
subjects) of the assessment of clinical signs and symptoms of CABP
at each time point throughout the study were presented by treatment
group in the ITT population. The number and percentage of subjects
with resolution of signs and symptoms present at Screening (back to
pre-CABP status) were also provided by study visit. The number and
percentage of subjects with no worsening of clinical symptoms of
CABP and with the absence of new symptoms of CABP were provided by
treatment group in the ITT population.
[0525] The per-subject and per-pathogen microbiologic outcomes were
provided for the microlTT and ME populations at the EOT and PTE
visits. For example, the table below summarizes the overall
clinical success at PTE visit in the microlTT population, based on
investigator assessment by baseline pathogen from blood specimens,
respiratory specimens, urinary antigen tests, and/or serology.
TABLE-US-00028 Compound 1 Moxifloxacin (N = 204) (N = 182) Clinical
Success Clinical Success Baseline Pathogen N1 n (%) N1 n (%)
Gram-Positive Bacteria (aerobes) 61 52 (85.2) 56 49 (87.5)
Streptococcus pneumoniae.sup.[1] 43 37 (86.0) 34 31 (91.2) MDRSP 7
7 (100.0) 6 6 (100.0) PSSP 26 23 (88.5) 22 21 (95.5) Macrolide
Resistant 10 10 (100.0) 5 5 (100.0) Staphylococcus aureus 11 8
(72.7) 11 9 (81.8) MRSA 0 0 1 1 (100.0) MSSA 11 8 (72.7) 10 8
(80.0) Beta Hemolytic Streptococcus 2 2 (100.0) 3 1 (33.3)
Streptococcus agalactiae 2 2 (100.0) 3 1 (33.3) Streptococcus
anginosus 0 0 1 0 Streptococcus constellatus 1 1 (100.0) 1 1
(100.0) Streptococcus gordonii 0 0 1 1 (100.0) Streptococcus mitis
3 3 (100.0) 5 3 (60.0) Streptococcus mitis group 1 1 (100.0) 2 2
(100.0) Streptococcus oralis 1 1 (100.0) 0 0 Streptococcus
parasanguinis 0 0 2 1 (50.0) Streptococcus salivarius 1 1 (100.0) 3
3 (100.0) Streptococcus sanguinis 0 0 2 1 (50.0) Streptococcus
sanguis ii 2 2 (100.0) 0 0 Gram-Negative Bacteria 79 67 (84.8) 68
55 (80.9) (aerobes) Acinetobacter baumanii 0 0 1 1 (100.0)
Acinetobacter baumanii complex 0 0 1 0 Acinetobacter junii 1 1
(100.0) 0 0 Acinetobacter lwoffii 1 1 (100.0) 0 0 Citrobacter
braakii 0 0 1 1 (100.0) Citrobacter freundii 0 0 1 1 (100.0)
Enterobacter cloacae 2 2 (100.0) 4 3 (75.0) Escherichia coli 6 4
(66.7) 7 4 (57.1) Haemophilus haemolyticus 1 1 (100.0) 0 0
Haemophilus influenzae 32 26 (81.3) 16 16 (100.0) Haemophilus
parahaemolyticus 2 2 (100.0) 2 1 (50.0) Haemophilus parainfluenzae
18 15 (83.3) 17 13 (76.5) Klebsiella oxytoca 1 0 4 4 (100.0)
Klebsiella pneumoniae 13 10 (76.9) 13 11 (84.6) Moraxella
catarrhalis 4 4 (100.0) 1 1 (100.0) Morganella morganii 1 1 (100.0)
0 0 Neisseria meningitidis 1 1 (100.0) 1 1 (100.0) Proteus
mirabilis 2 1 (50.0) 2 2 (100.0) Pseudomonas aeruginosa 3 2 (66.7)
5 5 (100.0) Pseudomonas putida 0 0 1 1 (100.0) Serratia marcescens
1 1 (100.0) 0 0 Stenotrophomonas maltophilia 0 0 2 1 (50.0)
Atypical Pathogens 118 109 (92.4) 106 97 (91.5) Mycoplasma
pneumoniae 70 66 (94.3) 57 50 (87.7) Chlamydophila pneumoniae 28 25
(89.3) 28 25 (89.3) Legionella pneumophila.sup.[2] 37 35 (94.6) 37
36 (97.3) Gram-negative organisms 0 0 1 0 (anaerobes) Prevotella
oris 0 0 1 0 .sup.[1]Overall tabulation of Streptococcus pneumoniae
includes identification from urinary antigen only which will not
have susceptibility data. .sup.[2]Legionella pneumophila may be
detected from culture, serology and/or urinary antigen test.
Subjects with the same pathogen isolated from multiple specimens
are counted only once for that pathogen. Subjects with the same
pathogen from a blood specimen, respiratory specimen, urinary
antigen test, and/or serology are counted only once for that
pathogen. Subjects are counted only once in the overall tabulations
if they have more than one respective pathogen at baseline. PTE =
Post Treatment Evaluation. N = Number of subjects in the microITT
population. N1 = Number of subjects with the specific baseline
pathogen, n = Number of subjects in the specific category.
Percentages are based on the number of subjects with the specific
baseline pathogen.
[0526] For selected pathogens that have 10 or more isolates in the
Compound 1 treatment arm, data was extracted and shown in FIG.
4.
[0527] Two-sided unadjusted 95% CIs were provided for the
difference in per-subject microbiological favorable outcome rates.
A concordance analysis of Early Clinical Response and
Investigator's Assessment of Clinical Response at PTE in the ITT
analysis set were also presented.
[0528] f) Safety Outcome Measures
[0529] Safety variables included the incidence rate of AEs, change
in vital signs, ECG parameters and laboratory test results obtained
during the course of the study.
