U.S. patent application number 13/657655 was filed with the patent office on 2013-11-28 for methods useful for the treatment of pain, arthritic conditions or inflammation associated with a chronic condition.
This patent application is currently assigned to Durect Corporation. The applicant listed for this patent is Durect Corporation. Invention is credited to Wendy Chao, Roger Fu, Su Il Yum, Michael Zamloot.
Application Number | 20130317049 13/657655 |
Document ID | / |
Family ID | 40427334 |
Filed Date | 2013-11-28 |
United States Patent
Application |
20130317049 |
Kind Code |
A1 |
Yum; Su Il ; et al. |
November 28, 2013 |
Methods Useful for the Treatment of Pain, Arthritic Conditions or
Inflammation Associated with a Chronic Condition
Abstract
Methods, including those for administering novel pharmaceutical
compositions, dosage forms containing an opioid active
pharmaceutical ingredient, are useful for treating pain, arthritic
conditions and/or inflammation associated with a chronic condition,
including pain from arthritis and inflammation.
Inventors: |
Yum; Su Il; (Los Altos,
CA) ; Chao; Wendy; (San Jose, CA) ; Fu;
Roger; (Saratoga, CA) ; Zamloot; Michael;
(Hillsborough, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Durect Corporation |
Cupertino |
CA |
US |
|
|
Assignee: |
Durect Corporation
Cupertino
CA
|
Family ID: |
40427334 |
Appl. No.: |
13/657655 |
Filed: |
October 22, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12315740 |
Dec 5, 2008 |
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13657655 |
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61198201 |
Nov 3, 2008 |
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61005685 |
Dec 6, 2007 |
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61005681 |
Dec 6, 2007 |
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Current U.S.
Class: |
514/282 |
Current CPC
Class: |
A61K 31/485 20130101;
A61P 43/00 20180101; A61K 9/4866 20130101; A61K 31/4402 20130101;
A61P 35/00 20180101; A61K 9/48 20130101; A61P 25/36 20180101; A61P
25/04 20180101; A61P 19/02 20180101; A61K 31/137 20130101; A61K
9/4858 20130101; A61P 25/24 20180101; A61P 25/00 20180101; A61K
31/4458 20130101; A61P 25/26 20180101; A61P 25/20 20180101; A61P
19/00 20180101; A61P 29/00 20180101 |
Class at
Publication: |
514/282 |
International
Class: |
A61K 31/485 20060101
A61K031/485 |
Claims
1. A method for treating pain, said method comprising administering
to a subject a pharmaceutical composition for oral administration
which comprises: (a) an opioid; (b) sucrose acetate isobutyrate;
(c) triacetin; (d) isopropyl myristate; (e) cellulose acetate
butyrate; (f) hydroxyethyl cellulose; (g) colloidal silicon
dioxide; and (h) butylated hydroxytoluene, wherein one or more
symptoms or signs associated with the subject's pain is
alleviated.
2. The method of claim 1, wherein: (i) the opioid is in the form of
a free base or a salt, and/or (ii) the opioid is micronized, and/or
(iii) the opioid is oxycodone, oxymorphone, hydrocodone or
hydromorphone.
3. The method of claim 1, wherein the pharmaceutical composition is
administered no more than twice in a 24-hour period.
4. The method of claim 1, wherein the pharmaceutical composition is
encapsulated.
5. The method of claim 1, wherein the pain is associated with
cancer or the pain is chronic pain such as chronic pain that is
associated with an arthritic condition.
6. A method for treating an arthritic condition, said method
comprising administering to a subject a pharmaceutical composition
for oral administration which comprises: (a) an opioid; (b) sucrose
acetate isobutyrate; (c) triacetin; (d) isopropyl myristate; (e)
cellulose acetate butyrate; (f) hydroxyethyl cellulose; (g)
colloidal silicon dioxide; and (h) butylated hydroxytoluene,
wherein one or more symptoms or signs associated with the subject's
arthritic condition are alleviated.
7. The method of claim 6, wherein: (i) the opioid is in the form of
a free base or a salt, and/or (ii) the opioid is micronized, and/or
(iii) the opioid is oxycodone, oxymorphone, hydrocodone or
hydromorphone.
8. The method of claim 6, wherein the pharmaceutical composition is
administered no more than twice in a 24-hour period.
9. The method of claim 6, wherein the arthritic condition is
associated with a joint, hip, knee, back, neck, or lower back of
the subject.
10. A method for treating inflammation, said method comprising
administering to a subject a pharmaceutical composition for oral
administration which comprises: (a) an opioid; (b) sucrose acetate
isobutyrate; (c) triacetin; (d) isopropyl myristate; (e) cellulose
acetate butyrate; (f) hydroxyethyl cellulose; (g) colloidal silicon
dioxide; and (h) butylated hydroxytoluene, wherein one or more
symptoms or signs associated with the subject's inflammation are
alleviated.
11. The method of claim 10, wherein: (i) the opioid is in the form
of a free base or a salt, and/or (ii) the opioid is micronized,
and/or (iii) the opioid is oxycodone, oxymorphone, hydrocodone or
hydromorphone.
12. The method of claim 10, wherein the pharmaceutical composition
is administered no more than twice in a 24-hour period.
13. The method of claim 10, wherein the inflammation is associated
with an arthritic condition which preferably is associated with a
joint, hip, knee, back, neck, or lower back of the subject.
14. A pharmaceutical composition for oral administration to a human
subject, the pharmaceutical composition comprising: (a) an opioid;
(b) sucrose acetate isobutyrate; (c) triacetin; (d) isopropyl
myristate; (e) cellulose acetate butyrate; (f) hydroxyethyl
cellulose; (g) colloidal silicon dioxide; and (h) butylated
hydroxytoluene.
15. The composition of claim 14, wherein: (i) the opioid is in the
form of a free base or a salt, and/or (ii) the opioid is
micronized, and/or (iii) the opioid is oxycodone, oxymorphone,
hydrocodone or hydromorphone.
16. The composition of claim 14, wherein said composition is
intended for administration to a subject no more than twice in a
24-hour period.
17. The composition of claim 14, wherein said composition is
encapsulated.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to methods, including novel
methods of administration, useful for the treatment of pain,
arthritic conditions, and/or inflammation associated with a chronic
condition, using opioid compositions. The methods provide human
subjects with an alleviation of one or more symptoms or signs of
pain, an arthritic condition or inflammation associated with a
chronic condition, including, for example, reduced pain, reduced
stiffness and/or improved physical function.
BACKGROUND OF THE INVENTION
[0002] Opioids are a broad class of drugs used clinically in the
management of pain, but their use is limited by a constellation of
undesirable side effects, including their potential for dependence
and abuse. The principle actions and therapeutic value of opioids
are analgesia and sedation. The precise mechanisms of action for
these effects are unknown; however, specific central nervous system
opioid receptors for endogenous compounds with opioid-like activity
have been identified throughout the brain and spinal cord, and
likely play a role in the analgesic effects of opioid drugs.
[0003] Controlled-release formulations of opioids, such as
oxycodone, have several advantages over immediate-release
formulations. Lower peak concentrations of opioids in the blood may
allow for decreased dose-dependent opioid-related adverse events
(AEs). In controlled release formulations, if blood levels of
opioids, such as oxycodone, are sustained over longer periods, this
should allow for more convenient dosing regimens. However, marketed
versions of controlled-release oxycodone have been the subject of
intense media scrutiny due to an epidemic of misuse, abuse and
diversion. For example, OxyContin introduced dosage strengths that
contained much higher amounts of oxycodone than previously
available to the market. Abusers can easily disrupt the
controlled-release mechanism of OxyContin by crushing, chewing or
dissolving tablets or capsules in alcohol, leading to an immediate
surge in oxycodone blood levels, which can produce a sense of
euphoria but can also lead to respiratory depression and even
death.
SUMMARY OF THE INVENTION
[0004] The present invention provides methods, including novel
methods of administration, useful for the treatment of pain (e.g.,
chronic pain), arthritic conditions and/or inflammation associated
with a chronic condition using a novel oral opioid pharmaceutical
composition. Methods of the invention provide treatment for pain,
including wherein the pain is moderate to severe and including pain
from cancer, arthritic conditions and/or inflammation. Methods of
the present invention provide subjects with alleviation of one or
more symptoms or signs of the pain, arthritic condition,
inflammation associated with a chronic condition, including, for
example, alleviation of pain, alleviation of stiffness and/or
improvement of physical function. Methods of the invention
comprising administration of the oral opioid composition may
optionally include one or more additional therapeutic agents.
[0005] Methods are provided for treating pain in a subject that
comprise administering to a subject a pharmaceutical composition
for oral administration. The pharmaceutical composition comprises:
an opioid active pharmaceutical ingredient (API), a sucrose acetate
isobutyrate liquid carrier material, triacetin, isopropyl
myristate, cellulose acetate butyrate, hydroxyethyl cellulose,
colloidal silicon dioxide and butylated hydroxytoluene, wherein one
or more symptoms or signs associated with the pain is
alleviated.
[0006] Methods are also provided for treating an arthritic
condition in a subject that comprise administering to the subject a
pharmaceutical composition for oral administration that comprises:
an opioid API, sucrose acetate isobutyrate, triacetin, isopropyl
myristate, cellulose acetate butyrate, hydroxyethyl cellulose,
colloidal silicon dioxide and butylated hydroxytoluene, wherein one
or more symptoms or signs associated with the arthritic condition
are alleviated.
[0007] Methods are provided for treating inflammation in a subject
that comprise administering to the subject a pharmaceutical
composition for oral administration that comprises: an opioid API,
sucrose acetate isobutyrate, triacetin, isopropyl myristate,
cellulose acetate butyrate, hydroxyethyl cellulose, colloidal
silicon dioxide and butylated hydroxytoluene, wherein one or more
symptoms or signs associated with inflammation are alleviated.
[0008] In some embodiments, the opioid API is in the form of a free
base. In some embodiments, the opioid is in the form of a salt. In
some embodiments, the opioid is micronized. Preferred opioids
include oxycodone, oxymorphone, hydrocodone and hydromorphone.
Particularly preferred is oxycodone.
[0009] In some embodiments, the subject is a human.
[0010] In some embodiments, the pain is chronic pain. Chronic pain
may result from various abnormal or compromised states (e.g.,
diseased), including but not limited to osteoarthritis, rheumatoid
arthritis, psoriatic arthritis, back pain, cancer, injury or
trauma.
[0011] In some embodiments, the chronic pain is associated with an
arthritic condition. In some embodiments, the chronic pain results
from osteoarthritis, rheumatoid arthritis, psoriatic arthritis,
gout, spondylarthropathris, ankylosing spondylitis, Reiter's
syndrome, psoriatic arthropathy, enterapathric spondylitis,
juvenile arthropathy, juvenile ankylosing spondylitis, reactive
arthropathy, infectious or post-infectious arthritis, gonoccocal
arthritis, tuberculous arthritis, viral arthritis, fungal
arthritis, syphlitic arthritis, Lyme disease, calcium crystal
deposition arthropathies, pseudo gout, non-articular rheumatism,
bursitis, tenosynomitis, epicondylitis, carpal tunnel syndrome, a
repetitive use injury, neuropathic joint disease, hemarthrosis,
Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, or
multicentric reticulohistiocytosis. In some embodiments, the
chronic pain results from an arthritis associated with a vasculitic
syndrome, polyarteritis nodosa, hypersensitivity vasculitis,
Luegenec's granulomatosis, polymyalgin rheumatica, joint cell
arteritis, surcoilosis, hemochromatosis, sickle cell disease or
another hemoglobinopathry, hyperlipo proteineimia,
hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial
Mediterranean fever, Behat's Disease, lupus, systemic lupus
erythematosis, hemophilia, or relapsing polychondritis.
[0012] In some embodiments, the chronic pain is associated with a
joint, hip, knee, back, neck, or lower back of the subject. In some
embodiments, the pain is measured as pain intensity. In some
embodiments, the pain intensity is attenuated as compared to a pain
intensity baseline of the subject. In some embodiments the pain is
measured on the pain subscale of the WOMAC Osteoarthritis Index. In
some embodiments, the pain measurement of the subject is improved
with administration of the opioid as compared to baseline pain
measurement of the subject on the WOMAC pain subscale baseline of
the subject.
[0013] In some embodiments, the pain is measured by a patient or
physician assessment. In some embodiments, the pain is measured on
an 11-point numerical scale. In some embodiments, the pain is
reduced by at least 1 point with administration of the opioid, as
compared to the pain where a subject is administered a placebo.
[0014] In some embodiments, the pain felt by the subject when
walking on a flat surface, when going up or down stairs, at night
while in bed, that disturbs the sleep of the subject, while sitting
or lying down, or while standing is attenuated.
[0015] In some embodiments, the methods further comprise
administering to the subject an additional therapeutic agent that
is a non-steroidal anti-inflammatory drug, cytokine inhibitor,
corticosteroid, anti-rheumatic drug, anticonvulsant agent,
tricyclic antidepressant agent, anti-dynorphin agent, or glutamate
receptor antagonist agent. In some embodiments, the additional
therapeutic agent is a TNF-.alpha. inhibitor, corticosteroid,
anti-rheumatic drug, non-steroidal anti-inflammatory drug,
celecoxib, ropecoxib, valdecoxib, etanercept, infiximab,
anti-TNF-.alpha., D2E7 human Mab, CDP-870, CDP-571, humicade,
PEGylated soluble TNF-.alpha. Receptor-1, TBP-1, PASSTNF-alpha,
AGT-1, ienercept, CytoTAB, TACE, small molecule TNF mRNA synthesis
inhibitor, PEGylated p75TNFR Fc mutein (Immunex), TNF-.alpha.
antisense inhibitor, methotrexate, leflunomide, D-Penicillamine,
sulfasalazine, a gold composition, minocycline, azathioprine,
hydroxychloroquine, an antimalarial drug, cyclosporine, or a
biologic agent that designed to either inhibit or supplement a
cytokine.
[0016] In some embodiments, the methods further comprise
administering to the subject an opioid antagonist, including, for
example, naloxone, naltrexone or nalmefene.
[0017] In some embodiments, the oral pharmaceutical composition is
administered no more than twice in a 24-hour period. In some
embodiments, the oral pharmaceutical composition is provided as a
solid oral dosage form or as a liquid oral dosage form.
[0018] In some embodiments, the arthritic condition is
osteoarthritis, rheumatoid arthritis, psoriatic arthritis, gout,
spondylarthropathris, ankylosing spondylitis, Reiter's syndrome,
psoriatic arthropathy, enterapathric spondylitis, juvenile
arthropathy, juvenile ankylosing spondylitis, reactive arthropathy,
infectious or post-infectious arthritis, gonoccocal arthritis,
tuberculous arthritis, viral arthritis, fungal arthritis, syphlitic
arthritis, Lyme disease, calcium crystal deposition arthropathies,
pseudo gout, non-articular rheumatism, bursitis, tenosynomitis,
epicondylitis, carpal tunnel syndrome, a repetitive use injury,
neuropathic joint disease, hemarthrosis, Henoch-Schonlein Purpura,
hypertrophic osteoarthropathy, or multicentric
reticulohistiocytosis. In some embodiments, the arthritic condition
is an arthritis associated with a vasculitic syndrome,
polyarteritis nodosa, hypersensitivity vasculitis, Luegenec's
granulomatosis, polymyalgin rheumatica, joint cell arteritis,
surcoilosis, hemochromatosis, sickle cell disease or another
hemoglobinopathry, hyperlipo proteineimia, hypogammaglobulinemia,
hyperparathyroidism, acromegaly, familial Mediterranean fever,
Behat's Disease, lupus, systemic lupus erythematosis, hemophilia,
or relapsing polychondritis. In some embodiments, the arthritic
condition is associated with a joint, hip, knee, back, neck, or
lower back of the subject.
[0019] In some embodiments, progression of the arthritic condition
is inhibited. In some embodiments, damage associated with an
arthritic condition is reversed.
[0020] In some embodiments, tissue or cellular damage resulting
from inflammation associated with a chronic condition is inhibited.
In some embodiments, tissue or cellular damage resulting from
inflammation associated with a chronic condition is reversed
[0021] The pharmaceutical compositions that are provided for oral
administration to a subject comprise an opioid API (e.g.,
oxycodone), sucrose acetate isobutyrate, triacetin, isopropyl
myristate, cellulose acetate butyrate, hydroxyethyl cellulose,
colloidal silicon dioxide or butylated hydroxytoluene).
[0022] Particular pharmaceutical compositions that are provided for
oral administration to a subject comprise: 5.13% opioid (e.g.,
oxycodone), 40.98% sucrose acetate isobutyrate, 27.32% triacetin,
14.23% isopropyl myristate, 4.74% cellulose acetate butyrate, 5.69%
hydroxyethyl cellulose, 1.90% colloidal silicon dioxide and 0.02%
butylated hydroxytoluene.
[0023] The pharmaceutical compositions may be encapsulated,
including, for example, in hard gelatin capsules or soft gelatin
capsules.
[0024] One or more symptoms and signs of pain, arthritic conditions
or inflammation associated with chronic conditions are alleviated
(e.g., ameliorated, attenuated, reduced, diminished, blocked,
inhibited or prevented), by methods of the invention, for example,
as measured by an alleviation (e.g., amelioration, attenuation,
reduction, diminishment, blockage, inhibition or prevention) of
pain, stiffness, or difficulty in physical function.
[0025] The present invention is directed to the use of novel
pharmaceutical compositions, provided as novel dosage forms, kits,
and other materials comprising an opioid API for use in or with the
foregoing methods including, for example, methods for alleviating
one or more symptoms or signs associated with pain (e.g., chronic
pain), an arthritic condition and/or inflammation associated with a
chronic condition, wherein the amount of the opioid that is
administered is effective for alleviating one or more symptoms or
signs associated with pain, an arthritic condition, or inflammation
associated with a chronic condition.
[0026] Symptoms and signs of arthritic conditions and inflammation
resulting from chronic conditions are alleviated (e.g.,
ameliorated, attenuated, reduced, diminished, blocked, inhibited or
prevented) by practice of the methods of the invention, for
example, as measured by an alleviation (e.g., amelioration,
attenuation, reduction, diminishment, blockage, inhibition or
prevention) of pain, stiffness, and/or difficulty in physical
function.
[0027] Advantages of methods of the invention include enhanced and
prolonged analgesia, prevention of tolerance and continued
protection against tolerance even with chronic administration,
reversal of opioid-induced hyperalgesia, prevention of physical
dependence or withdrawal, decreased rewarding/euphoric side effect,
and/or decreased potential for relapse/addiction.
POINTS OF THE INVENTION
[0028] 1. A method for treating pain comprising administering to a
subject a pharmaceutical composition for oral administration that
comprises:
[0029] (a) an opioid;
[0030] (b) sucrose acetate isobutyrate;
[0031] (c) triacetin;
[0032] (d) isopropyl myristate;
[0033] (e) cellulose acetate butyrate;
[0034] (f) hydroxyethyl cellulose;
[0035] (g) colloidal silicon dioxide; and
[0036] (h) butylated hydroxytoluene,
[0037] wherein one or more symptoms or signs associated with the
pain is alleviated.
[0038] 2. The method of point 1, wherein the opioid is in the form
of a free base.
[0039] 3. The method of point 1, wherein the opioid is in the form
of a salt.
[0040] 4. The method of point 1, wherein the opioid is
micronized.
[0041] 5. The method of any one of points 1, 2, 3 or 4, wherein the
opioid is oxycodone, oxymorphone, hydrocodone or hydromorphone.
[0042] 6. The method of any one of points 1, 2, 3 or 4, wherein the
opioid is oxycodone.