[0530] Summary tables were provided for all treatment-emergent
adverse events (TEAEs), defined as an AE with a start date and time
on or after the first dose of test article. AEs were summarized by
presenting the number and percentage of subjects having each TEAE
for each treatment group by system organ class (SOC) and preferred
term (PT). Additional tabulations provided summaries by SOC and PT
of subjects experiencing SAEs, severe TEAEs, TEAEs judged to be
related to test article, TEAEs leading to discontinuation of test
article, TEAEs leading to dose interruption of test article, and
TEAEs of special interest.
[0531] The following table provides an overview of Adverse Events
(AEs) within the safety population.
TABLE-US-00029 Compound 1 Moxifloxacin All Subjects (N = 382) (N =
388) (N = 770) Parameter n (%) n (%) n (%) Total Number of AEs 434
520 954 Total Number of TEAEs 376 461 837 Subjects with at Least
One, n (%) Adverse Events (AE) 170 (44.5) 200 (51.5) 370 (48.1)
TEAE 157 (41.1) 188 (48.5) 345 (44.8) Drug-Related TEAE 39 (10.2)
69 (17.8) 108 (14.0) Severe TEAE 25 (6.5) 26 (6.7) 51 (6.6) Serious
TEAE 23 (6.0) 26 (6.7) 49 (6.4) Drug-Related Serious TEAE 2 (0.5) 2
(0.5) 4 (0.5) Serious TEAE Leading to Death* 8 (2.1) 4 (1.0) 12
(1.6) TEAE Leading to Premature Discontinuation of Test Article 21
(5.5) 27 (7.0) 48 (6.2) TEAE Leading to Premature Discontinuation
of Study 7 (1.8) 9 (2.3) 16 (2.1) TEAE Leading to Dose Interruption
0 0 0 Serious TEAEs Leading to Premature Discontinuation of Test
Article 10 (2.6) 11 (2.8) 21 (2.7) Subjects who died, n (%) 8 (2.1)
4 (1.0) 12 (1.6) *All deaths occurred in patients >65 years of
age; frequency consistent with recently completed CABP studies.
Percentages are based on the Safety population. A TEAE is defined
as an AE occurring after first dose of active test article. AE =
Adverse Events; TEAE = Treatment-Emergent Adverse Event.
[0532] The following table provides a summary of selected TEAEs by
Preferred Term within the safety population. With few exceptions,
the selected TEAEs have a rate of occurrence of at least about 2%
in the Compound 1 treatment group.
TABLE-US-00030 Omadacycline Moxifloxacin All Subjects (N = 382) (N
= 388) (N = 770) Preferred Term (PT) n (%) n (%) n (%) Subjects
with at Least One TEAE 157 (41.1) 188 (48.5) 345 (44.8) Alanine
Aminotransferase Increased 14 (3.7) 18 (4.6) 32 (4.2) Hypertension
13 (3.4) 11 (2.8) 24 (3.1) Gamma-Glutamyltransferase Increased 10
(2.6) 8 (2.1) 18 (2.3) Insomnia 10 (2.6) 8 (2.1) 18 (2.3) Vomiting
10 (2.6) 6 (1.5) 16 (2.1) Constipation 9 (2.4) 6 (1.5) 15 (1.9)
Nausea 9 (2.4) 21 (5.4) 30 (3.9) Aspartate Aminotransferase
Increased 8 (2.1) 14 (3.6) 22 (2.9) Headache 8 (2.1) 5 (1.3) 13
(1.7) . . . Diarrhoea 4 (1.0) 31 (8.0) 35 (4.5) Dyspepsia 4 (1.0) 2
(0.5) 6 (0.8) Clostridium Difficile Colitis 0 1 (0.3) 1 (0.1)
Clostridium Difficile Infection 0 6 (1.5) 6 (0.8) Pseudomembranous
Colitis 0 1 (0.3) 1 (0.1) Coding of Preferred Term is based on
MedDRA Version 17.1. Percentages are based on the Safety
population. A TEAE is defined as an AE occurring after the first
dose of active test article. If a subject has more than one TEAE
that codes to the same MedDRA category, the subject is counted only
once. PTs are sorted by decreasing frequency within the Compound 1
column.
[0533] Thus, it is apparent that gastrointestinal (GI) adverse
events (AEs, including vomiting, nausea, diarrhea, and dyspepsia)
associated with treatment with Compound 1 are mild.
[0534] The following table summarizes selected TEAEs that led to
discontinuation of treatment.
TABLE-US-00031 Compound 1 Moxifloxacin All Subjects System Organ
Class (SOC) (N = 382) (N = 388) (N = 770) Preferred Term (PT) n (%)
n (%) n (%) Subjects with at Least One 21 (5.5) 27 (7.0) 48 (6.2)
TEAE Leading to Study Drug Discontinuation Gastrointestinal
Disorders 2 (0.5) 2 (0.5) 4 (0.5) Vomiting 2 (0.5) 0 2 (0.3) Nausea
1 (0.3) 0 1 (0.1) Diarrhoea 0 1 (0.3) 1 (0.1) Dyspepsia 0 1 (0.3) 1
(0.1) Coding of System Organ Class (SOC) and Preferred Term (PT)
was based on MedDRA Version 17.1. Percentages were based on the
Safety population. A TEAE was defined as an AE occurring after the
first dose of active test article. If a subject had more than one
TEAE that coded to the same MedDRA category, the subject was
counted only once. SOC terms were sorted alphabetically, then PTs
were sorted within each SOC term by decreasing frequency within the
Compound 1 column.
[0535] The following variables were analyzed descriptively as vital
signs: [0536] Vital signs (systolic and diastolic BP, pulse rate,
body temperature, RR) including change from Screening by visit
[0537] Clinically notable vital signs (meeting predefined criteria
as specified in the SAP) by visit
[0538] Electrocardiogram data (RR interval, PR interval, QRS
interval, Corrected QT interval [QTc], QTc Bazzett's Correction
Formula [QTcB], and QTc Fridericia's Correction Formula [QTcF]) was
summarized descriptively at each scheduled evaluation and for the
overall worst post-Screening value. Changes from Screening at each
visit were also provided. An outlier analysis was conducted based
on the worst post-Screening value.
[0539] The following variables were analyzed descriptively for
laboratory tests: [0540] Laboratory variables by visit [0541]
Change from Screening of laboratory variable by visit [0542]
Clinically notable laboratory values (meeting predefined criteria
specified in SAP) by visit
[0543] g) PK
[0544] Population PK analysis was conducted to characterize PK
parameters. A population PK data set including subjects with 1 or
more quantified Compound 1 concentration determinations was
constructed from the dates and times of the doses and blood samples
along with all the bioanalytical determinations and subject
background information. If the actual date or time for a blood
sample or dose was missing, the related bioanalytical determination
of the PK concentration was excluded from all analyses. Compound 1
concentrations below the limit of quantification were treated as
missing data in summary statistics and for the calculation of PK
parameters.
[0545] Variables including age (years), body weight (kg), gender,
and race/ethnicity along with other covariates previously
determined to be important were incorporated into the population PK
database. Based on the subjects in the population analysis data
set, descriptive summaries at Screening for these variables were
reported. Outliers may be excluded from the analysis. These were
determined by a scatter plot of the observed concentration versus
time post dose and reported. The distribution of the number of
samples contributed per subject to the model-based analysis was
tabulated. Also, simple summary descriptive statistics for the
concentration of samples by study day or week was computed.
[0546] Regarding population PK modeling, results from Phase 1
studies indicated that Compound 1 PK was linear and that following
iv infusion, plasma concentration-time profiles show a
3-compartmental disposition. Therefore, the probable structural PK
model would be a 3-compartment model with zero order input for iv
infusion and first order input for po administration. This PK model
contained the parameters clearance, volume of distribution,
bioavailability and absorption rate constant. The associated
population models were nonlinear mixed-effects models. The
population model added random effects and covariates for the PK
parameters in order to recognize differences among individuals and
similarities across observations corresponding to the same subject.
At the time of the population modeling, previously reported
structural PK models were considered first. A residual error model
combining additive error and proportional error was also
considered. Simplifications (e.g., fewer random effects, or an
alternative residual error model) may be appropriate if the
diagnostics for the model suggest false convergence. Additional
covariates were investigated graphically (gender, race/ethnicity,
age) as part of the model diagnostics and some may be retained in
the final model and additional ones in a competing model to deliver
estimates of arguably insignificant effects. Scatter plots of the
observed concentrations versus population-estimated and
individually estimated concentrations were used as part of the
overall assessment of the overall quality of the fit. During
modeling, the broad principles outlined by the FDA were followed.
The individual model-based exposure measures at steady state (area
under the Concentration/Time curve [AUC.sub.0-24,ss], time to
maximum plasma concentration [T.sub.max,ss], maximum plasma
concentration [.sub.Cmax,ss]) were computed and summarized.
[0547] The relationship between Compound 1 exposure and response
(efficacy and safety) was examined as appropriate for the data. A
population PK model was used to calculate individual subject AUCs
and, subsequently, possible AUC/MIC breakpoints.
Example 4 a Phase I, Randomized, Double-Blind, 3-Period, Crossover
Study to Evaluate Safety, Tolerability, and Pharmacokinetics of
Multiple Oral Doses of Omadacycline or Placebo in Healthy Adult
Subjects
[0548] The primary objective of this study was to assess and
compare the pharmacokinetics (PK) of 300-, 450-, and 600-mg doses
of oral omadacycline administered daily over 5 days. The secondary
objective of the study was to evaluate the safety and tolerability
of multiple doses of omadacycline in healthy adult subjects.
[0549] For the treatment of CABP, the then anticipated therapeutic
daily oral dose (excluding any loading dose) was 300 mg. For
potential future studies, or for administration of a loading dose
using the oral formulation, it is possible that a daily dose higher
than 300 mg could be used to achieve omadacycline concentrations
sufficient to treat target bacteria in the organs/tissues of
interest. One early clinical study evaluated single oral doses of
omadacycline up to 600 mg, but no studies have evaluated multiple
daily doses higher than 300 mg. This study was designed to obtain
data on the safety, tolerability, and pharmacokinetics (dose
linearity and proportionality) of multiple oral doses of
omadacycline at daily doses higher than 300 mg. Placebo groups were
included as a reference to minimize potential bias in assessing
tolerability.
[0550] Multiple daily oral doses of 300, 450, and 600 mg
omadacycline or placebo were chosen to be administered in this
study. The lowest dose of 300 mg had been evaluated in multiple
dose studies and had been well tolerated; this daily dose has also
been studied in Phase 3 studies in ABSSSI. Single oral doses up to
600 mg were administered in capsules to healthy adult subjects in 1
early clinical study and were determined to have an acceptable
safety profile. There was some increased incidence of GI AEs at
oral doses of 400 mg or greater, though events were typically mild
(none were severe), and it is possible that some of these events
may have been related to the oral formulation. Multiple daily doses
of up to 600 mg using the final optimized tablet formulation of
omadacycline were expected to have acceptable safety profiles, but
this was important to assess in a small carefully controlled Phase
1 study before evaluating these doses in larger clinical
studies.
[0551] Thus the study was designed as a Phase 1, randomized,
double-blind, 3-period, crossover study in healthy adult subjects.
The study consisted of a screening period (Day -21 through Day -2),
3 baseline periods (Day -1 of each period), 3 treatment periods
(Day 1 through Day 6 of each period), and a study completion visit
(within 6 to 10 days after the last dose of study drug in Period
3). There was a washout of at least 5 days between the last dose in
one period and the first dose in the next period. Subjects were
confined to the study site from Day -1 of Period 1 until discharge
on Day 6 of Period 3, after the 24-hour blood sampling, urine
sampling, and safety assessments were completed. Subjects returned
to the study center 6 to 10 days after the last dose of study drug
in Period 3 for the study completion visit.