[0043] 7. The method of point 1, wherein the pharmaceutical
composition is encapsulated.
[0044] 8. The method of point 1, wherein the subject is a
human.
[0045] 9. The method of point 1, wherein the pain is associated
with cancer.
[0046] 10. The method of point 1, wherein the pain is chronic
pain.
[0047] 11. The method of point 10, wherein the chronic pain is
associated with an arthritic condition.
[0048] 12. The method of point 10, wherein the chronic pain results
from osteoarthritis, rheumatoid arthritis, psoriatic arthritis,
gout, spondylarthropathris, ankylosing spondylitis, Reiter's
syndrome, psoriatic arthropathy, enterapathric spondylitis,
juvenile arthropathy, juvenile ankylosing spondylitis, reactive
arthropathy, infectious or post-infectious arthritis, gonoccocal
arthritis, tuberculous arthritis, viral arthritis, fungal
arthritis, syphlitic arthritis, Lyme disease, calcium crystal
deposition arthropathies, pseudo gout, non-articular rheumatism,
bursitis, tenosynomitis, epicondylitis, carpal tunnel syndrome, a
repetitive use injury, neuropathic joint disease, hemarthrosis,
Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, or
multicentric reticulohistiocytosis.
[0049] 13. The method of point 10, wherein the chronic pain results
from an arthritis associated with a vasculitic syndrome,
polyarteritis nodosa, hypersensitivity vasculitis, Luegenec's
granulomatosis, polymyalgin rheumatica, joint cell arteritis,
surcoilosis, hemochromatosis, sickle cell disease or another
hemoglobinopathry, hyperlipo proteineimia, hypogammaglobulinemia,
hyperparathyroidism, acromegaly, familial Mediterranean fever,
Behat's Disease, lupus, systemic lupus erythematosis, hemophilia,
or relapsing polychondritis.
[0050] 14. The method of point 10, wherein the chronic pain is
associated with a joint, hip, knee, back, neck, or lower back of
the subject.
[0051] 15. The method of point 10 wherein the pain is measured as
pain intensity.
[0052] 16. The method of point 15, wherein the pain intensity is
attenuated as compared to a pain intensity baseline of the
subject.
[0053] 17. The method of point 10, wherein the pain is measured on
the pain subscale of the WOMAC Osteoarthritis Index.
[0054] 18. The method of point 17, wherein the pain measurement of
the subject is improved as compared to baseline pain measurement of
the subject on the WOMAC pain subscale baseline of the subject.
[0055] 19. The method of point 10, wherein the pain is measured by
a patient or physician assessment.
[0056] 20. The method of point 10, wherein the pain is measured on
an 11-point numerical scale.
[0057] 21. The method of point 20, wherein the pain is reduced by
at least 1 point, as compared to the pain where a human subject is
administered a placebo.
[0058] 22. The method of point 10, wherein the pain felt by the
subject when walking on a flat surface, when going up or down
stairs, at night while in bed, that disturbs the sleep of the
subject, while sitting or lying down, or while standing is
attenuated.
[0059] 23. The method of point 1 further comprising administering
to the subject an additional therapeutic agent that is a
non-steroidal anti-inflammatory drug, cytokine inhibitor,
corticosteroid, anti-rheumatic drug, anticonvulsant agent,
tricyclic antidepressant agent, anti-dynorphin agent, or glutamate
receptor antagonist agent.
[0060] 24. The method of point 23, wherein the additional
therapeutic agent is a TNF-.alpha. inhibitor, corticosteroid,
anti-rheumatic drug, non-steroidal anti-inflammatory drug,
celecoxib, ropecoxib, valdecoxib, etanercept, infiximab,
anti-TNF-.alpha., D2E7 human Mab, CDP-870, CDP-571, humicade,
PEGylated soluble TNF-.alpha. Receptor-1, TBP-1, PASSTNF-alpha,
AGT-1, ienercept, CytoTAB, TACE, small molecule TNF mRNA synthesis
inhibitor, PEGylated p75TNFR Fc mutein (Immunex), TNF-.alpha.
antisense inhibitor, methotrexate, leflunomide, D-Penicillamine,
sulfasalazine, a gold composition, minocycline, azathioprine,
hydroxychloroquine, an antimalarial drug, cyclosporine, or a
biologic agent that designed to either inhibit or supplement a
cytokine.
[0061] 25. The method of points 1, wherein the pharmaceutical
composition is administered no more than twice in a 24-hour
period.
[0062] 26. The method of point 1, wherein the oral dosage form is a
solid oral dosage form or a liquid oral dosage form.
[0063] 27. A method for treating an arthritic condition in a
subject comprising administering to the subject a pharmaceutical
composition for oral administration that comprises:
[0064] (a) an opioid;
[0065] (b) sucrose acetate isobutyrate;
[0066] (c) triacetin;
[0067] (d) isopropyl myristate;
[0068] (e) cellulose acetate butyrate;
[0069] (f) hydroxyethyl cellulose;
[0070] (g) colloidal silicon dioxide; and
[0071] (h) butylated hydroxytoluene,
[0072] wherein one or more symptoms or signs associated with the
arthritic condition are alleviated.
[0073] 28. The method of point 27, wherein the opioid is in the
form of a free base.
[0074] 29. The method of point 27, wherein the opioid is in the
form of a salt.
[0075] 30. The method of point 27, wherein the opioid is
micronized.
[0076] 31. The method of any one of points 27, 28, 29 or 30,
wherein the opioid is oxycodone, oxymorphone, hydrocodone or
hydromorphone.
[0077] 32. The method of any one of points 27, 28, 29 or 30,
wherein the opioid is oxycodone.
[0078] 33. The method of point 27, wherein the pharmaceutical
composition is encapsulated.
[0079] 34. The method of point 27, wherein the subject is a
human.
[0080] 35. The method of point 27, wherein the arthritic condition
is osteoarthritis, rheumatoid arthritis, psoriatic arthritis, gout,
spondylarthropathris, ankylosing spondylitis, Reiter's syndrome,
psoriatic arthropathy, enterapathric spondylitis, juvenile
arthropathy, juvenile ankylosing spondylitis, reactive arthropathy,
infectious or post-infectious arthritis, gonoccocal arthritis,
tuberculous arthritis, viral arthritis, fungal arthritis, syphlitic
arthritis, Lyme disease, calcium crystal deposition arthropathies,
pseudo gout, non-articular rheumatism, bursitis, tenosynomitis,
epicondylitis, carpal tunnel syndrome, a repetitive use injury,
neuropathic joint disease, hemarthrosis, Henoch-Schonlein Purpura,
hypertrophic osteoarthropathy, or multicentric
reticulohistiocytosis.
[0081] 36. The method of point 27, wherein the arthritic condition
is an arthritis associated with a vasculitic syndrome,
polyarteritis nodosa, hypersensitivity vasculitis, Luegenec's
granulomatosis, polymyalgin rheumatica, joint cell arteritis,
surcoilosis, hemochromatosis, sickle cell disease or another
hemoglobinopathry, hyperlipo proteineimia, hypogammaglobulinemia,
hyperparathyroidism, acromegaly, familial Mediterranean fever,
Behat's Disease, lupus, systemic lupus erythematosis, hemophilia,
or relapsing polychondritis.
[0082] 37. The method of point 36, wherein the arthritic condition
is associated with a joint, hip, knee, back, neck, or lower back of
the subject.
[0083] 38. The method of point 37, wherein the symptom or sign is
pain.
[0084] 39. The method of point 38, wherein the pain is measured as
pain intensity.
[0085] 40. The method of point 39, wherein the pain intensity
measurement is attenuated as compared to a pain intensity baseline
measurement of the subject.
[0086] 41. The method of point 40, wherein the pain is measured on
the pain subscale of the WOMAC Osteoarthritis Index.
[0087] 42. The method of point 41, wherein the pain measurement of
the subject is improved as compared to a baseline pain measurement
of the subject on the WOMAC pain subscale.
[0088] 43. The method of point 40, wherein the pain is measured by
a patient or physician assessment.
[0089] 44. The method of point 40, wherein the pain is measured on
an 11-point numerical scale.
[0090] 45. The method of point 44, wherein the pain is reduced by
at least 1 point, as compared to the pain where a human subject is
administered a placebo.
[0091] 46. The method of point 38, wherein the pain felt by the
subject when walking on a flat surface, when going up or down
stairs, while in bed, disturbs the sleep of the subject, while
sitting or lying down, or while standing, is attenuated.
[0092] 47. The method of point 27, wherein the symptom or sign is
stiffness.
[0093] 48. The method of point 47, wherein the stiffness is
attenuated, as compared to a stiffness baseline of the subject.
[0094] 49. The method of point 48, wherein the stiffness is
measured by a patient or physician assessment.
[0095] 50. The method of point 49, wherein the stiffness is
measured on the stiffness subscale of the WOMAC Osteoarthritis
index.
[0096] 51. The method of point 50, wherein the stiffness
measurement of the subject is improved as compared to a baseline
stiffness measurement of the subject on the WOMAC stiffness
subscale.
[0097] 52. The method of point 47, wherein the stiffness felt by
the patient after the subject first wakes up in the morning, after
sitting or lying down later in the day, or while resting later in
the day, is attenuated.
[0098] 53. The method of point 27, wherein the symptom or sign is
difficulty in physical function had by the subject.
[0099] 54. The method of point 53, wherein the difficulty in
physical function is attenuated, as compared to a baseline physical
function measurement of the subject.
[0100] 55. The method of point 53, wherein the difficulty in
physical function is measured by a patient or physician
assessment.
[0101] 56. The method of point 53 wherein the difficulty in
physical function is measured on the physical function subscale of
the WOMAC Osteoarthritis index.
[0102] 57. The method of point 56, wherein the physical function
measurement of the subject is improved, as compared to a baseline
physical function measurement of the subject on the WOMAC physical
function subscale.
[0103] 58. The method of point 53, wherein the difficulty had by
the subject when going down stairs, when going up stairs, when
getting up from a sitting position, while standing, when bending to
the floor, when walking on a flat surface, when getting in or out
of a car or bus, while going shopping, when getting out of bed,
when putting on socks or panty hose or stockings, while lying in
bed, when getting in or out of the bathtub, while sitting, when
getting on or off the toilet, while doing heavy household chores,
or while doing light household chores, is attenuated.
[0104] 59. The method of point 27, wherein the total score of the
subject on the WOMAC Osteoarthritis Index is attenuated.
[0105] 60. The method of point 27, wherein progression of the
arthritic condition is inhibited.
[0106] 61. A method for treating inflammation in a subject
comprising administering to the subject a pharmaceutical
composition for oral administration that comprises:
[0107] (a) an opioid;
[0108] (b) sucrose acetate isobutyrate;
[0109] (c) triacetin;
[0110] (d) isopropyl myristate;
[0111] (e) cellulose acetate butyrate;
[0112] (f) hydroxyethyl cellulose;
[0113] (g) colloidal silicon dioxide; and
[0114] (h) butylated hydroxytoluene,
[0115] wherein one or more symptoms or signs associated with
inflammation are alleviated.
[0116] 62. The method of point 61, wherein the opioid is in the
form of a free base.
[0117] 63. The method of point 61, wherein the opioid is in the
form of a salt.
[0118] 64. The method of point 61, wherein the opioid is
micronized.
[0119] 65. The method of any one of points 61, 62, 63 or 64,
wherein the opioid is oxycodone, oxymorphone, hydrocodone or
hydromorphone.
[0120] 66. The method of any one of points 61, 62, 63 or 64,
wherein the opioid is oxycodone.
[0121] 67. The method of point 61, wherein the pharmaceutical
composition is encapsulated.
[0122] 68. The method of point 61, wherein the subject is a
human.
[0123] 69. The method of point 61, wherein the inflammation is
associated with an arthritic condition.
[0124] 70. The method of point 69, wherein the arthritic condition
is osteoarthritis, rheumatoid arthritis, psoriatic arthritis, gout,
spondylarthropathris, ankylosing spondylitis, Reiter's syndrome,
psoriatic arthropathy, enterapathric spondylitis, juvenile
arthropathy, juvenile ankylosing spondylitis, reactive arthropathy,
infectious or post-infectious arthritis, gonoccocal arthritis,
tuberculous arthritis, viral arthritis, fungal arthritis, syphlitic
arthritis, Lyme disease, calcium crystal deposition arthropathies,
pseudo gout, non-articular rheumatism, bursitis, tenosynomitis,
epicondylitis, carpal tunnel syndrome, a repetitive use injury,
neuropathic joint disease, hemarthrosis, Henoch-Schonlein Purpura,
hypertrophic osteoarthropathy, or multicentric
reticulohistiocytosis.
[0125] 71. The method of point 70, wherein the arthritic condition
is an arthritis associated with a vasculitic syndrome,
polyarteritis nodosa, hypersensitivity vasculitis, Luegenec's
granulomatosis, polymyalgin rheumatica, joint cell arteritis,
surcoilosis, hemochromatosis, sickle cell disease or another
hemoglobinopathry, hyperlipo proteineimia, hypogammaglobulinemia,
hyperparathyroidism, acromegaly, familial Mediterranean fever,
Behat's Disease, lupus, systemic lupus erythematosis, hemophilia,
or relapsing polychondritis.
[0126] 72. The method of point 69, wherein the arthritic condition
is associated with a joint, hip, knee, back, neck, or lower back of
the subject.
[0127] 73. The method of point 61, wherein the symptom or sign is
pain.
[0128] 74. The method of point 73, wherein the pain is measured as
pain intensity.
[0129] 75. The method of point 74, wherein the pain intensity
measurement is attenuated as compared to a pain intensity baseline
measurement of the subject.
[0130] 76. The method of point 75, wherein the pain is measured on
the pain subscale of the WOMAC Osteoarthritis Index.
[0131] 77. The method of point 76, wherein the pain measurement of
the subject is improved as compared to a baseline pain measurement
of the subject on the WOMAC pain subscale.
[0132] 78. The method of point 75, wherein the pain is measured by
a patient or physician assessment.
[0133] 79. The method of point 75, wherein the pain is measured on
an 11-point numerical scale.
[0134] 80. The method of point 79, wherein the pain is reduced by
at least 1 point, as compared to the pain where a human subject is
administered a placebo.
[0135] 81. The method of point 73, wherein the pain felt by the
subject when walking on a flat surface, when going up or down
stairs, while in bed, disturbs the sleep of the subject, while
sitting or lying down, or while standing, is attenuated.
[0136] 82. The method of point 67, wherein the symptom or sign is
stiffness.
[0137] 83. The method of point 82, wherein the stiffness is
attenuated, as compared to a stiffness baseline of the subject.
[0138] 84. The method of point 83, wherein the stiffness is
measured by a patient or physician assessment.
[0139] 85. The method of point 84, wherein the stiffness is
measured on the stiffness subscale of the WOMAC Osteoarthritis
index.
[0140] 86. The method of point 85, wherein the stiffness
measurement of the subject is improved as compared to a baseline
stiffness measurement of the subject on the WOMAC stiffness
subscale.
[0141] 87. The method of point 82, wherein the stiffness felt by
the patient after the subject first wakes up in the morning, after
sitting or lying down later in the day, or while resting later in
the day.
[0142] 88. The method of point 61, wherein the symptom or sign is
difficulty in physical function had by the subject.
[0143] 89. The method of point 88, wherein the difficulty in
physical function is attenuated, as compared to a baseline physical
function measurement of the subject.
[0144] 90. The method of point 88, wherein the difficulty in
physical function is measured by a patient or physician
assessment.
[0145] 91. The method of point 88, wherein the difficulty in
physical function is measured on the physical function subscale of
the WOMAC Osteoarthritis index.
[0146] 92. The method of point 91, wherein the physical function
measurement of the subject is improved, as compared to a baseline
physical function measurement of the subject on the WOMAC physical
function subscale.
[0147] 93. The method of point 88, wherein the difficulty had by
the subject when going down stairs, when going up stairs, when
getting up from a sitting position, while standing, when bending to
the floor, when walking on a flat surface, when getting in or out
of a car or bus, while going shopping, when getting out of bed,
when putting on socks or panty hose or stockings, while lying in
bed, when getting in or out of the bathtub, while sitting, when
getting on or off the toilet, while doing heavy household chores,
or while doing light household chores, is attenuated.
[0148] 94. The method of point 61, wherein the total score of the
subject on the WOMAC Osteoarthritis index is attenuated.
[0149] 95. A pharmaceutical composition for oral administration to
a human subject, the pharmaceutical composition comprising:
[0150] (a) an opioid;
[0151] (b) sucrose acetate isobutyrate;
[0152] (c) triacetin;
[0153] (d) isopropyl myristate;
[0154] (e) cellulose acetate butyrate;
[0155] (f) hydroxyethyl cellulose;
[0156] (g) colloidal silicon dioxide; and
[0157] (h) butylated hydroxytoluene.
[0158] 96. A pharmaceutical composition for oral administration to
a human subject, the pharmaceutical composition comprising:
[0159] (a) 5.13% opioid;
[0160] (b) 40.98% sucrose acetate isobutyrate;
[0161] (c) 27.32% triacetin;
[0162] (d) 14.23% isopropyl myristate;
[0163] (e) 4.74% cellulose acetate butyrate;
[0164] (f) 5.69% hydroxyethyl cellulose;
[0165] (g) 1.90% colloidal silicon dioxide; and
[0166] (h) 0.02% butylated hydroxytoluene.
[0167] 97. The pharmaceutical composition of any one of points 95
or 96, wherein the opioid is in the form of a free base.
[0168] 98. The pharmaceutical composition of any one of points 95
or 96, wherein the opioid is in the form of a salt.
[0169] 99. The pharmaceutical composition of any one of points 95
to 98, wherein the opioid is micronized.
[0170] 100. The pharmaceutical composition of any one of points 95
to 99, wherein the opioid is oxycodone, oxymorphone, hydrocodone or
hydromorphone.
[0171] 101. The pharmaceutical composition of any one of points 95
to 100, wherein the opioid is oxycodone.
[0172] 102. The pharmaceutical composition of any one of points 95
to 101 wherein the composition is encapsulated.
[0173] 103. The pharmaceutical composition of any one of points 95
to 102 wherein the composition comprises:
[0174] (a) 5.0 mg micronized oxycodone base;
[0175] (b) 40.0 mg sucrose acetate isobutyrate;
[0176] (c) 26.6 mg triacetin;
[0177] (d) 13.9 mg isopropyl myristate;
[0178] (e) 4.6 mg cellulose acetate butyrate;
[0179] (f) 5.5 mg hydroxyethyl cellulose;
[0180] (g) 1.8 mg colloidal silicon dioxide; and
[0181] (h) 0.02 mg butylated hydroxytoluene.
[0182] 104. The pharmaceutical composition of any one of points 95
to 102, wherein the composition comprises:
[0183] (a) 10.0 mg micronized oxycodone base;
[0184] (b) 79.9 mg sucrose acetate isobutyrate;
[0185] (c) 53.3 mg triacetin;
[0186] (d) 27.7 mg isopropyl myristate;
[0187] (e) 9.2 mg cellulose acetate butyrate;
[0188] (f) 11.1 mg hydroxyethyl cellulose;
[0189] (g) 3.7 mg colloidal silicon dioxide; and
[0190] (h) 0.04 mg butylated hydroxytoluene.