[0552] Subject Selection
[0553] Healthy, non-smoking, male and female subjects were eligible
for participation in the study if they were between 18 and 55 years
of age (inclusive), weighed .gtoreq.50 kg, had a body mass index
between 18 and 30 kg/m2 (inclusive), met all eligibility criteria
during screening (performed within 21 days before dosing in Period
1) and at baseline (Day -1) for Period 1, and provided written
informed consent. Health status was determined by past medical
history, clinical laboratory tests, vital signs (oral body
temperature, systolic blood pressure, diastolic blood pressure, and
heart rate), 12-lead electrocardiogram (ECG), and physical
examination at screening. Eligibility criteria included ability to
swallow up to 4 tablets in succession.
[0554] Subjects were excluded from participation in the study for
prior treatment with omadacycline, recent use of other
investigational drugs; ECG abnormalities; inability to tolerate
oral medications; pregnancy or breastfeeding; use of tobacco
products, prescription drugs, herbal supplements, or
over-the-counter medications or intake of xanthine (e.g.,
caffeine)--containing food or beverages within a specified time
frame before study initiation; blood loss/donation; low hemoglobin
levels; high creatinine or blood urea nitrogen levels; urinary
obstruction/difficulty voiding; positive alcohol or drug test;
hypersensitivity or allergy to any tetracycline; signs of liver
disease or liver injury; significant illness within 2 weeks of
study initiation; any planned medical intervention that might
interfere with the study; or a history of diseases or medical
conditions as specified in the study protocol.
[0555] Study Design
[0556] On Day 1 through Day 5 of each period, subjects received
once-daily, after a fast of 6 hours, one of the following
treatments (omadacycline or placebo) according to the randomization
schedule: [0557] A. 300 mg omadacycline (2.times.150-mg tablets)
[0558] AP. Placebo for 300 mg omadacycline (2.times.placebo
tablets) [0559] B. 450 mg omadacycline (3.times.150-mg tablets)
[0560] BP. Placebo for 450 mg omadacycline (3.times.placebo
tablets) [0561] C. 600 mg omadacycline (4.times.150-mg tablets)
[0562] CP. Placebo for 600 mg omadacycline (4.times.placebo
tablets)
[0563] All doses of study drug were administered in the morning
with no food or drink except for water at least 6 hours prior to
dosing. Subjects then had no food or drink except water for at
least 2 hours after dosing and no dairy products, antacids, or
multivitamins for 4 hours after dosing.
[0564] Before the dosing, subjects underwent screening evaluations
to determine eligibility within 21 days before dosing in Period 1.
Subjects were then admitted to the clinical site on the day before
dosing (Day -1 of Period 1) for baseline evaluations. Before dosing
on Day 1 of Period 1, up to 30 subjects (24 omadacycline, 6
placebo) were randomly assigned to 1 of 3 treatment sequences using
a Latin Square design as presented in the following table:
TABLE-US-00032 Number of Period Period Period Sequence Subsequence
Subjects 1 2 3 1 1A 8 omadacycline A C S 1B 2 placebo AP CP BP 2 2A
8 omadacycline B A C 2B 2 placebo BP AP CP 3 3A 8 omadacycline C B
A 3B 2 placebo CP BP AP
[0565] About ten subjects were randomly assigned to each sequence.
Placebo was administered to 2 subjects in each sequence as a
reference to assess tolerability. Subjects assigned to omadacycline
received omadacycline during all 3 periods and at all tested dose
levels. Subjects assigned to placebo received placebo during all 3
periods. Investigators and subjects were blinded to whether the
subject was receiving omadacycline or placebo.
[0566] Study Asessment
[0567] 1. Plasma Pharmacokinetics
[0568] Serial blood samples for pharmacokinetic (PK) analysis of
omadacycline were collected at specified time points through 24
hours after dosing on Day 1 and Day 5 of each period. Specifically,
blood samples for PK assessments of omadacycline were collected
from all subjects at the following time points: before dosing
(predose) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24
hours after dosing on Day 1 and Day 5 in each period. The 24-hour
blood sample for Day 1 was collected prior to dosing on Day 2 for
each period.
[0569] Non-compartmental PK parameters were determined on Days 1
and 5 of each period from plasma omadacycline concentration and
actual time data using Phoenix.RTM. WinNonlin.RTM. (Certara,
Princeton, N.J.) Version 6.2.1., including area under the plasma
concentration versus time curve (AUC) from time 0 to 24 hours after
dosing (AUC.sub.0-24), AUC from time 0 to the last quantifiable
concentration (AUC.sub.iast), maximum observed plasma concentration
(C.sub.max), time to reach maximum observed plasma concentration
(T.sub.max), terminal elimination half-life (T.sub.1/2), terminal
phase rate constant (.lamda..sub.z) and the accumulation factor
(Rac) of AUC.sub.0-24 and C.sub.max.
[0570] Subjects that received omadacycline and had at least one
evaluable PK parameter were included in the PK analysis population;
however, subjects may have been excluded from the PK population if
they missed doses, had diarrhea, or had vomiting at or before a
time equal to twice the median T.sub.max.
[0571] 2. Urine Pharmacokinetics
[0572] Urine samples were collected from a subset of subjects at
specified intervals on Day 5 of Period 2 and on Day 1 and Day 5 of
Period: predose, 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours after
dosing. The 12 to 24-hour interval urine sample for Day 1 was
collected prior to dosing on Day 2. Urine samples were only
collected from a subset of subjects because analysis of urine PK
was added by an amendment to the study protocol after the study was
already underway.
[0573] The following urine PK parameters were determined from urine
omadacycline concentration and collection interval data using SAS
Version 9.2: renal clearance (CLr), fraction of the dose excreted
unchanged in urine from 0 to 24 hours after dosing (Fe.sub.0-24),
and amount of drug excreted unchanged in urine over 24 hours after
dosing (Ae.sub.t1-t2). Additional parameters Ae.sub.0-4,
Ae.sub.4-8, Ae.sub.8-12, Ae.sub.12-24, and Ae.sub.0-24 were also
calculated.