[0191] 105. The pharmaceutical composition of any one of points 95
to 102, wherein the composition comprises:
[0192] (a) 20.0 mg micronized oxycodone base;
[0193] (b) 159.8 mg sucrose acetate isobutyrate;
[0194] (c) 106.5 mg triacetin;
[0195] (d) 55.5 mg isopropyl myristate;
[0196] (e) 18.5 mg cellulose acetate butyrate;
[0197] (f) 22.2 mg hydroxyethyl cellulose;
[0198] (g) 7.4 mg colloidal silicon dioxide; and
[0199] (h) 0.08 mg butylated hydroxytoluene.
[0200] 106. The pharmaceutical composition of any one of points 95
to 102, wherein the composition comprises:
[0201] (a) 30.0 mg micronized oxycodone base;
[0202] (b) 239.7 mg sucrose acetate isobutyrate;
[0203] (c) 159.8 mg triacetin;
[0204] (d) 83.2 mg isopropyl myristate;
[0205] (e) 27.8 mg cellulose acetate butyrate;
[0206] (f) 33.3 mg hydroxyethyl cellulose;
[0207] (g) 11.1 mg colloidal silicon dioxide; and
[0208] (h) 0.12 mg butylated hydroxytoluene.
[0209] 107. The pharmaceutical composition of any one of points 95
to 102, wherein the composition comprises:
[0210] (a) 40.0 mg micronized oxycodone base;
[0211] (b) 319.6 mg sucrose acetate isobutyrate;
[0212] (c) 213.1 mg triacetin;
[0213] (d) 111.0 mg isopropyl myristate;
[0214] (e) 37.0 mg cellulose acetate butyrate;
[0215] (f) 44.4 mg hydroxyethyl cellulose;
[0216] (g) 14.8 mg colloidal silicon dioxide; and
[0217] (h) 0.16 mg butylated hydroxytoluene.
DETAILED DESCRIPTION OF THE INVENTION
[0218] The present invention provides for the use of novel
long-acting, that is, controlled release compositions, formulations
and/or dosage forms containing an opioid API such as oxycodone and
that are formulated to resist common physical and chemical
challenges that attempt to defeat the long-acting feature of the
dosage form and thereby lead to rapid release and absorption of a
potentially fatal dose of the opioid. Such abuse-resistant
compositions, formulations and dosage forms can prevent accidental
overdose or intentional misuse that occur with currently marketed
long-acting opioid pharmaceuticals, such as long-acting oxycodone
formulations.
[0219] The pharmaceutical compositions (the controlled release
formulations and dosage forms/kits containing such formulations)
that are used herein comprise an opioid API, such as oxycodone,
provided in a controlled release formulation that includes a
sucrose acetate isobutyrate ("SAIB", a high viscosity liquid
controlled release material), triacetin, isopropyl myristate,
cellulose acetate butyrate, hydroxyethyl cellulose, colloidal
silicon dioxide and butylated hydroxytoluene. Such compositions may
be encapsulated, for example, in a gelatin capsule dosage form.
When administered, the gelatin capsule dissolves and the opioid API
is delivered from the long-acting controlled release matrix by
diffusion as the dosage form transits the GI tract. In addition to
controlling the rate of opioid release, the components in the
controlled release matrix provide the material properties that
impart abuse-resistance to the compositions, formulations and
dosage forms.
[0220] The present invention provides methods, including the use or
administration of novel pharmaceutical compositions, formulations
and/or dosage forms containing an opioid API that are useful for
the treatment of pain, arthritic conditions and/or inflammation
associated with a chronic condition. The methods of the invention
provide human subjects with alleviation of one or more of such
symptoms or signs including, for example, reduced pain, reduced
stiffness and/or improved physical function. The methods of the
invention further comprise administration of a pharmaceutical
composition comprising an opioid and, optionally, one or more
additional active pharmaceutical ingredient (therapeutic
agents).
[0221] The present invention provides methods, including the use or
administration of novel pharmaceutical compositions, formulations
and/or dosage forms containing an opioid API for treating pain,
arthritic conditions and/or inflammation associated with chronic
conditions in a human subject. For example, the pharmaceutical
compositions that are administered to the subject contain an amount
of an opioid API that is effective for alleviating one or more
symptoms or signs associated with pain, an arthritic condition
and/or inflammation associated with a chronic condition, for
example, symptoms or signs such as pain, stiffness or difficulty in
physical function.
[0222] The present invention provides methods, including the use or
administration of novel pharmaceutical compositions, formulations
and/or dosage forms containing an opioid API for inhibiting
progression of an arthritic condition or inflammation associated
with chronic conditions in a human subject. For example, the amount
of the opioid API in the pharmaceutical composition that is
administered to the subject is effective for inhibiting progression
of the arthritic condition or chronic conditions associated with
inflammation. The present invention thus provides methods and
materials for inhibiting the change or progression in a subject
from a normal or uncompromised state (e.g., healthy) to an abnormal
or compromised state (e.g., diseased), as indicated, for example,
by a symptom or sign associated with an arthritic condition,
inflammation from a chronic condition or chronic pain. The
progression of an arthritic condition or inflammation associated
with a chronic condition can be measured by a variety of methods,
including by radiography, by measuring levels of cytokines and/or
by measuring B cell and T cell subtype ratios.
[0223] The present invention provides methods, including the use or
administration of novel pharmaceutical compositions, formulations
and/or dosage forms containing an opioid API for reversing damage
associated with an arthritic condition or inflammation associated
with chronic conditions in a human subject. For example, the amount
of the opioid in the composition is an amount effective for
reversing damage due to the arthritic condition or inflammation
associated with chronic conditions. The present invention thus
provides methods for reversing the change or progression in a
subject from a normal or uncompromised state to an abnormal or
compromised state as indicated, for example, by a symptom or sign
associated with an arthritic condition, inflammation from a chronic
condition or chronic pain. The progression of the arthritic
condition or inflammation associated with chronic conditions can be
measured by a variety of methods, including by radiography, by
measuring levels of cytokines and/or by measuring B cell and T cell
subtype ratios.
[0224] The present invention provides methods, including the use of
novel pharmaceutical compositions, formulations and/or dosage forms
containing an opioid API for treating pain (e.g., chronic pain),
such as wherein a pharmaceutical composition comprising an opioid
API is administered to a human subject suffering from chronic pain.
Chronic pain can include pain that is headache, lower back pain,
cancer pain, arthritis pain, infection pain, neurogenic pain or
psychogenic pain. The methods of the invention are effective for
the treatment of moderate to severe pain and particularly severe
pain. For example, the amount of the opioid API in the
pharmaceutical compositions is an amount effective for alleviating
chronic pain. The pain intensity of the chronic pain is thereby
alleviated (e.g., ameliorated, attenuated, reduced, diminished,
blocked, inhibited or prevented).
[0225] In the treatment of chronic pain, an arthritic condition
and/or inflammation associated with a chronic condition, a
pharmaceutical composition containing an opioid can be administered
at least once or twice daily for at least one week, alternatively
at least once or twice daily for at least two weeks, at least once
or twice daily for at least three weeks, or at least once or twice
daily for a longer time. The method for treating pain, treating an
arthritic condition or treating inflammation associated with a
chronic condition may comprise administering the pharmaceutical
composition no more than once or twice daily for at least one week,
alternatively no more than once or twice daily for at least two
weeks, alternatively no more than once or twice daily for at least
three weeks, or no more than once or twice daily for a longer time.
The method for treating pain, treating an arthritic condition
and/or treating inflammation associated with a chronic condition,
may comprise administering to the subject a sufficient number or
strength of dosage form to provide a daily amount of the opioid API
that is less than or equal to 80 mg, alternatively less than or
equal to 60 mg, alternatively less than or equal to 40 mg,
alternatively less than or equal to 30 mg, alternatively less than
or equal to 20 mg or alternatively less or equal to than 10 mg.
[0226] It is contemplated that the present methods may be employed
for the treatment of inflammation associated with chronic
conditions (including inhibiting progression of and/or reversing
damage associated with inflammation), including chronic conditions
associated with inflammation in and around joints, muscles, bursae,
tendons vertebrae, or fibrous tissue. Such methods provide reduced
pain, reduced stiffness and/or improved physical function.
[0227] It is also contemplated that the present methods may be
employed for the treatment of chronic conditions (including
inhibiting progression of and/or reversing damage associated with
chronic conditions). Chronic conditions include, for example,
arthritic conditions such as osteoarthritis, rheumatoid arthritis,
and psoriatic arthritis. For example, the present methods may be
used to treat one or more symptoms or signs of osteoarthritis of
the joint, (such as a hip or knee) or the back (for example, the
lower back). Chronic conditions also include, for example,
conditions associated with or resulting from pain such as chronic
pain, including pain associated with or arising from cancer, from
infection or from the nervous system (e.g., neurogenic pain such as
peripheral neurogenic pain following pressure upon or stretching of
a peripheral nerve or root or having its origin in stroke, multiple
sclerosis or trauma, including of the spinal cord). Chronic
conditions also include, for example, conditions associated with or
arising from psychogenic pain (e.g., pain not due to past disease
or injury or visible sign of damage inside or outside the nervous
system).
[0228] The present methods may also be employed for the treatment
of other arthritic conditions, including gout and
spondylarthropathris (including ankylosing spondylitis, Reiter's
syndrome, psoriatic arthropathy, enterapathric spondylitis,
juvenile arthropathy or juvenile ankylosing spondylitis, and
reactive arthropathy). The present methods may be used for the
treatment of infectious or post-infectious arthritis (including
gonoccocal arthritis, tuberculous arthritis, viral arthritis,
fungal arthritis, syphlitic arthritis, and Lyme disease).
[0229] Additionally, the present methods may be used for the
treatment of arthritis associated with various syndromes, diseases,
and conditions, such as arthritis associated with vasculitic
syndrome, arthritis associated with polyarteritis nodosa, arthritis
associated with hypersensitivity vasculitis, arthritis associated
with Luegenec's granulomatosis, arthritis associated with
polymyalgin rheumatica, and arthritis associated with joint cell
arteritis. Other preferred indications contemplated for employing
the methods disclosed herein include calcium crystal deposition
arthropathies (such as pseudo gout), non-articular rheumatism (such
as bursitis, tenosynomitis, epicondylitis, carpal tunnel syndrome,
and repetitive use injuries), neuropathic joint disease,
hemarthrosis, Henoch-Schonlein Purpura, hypertrophic
osteoarthropathy, and multicentric reticulohistiocytosis. Other
preferred indications contemplated for employing the methods herein
include arthritic conditions associated with surcoilosis,
hemochromatosis, sickle cell disease and other hemoglobinopathries,
hyperlipo proteineimia, hypogammaglobulinemia, hyperparathyroidism,
acromegaly, familial Mediterranean fever, Behat's Disease, lupus
(including systemic lupus erythrematosis), hemophilia, and
relapsing polychondritis.
[0230] The methods for treating pain, arthritic conditions, or
inflammation associated with chronic conditions alleviate (e.g.,
ameliorate, attenuate, reduce, diminish, block, inhibit or prevent)
at least one symptom or sign of pain, an arthritic condition or
inflammation associated with a chronic condition. For example, the
methods herein may alleviate one or more of pain intensity,
stiffness, or difficulty in physical functions. The methods may
attenuate one or more symptoms or signs of pain, an arthritic
condition, or inflammation associated with a chronic condition,
wherein the sign or symptom after administration of the
pharmaceutical composition is ameliorated as compared to the sign
or symptom before administration of the pharmaceutical
composition.
[0231] The present invention is directed to administration of novel
pharmaceutical compositions, formulations, dosage forms, and kits
(e.g., blister packs) containing an opioid API, wherein the amount
of the opioid is effective to alleviate (e.g., ameliorate,
attenuate, reduce, diminish, block, inhibit or prevent) one or more
symptoms or signs of pain, an arthritic condition, or inflammation
associated with a chronic condition. Optionally, the present
methods may comprise administration of an additional therapeutic
agent, either in the same pharmaceutical composition or in
combination therewith.
[0232] The present invention also provides methods for treating a
subject with pain from an arthritic condition or inflammation
associated with a chronic condition, comprising administering a
pharmaceutical composition containing an amount of an opioid API to
the subject, preferably a human, in need thereof, whereby the pain
is alleviated.
[0233] The present invention also provides methods for treating an
arthritic condition or inflammation associated with chronic
conditions. The methods comprise administering to a human subject a
pharmaceutical composition containing an amount of an opioid that
is effective to alleviate one or more symptoms or signs of an
arthritic condition or inflammation associated with a chronic
condition, including for example, as measured by a suitable index,
scale or measure. The attenuation of one or more symptoms or signs
of an arthritic condition or of inflammation associated with a
chronic condition may be measured on the WOMAC Osteoarthritis Index
or one of its subscales (in other words, the pain, stiffness, or
physical function subscales of the WOMAC Osteoarthritis Index). Any
suitable version of the WOMAC OA Index may be used, including, for
example, Version 3.0 or Version 3.1. Any suitable scale may be used
as well. The WOMAC OA Index is available in Likert and Visual
Analog scaled formats, either of which may be employed in the
present methods. WOMAC values can be considered as surrogate
markers for the diagnosis, prognosis, monitoring or treatment of an
arthritic condition, inflammation from a chronic condition, and/or
chronic pain. The WOMAC values represent a subjective surrogate
marker. Alternatively or additionally, the attenuation of one or
more symptoms or signs may be measured on another suitable index,
scale or measure, such the Australian/Canadian (AUSCAN)
Osteoarthritis Hand Index or the Osteoarthritis Global Index (OGI).
The AUSCAN 3.0 Index and User Guide are currently available from
http://www.womac.org/contact/index.cfm, as are the WOMAC 3.1
Osteoarthritis Index and User Guide. Another suitable measure of
attenuation is the Definition of Improvement in Rheumatoid
Arthritis described in Felson et al (1995), Arthritis &
Rheumatism 38:727-735 incorporated herein by reference. This
measure, which also may be designated as the ACR (American College
of Rheumatology) 20 improvement, is a composite defined as both
improvement of 20% in the number of tender and number of swollen
joints, and a 20% improvement in three of the following five:
patient global, physician global, patient pain, patient function
assessment, and C-reactive protein (CRP). Another suitable measure
is described by Paulus et al (1990) Arthritis & Rheumatism
33:477-484 incorporated herein by reference. Paulus et al. provides
a definition of improvement based on a set of measures that
discriminate between active second-line drug treatment and placebo.
These include a 20% improvement in morning stiffness, erythrocyte
sedimentation rate (ESR), joint tenderness score, and joint
swelling score and improvement by at least 2 grades on a 5-grade
scale (or from grade 2 to grade 1) for patient and physician global
assessments of current disease severity. Current disease severity
can be measured in a variety of ways, including patient or
physician global assessments, patient or physician assessments of
joint tenderness, joint swelling stiffness, pain, or physical
function, cytokine levels, B-cell or T-cell subtype ratios,
erythrocyte sedimentation rate (ESR), or C-reactive protein.
Suitable measures of attenuation of one or more symptoms or signs,
of inhibiting the progression of an arthritic condition or chronic
condition, or of reversing tissue or cellular damage include
measuring current disease severity. Other indexes, definitions,
measures, or scales may also be used for measuring attenuation of
one or more symptoms or signs, inhibition of progression, or
reversal of tissue or cellular damage.
[0234] The present invention provides methods for alleviating pain
associated with arthritic conditions or inflammation associated
with chronic conditions. For example, the amount of the opioid API
in the novel compositions that are administered to the subject may
be effective to attenuate (e.g., ameliorate, alleviate, reduce,
diminish, block, inhibit or prevent) (1) the pain felt by the
subject when walking on a flat surface; (2) the pain felt by the
subject when going up or down stairs; (3) the pain felt by the
subject at night while in bed; (4) the pain felt by the subject
that disturbs the sleep of the subject; (5) the pain felt by the
subject while sitting or lying down; and/or (6) the pain felt by
the subject while standing.
[0235] Alternatively or additionally, the present invention
provides methods for alleviating stiffness associated with
arthritic conditions or inflammation associated with chronic
conditions. For example, the amount of the opioid API in the novel
compositions that are administered to the subject may be effective
to attenuate (e.g., ameliorate, alleviate, reduce, diminish, block,
inhibit or prevent) (1) the severity of the stiffness felt by the
patient after the subject first woke up in the morning; (2) the
severity of the stiffness felt by the subject after sitting or
lying down later in the day; and/or (3) the severity of the
stiffness felt by the subject while resting later in the day.
[0236] Alternatively or additionally, the present invention
provides methods and materials for alleviating difficulty in
physical function associated with arthritic conditions or
inflammation associated with chronic conditions. For example, the
amount of the opioid API in the novel compositions that are
administered to the subject may be effective to attenuate (e.g.,
ameliorate, alleviate, reduce, diminish, block, inhibit or prevent)
(1) the difficulty had by the subject when going down stairs; (2)
the difficulty had by the human subject when going up stairs; (3)
the difficulty had by the subject when getting up from a sitting
position; (4) the difficulty had by the subject while standing; (5)
the difficulty had by the subject when bending to the floor; (6)
the difficulty had by the patient when walking on a flat surface;
(7) the difficulty had by the human subject when getting in or out
of a car or bus; (8) the difficulty had by the subject while going
shopping; (9) the difficulty had by the patient when getting out of
bed; (10) the difficulty had by the subject when putting on socks,
or panty hose or stockings; (11) the difficulty had by the subject
while lying in bed; (12) the difficulty had by the subject when
getting in or out of the bathtub; (13) the difficulty had by the
subject while sitting; (14) the difficulty had by the patient when
getting on or off the toilet; (15) the difficulty had by the
subject while doing heavy household chores; and/or (16) the
difficulty had by the subject while doing light household
chores.
[0237] An "effective amount to alleviate" (e.g., ameliorate,
attenuate, reduce, diminish, block, inhibit or prevent) symptom or
sign of an arthritic condition or inflammation associated with
chronic conditions refers to the amount of opioid API contained in
the pharmaceutical composition (with or without one or more
additional therapeutic agents) which elicits alleviation (e.g.,
amelioration, attenuation, reduction, diminishment, blockage,
inhibition or prevention) of at least one symptom or sign of an
arthritic condition or inflammation associated with chronic
conditions (e.g., pain) upon administration to a subject (e.g.,
patient) in need thereof. The amount of the opioid or another
therapeutic agent can refer to the weight of the salt or the weight
of the free base of such opioid or agent.
[0238] Opioids refer to compounds or compositions, including
metabolites of the compounds or compositions, that bind to specific
opioid receptors and have agonist (activation) or antagonist
(inactivation) effects at the opioid receptors. Preferred opioids
include oxycodone, oxymorphone, hydrocodone and hydromorphone.
Particularly preferred is oxycodone.
[0239] Inhibitory opioid receptors refer to opioid receptors that
mediate inhibitory opioid receptor functions, such as
analgesia.
[0240] Opioid receptor agonist or opioid agonist refers to an
opioid compound or composition, including any active metabolite of
such compound or composition, that binds to and activates opioid
receptors on neurons that mediate pain.
[0241] An opioid receptor antagonist or opioid antagonist refers to
an opioid compound or composition, including any active metabolite
of such compound or composition, that binds to and blocks opioid
receptors on neurons that mediate pain. An opioid antagonist
attenuates (e.g., blocks, inhibits, prevents, or competes with) the
action of an opioid agonist. Preferred opioid antagonists include
naloxone, naltrexone and nalmefene.
[0242] Pharmaceutically acceptable refers to those compounds,
materials, compositions, and/or dosage forms which are, within the
scope of sound medical judgment, suitable for use in contact with
the tissues of human beings and animals without excessive toxicity,
irritation, allergic response, or other problems or complications,
commensurate with a reasonable benefit/risk ratio.
[0243] Pharmaceutically acceptable salts refer to derivatives of
the disclosed compounds wherein the compounds are modified by
making at least one acid or base salt thereof, and includes
inorganic and organic salts.
[0244] An analgesic amount of an opioid API refers to an amount of
the opioid that causes analgesia in a subject, and includes
standard doses of the opioid which are typically administered in
commercially available dosage forms to cause analgesia (e.g. mg
doses).
[0245] A subanalgesic amount of opioid refers to an amount which
does not cause analgesia in a subject administered that amount of
the opioid.
[0246] An effective antagonistic amount of opioid refers to an
amount that effectively attenuates (e.g. ameliorates, reduces,
diminishes, blocks, inhibits, prevents, or competes with) the
analgesic activity of an opioid.
[0247] A therapeutically effective amount of a pharmaceutical
composition refers to a composition containing an amount of the API
that elicits alleviation (e.g., amelioration, attenuation,
reduction, diminishment, blockage, inhibition or prevention) of at
least one sign or symptom of an arthritic condition, inflammation
associated with a chronic condition, or pain, including chronic
pain, upon administration to a patient in need thereof.
[0248] Potency may refer to the strength of an active
pharmaceutical ingredient (or treatment employing such API) in
producing desired effects, for example, improved pain relief,
improved pain control, reduced stiffness, and/or improved physical
function. Potency also may refer to the effectiveness or efficacy
of a treatment in eliciting desired effects, for example, improved
pain relief, improved pain control, reduced stiffness, and/or
improved physical function. For example, enhanced potency may refer
to the lowering of a dose in achieving desired effects or to an
increased therapeutic benefit including that not previously seen.
In therapeutics, for example, potency may refer to the relative
pharmacological activity of a compound or a composition.
[0249] In the pharmaceutical compositions for use in methods
according to the present invention, the opioid may be present in
its original form or in the form of a pharmaceutically acceptable
salt. The opioid APIs that may be used in methods according to the
present invention include: alfentanil, allylprodine, alphaprodine,
anileridine, apomorphine, apocodeine, benzylmorphine, bezitramide,
butorphanol, clonitazene, codeine, cyclazocine, cyclorphen,
cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide,
dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,
dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine,
ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,
fentanyl, heroin, hydrocodone, hydroxymethylmorphinan,
hydromorphone, hydroxypethidine, isomethadone, ketobemidone,
levallorphan, levorphanol, levophenacylmorphan, lofentanil,
meperidine, meptazinol, metazocine, methadone, methylmorphine,
metopon, morphine, myrophine, narceine, nicomorphine,
norlevorphanol, normethadone, nalorphine, normorphine, norpipanone,
ohmefentanyl, opium, oxycodone, oxymorphone, papavereturn,
phenadoxone, phenomorphan, phenazocine, phenoperidine, pholcodine,
piminodine, piritramide, propheptazine, promedol, profadol,
properidine, propiram, propoxyphene, remifentanyl, sufentanyl,
tramadol, tilidine, salts thereof, mixtures of any of the
foregoing, mixed mu-agonists/antagonists, mu-antagonist
combinations, or others known to those skilled in the art.
Preferred opioids for use in methods according to the present
invention include morphine, hydrocodone, oxycodone, codeine,
fentanyl (and its relatives), hydromorphone, meperidine, methadone,
oxymorphone, propoxyphene or tramadol, or mixtures thereof. More
preferred opioids include oxycodone, oxymorphone, hydrocodone and
hydromorphone. Opioids include exogenous or endogenous opioids.
Endogenous opioids include endorphin, beta-endorphin, enkephalin,
met-enkephalin, dynorphin, orphanin FQ, neuropeptide FF,
nociceptin, endomorphin, endormorphin-1, endormorphin-2.
[0250] The opioid API may be present in the pharmaceutical
composition in an amount that is analgesic or subanalgesic (e.g.,
non-analgesic) in the human subject. The subject compositions may
be administered in dosage forms containing from about 5 mg to about
40 mg of the opioid API. The opioid is included in the dosage form
in an amount sufficient to produce the desired effect upon the
process or condition of pain, including inflammatory pain, such as
alleviation (e.g., amelioration, attenuation, reduction,
diminishment, blockage, inhibition or prevention) of at least one
symptom of pain, including inflammatory pain. Symptoms and signs
include, for example, pain (including chronic pain), stiffness or
difficulty in physical function.
[0251] Optimized amounts of an opioid administered separately or in
combination with one or more additional active pharmaceutical
ingredient will of course depend upon the particular opioid and
API(s) used, the particular components of the composition, the
route of administration, and/or the pharmacokinetic properties of
the subject being treated. Effective administration levels of
opioid and other API will vary upon the state and circumstances of
the subject being treated. As those skilled in the art will
recognize, many factors that modify the action of an active
pharmaceutical ingredient will be taken into account by a treating
physician, such as the age, body weight, sex, diet, and condition
of the subject, the lapse of time between the condition or injury
and the administration of the present compositions, and the
administration technique. A person of ordinary skill in the art
will be able to ascertain the optimal dosage for a given set of
conditions in view of the disclosure herein.
[0252] The opioid API can be present in the present pharmaceutical
compositions, formulations and/or dosage forms as an acid, base, or
pharmaceutically acceptable salt. The term "pharmaceutically
acceptable salt" embraces inorganic or organic salts. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts. The pharmaceutically acceptable
salts include the conventional non-toxic salts made, for example,
from non-toxic inorganic or organic acids. For example, such
conventional non-toxic salts include those derived from inorganic
acids such as hydrochloric, hydrobromic, sulfuric, sulfonic,
sulfamic, phosphoric, nitric and others known to those skilled in
the art; and the salts prepared from organic acids such as amino
acids, acetic, propionic, succinic, glycolic, stearic, lactic,
malic, malonic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, glucuronic,
and other acids. Other pharmaceutically acceptable salts and
variants include mucates, phosphate (dibasic), phosphate
(monobasic), acetate trihydrate, bi(heptafluorobutyrate),
bi(methylcarbamate), bi(pentafluoropropionate), mesylate,
bi(pyridine-3-carboxylate), bi(trifluoroacetate), bitartrate,
chlorhydrate, and sulfate pentahydrate. An oxide, though not
usually referred to by chemists as a salt, is also a
"pharmaceutically acceptable salt" for the purposes of the present
invention. For acidic compounds, the salt may include an
amine-based (primary, secondary, tertiary or quaternary amine)
counter ion, an alkali metal cation, or a metal cation. Lists of
suitable salts are found in texts such as Remington's
Pharmaceutical Sciences, 18.sup.th Ed. (Alfonso R. Gennaro, ed.;
Mack Publishing Company, Easton, Pa., 1990); Remington: the Science
and Practice of Pharmacy 19.sup.th Ed. (Lippincott, Williams &
Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3.sup.rd Ed.
(Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc., 1999); the
Pharmaceutical Codex Principles and Practice of Pharmaceutics
12.sup.th Ed. (Walter Lund ed.; Pharmaceutical Press, London,
1994); The United States Pharmacopeia: The National Formulary
(United States Pharmacopeial Convention); and Goodman and Gilman's:
the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee
E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are
all incorporated herein by reference. Additional representative
salts include hydrobromide, hydrochloride, mucate, succinate,
n-oxide, sulfate, malonate, acetate, phosphate dibasic, phosphate
monobasic, acetate trihydrate, bi(heplafluorobutyrate), maleate,
bi(methylcarbamate), bi(pentafluoropropionate), mesylate,
bi(pyridine-3-carboxylate), bi(trifluoroacetate), bitartrate,
chlorhydrate, fumarate, and sulfate pentahydrate.
[0253] The methods of the invention may further comprise
administering to the subject another therapeutic agent, for
example, non-steroidal anti-inflammatory agents or local anesthetic
and/or analgesic agents, TNF-.alpha. antagonists, corticosteroids,
disease-modifying anti-rheumatic drugs (DMARDs), anticonvulsant
agents, tricyclic antidepressant agents, anti-dynorphin agents,
glutamate receptor antagonist agents. In particularly, it is
specifically completed that, in addition to the opioid, the subject
may be administered TNF-.alpha. antagonists, P38 inhibitors, and
cytokines inhibitors (including but not limited to IL-2, IL-6,
IL-8, and GM-CSF). The opioid and other therapeutic agent may be
administered to the subject in a combined dosage form or in
separate dosage forms. If in separate dosage forms, the opioid and
other therapeutic agent may be administered together or before or
after the administration of the other.
[0254] An NSAID refers to a non-steroidal anti-inflammatory drug
and includes anti-inflammatory drugs such as aspirin, members of
the cycloxygenease I, II and III inhibitors, and includes naproxen
sodium, diclofenac and misoprostol, valdecoxib, diclofenac,
celecoxib, sulindac, oxaprozin, diflunisal, piroxicam,
indomethacin, meloxicam, ibuprofen, naproxen, mefenamic acid,
nabumetone, ketorolac, choline or magnesium salicylates, rofecoxib,
tolmetin sodium, phenylbutazone, oxyphenbutzone, meclofenamate
sodium or diflusenal.
[0255] In an embodiment, the pharmaceutical compositions comprise
an opioid API and at least one non-narcotic analgesic, such as a
nonsteroidal anti-inflammatory agent (NSAID). Representative
nonsteroidal anti-inflammatory agents include aspirin, diclofenac,
diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,
flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,
meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin,
phenylbutazone, piroxican, sulindac, tolmetin, and zomepirac.
NSAIDs include Celebrex.RTM., Vioxx.RTM., Anaprox.RTM.,
Arthrotec.RTM., Bextra.RTM., Cataflam.RTM., Clinoril.RTM.,
DayPro.RTM., Dolobid.RTM., Feldene.RTM., Indocin.RTM., Mobic.RTM.,
Motrin.RTM., Negprelen.RTM., Naprosyn.RTM., Ponstel.RTM.,
Relafen.RTM. and Toradol.RTM..
[0256] In another embodiment, the pharmaceutical compositions may
further comprise an analgesic, antipyretic, and/or
anti-inflammatory therapeutic agent. For example, the composition
may further comprise one or more of aspirin, sodium salicylate,
choline magnesium trisalicylate, salsalate, diflunisal,
sulfasalazine, olsalazine, acetaminophen, indomethacin, sulindac,
tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen,
ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic
acid, piroxicam, meloxicam, nabumetone, refecoxib, celecoxib,
etodolac, and nimesulide.
[0257] With regard to dosage levels, the non-narcotic analgesic may
be present in a pain-alleviating amount, or in an amount that is
not pain-alleviating alone but is pain-alleviating in combination
with the opioid API. This amount is at a level corresponding to the
generally recommended adult human dosages for a particular
non-narcotic analgesic. An effective pain-alleviating amount of the
opioid can be present at a level that potentiates the
pain-alleviating effectiveness of the non-narcotic analgesic.
Specific dosage levels for the non-narcotic analgesic that can be
used herein as given, inter alia, in the "Physicians' Desk
Reference", 2003 Edition (Medical Economics Data Production
Company, Montvale, N.J.) as well as in other reference works
including Goodman and Gilman's "The Pharmaceutical Basis of
Therapeutics" and "Remington's Pharmaceutical Sciences," the
disclosures of all are incorporated herein by reference. As is well
known to one of ordinary skill in the art, there can be a wide
variation in the dosage level of the non-narcotic analgesic,
wherein the dosage level depends to a large extent on the specific
non-narcotic analgesic being administered. These amounts can be
determined for a particular drug combination by employing routine
experimental testing.
[0258] In yet another embodiment, the pharmaceutical compositions
may further comprise at least one inhibitor of TNF-.alpha..
Inhibitors of TNF-.alpha. may also be designated TNF-.alpha.
antagonists. TNF-.alpha. antagonists are compounds that are capable
of, directly or indirectly, counteracting, reducing or inhibiting
the biological activity of TNF-.alpha., or the activation of
receptors therefor. Tumor necrosis factor (TNF) is a key
proinflammatory cytokine released by a number of cell types,
particularly activated macrophages and monocytes. Two forms of TNF
are released--TNF-.alpha. and TNF-beta. TNF-.alpha. is a soluble
homotrimer of 17 kD protein subunits (Smith et al. (1987) J. Biol.
Chem. 262:6951-6954. A membrane-bound 26 kD precursor form of TNF
also exists as a pro-protein and must be cleaved to produce the 17
kD TNF. (Kriegler, et al. (1988) Cell, 53:45-53). Without
limitation, the TNF-.alpha. antagonist can be a compound that
affects the synthesis of TNF-.alpha., or one that affects the
maturation of TNF-.alpha., or one that inhibits the binding of
TNF-.alpha. with a receptor specific for TNF-.alpha., or one that
interferes with intracellular signaling triggered by TNF.alpha.
binding with a receptor. Additional details regarding the
manufacture and use of TNF-.alpha. antagonists are available in
U.S. Patent Application Publication No. US 2003/0157061 A1, which
is incorporated herein by reference.
[0259] Preferred TNF-.alpha. antagonists for the present invention
include ENBREL.RTM. (etanercept) from Wyeth-Ayerst
Laboratories/Immunex; REMICADE.RTM., infiximab, which is an
anti-TNF chimeric Mab (Centocor; Johnson & Johnson);
anti-TNF-.alpha., D2E7 human Mab (Cambridge Antibody Technology)
and HUMIRA.RTM. (Abbott); CDP-870, which is a PEGylated antibody
fragment (Celltech); CDP-571; Humicade, which is a humanized Mab
described in U.S. Pat. No. 5,994,510 (Celltech); PEGylated soluble
TNF-.alpha. Receptor-1 (Amgen); TBP-1, which is a TNF binding
protein (Ares Serono); PASSTNF-alpha.RTM., which is an
anti-TNF-.alpha. polyclonal antibody (Verigen); AGT-1, which is a
mixture of three anti-cytokine antibodies to IFN-alpha, IFN-gamma,
and TNF (Advanced Biotherapy Concepts); TENEFUSE.RTM., ienercept,
which is a TNFR-Ig fusion protein (Roche); CytoTAB.RTM.
(Protherics); TACE, which is a small molecule TNF-.alpha.
converting enzyme inhibitor (Immunex); small molecule TNF mRNA
synthesis inhibitor (Nereus); PEGylated p75TNFR Fc mutein
(Immunex); and TNF-.alpha. antisense inhibitor.
[0260] With regard to dosage levels, the TNF-.alpha. antagonist is
present at an amount effective to inhibit progression or reduce
damage from an arthritic condition or a chronic condition
associated with inflammation. Alternatively, the TNF-.alpha.
antagonist is present in an amount that is not effective to inhibit
progression or reduce damage alone but is effective to inhibit
progression or reduce damage in combination with an opioid
according to the invention. This amount is at a level corresponding
to the generally recommended adult human dosages for a particular
TNF-.alpha. antagonist. The effective pain-alleviating amount of
the opioid can be present at a level that potentiates the
effectiveness of a TNF-.alpha. antagonist. Specific dosage levels
for TNF-.alpha. antagonists that can be used herein as given, inter
alia, are included, for example, in the "Physicians' Desk
Reference", 2003 Edition (Medical Economics Data Production
Company, Montvale, N.J.) as well as in other reference works
including Goodman and Gilman's "The Pharmaceutical Basis of
Therapeutics" and "Remington's Pharmaceutical Sciences," the
disclosure of all are incorporated herein by reference. As is well
known to one of ordinary skill in the art, there can be a wide
variation in the dosage level of the TNF-.alpha. antagonist,
wherein the dosage level depends to a large extent on the specific
TNF-.alpha. antagonist being administered. These amounts can be
determined for a particular drug combination by employing routine
experimental testing.
[0261] In another embodiment, the pharmaceutical compositions may
further comprise at least one anti-rheumatic drug. Anti-rheumatic
drugs include those referred to as Disease-modifying antirheumatic
drugs (DMARDs). Anti-rheumatic drugs include methotrexate
(RHEUMATREX, TREXALL), leflunomide (ARAVA), D-Penicillamine,
sulfasalazine, gold therapy, minocycline, azathioprine,
hydroxychloroquine (PLAQUENIL) and other antimalarials,
cyclosporine and biologic agents. Biologic response modifiers,
often referred to as biologic agents or simply biologics, are
designed to either inhibit or supplement immune system components
called cytokines. Cytokines play a role in either fueling or
suppressing the inflammation that causes damage in RA and some
other diseases. The four biologics currently approved for
rheumatoid arthritis all work by inhibiting inflammatory cytokines.
Adalimumab (HUMIRA), etanercept (ENBREL) and infliximab (REMICADE)
work to inhibit a cytokine called tumor necrosis factor (TNF).
Anakinra (KINERET) blocks the action of the cytokine interleukin-1
(IL-1).
[0262] With regard to dosage levels, the anti-rheumatic drug is
present at an amount that attenuates a symptom or sign of
rheumatism or an amount that does not attenuate such a symptom or
sign alone but does attenuate such a symptom or sign in combination
with an opioid according to the invention. This amount is at a
level corresponding to the generally recommended adult human
dosages for a particular anti-rheumatic drug. The effective amount
of the opioid API can be present at a level that potentiates the
effectiveness of the anti-rheumatic drug. Specific dosage levels
for anti-rheumatic drugs that can be used herein as given, inter
alia, are included, for example, in the "Physicians' Desk
Reference", 2003 Edition (Medical Economics Data Production
Company, Montvale, N.J.) as well as in other reference works.
[0263] In an embodiment, the present compositions further comprise
at least one anticonvulsant or anti-epileptic agent. Any
therapeutically effective anticonvulsant may be used according to
the invention. For extensive listings of anticonvulsants, see,
e.g., Goodman and Gilman's "The Pharmaceutical Basis Of
Therapeutics", 8th ed., McGraw-Hill, Inc. (1990), pp. 436-462, and
"Remington's Pharmaceutical Sciences", 17th ed., Mack Publishing
Company (1985), pp. 1075-1083 (the disclosures of which are
incorporated herein by reference). Representative anticonvulsants
that can be used herein include lamotrigine, gabapentin, valproic
acid, topiramate, famotodine, phenobarbital, diphenylhydantoin,
phenytoin, mephenytoin, ethotoin, mephobarbital, primidone,
carbamazepine, ethosuximide, methsuximide, phensuximide,
trimethadione, benzodiazepine, phenacemide, acetazolamide,
progabide, clonazepam, divalproex sodium, magnesium sulfate
injection, metharbital, paramethadione, phenytoin sodium, valproate
sodium, clobazam, sulthiame, dilantin, diphenylan and
L-5-hydroxytryptophan. Currently marketed
anticonvulant/anti-epileptic drugs include Keppra.RTM.,
Lamictol.RTM., Neurontin.RTM., Tegretol.RTM., Carbatrol.RTM.,
Topiramate.RTM., Trileptal.RTM., and Zonegran.RTM..
[0264] With regard to dosage levels, the anticonvulsant is present
at a pain-alleviating amount or an amount that is not
pain-alleviating alone but is pain-alleviating in combination with
the opioid API administered according to the invention. This amount
is at a level corresponding to the generally recommended adult
human dosages for a particular anticonvulsant. The effective
pain-alleviating amount of the opioid can be present at a level
that potentiates the pain-alleviating effectiveness of the
anticonvulsant. Specific dosage levels for anticonvulsants that can
be used herein as given, inter alia, are included, for example, in
the "Physicians' Desk Reference", 2003 Edition (Medical Economics
Data Production Company, Montvale, N.J.) as well as in other
reference works including Goodman and Gilman's "The Pharmaceutical
Basis of Therapeutics" and "Remington's Pharmaceutical Sciences,"
the disclosure of all are incorporated herein by reference. As is
well known to one of ordinary skill in the art, there can be a wide
variation in the dosage level of the anticonvulsant, wherein the
dosage level depends to a large extent on the specific
anticonvulsant being administered. These amounts can be determined
for a particular drug combination by employing routine experimental
testing.