[0574] 3. Safety and Tolerability
[0575] Safety assessments include monitoring of adverse events
(AEs), clinical laboratory test results, vital sign measurements,
12-lead electrocardiogram (ECG) results, and physical examination
findings. All randomly assigned subjects who received at least one
dose of any study drug (omadacycline or placebo) were included in
the safety analysis population. Adverse events were coded by
preferred term and system organ class using MedDRA Version
17.1.
[0576] Safety and tolerability were assessed by the monitoring and
recording of AEs, clinical laboratory test results (hematology,
serum chemistry, and urinalysis), vital sign measurements (oral
body temperature, systolic blood pressure, diastolic blood
pressure, and HR), 12-lead ECG results, and physical examination
findings.
[0577] Statistical Analysis for Pharmacokinetic Study:
[0578] Individual plasma and urine concentration and time deviation
data were presented in data listings. Plasma and urine
concentration data were summarized by day and time point or
interval for each treatment using descriptive statistics (number of
subjects, mean, SD, coefficient of variation [CV], median, minimum,
and maximum). Concentrations that were below the limit of
quantification (BLQ) were treated as zero in the plasma and urine
concentration descriptive statistics summaries. Mean and individual
plasma concentration versus time profiles were presented in figures
on both linear and semilogarithmic scales.
[0579] Noncompartmental PK parameters were determined from plasma
concentration and actual time data using Phoenix.RTM.
WinNonlin.RTM. (Certara, Princeton, N.J.) Version 6.2.1 or higher.
Urine PK parameters were determined from urine concentration and
collection interval data using SAS Version 9.2 or higher. All
further statistical analyses were performed using SAS.RTM. software
(SAS Institute, Cary, N.C.), Version 9.2.
[0580] For the PK analysis, BLQ values were treated as zero with
the exception that a BLQ value between 2 quantifiable
concentrations were set as missing. Missing concentrations were
treated as missing from the PK parameter calculations. If
consecutive BLQ concentrations were followed by quantifiable
concentrations in the terminal phase, those concentrations after
BLQ concentrations were treated as missing.
[0581] The individual PK parameters were presented in data
listings. Descriptive statistics (number of subjects, mean, SD, CV,
median, minimum, and maximum) were calculated for the PK parameter
estimates after dosing on Day 1 and Day 5 of each period (e.g.,
AUC.sub.0-24, AUC.sub.last, C.sub.max, T.sub.max, T.sub.1/2, and
Rac [Day 5 only] from plasma concentrations; CLr, Fe.sub.0-24, and
Ae.sub.0-24 from urine concentrations). Geometric means were
included for AUC.sub.0-24, AUC.sub.last, and C.sub.max.
[0582] A linear mixed-effect model (SAS PROC MIXED) with treatment
(A, B, and C), sequence (1A, 2A, and 3A), and treatment period as
fixed effects and subject nested within sequence as a random effect
were fitted to the natural log-transformed dose normalized PK
parameters AUC.sub.0-24/Dose, AUC.sub.last/Dose, and C.sub.max/Dose
after dosing on Day 1 and Day 5 of each period for use in
estimation of effects and construction of confidence intervals
(CIs). Point estimates and 90% CIs for differences on the log scale
were exponentiated to obtain estimates for the ratios of geometric
means and respective 90% CIs on the original scale. No adjustment
was made for multiplicity.
[0583] Dose linearity across all 3 dose levels was assessed by
fitting omadacycline C.sub.max, AUC.sub.last, and AUC.sub.0-24
after both the Day 1 and Day 5 doses to a power model (10):
ln(PK)=a +b.times.ln(Dose)+error, where PK was the PK parameter, a
was the intercept and b was the slope. The estimates of slope b
were reported along with the corresponding 2-sided 90% CIs.
[0584] For statistical analysis of accumulation of omadacycline, a
linear mixed-effect model with day as a fixed effect and subject as
random effect was fitted to the natural log-transformed C.sub.max
and AUC.sub.0-24 to construct 90% CIs for Day 5 compared with Day 1
(at each dose level separately).
[0585] Results
[0586] a. Demographics, Baseline Characteristics, and Disposition
of Study Subjects
[0587] Of the 33 subjects enrolled in the study, 26 were assigned
to receive omadacycline and 7 were assigned to receive placebo.
Demographic and baseline characteristics were generally similar
between omadacycline and placebo treatment groups (Table 4-1) and
across all omadacycline treatment sequences (data not shown). The
majority of subjects in the study were white (57.6%) and male
(81.8%). The overall mean age of subjects was 36.9 years, with a
range of 21 to 55 years.
TABLE-US-00033 TABLE 4-1 Demographics and Baseline Characteristics
of Subjects in the Study.sup.a Omadacycline Placebo Overall (N =
26) (N = 7) (N = 33) Age, years Mean (.+-.SD) 35.6 (.+-.10.4) 41.9
(.+-.11.6) 36.9 (.+-.10.8) Min, max 21, 55 25, 53 21, 55 Sex, n (%)
Male 21 (80.8) 6 (85.7) 27 (81.8) Female 5 (19.2) 1 (14.3) 6 (18.2)
Race, n (%) White 15 (57.7) 4 (57.1) 19 (57.6) Black or African
American 9 (34.6) 3 (42.9) 12 (36.4) Asian 2 (7.7) 0 2 (6.1)
Ethnicity, n (%) Hispanic or Latino 10 (38.5) 3 (42.9) 13 (39.4)
Not Hispanic or Latino 16 (61.5) 4 (57.1) 20 (60.6) Height, cm Mean
(.+-.SD) 173.12 (.+-.9.17) 172.89 (.+-.4.31) 173.07 (.+-.8.32) Min,
max 155.2, 192.4 165.6, 177.4 155.2, 192.4 Weight, kg Mean (.+-.SD)
78.67 (.+-.10.33) 83.77 (.+-.4.80) 79.75 (.+-.9.60) Min, max 62.7,
101.4 76.7, 90.4 62.7, 101.4 Body mass index, kg/m.sup.2 Mean
(.+-.SD) 26.25 (.+-.2.72) 28.04 (.+-.1.45) 26.63 (.+-.2.59) Min,
max 19.4, 29.8 25.8, 29.9 19.4, 29.9 .sup.aResults for Safety
Population
[0588] All 33 subjects received at least one dose of study drug
(omadacycline or placebo) and were included in the safety analysis
population. Twenty-five of the 26 omadacycline-treated subjects
(96.2%) were included in the PK analysis population (one subject
was excluded from this population due to vomiting after dosing).