[0265] The following examples are provided for illustrative
purposes and are not to be construed to limit the scope of the
invention in any manner whatsoever.
EXAMPLES
Example 1
Evaluation of the Efficacy and Safety of an Oral Opioid
Pharmaceutical Composition
[0266] A clinical trial of an exemplary oral opioid pharmaceutical
composition was conducted as follows. The "study drug" used in the
clinical trial is a controlled release oral formulation containing
oxycodone as the API. The clinical trial was conducted in subjects
with moderate to severe chronic pain due to osteoarthritis of the
hip or knee. A primary objective of the clinical trial was to study
the efficacy and safety of the study drug in these subjects. A
secondary objective of the clinical trial was to compare quality of
life measures in these subjects with moderate to severe chronic
pain due to osteoarthritis of the hip or knee who receive the study
drug as compared with those who receive placebo.
[0267] For this clinical trial, a multicenter, randomized,
double-blind, placebo-controlled, phase III study was conducted in
approximately four hundred subjects with moderate to severe chronic
pain due to osteoarthritis of the hip or knee. The study evaluated
the efficacy and safety of the study drug relative to placebo over
a twelve week double-blind treatment period. Subjects that met
eligibility criteria enter a two week open-label titration phase in
which subjects are administered 5 mg study drug titrated up to 20
mg study drug. Approximately four hundred subjects were selected
that tolerate 20 mg study drug (e.g., no unacceptable adverse
events). The selected subjects were randomized in a 1:1 ratio to
receive the study drug or placebo with dose adjustments allowed
during the first four weeks of the double-blind treatment period.
The randomization schedule was generated using a permuted block
algorithm and randomly allocated study medication to randomization
numbers. The randomization numbers were assigned sequentially
through a central IVRS system as subjects are entered into the
study.
[0268] Prior to the open-label titration period, subjects were put
through a four to ten day washout period during which they stopped
taking all pain medication other than acetaminophen (500 mg every
four to six hours PRN [a maximum of 3000 mg/day] was permitted). A
daily diary (via touch tone phone system) is utilized to record
each of the subjects overall pain intensity (PI) each day during
the washout period.
[0269] Subjects were permitted to enter the open-label titration
period if the mean value of the diary PI over the last two days of
the washout period (Baseline PI) is .gtoreq.5; if IVRS diary
compliance was .gtoreq.75%; and, if the subject continued to meet
all inclusion/exclusion criteria. Baseline functional assessments
were conducted using the Short Form 12 Question Health Survey
(SF-12) (Table 1 below) and the Western Ontario and MacMaster
Universities Osteoarthritis Index (WOMAC) (Table 2 below).
[0270] During the open-label titration period, subjects were
titrated from 5 mg study drug to 20 mg study drug over two weeks as
follows:
TABLE-US-00001 Dose of Week Day Study Drug Week 1 Days 1-3 5 mg
Open- Days 4-7 10 mg Label Week 2 Days 1-3 15 mg Open- Days 4-7 20
mg Label
[0271] Subjects were instructed to take a dose of study drug with
breakfast and with dinner, to administer doses at least eight hours
apart and to take the study drug with meals. Additionally, subjects
recorded their overall PI every twenty-four hours by calling in
their daily diary information (via touch tone phone) immediately
before bedtime.
[0272] At the end of each week during the open-label titration
period, subjects returned to the study center and opioid toxicity
assessments, adverse events, concomitant medications, drug
accountability, and vital signs are performed.
[0273] At the end of the open-label titration period, subjects were
enrolled in the double-blind placebo-controlled study if the
subjects were able to tolerate 20 mg study drug (e.g., no
unacceptable adverse events) and if IVRS diary compliance is
.gtoreq.75%. Approximately 400 subjects selected from the
open-label titration period are randomized in a 1:1 ratio to
receive the study drug or placebo. Randomization of the subjects
was stratified by both baseline PI (<7.5 vs. .gtoreq.7.5) and by
the average PI over the last two days of the open-label titration
period (<5 vs. .gtoreq.5). During the first four weeks of the
double-blind treatment period, subjects were titrated (up or down)
to analgesic effect. At the conclusion of four weeks, the dose was
fixed for an additional 8 weeks.
[0274] The patient characteristics of the 558 patients that
enrolled in the open label study are shown in Table 3.
TABLE-US-00002 TABLE 3 PATIENT CHARACTERISTICS OPEN-LABEL TITRATION
PERIOD ANALYSIS POPULATION: OPEN-LABEL SAFETY POPULATION OXY BID (N
= 558) AGE (YEARS) MEAN (SD) 58.9(8.23) .sup. MEDIAN 59.1 MIN, MAX
40.4, 75.7 N 558 <=60 301(53.9%) >60 257(46.1%) SEX FEMALE
387(69.4%) MALE 171(30.6%) TOTAL 558(100.0%) ETHNICITY HISPANIC OR
LATINO 35(6.3%) NOT HISPANIC OR LATINO 521(93.4%) RACE AMERICAN
INDIAN OR ALASKA NATIVE 5(0.9%) ASIAN 1(0.2%) BLACK OR AFRICAN
AMERICAN 83(14.9%) NATIVE HAWAIIAN OR OTHER PACIFIC 0(0.0%)
ISLANDER WHITE 469(84.1%) HEIGHT(CM) MEAN (SD) 167.5(9.58) .sup.
MEDIAN 165.6 MIN, MAX 137.2, 208.3 N 556 WEIGHT (KG) MEAN (SD)
94.2(19.55) .sup. MEDIAN 93.8 MIN, MAX 50.4, 136.2 N 558 PRIOR
OPIOID USE WITHIN 30 DAYS OF FIRST DOES OF OPEN-LABEL STUDY DRUG
YES 152(27.2%) NO 406(72.8%) TARGET JOINT HIP 122(21.9%) KNEE
436(78.1%) WASHOUT PERIOD ACETAMINOPHEN USAGE YES 532(95.3%) NO
26(4.7%) SCREENING CLINIC PI MEAN (SD) 7.0(1.40) .sup. MEDIAN 7.0
MIN, MAX 4.0, 10.0 N 558 BASELINE PI MEAN(SD) 7.5(1.33) .sup.
MEDIAN 7.5 MIN, MAX 5.0, 10.0 N 558 <7.5 255(45.7%) >=7.5
303(54.3%) PRE-RANDOMIZATION PI MEAN(SD) 5.3(2.15) .sup. MEDIAN 5.5
MIN, MAX 0.0, 10.0 N 412 <5 .sup. 145(26.MCNI0%) >=5
267(47.8%) NOTE: OPEN-LABEL SAFETY POPULATION - ALL PATIENTS WHO
TAKE AT LEAST ONE DOSE OF STUDY MEDICATION IN OPEN-LABEL
PERIOD.
[0275] All subjects enrolled in the open-label titration period
received study drug BID as shown in Table 4. Subjects that
tolerated the study drug were randomized to receive study drug BID
or placebo BID for the remainder of the clinical trial.
TABLE-US-00003 TABLE 4 ENROLLMENT AND RANDOMIZATION STATUS PLACEBO
BID OXY BID TOTAL OPEN-LABEL SAFETY [1] 58 558 DOUBLE-BLIND SAFETY
[2] 207 205 412 ITT [3] 207 203 410 [1] OPEN-LABEL SAFETY
POPULATION - ALL PATIENTS WHO TAKE AT LEAST ONE DOSE OF STUDY
MEDICATION IN OPEN-LABEL PERIOD. [2] DOUBLE-BLIND SAFETY POPULATION
- ALL PATIENTS WHO TAKE AT LEAST ONE DOSE OF STUDY MEDICATION IN
DOUBLE-BLIND PERIOD. [3] INTENT TO TREAT POPULATION - ALL
RANDOMIZED PATIENTS WHO TAKE ANY STUDY MEDICATION AND HAVE AT LEAST
ONE POST-RANDOMIZATION PAIN INTENSITY (PI) ASSESSMENT.
[0276] Causes of early termination from study drug BID during the
open-label titration period are shown in Table 5. Out of the 146
subjects that terminated during the open label titration period 124
terminated due to adverse events. This constituted 22.2% of the
total population of 558 subjects that enrolled in open-label
period.
TABLE-US-00004 TABLE 5 TERMINATION FROM STUDY DRUG DURING THE
OPEN-LABEL TITRATION PERIOD ANALYSIS POPULATION: OPEN-LABEL SAFETY
POPULATION OXY BID (N = 146) DID THE PATIENT TERMINATE STUDY DRUG
EARLY? NO 0 (0.0%) YES 146 (26.2%) INADEQUATE PAIN RELIEF 4 (0.7%)
ADVERSE EVENT 124 (22.2%) PROTOCOL VIOLATION 10 (1.8%)
INAPPROPRIATE ENROLLMENT 5 NEED FOR PROHIBITED MEDICATION 0 OTHER 5
PATIENT REQUEST UNRELATED TO STUDY 5 (0.9%) OTHER 3 (0.5%) NOTE:
OPEN-LABEL SAFETY POPULATION - ALL PATIENTS WHO TAKE AT LEAST ONE
DOSE OF STUDY MEDICATION IN OPEN-LABEL PERIOD. NOTE: THIS TABLE IS
FOR OPEN-LABEL SAFETY PERIOD - ONLY PATIENTS WHO EARLY TERMINATED
DURING OPEN-LABEL TITRATION.
[0277] The types of adverse events and their incidences reported by
the subjects that terminated during the open-label titration period
are shown in Table 6. The most frequent of these adverse events
(AEs) were those commonly associated with opioid medications:
dizziness, constipation, dry mouth, nausea, vomiting, somnolence,
and pruritis.
TABLE-US-00005 TABLE 6 ADVERSE EVENTS CAUSING DISCONTINUATION OF
STUDY MEDICATION DURING THE OPEN-LABEL TITRATION PERIOD [1]
ANALYSIS POPULATION: OPEN-LABEL SAFETY POPULATION NUMBER (%) OF
PATIENTS REPORTING SYSTEM ORGAN CLASS EVENTS OXY PREFERRED TERM BID
(N = 558) GASTROINTESTINAL DISORDERS 65 (11.6%) ABDOMINAL PAIN
UPPER 3 (0.5%) CONSTIPATION 13 (2.3%) DIARRHOEA 2 (0.4%) DRY MOUTH
1 (0.2%) NAUSEA 45 (8.1%) STOMACH DISCOMFORT 2 (0.4%) VOMITING 10
(1.8%) GENERAL DISORDERS AND ADMINISTRATION 14 (2.5%) SITE
CONDITIONS ASTHENIA 1 (0.2%) CHEST PAIN 1 (0.2%) FATIGUE 9 (1.6%)
IRRITABILITY 1 (0.2%) OEDEMA 1 (0.2%) OEDEMA PERIPHERAL 1 (0.2%)
PAIN 1 (0.2%) PYREXIA 1 (0.2%) INFECTIONS AND INFESTATIONS 1 (0.2%)
SINUSITIS 1 (0.2%) INVESTIGATIONS 1 (0.2%) HEPATIC ENZYME INCREASED
1 (0.2%) METABOLISM AND NUTRITION DISORDERS 1 (0.2%) ANOREXIA 1
(0.2%) MUSCULOSKELLETAL AND CONNECTIVE 3 (0.5%) TISSUE DISORDERS
ARTHRIALGIA 1 (0.2%) MYALGIA 1 (0.2%) PAIN IN EXTREMITY 1 (0.2%)
NERVOUS SYSTEM DISORDER 68 (12.2%) DISTURBANCE IN ATTENTION 2
(0.4%) DIZZINESS 24 (4.3%) DYSARTHRIA 4 (0.7%) HEADACHE 8 (1.4%)
LETHARGY 3 (0.5%) MEMORY IMPAIRMENT 1 (0.2%) SCIATICA 1 (0.2%)
SEDATION 1 (0.2%) SOMNOLENCE 41 (7.3%) PSYCHIATRIC DISORDERS 21
(3.8%) ABNORMAL DREAMS 1 (0.2%) AGITATION 1 (0.2%) ANXIETY 1 (0.2%)
CONFUSIONAL STATE 11 (2.0%) DEPRESSION 1 (0.2%) DISORIENTATION 1
(0.2%) EUPHORIC MOOD 1 (0.2%) HALLUCINATION 1 (0.2%) HALLUCINATION,
AUDITORY 1 (0.2%) HALLUCINATION, VISUAL 1 (0.2%) INSOMNIA 1 (0.2%)
LIBIDO DECREASED 1 (0.2%) MENTAL STATUS CHANGES 3 (0.5%) MOOD
SWINGS 1 (0.2%) PERSONALITY CHANGE 1 (0.2%) REPRODUCTIVE SYSTEM AND
BREAST 1 (0.2%) DISORDERS ERECTILE DYSFUNCTION 1 (0.2%)
RESPIRATORY, THORACIC AND 3 (0.5%) MEDIASTINAL DISORDERS COUGH 2
(0.4%) DYSPNOEA 1 (0.2%) SKIN AND SUBCUTANEOUS TISSUE 19 (3.4%)
DISORDERS HYPERHIDROSIS 4 (0.7%) PRURITUS 14 (2.5%) RASH 2 (0.4%)
SWELLING FACE 1 (0.2%) VASCULAR DISORDERS 3 (0.5%) HOT FLUSH 1
(0.2%) HYPOTENSION 1 (0.2%) ORTHOSTATIC HYPOTENSION 1 (0.2%) NOTE:
OPEN-LABEL SAFETY POPULATION - ALL PATIENTS WHO TAKE AT LEAST ONE
DOSE OF STUDY MEDICATION IN OPEN-LABEL PERIOD. [1] ADVERSE EVENT
START DATE IS BETWEEN THE FIRST DOSE DATE OF STUDY MEDICATION IN
THE OPEN-LABEL TITRATION PERIOD THROUGH THE LAST DOSE DATE OF STUDY
MEDIATION IN THE OPEN-LABEL TITRATION PERIOD.
[0278] The characteristics of the 412 subjects enrolled in the
twelve week double-blind treatment period are shown in Table 7.
Thus, 412 subjects that tolerated study drug administered during
the open-label titration period continued in the double-blind
treatment period.
TABLE-US-00006 TABLE 7 PATIENT CHARACTERISTICS 12-WEEK DOUBLE-BLIND
PERIOD ANALYSIS POPULATION: DOUBLE-BLIND SAFETY POPULATION PLACEBO
BID OXY BID TOTAL (N = 207) (N = 205) (N = 412) AGE (YEARS) MEAN
(SD) 58.5 (8.44) 58.0 (7.86) 58.2 (8.15) MEDIAN 58.5 57.5 57.7 MIN,
MAX 40.4, 75.7 40.4, 75.0 40.4, 75.7 N 207 205 412 <=60 119
(57.5%) 119 (58.0%) 238 (57.8%) >60 88 (42.5%) 86 (42.0%) 174
(42.2%) SEX FEMALE 141 (68.1%) 147 (71.7%) 288 (69.9%) MALE 66
(31.9%) 58 (28.3%) 124 (30.1%) TOTAL 207 (100.0%) 205 (100.0%) 412
(100.0%) ETHNICITY HISPANIC OR 17 (8.2%) 4 (2.0%) 21 (5.1%) LATINO
NOT 187 (91.3%) 200 (97.6%) 389 (94.4%) HISPANIC OR LATINO RACE
AMERICAN 2 (1.0%) 3 (1.5%) 5 (1.2%) INDIAN OR ALASKA NATIVE ASIAN 0
(0.0%) 0 (0.0%) 0 (0.0%) BLACK OR 33 (15.9%) 36 (17.6%) 69 (16.7%)
AFRICAN AMERICAN NATIVE 0 (0.0%) 0 (0.0%) 0 (0.0%) HAWAIIAN OR
OTHER PACIFIC ISLANDER WHITE 171 (82.6%) 167 (81.5%) 338 (82.0%)
HEIGHT (CM) MEAN (SD) 168.0 (9.98) 166.6 (10.14) 167.3 (10.07)
MEDIAN 165.1 165.1 165.1 MIN, MAX 147.3, 193.0 137.2, 208.3 137.2,
208.3 N 207 204 411 WEIGHT (KG) MEAN (SD) 96.7 (19.77) 94.4 (20.05)
95.6 (19.92) MEDIAN 97.6 96.2 97.2 MIN, MAX 50.4, 136.2 50.8, 136.2
50.4, 136.2 N 207 205 412 TARGET JOINT HIP 43 (20.8%) 46 (22.4%) 89
(21.6%) KNEE 164 (79.2%) 159 (77.6%) 323 (78.4%) WASHOUT PERIOD
ACET- AMINOPHEN USAGE YES 201 (97.1%) 196 (95.6%) 397 (96.4%) NO 6
(2.9%) 9 (4.4%) 15 (3.6%) SCREENING CLINIC PI MEAN (SD) 7.0 (1.38)
7.1 (1.48) 7.0 (1.43) MEDIAN 7.0 7.0 7.0 MIN, MAX 5.0, 10.0 4.0,
10.0 4.0, 10.0 N 207 205 412 BASELINE PI MEAN (SD) 7.6 (1.36) 7.6
(1.35) 7.6 (1.35) MEDIAN 7.5 7.5 7.5 MIN, MAX 5.0, 10.0 5.0, 10.0
5.0, 10.0 N 207 205 412 <7.5 90 (43.5%) 89 (43.4%) 179 (43.4%)
>=7.5 117 (56.5%) 116 (56.6%) 233 (56.6%) PRE- RANDOM- IZATION
PI MEAN (SD) 5.4 (2.11) 5.2 (2.19) 5.3 (2.15) MEDIAN 5.5 5.5 5.5
MIN, MAX 0.0, 10.0 0.0, 10.0 0.0, 10.0 N 207 205 412 <5 72
(34.8%) 73 (35.6%) 145 (35.2%) =5 135 (65.2%) 132 (64.4%) 267
(64.8%)
[0279] All subjects begin dosing at 20 mg study drug BID (or
placebo BID). Subjects in the placebo group were titrated down over
the first two weeks of the double-blind treatment period to prevent
the emergence of opioid withdrawal symptoms (15 mg BID for the
first 3 days of Week 1, 10 mg BID for the remainder of Week 1, and
5 mg BID for Week 2). Subjects returned to the clinic at the end of
each week (.+-.1 day) for the first four weeks and then every two
weeks (14-16 days) for the remainder of the double-blind fixed-dose
treatment period.
[0280] During the 12-week treatment period, subjects recorded their
PI every 24 hours in their daily diary immediately before their
bedtime dose. In addition, subjects recorded adverse events and
date/time of taking the study medication in the daily diary. At
each study center visit, the investigator collected additional
data, including quality of analgesia, pain control, the SF-12
Health Survey, the WOMAC Osteoarthritis Index and a global
assessment of study medication. Unscheduled study center visits
were allowed throughout the study for treatment of adverse events.
Adverse events, opioid toxicity assessments, drug accountability,
concomitant medication and vital signs were performed at each
scheduled study center visit.
[0281] Subjects were allowed to increase their dose of study drug
during study center visits at the end of Weeks 1, 2, and 3 of the
double-blind treatment period if the following criteria are met:
(1) the subject tolerated the study drug (no unacceptable adverse
events); the subject's Pain Intensity (PI) score was >2; and (3)
both the Investigator and the subject agreed that dose should be
increased. Subjects may choose not to increase dose of study drug
if they had a PI>2 that they found acceptable. Subjects may also
decrease their dose of study medication during the first four weeks
of the double-blind treatment period if they had unacceptable
adverse events. At the end of Week 4 the final dosage of study drug
was fixed for the remainder of the double-blind fixed-dose
treatment period.
[0282] The following titration schedule outlines the allowed dose
increments for subjects requiring dose adjustments of study drug.
The maximum allowed dose for study drug is 40 mg BID (total daily
dose 80 mg). Subjects were not allowed to skip a dose increment if
a dose was titrated up or down. Titrating up more than one dose
increment may lead to study drug-related adverse events, and
titrating down more than one dose increment may lead to inadequate
analgesia. Subjects were dispensed one or two blister packets of
study drug at each study center visit.
TABLE-US-00007 Study Drug 5 mg BID Study Drug 10 mg BID Study Drug
15 mg BID Study Drug 20 mg BID Study Drug 30 mg BID Study Drug 40
mg BID
[0283] At the conclusion of the 12-week double-blind treatment
period, subjects were gradually tapered off of study drug over a
period of 0 to 15 days, depending on the final fixed dose, to
prevent the emergence of opioid withdrawal symptoms as follows:
TABLE-US-00008 Days Days 0-3 Days 4-6 Days 7-9 Days 10-12 13-15
Final Fixed Taper Taper Taper Taper Taper Dose Period Period Period
Period Period 40 mg BID 30 mg 20 mg 15 mg 10 mg 5 mg 30 mg BID 20
mg 15 mg 10 mg 5 mg -- 15 or 20 10 mg 5 mg -- -- -- 5 or 10 mg No
taper required
[0284] Also at the conclusion of the clinical trial, subjects were
educated about the possibility of study drug withdrawal symptoms.
Any subject experiencing symptoms of study drug withdrawal could
return to the study center for an additional visit for treatment.
Subjects were required to return to the study center for a
post-treatment follow-up visit approximately one week (.+-.two
days) after the final dose of study drug.
[0285] Safety of the study drug was evaluated by vital signs (blood
pressure, heart rate, respiratory rate and temperature), physical
examinations, electrocardiograms (EKGs), clinical laboratory tests,
adverse event monitoring, and opioid toxicity assessments. Subjects
could return to the study center in-between scheduled visits for
treatment of study drug-related adverse events and investigators
were encouraged to treat opioid-related adverse events (e.g.,
constipation, nausea, vomiting, dizziness, and pruritis) as soon as
they occurred to avoid unnecessary dropouts from the study.
[0286] Inclusion criteria were as follows:
[0287] (1) Males and females who are 40 and 75 years of age;
[0288] (2) Subject had moderate to severe pain in one or more hip
or knee joint(s) for at least three months prior to the Screening
Visit due to osteoarthritis as demonstrated by clinical and
radiographic evidence according to the American College of
Rheumatology (ACR) criteria for the diagnosis of osteoarthritis of
the hip or knee;
[0289] (3) Subject had moderate to severe pain in the hip or knee
joint(s) while taking .gtoreq.4 days/week every week for the past
four weeks prior to the Screening Visit one or more of the
following types of oral analgesic medication(s): NSAIDs, COX-2
inhibitors, tramadol, opioids;
[0290] (4) Subject had received: no opioids within 72 hours of the
Screening Visit and either: no opioids or an average daily opioid
dose equivalent of oxycodone .ltoreq.20 mg or tramadol .ltoreq.200
mg within one week prior to the Screening Visit; or a daily opioid
dose equivalent of oxycodone (>20 mg and .ltoreq.80 mg) or
tramadol >200 mg within one week prior to the Screening Visit
and had undergone an opioid taper prior to study entry;
[0291] (5) Subject had a pain intensity score of .gtoreq.5 on an
11-point numerical scale at the Screening Visit;
[0292] (6) Subject had a mean daily diary overall pain intensity of
.gtoreq.5 on an 11-point numerical scale during the last two days
of the washout period (Baseline PI; calculated by IVRS);
[0293] (7) Subject completed daily telephone diary pain intensity
assessments for .gtoreq.75% days (calculated by IVRS) during the
washout period and during the open-label titration period;
[0294] (8) Subject completed the open-label titration period and
was able to tolerate study drug at 20 mg BID;
[0295] (9) Subject agreed to refrain from taking any pain
medications other than study drug during the study period. [Aspirin
(up to 325 mg/day) was permitted for cardiovascular prophylaxis if
at a stable dose one month prior to the Screening Visit.
Acetaminophen was allowed during the washout period only];
[0296] (10) Subject must be ambulatory;
[0297] (11) Females who were postmenopausal, physically incapable
of childbearing, or practicing an acceptable method of birth
control. Acceptable methods of birth control include surgical
sterilization, hormonal contraceptives, or double-barrier methods
(condom or diaphragm with a spermicidal agent or intrauterine
device [IUD]). If practicing an acceptable method of birth control,
a negative urine pregnancy test result has been obtained prior to
starting the open-label titration period; and
[0298] (12) Subject was able to understand and cooperate with study
procedures, has access to a touch-tone telephone at home, and has
signed a written informed consent form prior to any study
procedures.
[0299] Exclusion criteria for subjects were as follows:
[0300] (1) Subject had a positive urine drug screen at the Baseline
Visit;
[0301] (2) Subject had received a daily opioid dose equivalent of
oxycodone >80 mg for 4 or more days/week during the week prior
to the initial Screening Visit;
[0302] (3) Subject had pain in the hip(s) or knee(s) caused by
conditions other than osteoarthritis, e.g., malignancy, gout,
inflammatory disease such as rheumatoid arthritis, fibromyalgia,
recent trauma within the past six months, or infection;
[0303] (4) Subject had a history of Paget's disease, or autoimmune
diseases associated with arthritis (e.g. rheumatoid arthritis,
lupus, Sjogren's are exclusionary diagnoses);
[0304] (5) Subject had major surgery within three months prior to
the Screening Visit or had surgery planned during the proposed
study period;
[0305] (6) Subject had received oral, intra-articular, or
parenteral corticosteroid therapy within one month prior to the
Screening Visit;
[0306] (7) Subject had received an intra-articular injection of
hyaluronic acid in the hip or knee within six months prior to the
Screening Visit;
[0307] (8) Subject weighed more than 300 lbs or less than 100
lbs;
[0308] (9) Subject was pregnant or breast-feeding;
[0309] (10) Subject had received an epidural or intrathecal
infusion of any analgesic medication(s) within one month prior to
the Screening Visit;
[0310] (11) Subject had severe impairment of pulmonary function,
hypercarbia, hypoxia, cor pulmonale, sleep apnea syndrome,
severe/uncontrolled asthma, chronic obstructive pulmonary disease,
or a history of respiratory depression;
[0311] (12) Subject had a history of gastric bypass surgery; any
gastric or small intestine surgery leading to malabsorption; or any
disease that causes clinical malabsorption;
[0312] (13) Subject had unstable cardiac disease (e.g. inadequately
controlled hypertension, congestive heart failure, a history of
myocardial infarction within the previous year); or subject has any
health condition(s) that pose a significant health risk in the
event of opioid withdrawal;
[0313] (14) Subject had started, stopped, or changed the dose of
the following medications within four weeks prior to the Screening
Visit: monoamine oxidase inhibitors, tricyclic antidepressants,
serotonin reuptake inhibitors or other antidepressants; gabapentin,
pregabalin, and glucosamine/chondroitin;
[0314] (15) Subject had started or stopped physical therapy,
transcutaneous electrical nerve stimulation, chiropractic,
osteopathic, acupuncture, or other complementary treatment within
four weeks prior to the Screening Visit or is expected to undergo
any changes in these therapies during the study;
[0315] (16) Subject had received high doses of sedatives, hypnotics
or tranquilizers that may, in the opinion of the investigator,
increase the risk of opioid toxicity;
[0316] (17) Subject had received phenothiazines or other agents
that compromise vasomotor tone. (Promethazine is allowed);
[0317] (18) Subject had a history of alcohol or drug abuse within
the past 5 years;
[0318] (19) Subject had a medical illness/condition, psychiatric
illness, and/or abnormal diagnostic finding that would interfere
with the completion of the study, confound the results of the
study, or pose risk to the subject;
[0319] (20) Subject had a history of leukemia, lymphoma,
myeloproliferative disease, multiple myeloma, or metastatic cancer;
subject has a history of prostate, breast, thyroid or lung cancer
within five years of study entry; or subject had a history of any
other localized malignancy within two years of study entry.
(Subjects with treated localized prostate, breast, thyroid or lung
cancer without recurrence for five years, any other treated
localized malignancy without recurrence for 2 years, or a history
of curative treatment of basal or squamous cell carcinoma of the
skin were not excluded.);
[0320] (21) Subject had a history of an allergic reaction or
hypersensitivity to any of the study medications or structurally
similar compounds: oxycodone, morphine, hydromorphone, hydrocodone,
levorphanol, pentazocine, codeine, etc. or acetaminophen;
[0321] (22) Subject had AST, ALT, or alkaline phosphatase >2
times the upper limit of normal; hematocrit <30%; creatinine
.gtoreq.1.8; or ESR >20 from the Screening Visit;
[0322] (23) Subject had previously received the study drug;
[0323] (24) Subject had participated in another investigational
drug trial or therapeutic trial within 30 days of the Screening
Visit;
[0324] (25) Subject had taken analgesic medication (other than
acetaminophen) during the washout period prior to enrollment; or
subject had taken any analgesic medication (other than study drug)
during the open-label titration period prior to randomization.
[0325] The physical descriptions of the study drugs used for this
clinical trial study were as follows. The study drugs were
available in capsules containing study drug or placebo. The study
drug capsules were available in 5 mg, 10 mg, 15 mg 20 mg, 30 mg and
40 mg. Dosage strengths came in four different sized capsules. The
5 mg dosage strength came in Size 4 (small) capsules, the 10 mg
dosage strength came in Size 2 (medium) capsules, the 15 and 20 mg
dosage strengths came in Size 1 (large) capsules, and the 30 and 40
mg dosage strengths came in Size 00 (extra large) capsules. Placebo
capsules were indistinguishable from the study drug capsules. For
the 4- to 10-day washout period, a container of acetaminophen (500
mg caplets) was dispensed at the Screening Visit in a sufficient
quantity for dosing up to six caplets per day. The investigational
drug supplies were in capsule dosage forms containing study drug
BID or placebo BID. All of the capsule dosage forms were
indistinguishable from one another to facilitate blinding.
[0326] One or two containers of acetaminophen (APAP) were dispensed
at the Screening Visit for the 4- to 10-day washout period. A
commercially available source of acetaminophen tablets (500 mg) was
supplied. A single panel label was applied to commercially sourced
plastic bottles of acetaminophen to obscure the original dosing
instructions.
[0327] Throughout the study, investigational drug supplies (study
drug) were dispensed in child-resistant blister cards. Each blister
card contained a one-week (Days 1-7) supply of study drug as well
as extra study drug (Days 8-10) to allow for flexibility in
planning return clinic visits. Blister cards for the double-blind
taper period contained a 6- to 15-day supply of study drug,
depending on the subject's final fixed dose. The extra study drug
had to remain intact within its original packaging so that it could
be returned at each clinic visit.
[0328] During the open-label titration period, capsules were
arranged on each blister card by day and contained two capsules per
day. For the first week, the blister card contained 20 capsules
(Days 1-10) consisting of Size 4 and Size 2 capsules; the first
three days were 5 mg capsules and the remaining days were 10 mg
capsules. The Week 2 blister card contained Size 1 capsules; the
first three days were 15 mg capsules and the remaining days were 20
mg capsules.
[0329] During the first two weeks of the double-blind treatment
period, the blister card contained 40 capsules. Capsules were
arranged on each blister card by day (Days 1-10) and contained four
capsules per day. All subjects were instructed to take two capsules
with breakfast and two capsules with dinner for the first two weeks
of the double-blind treatment period. The purpose of this change in
the number of capsules was to allow placebo subjects to be titrated
off of PTI-821 to prevent opioid withdrawal while still maintaining
the double-blind.
[0330] During the remainder of the double-blind treatment period up
until the end of the fixed-dose treatment period, the blister cards
contained 20 capsules. Capsules were arranged on each blister card
by days (Days 1-10) and contained two capsules per day. Subjects
were instructed to take one capsule of study drug BID for the
remainder of the study.
[0331] At the conclusion of the 12-week fixed dose portion of the
double-blind treatment period, subjects who had been on study drug
for at least four weeks (including the open-label titration period)
were tapered off of study drug over a period of 0-15 days,
depending on the final fixed dose. Tapering was performed in a
blinded fashion. Subjects taking 40 mg BID required a 15 day taper,
subjects taking 30 mg BID required a 12 day taper, subjects taking
15 or 20 mg BID required a 6 day taper, and subjects taking 10 or 5
mg BID did not require a taper. Each blister card contained 12, 24,
or 30 capsules. Capsules were arranged on each blister card by days
and contained two capsules per day. Subjects were instructed to
take one capsule of study drug BID until there are no capsules
remaining in the blister card.
[0332] The label on each blister card contained a unique kit number
that was assigned to patients at weekly or biweekly intervals. An
Interactive Voice Response System (IVRS) provided assignment of kit
numbers.
[0333] One blister card was dispensed for each week of the
open-label titration period and for the first four weeks of the
double-blind fixed-dose treatment period. Two blister cards were
dispensed at the biweekly visits for the remainder of the 12-week
double-blind fixed-dose treatment period. If the subject required a
taper, one blister card was dispensed at the end of treatment
visit.
[0334] Each blister card had a label consisting of two parts. One
part remained attached to the kit and the other was a tear-off
label, which was adhered onto the appropriate Case Report Form
(CRF). The information included on the label was in accordance with
local requirements. All blister cards, empty or containing unused
capsules, were saved for final disposition by the sponsor or
designee.
[0335] The study procedures were as follows. Prior to any
study-related activities, written informed consent was signed and
dated by the subject. Clinical examinations were performed that
comprised the standard-of-care evaluations routinely performed as
part of ongoing care for subjects with moderate to severe chronic
pain due to osteoarthritis of the hip or knee. Pain assessments
were performed by assessing: (1) Pain Intensity, (2) Quality of
Analgesia, (3) Pain Control, and (4) Global Assessment of Study
Medication.
[0336] Pain Intensity was assessed by prompting the subject with
the question, "How would you rate your overall pain intensity at
this time?", and the PI score was recorded in the clinic. Pain
Intensity was also assessed by prompting the subject with the
question, "How would you rate your overall pain intensity during
the past 24 hours?", and a daily PI diary score was recorded by the
subject at bedtime. For both Pain Intensity prompts, the response
is scored on an 11-point numerical scale (0=no pain and 10=severe
pain).
[0337] Quality of Analgesia was assessed weekly at clinic visits.
The subject was prompted with the question, "How would you rate the
quality of your pain relief at this time?", and responses were
selected from poor, fair, good, very good, and excellent.
[0338] Pain Control was also assessed weekly at clinic visits. The
subject was prompted with the question, "During the past week, how
would you describe your pain control during the course of each
day?" Responses were selected from: Pain was controlled for (1) a
few hours or less each day; (2) several hours each day; (3) most of
each day; and (4) throughout each day.
[0339] Global Assessment of Study Medication was also assessed
weekly at clinic visits. The subject was prompted with the
question, "How would you rate the study medication you received
this past week? (Please consider the quality of your pain relief,
your side effects, your activity level, your mood and sense of
well-being, etc. in this evaluation.)". Responses were selected
from poor, fair, good, very good, and excellent.
[0340] Additionally, functional assessments were conducted with the
SF-12 Health Survey (see Table 1) and the WOMAC Osteoarthritis
Index (see Table 2).
[0341] Safety procedures include taking vital signs (blood
pressure, respiratory rate, heart rate and temperature), physical
examinations, EKGs, clinical laboratory tests, adverse events,
opioid toxicity assessments and the assessment of opiate withdrawal
symptoms. The opioid toxicity assessment included: (a) CNS review
by assessing for (1) confusion, altered mental state, (2) excessive
drowsiness, lethargy, stupor, (3) slurred speech (new onset), (4)
respiratory, (5) hypoventilation, shortness of breath, apnea, (6)
hypoxia, hypercarbia; and (b) cardiac review by assessing for
bradycardia, hypotension, and shock. Subjects experiencing opioid
toxicity, as determined by the Investigator, were early terminated
from the study and had to stop taking study drug. If subjects were
terminated from the study, the Early Drug Termination assessments
and the Post-Treatment Follow-Up Visit were completed. Subjects who
were early terminated because of opioid toxicity did not have to
undergo a taper; study drug must be stopped immediately in order to
allow the blood levels of study drug to decline. Sites monitored
subjects who early terminated due to opioid toxicity closely, with
a minimum of daily telephone calls until resolution of symptoms. If
symptoms of opioid withdrawal occurred, the subject could return to
the study center for treatment.
[0342] Opioid toxicity assessments were performed at clinic visits
to evaluate dose escalation and to evaluate whether it was safe for
the patient to continue on the study medication. Opioid toxicity is
distinct from opioid-related adverse events in that it signifies an
unacceptable safety risk to the patient to remain on study
medication (e.g. risk of overdose from respiratory depression).
Opioid toxicity assessments had to be conducted by an MD or DO
Principal Investigator/Sub-Investigator. The assessments included a
review of the following:
TABLE-US-00009 Opioid Toxicity Assessment Organ System
Signs/Symptoms Central Nervous Confusion, altered mental status
System* Excessive drowsiness, lethargy, stupor Slurred speech (new
onset) Respiratory Apnea Decreased respiratory rate (<8/minute)
or cyanosis Cardiac Bradycardia, hypotension, or shock
[0343] Alterations in mental status had to be present in order to
make the diagnosis of opioid toxicity. Subjects experiencing opioid
toxicity, as determined by the Investigator, had to be early
terminated from the study and had to stop taking study drug. If
subjects had to be terminated from the study, the Early Drug
Termination assessments and the Post-Treatment Follow-Up Visit were
completed. Subjects who were early terminated because of opioid
toxicity did not undergo a taper; study drug had to be stopped
immediately in order to allow the blood levels of study drug to
decline. Study centers monitored patients who early terminated due
to opioid toxicity closely, with a minimum of daily telephone calls
until resolution of symptoms. If symptoms of opioid withdrawal
occurred, the patient could return to the study center for
treatment.
[0344] Additionally, adverse events were monitored throughout the
course of the study. An adverse event (AE) is any undesirable event
that occurs to a participant during the course of a clinical study,
whether or not that event is considered study drug-related.
Examples include:
[0345] (1) Any treatment-emergent signs and symptoms (e.g., events
that are marked by a change from the subject's baseline/entry
status such as an increase in severity or frequency of pre-existing
abnormality or disorder);
[0346] (2) All reactions from the study drug, an overdose, abuse of
drug, withdrawal phenomena, sensitivity or toxicity to the study
drug;
[0347] (3) Apparently unrelated illnesses;
[0348] (4) Injury or accidents (Note: if a medical condition is
known to have caused the injury or accident, the medical condition
and the accident should be reported as two separate medical events,
for example, for a fall secondary to dizziness, both "dizziness"
and "fall" should be recorded separately); and/or
[0349] (5) Extensions or exacerbations of symptoms, subjective
subject-reported events, new clinically significant abnormalities
in clinical laboratory, physiological testing or physical
examination.
[0350] All adverse events, whether or not related to the study
drug, were fully and completely documented on the adverse event
page of the case report form (CRF) and in the subject's clinical
chart. In the event that a subject was withdrawn from the study
because of an adverse event, it had to be recorded on the CRF.