Four omadacycline-treated subjects (15.4%) and one placebo-treated
subject (14.3%) discontinued the study; these early
discontinuations were due to treatment-emergent adverse events
(TEAEs) in 4 subjects (see below); in addition one
omadacycline-treated subject was lost to follow-up. Thus, 22
subjects received all 5 doses of 300-, 450-, and 600-mg
omadacycline and 6 subjects received all 5 doses of placebo in
Periods 1, 2, and 3. These subjects were considered to have
completed the study.
[0589] b. Plasma Pharmacokinetics
[0590] At all tested omadacycline dose levels on both Day 1 and Day
5 of each 5-day treatment period, mean plasma omadacycline
concentrations peaked 2.5 hours after dosing (T.sub.max) and
omadacycline was measurable in plasma for up to 24 hours after
dosing (the last sampling time) (FIG. 5 and Table 4-2).
TABLE-US-00034 TABLE 4-2 Plasma Pharmacokinetic Parameters of
Omadacycline by Dose on Days 1 and 5 of Dosing.sup.a Omadacycline
Dose Day 1 Day 5 300 mg 450 mg 600 mg 300 mg 450 mg 600 mg
Parameter (n = 25) (n = 24) (n = 24) (n = 23) (n = 24) (n = 23)
Mean AUC.sub.0-24, 6644.8 8976.5 10020.5 9267.2 13366.7 16420.3 ng
h/mL (25.3) (26.6) (25.7) (26.8) (26.0) (27.1) (CV) Mean C.sub.max,
ng/mL 648.8 874.2 954.5 808.8 1077.3 1305.5 (CV) (24.0) (26.6)
(23.2) (25.9) (25.0) (26.6) Mean T.sub.max, h 2.50 2.50 2.51 2.50
2.50 2.50 (Min, max) (1.50, 3.00) (1.50, 3.00) (1.00, 3.00) (1.00,
3.00) (1.50, 4.00) (2.00, 4.00) Mean T.sub.1/2, h 13.66 13.45 13.03
15.49 16.83 16.75 (CV) (12.5).sup.b (12.9).sup.c (11.8).sup.c
(10.7).sup.d (8.1).sup.c (6.8).sup.d .sup.aResults for
Pharmacokinetic Population .sup.bn = 24 (T.sub.1/2 was not
estimable for 1 subject) .sup.cn = 23 (T.sub.1/2 was not estimable
for 1 subject) .sup.dn = 21 (T.sub.1/2 was not estimable for 2
subjects) CV, coefficient of variation Note: One 300 mg
omadacycline subject and one 600 mg omadacycline subject were
excluded from the Day 5 summary due to vomiting before reaching the
pharmacokinetic steady state on Day 5 Omadacycline total exposure
(AUC.sub.0-24 and AUC.sub.last) and peak concentrations (C.sub.max)
increased with increasing omadacycline dose (300 vs 450 vs 600 mg)
on both Day 1 and Day 5, and were higher on Day 5 than on Day 1 for
corresponding doses (FIG. 5 and Table 4-2). The mean half-life of
omadacycline in plasma (T.sub.1/2) was similar across the 3 tested
dose levels, ranging from 13.03 to 13.66 hours on Day 1 and from
15.49 to 16.83 hours on Day 5 (Table 4-2). Between-subject
variability in systemic omadacycline exposure was low and was
similar at all three tested dose levels, with coefficients of
variation (CVs) ranging from 23.2% to 26.6% for C.sub.max,
AUC.sub.0-24, and AUC.sub.last on Day 1 and from 25.0% to 27.1% for
C.sub.max, AUC.sub.0-24, and AUC.sub.last on Day 5 (Table 4-2).
[0591] Although omadacycline AUC.sub.0-24, AUC.sub.last and
C.sub.max increased with increasing omadacycline dose, the observed
increases in exposure were less than dose proportional on both days
of analysis (Tables 4-2 and 4-3).