However, the withdrawn subject had to be followed and treated by
the Investigator until the abnormal parameter or symptom had
resolved or stabilized.
[0351] The Investigator had to report all directly observed adverse
events and all spontaneously reported adverse events. At each visit
the Investigator asked the subject a non-specific question (e.g.,
"Have you noticed anything different since your last visit?") to
assess whether any adverse events have been experienced since the
last report or visit. Adverse events (AEs) were identified and
documented on the adverse event CRF in appropriate medical
terminology. The severity and the relationship to the study drug
was determined and reported on the CRF.
[0352] In addition to reporting the medication on the Concomitant
Medication CRF, the investigator or designee needed to question
whether an adverse event had occurred when intermittent or as
needed ("prn") use of any medication (and specifically any newly
prescribed medication) were taken during treatment period for
conditions worsened from or not present before enrollment into
study. This may indicate the occurrence of an adverse event that
may also needed to be recorded on the adverse event CRF.
[0353] The severity of each adverse event was characterized and
then classified into one of three clearly defined categories as
follows:
[0354] (1) Mild--the adverse event does not interfere in a
significant manner with the subject's normal functioning level. It
may be an annoyance,
[0355] (2) Moderate--the adverse event produces some impairment of
functioning, but is not hazardous to health. It is uncomfortable or
an embarrassment, or
[0356] (3) Severe--the adverse event produces significant
impairment of functioning or incapacitation and is a definite
hazard to the subject's health.
[0357] These three categories were based on the Investigator's
clinical judgment, which in turn depended on consideration of
various factors such as the subject's report, the physician's
observations and the physician's prior experience. The severity of
the adverse event was recorded in the appropriate section of the
adverse event CRF.
[0358] The relationship of each adverse event to the study drug was
classified into one of three defined categories as follows:
[0359] (1) Unlikely--a causal relationship between the adverse
event and the study drug is unlikely,
[0360] (2) Possible--a causal relationship between the adverse
event and the study drug is possible, or
[0361] (3) Probable--a causal relationship between the adverse
event and the study drug is probable. For example, the adverse
event is a common adverse event known to occur with the
pharmacological class the study drug belongs to; or the adverse
event abated on study drug discontinuation and reappeared upon
rechallenge with the study drug.
[0362] These three categories are based on the Investigator's
clinical judgment, which in turn depends on consideration of
various factors such as the subject's report, the timing of the
adverse event in relationship to study drug
administration/discontinuation, the physician's observations and
the physician's prior experience. The relationship of the adverse
event to the study drug is recorded in the appropriate section of
the adverse event CRF.
[0363] Any adverse event that suggests a significant hazard,
contraindication, side effect or precaution is defined as a Serious
Adverse Event (SAE). An SAE includes (but is not limited to) an
experience occurring at any dose that results in any of the
following outcomes:
[0364] (1) Death;
[0365] (2) A life-threatening event (i.e., the subject is at
immediate risk of death from the reaction as it occurs).
"Life-threatening" does not include an event that, had it occurred
in a more serious form, might have caused death. For example,
drug-induced hepatitis that resolved without evidence of hepatic
failure would not be considered life-threatening even though
drug-induced hepatitis can be fatal;
[0366] Subject hospitalization (hospital admission, not an
emergency room visit) or prolongation of existing
hospitalization;
[0367] (4) A persistent or significant disability/incapacity (i.e.,
a substantial disruption of the subject's ability to carry out
normal life functions); and/or
[0368] (5) A congenital anomaly/birth defect.
[0369] In addition, medical and scientific judgment must be
exercised in deciding whether other situations are to be considered
an SAE (e.g., important medical events that may not be immediately
life-threatening or result in death, but may jeopardize the subject
or may require medical or surgical intervention to prevent one of
the other outcomes listed in the definition above). Examples of
such medical events include: allergic bronchospasm requiring
intensive treatment in an emergency room or at home, or blood
dyscrasias or new-onset seizures that do not result in subject
hospitalization.
[0370] An unexpected adverse event is one for which the specificity
or severity is not consistent with the current Investigator's
Brochure. For example, hepatic necrosis would be unexpected (by
virtue of greater severity) if the Investigator's Brochure only
listed elevated hepatic enzymes or hepatitis. Similarly, cerebral
thromboembolism and cerebral vasculitis would be unexpected (by
virtue of greater specificity) if the Investigator's Brochure only
listed cerebral vascular accidents.
[0371] The reporting of SAEs by the Sponsor to Regulatory
Authorities (e.g., Food and Drug Administration (FDA)) is a
regulatory requirement. Each Regulatory Agency has established a
timetable for reporting SAEs based upon established criteria.
Likewise, it is the responsibility of the Principal Investigator to
report SAEs to their ECs/IRBs immediately.
[0372] All SAEs must be reported immediately (within 24 hours of
learning of the event) by telephone to the Sponsor or Contract
Research Organization (CRO) designee. Any additional information,
if collected, can be reported to the Sponsor (or CRO designee) as a
follow-up to the initial report.
[0373] In the case of a death or other SAE that has occurred within
30 days after receiving study drug, the Principal Investigator must
also report such an event within 24 hours of being notified.
[0374] In the event of any SAE (other than death), the subject is
instructed to contact the study physician (Principal Investigator
or designee) using the phone number provided in the Informed
Consent Form. All subjects that experience a SAE are seen by a
Principal Investigator or designee as soon as feasible following
the report of an SAE.
[0375] At the first visit, pre-enrollment screening is performed.
The following assessments are conducted at Visit I (Screening
Visit):
[0376] (1) Obtain written informed consent from the subject;
[0377] (2) Screen subject's PI (must be .gtoreq.5 to continue the
screening process);
[0378] (3) Review inclusion and exclusion criteria;
[0379] (4) Obtain subject's detailed medical history including
concomitant medications taken one month prior to the Screening
Visit;
[0380] (5) Complete subject's physical examination including
height, weight and vital signs;
[0381] (6) Perform an EKG (QTc interval);
[0382] (7) Obtain blood samples for clinical laboratory tests;
[0383] (8) Obtain urine sample for urinalysis;
[0384] (9) Perform urine pregnancy test for all women of
childbearing potential;
[0385] (10) Obtain an X-ray of the subject's hip/knee. All subjects
must have radiographic evidence of osteoarthritis of the hip or
knee according to ACR diagnostic criteria. Subjects who do not have
an X-ray report that documents radiographic evidence of
osteoarthritis of the hip or knee within the past two years must
have an X-ray performed prior to the next (Baseline) visit;
[0386] (11) Contact IVRS to obtain a subject identification number
and to register the subject for the daily touch-tone phone
diary;
[0387] (12) Review each section of the diary with the subject and
provide written instructions for use of the diary; and
[0388] (13) IVRS provides an acetaminophen bottle number and
dispense acetaminophen to the subject.
[0389] At the conclusion of the visit the subject is given an
appointment card for the next study visit.
[0390] The study nurse thoroughly reviewed each section of the
diary with the subject. The subject is advised to telephone IVRS
prior to bedtime each day of the washout period to record their
overall PI over the past 24 hours.
[0391] At a second visit, four to ten days after the Screening
Visit, the subjects return to the study center for completion of
the pre-dose assessments (Baseline/Open-Label Titration Visit).
This visit includes the following:
[0392] (1) Screen the subject's urine sample using a rapid drug
screen kit;
[0393] (2) Contact IVRS to review the subject's daily diary PI
scores from the washout period to verify that: the mean daily
overall PI score collected in the diary over the last two days of
the washout period is .gtoreq.5 (on a scale of 0 to 10) while off
all analgesic medications (except acetaminophen), and that the
subject completed daily diary PI assessments .gtoreq.75% of the
days during the washout period;
[0394] (3) Collect the bottle of acetaminophen and perform
accountability; and,
[0395] (4) Review inclusion and exclusion criteria to verify that
the subject has radiographic evidence of OA of hip or knee within
the past two years (Inclusion #2) according to ACR diagnostic
criteria and that the clinical laboratory test results from the
Screening Visit are without significant clinical abnormalities
(Exclusion #22) (e.g., the urine pregnancy test is negative (if
required; Inclusion #11).
[0396] If subjects fail to meet inclusion/exclusion criteria, they
are considered screening failures. Subjects meeting all study entry
criteria continue in the screening process and receive the
following assessments:
[0397] (1) Obtain subject's interim medical history (to identify
any changes from the Screening Visit);
[0398] (2) Obtain the subject's vital signs; and
[0399] (3) Review and record the subject's concomitant
medications.
[0400] Subjects who have no clinically significant changes in
interim medical history and vital signs that would prohibit them
from entering the study and who have not taken any prohibited
medications (or stopped, started, or changed the dose of restricted
medications) can enter the open-label titration period. The
following assessments will be performed:
[0401] (1) WOMAC Osteoarthritis Index (select target joint to be
assessed throughout the study; Appendix 1). The subject must select
a target joint which is defined as the hip or knee joint with
osteoarthritis causing the subject the most pain. The subject must
refer to the same joint throughout the study when completing the
WOMAC; and
[0402] (2) SF-12 Health Survey.
[0403] Once these assessments and procedures are completed,
subjects are enrolled in the open-label titration period. IVRS is
telephoned to obtain a blister card for the subject for Week 1 of
the open-label titration period and one blister card of study
medication is dispensed to the subject with 3 days of 5 mg BID and
7 days of 10 mg BID. The blister card of study drug has a two-part
clinical label. The tear-off portion of the label is removed and
attached to the CRF.
[0404] An appointment card is provided to the subject before he/she
leaves the clinic for the next visit. The subject is instructed to
take one capsule of study drug with breakfast and one capsule of
study drug with dinner. The subjects are further instructed that
they must administer doses with meals at least eight hours apart
and the subjects are informed that taking the study drug on an
empty stomach may lead to insufficient pain relief.
[0405] The touch-tone daily diary is used to record overall PI in
the past 24 hours immediately prior to bedtime.
[0406] At a third visit (End of Week 1 of the Open-Label Titration
Period), subjects return to the study center for completion of the
pre-dose assessments (Baseline/Open-Label Titration Visit). This
visit includes the following assessments:
[0407] (1) Perform opioid toxicity assessments (must be performed
by MD or DO Principal Investigator/Sub-Investigator);
[0408] (2) Contact IVRS to review diary (overall daily PI and
subject compliance);
[0409] (3) Record new/changed adverse events and concomitant
medications. Subjects may experience opioid-related adverse events
during the titration period. Subjects are to be instructed that
mild opioid-related AEs (feeling drowsy, nausea, vomiting,
pruritis, dizziness) often go away within 24-48 hours of dose
titration, with the exception of constipation. Subjects may return
for additional visits to receive treatment of opioid-related AEs.
Investigators are encouraged to treat opioid-related adverse events
as soon as they occur to avoid subject discomfort/early
termination;
[0410] (4) Collect study medication from previous week and account
for used/unused supplies;
[0411] (5) Obtain the subject's vital signs;
[0412] (6) Telephone IVRS in order to assign subjects one blister
card for the remaining week of the open-label titration period;
and
[0413] (7) Dispense the blister card of study medication to the
subject with 3 days of 15 mg BID and 7 days of 20 mg BID. The
blister card of study drug has a two-part clinical label. Remove
the tear-off portion of the label and attach it to the CRF;
[0414] An appointment card is provided to the subject before he/she
leaves the clinic for the next visit. The subject is instructed to
take one capsule of study drug with breakfast and one capsule of
study drug with dinner. The subjects are further instructed that
they must administer doses with meals at least eight hours apart
and the subjects are informed that taking the study drug on an
empty stomach may lead to insufficient pain relief.
[0415] The touch-tone daily diary is used to record overall PI in
the past 24 hours immediately prior to bedtime.
[0416] At a fourth visit (End of the Open-Label Titration
Period/Randomization Visit or Early Drug Termination from
Open-Label Titration Period Visit), subjects return to the study
center at the end of the week (7-8 days after the last visit). In
addition, any subject who early terminates from the open-label
titration period and took at least one dose of study medication
must return for follow-up safety assessments. The following
assessments are performed:
[0417] (1) Opioid toxicity assessments (must be performed by MD or
DO Principal Investigator/Sub-Investigator);
[0418] (2) Contact IVRS to review diary (overall daily PI and
subject compliance);
[0419] (3) Verify that the subject completed daily diary
assessments .gtoreq.75% of the days during the open-label titration
period (Inclusion #7);
[0420] (4) Record new/changed adverse events and concomitant
medications;
[0421] (5) Verify that subject is able to tolerate AEs (if any)
associated with administration of study drug 20 mg (Inclusion
#8);
[0422] (6) Verify that the subject did not take any prohibited
analgesics during the open-label titration period (Exclusion #25);
and the subject did not start, stop or change the dose of any of
the medications listed in Exclusion #14;
[0423] (7) Collect study medication from previous week and account
for used/unused supplies;
[0424] (8) Obtain vital signs;
[0425] (9) Obtain blood samples for clinical laboratory tests;
and
[0426] (10) Obtain urine sample for urinalysis.
[0427] Subjects who continue to meet all inclusion/exclusion
criteria are randomized. Subjects who have early terminated from
the open-label titration period require no further assessments at
this visit, but must return for the Post-Treatment Follow-Up
Visit.
[0428] The following assessments are performed on continuing
subjects:
[0429] (1) WOMAC Osteoarthritis Index (target joint assessed
throughout study); and
[0430] (2) SF-12 Health Survey.
[0431] Once these assessments and procedures are completed,
subjects will be randomly assigned to one of the two treatment
groups. The following procedures were taken:
[0432] (1) Telephone IVRS to assign subjects a randomization number
and a blister card for Week 1 of the double-blind treatment period;
and
[0433] (2) Dispense a blister card of study medication to the
subject. The blister card will contain four capsules of study drug
per day. The blister card of study drug has a two-part clinical
label. Remove the tear-off portion of the label and attach it to
the CRF;
[0434] An appointment card is provided to the subject before he/she
leaves the clinic for the next visit. The subject is instructed to
take one capsule of study drug with breakfast and one capsule of
study drug with dinner. The subjects are further instructed that
they must administer doses with meals at least eight hours apart
and the subjects are informed that taking the study drug on an
empty stomach may lead to insufficient pain relief.
[0435] The touch-tone daily diary is used to record overall PI in
the past 24 hours immediately prior to bedtime. The touch-tone
diary is used to record the following information: (1) overall PI
in the past 24 hours (daily); (2) quality of analgesia (weekly),
and (3) global assessment of study medication (weekly). The weekly
assessment sections (quality of analgesia and global assessment of
study medication) of the touch-tone phone diary are thoroughly
reviewed with the subject.
[0436] At a fifth visit (End of Week 1 of the Double-Blind
Treatment Period (Titration), subjects return to the study center
at the end of Week 1 (.+-.one day). The following assessments are
performed:
[0437] (1) Opioid toxicity assessments (must be performed by MD or
DO Principal Investigator/Sub-Investigator);
[0438] (2) Contact IVRS to review diary (overall daily PI and
subject compliance);
[0439] (3) Record new/changed adverse events and concomitant
medications;
[0440] (4) Collect study medication from previous visit and account
for used/unused supplies; (5) Obtain vital signs;
[0441] (6) Determine if a dose increment or dose decrease is
required. Dose and adverse events will be evaluated. The dose may
be increased to the next dose level (30 mg BID) if the clinic PI is
>2, the subject is not experiencing any intolerable adverse
events, and the subject and Investigator agree that the dose should
be increased. Subjects may choose not to increase dose of study
drug if they have a PI>2 that they find acceptable. If a subject
reports experiencing any opioid-related adverse events, the
Investigator should offer treatment if not resolved (see Appendix
F). If the subject or Investigator finds the adverse events
unacceptable, the dose will be decreased to the previous level (15
mg BID);
[0442] (7) Telephone IVRS in order to assign subjects one blister
card; dispense one blister card to the subject. Each blister card
has a two-part clinical label. Remove the tear-off portion of the
label and attach it to the CRF; and
[0443] (9) Review the instructions on the blister card with the
subject.
[0444] An appointment card is provided to the subject before he/she
leaves the clinic for the next visit. The subject is instructed to
take one capsule of study drug with breakfast and one capsule of
study drug with dinner. The subjects are further instructed that
they must administer doses with meals at least eight hours apart
and the subjects are informed that taking the study drug on an
empty stomach may lead to insufficient pain relief.
[0445] The touch-tone daily diary is used to record overall PI in
the past 24 hours immediately prior to bedtime. The touch-tone
diary is used to record the following information: (1) overall PI
in the past 24 hours (daily); (2) quality of analgesia (weekly);
and (3) global assessment of study medication (weekly).
[0446] At visits 6 to 8 (End of Weeks 2, 3, and 4 of the
Double-Blind Treatment Period (Titration)), subjects return to the
study center at the end of Weeks 2, 3 and 4 (.+-.one day). The
following assessments are performed at each visit:
[0447] (1) Perform opioid toxicity assessments (must be performed
by MD or DO Principal Investigator/Sub-Investigator);
[0448] (2) Contact IVRS to review diary (overall daily PI and
subject compliance);
[0449] (3) Record new/changed adverse events and concomitant
medications;
[0450] (4) Collect study medication from previous visit and account
for used/unused supplies;
[0451] (5) Check vital signs;
[0452] (6) Determine if dose adjustment is required (increase
allowed only at End of Weeks 1, 2 or 3; decrease allowed at End of
Weeks 1, 2, 3 or 4). Dose and adverse events will be evaluated at
each visit. The dose may be increased to the next dose level at the
End of Weeks 1, 2, or 3 if the clinic PI is >2, the subject is
not experiencing any intolerable adverse events, and the subject
and Investigator agree that the dose should be increased. Subjects
may choose not to increase dose of study drug if they have a
PI>2 that they find acceptable. If a subject reports
experiencing any opioid-related adverse events, the Investigator
should offer treatment if not resolved. If the subject or
Investigator finds the adverse events unacceptable, the dose will
be decreased to the previous level. The dose may be decreased at
the End of Weeks 1, 2, 3, or 4. Subjects are required to remain on
the dose of study drug administered at the End of Week 4 for the
remainder of the study;
[0453] (7) Telephone IVRS in order to assign subjects one or two
(End of Week 4) blister cards; and
[0454] (8) Dispense one or two (End of Week 4) blister cards to the
subject. Each blister card has a two-part clinical label. Remove
the tear-off portion of the label and attach it to the CRF.
[0455] An appointment card is provided to the subject before he/she
leaves the clinic for the next visit. The subject is instructed to
take one capsule of study drug with breakfast and one capsule of
study drug with dinner. The subjects are further instructed that
they must administer doses with meals at least eight hours apart
and the subjects are informed that taking the study drug on an
empty stomach may lead to insufficient pain relief.
[0456] The touch-tone daily diary is used to record overall PI in
the past 24 hours immediately prior to bedtime. The touch-tone
diary is used to record the following information: (1) overall PI
in the past 24 hours (daily); (2) quality of analgesia (weekly);
and (3) global assessment of study medication (weekly).
[0457] At visits 9 to 11 (End of Weeks 6, 8, and 10 of the
Double-Blind Treatment Period (Fixed Dose)), subjects will return
to the study center every two weeks (14-16 days after the last
visit) for the remainder of the study. Subjects are required to
remain on the dose of study drug administered at the End of Week 4.
The following assessments are performed at each visit:
[0458] (1) Perform opioid toxicity assessments (must be performed
by MD or DO Principal Investigator/Sub-Investigator);
[0459] (2) Contact IVRS to review diary (overall daily PI and
subject compliance);
[0460] (3) Record new/changed adverse events and concomitant
medications;
[0461] (4) Collect study medication from previous visit and account
for used/unused supplies;
[0462] (5) Check vital signs. If a subject reports experiencing any
opioid-related adverse events, the Investigator should offer
treatment;
[0463] (6) Telephone IVRS in order to assign subjects two blister
cards; and
[0464] (7) Dispense two blister cards to the subject. Each blister
card has a two-part clinical label. Remove the tear-off portion of
the label and attach it to the CRF.