TABLE-US-00035 TABLE 4-3 Statistical Analysis of Dose-Normalized
Omadacycline Pharmacokinetic Parameters on Days 1 and 5 of
Dosing.sup.a Ratio of Geometric Treatment Geometric 90% CI of
Parameter Treatment N LS Means Comparison LS Means (%) Ratio (%)
Day 1 AUC.sub.0-24/Dose 300 mg 25 21.32 (ng h/mL/mg) 450 mg 24
18.64 450/300 87.44 (77.41, 98.77) 600 mg 24 16.18 600/450 86.79
(76.71, 98.20) 600/300 75.89 (67.20, 85.71) C.sub.max/Dose 300 mg
25 2.09 (ng/mL/mg) 450 mg 24 1.81 450/300 86.71 (76.17, 98.71) 600
mg 24 1.54 600/450 85.26 (74.76, 97.23) 600/300 73.92 (64.95,
84.14) Day 5 AUC.sub.0-24/Dose 300 mg 23 30.09 (ng h/mL/mg) 450 mg
24 28.83 450/300 95.82 (90.39, 101.59) 600 mg 23 26.46 600/450
91.78 (86.58, 97.30) 600/300 87.95 (82.96, 93.25) Cmax/Dose 300 mg
23 2.62 (ng/mL/mg) 450 mg 24 2.32 450/300 88.58 (83.19, 94.32) 600
mg 23 2.11 600/450 90.72 (85.20, 96.60) 600/300 80.36 (75.47,
85.58) .sup.aResults for Pharmacokinetic Population ANOVA analysis;
see Materials and Methods for details CI, confidence interval; LS,
least squares Note: One 300 mg omadacycline subject and one 600 mg
omadacycline subject were excluded from the Day 5 statistical
analysis due to vomiting before reaching the pharmacokinetic steady
state on Day 5
[0592] Statistical analyses showed that with an increase in dose
from 300 mg to 600 mg, omadacycline exposure (based on
dose-normalized AUC.sub.0-24) on Day 1 was 76% of that predicted if
exposure were perfectly dose-proportional (Table 4-3); on Day 5,
the observed increase in omadacycline exposure was 88% of predicted
(Table 4-3). Analysis of C.sub.max values similarly demonstrated
that omadacycline concentrations were dose-linear, but less than
dose-proportional in this study (Tables 4-2 and 4-3).
[0593] Statistical analyses also revealed accumulation of
omadacycline in plasma following once-daily dosing for 5
consecutive days. Depending on dose, accumulation ratios between
Day 5 and Day 1 ranged from 1.40 to 1.62 for AUC.sub.0-24 and from
1.24 to 1.35 for C.sub.max (data not shown). These findings are
consistent with the long half-life of omadacycline in plasma.
[0594] The above data showed that mean concentrations of
omadacycline peaked at 2.5 hours and remained measurable up to 24
hours (the last tested timepoint) at all omadacycline dosing levels
(300, 450, and 600 mg). On Day 5, mean steady state exposure
(AUC.sub.0-24) in subjects dosed with 300-mg omadacycline was 9267
ngh/mL, which is consistent with results of previous studies with
300 mg oral dosing. Both AUC.sub.0-24 and C.sub.max increased with
increasing dose and were nearly, but somewhat less than,
dose-proportional (74%-88% of expected). This was the case on both
Day 1 and Day 5 of dosing. Due to its relatively long half-life
(mean=.about.13 h on Day 1, .about.16 h on Day 5), omadacycline
accumulated in plasma over the course of 5 consecutive days of
dosing. Thus, at all tested dose levels, systemic exposure on Day 5
was .about.50% higher than on Day 1. This degree of accumulation is
also consistent with that observed following multiple once-daily
dosing of IV or oral formulations of omadacycline in early
pharmacology studies.
[0595] In terms of systemic exposure, this study showed that
omadacycline plasma concentrations on Day 1 of 450-mg dosing were
similar to those on Day 5 of 300-mg dosing (mean
AUC.sub.0-24=8976.5 and 9267.2 ngh/mL, respectively). For
indications in which the therapeutic dosing regimen incorporates
300 mg daily oral dosing, these data support a strategy of using an
initial oral "loading dose" of 450 mg once-daily for 1-2 days,
followed by 300-mg once-daily oral dosing. Such a strategy could
potentially eliminate the need for an IV phase of treatment.
[0596] c. Urine Pharmacokinetics
[0597] Because urine sample collection and PK analysis were added
to the study by protocol amendment after the study was underway,
only a limited number of samples were evaluated (samples from 9
subjects on Day 5 of Period 2 and samples from 8 subjects on Day 1
and Day 5 of Period 3). While this sample size was too small to
make meaningful comparisons between omadacycline dose groups, the
results of the analysis did provide an overall indication of
partial omadacycline renal clearance and urinary excretion.
[0598] For all omadacycline dose groups, the mean fraction of the
dose excreted unchanged in urine from 0 to 24 hours after dosing
(Fe.sub.0-24) ranged from -5% to .about.7% on Day 1 and from -7% to
.about.9% on Day 5. Renal clearance (CLr) ranged from 2.8 to 4.2
L/h on Day 1 and from 2.4 to 3.3 L/h on Day 5 (Table 4-4).
TABLE-US-00036 TABLE 4-4 Urine Pharmacokinetic Parameters of
Omadacycline by Dose on Days 1 and 5 of Dosing.sup.a Omadacycline
Dose Day 1 Day 5 300 mg 450 mg 600 mg 300 mg 450 mg 600 mg
Parameter.sup.b (n = 2) (n = 3) (n = 1) (n = 3) (n = 5) (n = 4)
Ae.sub.0-24 (mg) 20.37 (8.3) 25.06 (16.8) 31.96 26.14 (14.6) 30.81
(33.0) 51.82 (14.8) Fe.sub.0-24 (%) 6.79 (8.3) 5.57 (16.8) 5.33
8.71 (14.6) 6.85 (33.0) 8.64 (14.8) CLr (L/h) 3.01 (11.4) 2.80
(9.6) 4.17 3.28 (27.2) 2.38 (34.9) 3.05 (19.9) .sup.aResults for
Pharmacokinetic Population .sup.bMean (CV) CV, coefficient of
variation Note: One 600 mg omadacycline subject was excluded from
the summary due to vomiting before reaching the pharmacokinetic
steady state on Day 5
[0599] Urine PK analyses in a subset of subjects provided
preliminary indications of partial renal clearance and urinary
excretion of omadacycline. On Day 5, depending on dose level,
.about.7% to .about.9% of the administered oral dose was excreted
unchanged in the urine over 24 hours. This represents approximately
20% to 25% of the absorbed dose since it is known that the absolute
bioavailability of the tablet formulation used in this study is
35%. Presence of unchanged omadacycline in the urine suggests that
it may be useful in urinary tract infections, an indication that is
currently being explored.
[0600] d. Safety and Tolerability
[0601] Overall, 12 of the 33 subjects in the safety population
reported a total of 36 TEAEs during the study (Table 4-5).
TABLE-US-00037 TABLE 4-5 Summary of Treatment-Emergent Adverse
Events.sup.a Omadacycline Dose Omadacycline Placebo 300 mg 450 mg
600 mg Overall Overall (n = 26) (n = 24) (n = 24) (n = 26) (n = 7)
n (%) of subjects with: Any TEAE 5 (19.2) 3 (12.5) 6 (25.0) 10
(38.5) 2 (28.6) Treatment-related TEAE 4 (15.4) 2 (8.3) 6 (25.0) 9
(34.6) 1 (14.3) Most frequent TEAEs (seen in >1 study subject),
n (%) Nausea 2 (7.7) 1 (4.2) 4 (16.7) 6 (23.1) 0 Vomiting 2 (7.7) 0
1 (4.2) 3 (11.5) 0 Diarrhea 0 0 2 (8.3) 2 (7.7) 0 Dizziness 2 (7.7)
0 1 (4.2) 3 (11.5) 0 ALT increased 0 1 (4.2) 1 (4.2) 2 (7.7) 0
TEAEs leading to early discontinuation of study drug, n (%) All 1
(3.8) 1 (4.2) 1 (4.2) 3 (11.5) 1 (14.3) Nausea 1 (3.8) 0 0 1 (3.8)
0 Vomiting 1 (3.8) 0 0 1 (3.8) 0 ALT increased 0 1 (4.2) 0 1 (3.8)
0 Lipase increased 0 0 1 (4.2) 1 (3.8) 0 Syncope 0 0 0 0 1
(14.3).sup.b .sup.aResults for Safety Population .sup.bvasovagal
syncope following a blood draw ALT, alanine aminotransferase; TEAE,
treatment-emergent adverse event
[0602] TEAEs were reported by 38.5% of subjects that received
omadacycline and 28.6% of subjects that received placebo. The
highest percentage of TEAEs was classified as gastrointestinal (GI)
disorders. The most frequently reported TEAE was nausea, which
occurred in <7.7% of the omadacycline 300 and 450 mg dose groups
and 16.7% of the 600 mg group. All of the TEAEs reported in this
study were either mild or moderate in severity. There were no
serious TEAEs (SAEs) reported during the study. Four subjects
experienced TEAEs leading to study discontinuation, including one
subject at each of the 3 omadacycline dose levels and 1 subject in
the placebo group.
[0603] There were no clinically significant findings in analyses of
vital sign measurements, physical examination, ECG results,
hematology or urinalysis parameters. Serum chemistry analyses
showed that between baseline and Day 5 of each dosing period, the
median change in alanine aminotransferase (ALT) concentration was
-2.0, 5.0 and 19.5 IU/L in subjects dosed with 300, 450 and 600 mg
omadacycline, respectively. The corresponding changes in placebo
groups ranged from -5.0 to -1.0 IU/L. No substantial changes in
median aspartate aminotransferase (AST), bilirubin or other serum
chemistry parameters were noted. The highest individual ALT value
was 150 IU/L (2.7-fold above the upper limit of normal [ULN]),
which occurred in a subject who first received 450 mg omadacycline
in Period 1 then 300 mg in Period 2 and then was discontinued due
to the liver enzyme changes; this subject's bilirubin values
remained within the normal range at all time points assessed.
[0604] The plasma PK findings indicate that higher systemic drug
exposure can be achieved by increasing the amount of omadacycline
administered per dose during once-daily oral dosing, but that the
exposure benefit is not dose-proportional. Moreover, increasing
omadacycline dosing beyond a certain point appears to have adverse
effects in terms of safety and tolerability. While multiple doses
of 300, 450, and 600 mg were all generally well-tolerated in this
study (all TEAEs were either mild or moderate in severity), there
were some differences between the doses. The frequency of
treatment-related TEAEs did not increase with an increase in
omadacycline dose from 300 to 450 mg (15.4% vs 8.3%), but such
events were more frequent with 600 mg (25.0%). Within the most
frequent class of TEAEs, GI disorders, nausea occurred with
incidence at least 9% higher for the 600 mg dose level than for the
lower doses, and the only 2 reports of diarrhea occurred with 600
mg. In addition, serum chemistry analyses showed a small but
notable dose-dependent increase in median ALT concentrations. While
no individual ALT values exceeded 3-fold above the ULN, the higher
median ALT at 600 mg suggests an increased chance of more
significantly elevated serum transaminase levels with this dose.
Based on these findings, for situations in which an oral dose above
300 mg may be beneficial, 450 mg was identified as the oral dose
most likely to provide higher omadacycline exposure with favorable
safety and tolerability.
[0605] In summary, this phase 1 study investigated the
pharmacokinetics (PK) and safety/tolerability of multiple oral
omadacycline doses higher than 300 mg. Using a 3-period crossover
design, healthy adults were randomized to receive omadacycline
(300-, 450- and 600-mg in variable sequence; n=26) or placebo (n=7)
once daily for 5 consecutive days per period. In plasma,
omadacycline maximum concentration and total exposure increased
with increasing dose, but were less than dose-proportional (74% to
88% of expected). The kinetics of omadacycline plasma accumulation
were similar between dose levels; exposure on Day 5 was .about.50%
higher than on Day 1. Omadacycline plasma concentrations on Day 1
of 450 mg dosing were similar to those on Day 5 of 300 mg dosing.
Urine PK analyses indicated partial renal clearance and urinary
excretion of unchanged omadacycline. All doses were generally
well-tolerated. These results support the use of once-daily 450-mg
oral omadacycline as part of the oral only dosing regimen, such as
using once-daily 450-mg oral omadacycline (either one or two doses)
as loading dose before stepping down to once-daily 300-mg oral
omadacycline, or in a dosing regimen using once-daily 450-mg oral
omadacycline throughout the treatment.
* * * * *