[0465] An appointment card is provided to the subject before he/she
leaves the clinic for the next visit. The subject is instructed to
take one capsule of study drug with breakfast and one capsule of
study drug with dinner. The subjects are further instructed that
they must administer doses with meals at least eight hours apart
and the subjects are informed that taking the study drug on an
empty stomach may lead to insufficient pain relief.
[0466] The touch-tone daily diary is used to record overall PI in
the past 24 hours immediately prior to bedtime. The touch-tone
diary is used to record the following information: (1) overall PI
in the past 24 hours (daily); (2) quality of analgesia (weekly);
and (3) global assessment of study medication (weekly).
[0467] At visit 12 (End of Week 12 of Double-Blind Treatment
Period/Early Drug Termination), subjects return to the study center
at either the end of Week 12 (14-16 days after the last visit) or
after early drug termination for the following assessments:
[0468] (1) perform opioid toxicity assessments (must be performed
by MD or DO Principal Investigator/Sub-Investigator);
[0469] (2) contact IVRS to review daily diary (overall daily PI and
subject compliance);
[0470] (3) record new/changed adverse events and concomitant
medications;
[0471] (4) collect study medication and account for used/unused
supplies;
[0472] (5) complete physical examination and vital signs;
[0473] (6) perform EKG (QTc interval);
[0474] (7) obtain blood samples for clinical laboratory tests;
[0475] (8) obtain urine sample for urinalysis;
[0476] (9) WOMAC osteoarthritis index (target joint assessed
throughout the study); and
[0477] (10) SF-12 Health Survey.
[0478] Subjects may require a taper to prevent opioid withdrawal
depending on the duration of treatment with study drug and the
final dose of study drug administered during the fixed dose
treatment period. Subjects taking 5 or 10 mg BID do not require a
taper and are to return to the clinic in approximately one week for
a post-treatment follow-up visit. Subjects who early terminate from
the study require a taper if they have been on study drug for
greater than four weeks (including the open-label titration period)
and were on a dose >10 mg of study drug BID at the time of early
termination. For subjects requiring a taper, the following
procedures are performed:
[0479] (1) Telephone IVRS in order to assign subjects a blister
card; and
[0480] (2) Dispense 1 blister card to the subject. The tear-off
portion of the clinical label on the blister card is removed and
attached to the CRF. Subjects are given the following blister cards
depending on their final fixed dose: Final fixed dose of 40 mg BID,
blister card with 15 days of study drug, Final fixed dose of 30 mg
BID: blister card with 12 days of study drug, Final fixed dose of
15 or 20 mg BID: blister card with 6 days of study drug, or a Final
fixed dose of 5 or 10 mg BID: no taper required.
[0481] An appointment card is provided to the subject before he/she
leaves the clinic for the next visit to occur one week after the
subject's final dose of study medication (up to 22 days). The
subject is instructed to take one capsule of study drug with
breakfast and one capsule of study drug with dinner. The subjects
are further instructed that they must administer doses with meals
at least eight hours apart and the subjects are informed that
taking the study drug on an empty stomach may lead to insufficient
pain relief.
[0482] Subjects are educated about the possibility of opioid
withdrawal after study drug discontinuation. Subjects are
instructed to refrain from taking any opioid-containing medications
(including tramadol or combination medications such as Vicodin)
during the double-blind taper period and subjects are instructed to
contact the study center immediately if severe/intolerable symptoms
of opioid withdrawal are experienced. If required, subjects may
take non-opioid analgesics.
[0483] If a subject experiences intolerable pain during the
double-blind taper period in spite of maximal non-opioid analgesic
therapy, the Investigator may early terminate the subject from the
study and refer for appropriate pain management.
[0484] Subjects may telephone sites to request additional visits if
they experience opioid-related AEs. Subjects are to be instructed
that, with the exception of constipation, mild opioid-related AEs
(feeling drowsy, nausea, vomiting, pruritis, dizziness) often go
away within 24-48 hours. Subjects may return for additional visits
to receive treatment of opioid-related AEs. Investigators are
encouraged to treat opioid-related adverse events as soon as they
occur to avoid subject discomfort/early termination. The following
assessments are performed:
[0485] (1) Perform opioid toxicity assessment;
[0486] Record new/changed adverse events and concomitant
medications;
[0487] Obtain vital signs; and
[0488] Treat opioid-related AEs (if applicable).
[0489] If the subject is experiencing opioid toxicity, the subject
must be early terminated from the trial. If the subject is not
experiencing opioid toxicity but is experiencing significant
opioid-related adverse events, the Investigator is to offer
treatment for the following opioid-related AEs: nausea, vomiting,
pruritic, dizziness, or constipation. Unscheduled visits for
treatment of opioid-related adverse events are allowed throughout
the study.
[0490] At visit 13 (Post-Treatment Follow-up), subjects return to
the study center approximately one week (.+-.two days) after the
last dose of study medication for a post-treatment follow-up visit.
At this visit, the following assessments are completed:
[0491] (1) Collect study medication and account for used/unused
supplies for subjects requiring a taper; and
[0492] (2) Record new/changed adverse events and concomitant
medications.
[0493] Subjects could choose to discontinue study drug or study
participation at any time, for any reason, specified or
unspecified, and without prejudice. If a subject chooses to
discontinue study drug early during the open-label titration
period, the investigator must request that the subject return to
the clinic within 24 hours of stopping the study medication and
complete the assessments for early drug termination from the
open-label titration period. If a subject chooses to discontinue
study drug early during the double-blind treatment period, the
investigator must request that the subject return to the clinic
within 24 hours of stopping the study medication and complete the
End of Week 12/Early Drug Termination assessments. In addition, if
the subject has been on study drug for greater than four weeks
(including the open-label titration period), the subject is to be
tapered off of study drug according to the subject's current dose
at the time of discontinuation. Subjects who are early terminated
from the study because of opioid toxicity should not undergo a
taper and must stop taking study drug immediately.
[0494] Subjects must be educated about the possibility of
withdrawal after study drug discontinuation. Instruct the subject
to contact the study center immediately if severe/intolerable
symptoms of opioid withdrawal are experienced. The investigator
must also request that the subject complete the Post-Treatment
Follow-Up Visit and the double-blind taper period (if applicable)
for safety reasons.
[0495] The SF-12 evaluations, recorded at baseline and at the end
of each week, were scored as described in Ware et al., "SF-12: How
to score the SF-12 physical and mental health summary scales."
QualityMetric Inc., Lincoln, R.I., and the Health Assessment Lab,
Boston, Mass. (3d Ed. 1998), which is incorporated by reference
herein. The summarization and analysis of the WOMAC Osteoarthritis
Index were specified in the Statistical Analysis Plan per the WOMAC
User Guide, which is obtainable at the WOMAC organization website
www.womac.org/contact/index.cfm and incorporated by reference
herein.
[0496] Adverse events reported were mapped to preferred terms and
organ systems using the MedDRA mapping system. Adverse events were
associated with weeks according to their onset date. The number and
percentage of subjects reporting each event are summarized by
treatment group and week.
[0497] Treatment groups are examined for differences in the
incidence and severity of selected opioid-associated adverse
events, including constipation, dizziness, somnolence, headache,
pruritus, nausea, vomiting, urinary retention, and bradypnoea. The
homogeneity of response between males and females is investigated
descriptively.
[0498] All subjects that take at least one dose of study medication
following randomization and complete at least one
post-randomization pain intensity assessment are evaluable for
efficacy analyses. All subjects who take at least one dose of oral
study medication are evaluable for safety analyses.
[0499] The primary efficacy analysis population is the
intent-to-treat (ITT) population. The ITT population consists of
all randomized subjects who are administered any study medication,
have at least one post-randomization PI assessment and are used for
efficacy analyses. All subjects who take at least one dose of study
medication are used for safety analyses.
[0500] Demographic variables and subject characteristics are
summarized descriptively by treatment group. Demographic variables
include age, weight, height, gender, and race/ethnicity. Baseline
characteristics include target joint, mean daily overall PI
collected through the IVRS over the last two days of the washout
and open-label titration periods, screening clinic PI, washout
period acetaminophen usage, and baseline and pre-randomization
values of efficacy and quality of life variables. Baseline and
post-baseline patient characteristics include study drug
administration, prior and concomitant medications, final study drug
dose, and opioid use within one month prior to study.
[0501] The following endpoints are summarized and analyzed for
efficacy analysis:
[0502] Daily diary PI score are analyzed as weekly values as
follows: For each week, the PI recorded during all days of the week
are averaged. Baseline PI is defined as the average PI recorded
during the two days immediately prior to the Baseline visit.
Pre-randomization PI is defined as the average PI recorded during
the two days immediately prior to randomization at the end of the
open-label titration period;
[0503] (2) Quality of analgesia is assessed and analyzed
weekly;
[0504] (3) Global assessment of study medication is assessed and
analyzed weekly;
[0505] (4) WOMAC Osteoarthritis Index is assessed and analyzed at
baseline, pre-randomization and at the end of treatment; calculated
per the WOMAC User Guide; and
[0506] (5) SF-12 is assessed and analyzed at baseline,
pre-randomization and at the end of treatment, scored as described
in the documentation.
[0507] The following endpoints are summarized and analyzed for
safety analysis:
[0508] (1) Adverse events reported on case report forms are mapped
to preferred terms and body systems using the Medical Dictionary
for Regulatory Activities (MedDRA) coding dictionary;
[0509] (2) The number and percent of subjects reporting each event
are summarized during the open-label titration period and by
treatment group during the double-blind treatment period. Incidence
of adverse events by maximum reported severity are also tabulated.
Serious adverse events and adverse events leading to
discontinuation are displayed;
[0510] (3) Vital signs are summarized descriptively based on actual
value, change from baseline, and change from randomization. QTc
interval is summarized descriptively based on actual value and
change from baseline;
[0511] (4) Laboratory data are summarized descriptively based on
actual value, change from baseline and in terms of the normal
range. Physical examination results are summarized by number and
percentage of patients with abnormalities in each body system
examined.
[0512] For primary analysis of data, the primary efficacy endpoint
is the percent change from baseline in pain intensity at the
conclusion of the study. The primary efficacy variable is the area
under the curve (AUC) for the change in PI from randomization to
the end of the Week 12 fixed dose portion of the double-blind
treatment period. AUC is determined by linear trapezoidal method.
The primary efficacy analysis compares the mean AUC for the study
drug treatment group versus the placebo group, using treatment as a
factor and pre-randomization PI score as a covariate in an ANCOVA
model. Missing data is not imputed. For randomized patients who
drop out, whether for adverse events or lack of adequate pain
relief or use of rescue medication, only data prior to withdrawal
is used. Implicitly AUC assigns zero differences from baseline
after withdrawals. The double-blind taper period is not included in
the AUC calculation.
[0513] For secondary analysis of data, quality of analgesia, global
assessment of study medication, WOMAC Osteoarthritis Index, and the
SF-12 Health Survey are analyzed. The weekly averaged PI scores are
analyzed at the end of each week of titration and at the end of
each week of the double-blind fixed dose period. The change and
percent change from baseline and from randomization is compared
across treatment groups using the same ANCOVA as the primary
analysis. In addition, this data is presented by target joint, sex
and age.
[0514] The quality of analgesia and global assessment of study
medication are analyzed as categorical variables using a stratified
Cochran-Mantel-HaenszelT (CMH) test with baseline and
pre-randomization PI to define the strata. The comparisons across
treatment groups are presented overall, and by target joint, sex
and age.
[0515] The WOMAC Osteoarthritis Index (pain subscale, stiffness
subscale, physical function subscale, total score) and SF-12 are
analyzed at the end of treatment in terms of change and percent
change from randomization. The change and percent change from
randomization is compared across treatment groups using the same
ANCOVA as the primary analysis. The change and percent change from
baseline is also analyzed. In addition, the comparison is made by
target joint, sex and age.
[0516] AUC is calculated for the change from baseline PI including
the two-week open-label titration period for each treatment group
using treatment as a factor and baseline PI score as a covariate in
an ANCOVA model. AUC is determined by linear trapezoidal method.
Comparative analysis will follow the ANCOVA model as the primary
analysis.
[0517] For the purpose of sample size and power calculations,
placebo subjects who complete the study period are assumed to have
at least a mean decrease in change from baseline P1 of up to 25%.
The majority of withdrawals in enrichment designs occur during the
open-label titration phase. The assumed withdrawal rate after
randomization is 25%.
[0518] To design a study with greater than 90% power, with a common
standard deviation of 30%, a mean difference of 10% in average AUC
in PI requires a sample size of 200 patients per treatment group
(400 total) using a 0.05 two-sided significance level.
[0519] Unless otherwise indicated, all testing of statistical
hypotheses is two-sided, and a difference resulting in a p-value of
less than or equal to 0.05 is considered statistically
significant.
[0520] Causes of early termination from study drug during the
double-blind treatment period are shown in Table 8. The majority of
subjects who terminated from the trial (10.6% of subjects taking
placebo BID and 21.0% of subjects taking study drug BID)
experienced an adverse event. Out of the 145 subjects that
terminated during the double-blind period 65 (15.8%) terminated due
to adverse events. This constituted (10.6%) of the subjects
administered placebo BID and (21.0%) of subjects administered study
drug BID.
TABLE-US-00010 TABLE 8 TERMINATION FROM STUDY DRUG DURING THE
12-WEEK DOUBLE-BLIND PERIOD ANALYSIS POPULATION: DOUBLE-BLIND
SAFETY POPULATION PLACEBO BID OXY BID TOTAL (N = 207) (N = 205) (N
= 412) DID THE PATIENT TERMINATE STUDY DRUG EARLY? NO 132 (63.8%)
131 (63.9%) 263 (63.8%) YES 75 (36.2%) 70 (34.1%) 145 (35.2%)
INADEQUATE PAIN 38 (18.4%) 12 (5.9%) 50 (12.1%) RELIEF ADVERSE
EVENT 22 (10.6%) 43 (21.0%) 65 (15.8%) PROTOCOL 6 (2.9%) 7 (3.4%)
13 (3.2%) VIOLATION INAPPROPRIATE 1 1 2 ENROLLMENT NEED FOR 2 2 4
PROHIBITED MEDICATION OTHER 3 4 7 PATIENT REQUEST 4 (1.9%) 8 (3.9%)
12 (2.9%) UNRELATED TO STUDY OTHER 5 (2.4%) 0 (0.0%) 5 (1.2%) NOTE:
DOUBLE-BLIND SAFETY POPULATION - ALL PATIENTS WHO TAKE AT LEAST ONE
DOSE OF STUDY MEDICATION IN DOUBLE-BLIND PERIOD.
[0521] The most frequent adverse events (AEs) reported were those
commonly associated with opioid medications: dizziness,
constipation, dry mouth, nausea, vomiting, somnolence, and
pruritis. Table 9 shows the AEs that caused termination from the
clinical trial from randomization through the post-treatment
follow-up visit.
TABLE-US-00011 TABLE 9 ADVERSE EVENTS CAUSING DISCONTINUATION OF
STUDY MEDIATION FROM RANDOMIZATION THROUGH THE POST-TREATMENT
FOLLOW-UP VISIT [1] ANALYSIS POPULATION: DOUBLE-BLIND SAFETY
POPULATION PLACEBO BID OXY BID TOTAL (N = 207) (N = 205) (N = 412)
CARDIAC DISORDERS 0 (0.0%) 1 (0.5%) 1 (0.2%) PALPITATIONS 0 (0.0%)
1 (0.5%) 1 (0.2%) GASTROINTESTINAL DISORDERS 7 (3.4%) 16 (7.8%) 23
(5.6%) ABDOMINAL PAIN 1 (0.5%) 1 (0.5%) 2 (0.5%) CONSTIPATION 1
(0.5%) 2 (1.0%) 3 (0.7%) DIARRHEA 0 (0.0%) 1 (0.5%) 1 (0.2%) DRY
MOUTH 0 (0.0%) 1 (0.5%) 1 (0.2%) FAECALOMA 0 (0.0%) 1 (0.5%) 1
(0.2%) NAUSEA 5 (2.4%) 9 (4.4%) 14 (3.4%) VOMITING 2 (1.0%) 4
(2.0%) 6 (1.5%) GENERAL DISORDERS AND 3 (1.4%) 2 (1.0%) 5 (1.2%)
ADMINISTRATION SITE CONDITIONS ASTHENIA 1 (0.5%) 0 (0.0%) 1 (0.2%)
CHEST PAIN 0 (0.0%) 1 (0.5%) 1 (0.2%) CHILLS 0 (0.0%) 1 (0.5%) 1
(0.2%) FATIGUE 1 (0.5%) 0 (0.0%) 1 (0.2%) OEDEMA 1 (0.5%) 0 (0.0%)
1 (0.2%) PYREXIA 0 (0.0%) 1 (0.5%) 1 (0.2%) HEPATOBILIARY DISORDERS
1 (0.5%) 0 (0.0%) 1 (0.2%) CHOLELITHIASIS 1 (0.5%) 0 (0.0%) 1
(0.2%) INFECTIONS AND INFESTATIONS 0 (0.0%) 1 (0.5%) 1 (0.2%)
BRONCHITIS 0 (0.0%) 1 (0.5%) 1 (0.2%) INJURY, POISONING AND 1
(0.5%) 0 (0.0%) 1 (0.2%) PROCEDURAL COMPLICATIONS INCISION SITE
COMPLICATION 1 (0.5%) 0 (0.0%) 1 (0.2%) INVESTIGATIONS 1 (0.5%) 0
(0.0%) 1 (0.2%) ASPARTATE AMINOTRANSFERASE 1 (0.5%) 0 (0.0%) 1
(0.2%) INCREASED METABOLISM AND NUTRITION 1 (0.5%) 2 (1.0%) 3
(0.7%) DISORDERS ANOREXIA 0 (0.0%) 2 (1.0%) 2 (0.5%) GOUT 1 (0.5%)
0 (0.0%) 1 (0.2%) MUSCULOSKELETAL AND 2 (1.0%) 1 (0.5%) 3 (0.7%)
CONNECTIVE TISSUE DISORDERS ARHRALGIA 1 (0.5%) 1 (0.5%) 2 (0.5%)
BACK PAIN 1 (0.5%) 0 (0.0%) 1 (0.2%) OSTEOARTHRITIS 1 (0.5%) 0
(0.0%) 1 (0.2%) PAIN IN EXTREMITY 1 (0.5%) 0 (0.0%) 1 (0.2%)
NERVOUS SYSTEM DISORDERS 6 (2.9%) 11 (5.4%) 17 (4.1%) DIZZINESS 3
(1.4%) 3 (1.5%) 6 (1.5%) DYSARTHRIA 0 (0.0%) 1 (0.5%) 1 (0.2%)
DYSGEUSIA 0 (0.0%) 1 (0.5%) 1 (0.2%) LETHARGY 1 (0.5%) 0 (0.0%) 1
(0.2%) PARAESTHESIA 0 (0.0%) 1 (0.5%) 1 (0.2%) SOMNOLENCE 1 (0.5%)
6 (2.9%) 7 (1.7%) STUPOR 0 (0.0%) 1 (0.5%) 1 (0.2%) TRANSIENT
ISCHAEMIC 0 (0.0%) 1 (0.5%) 1 (0.2%) ATTACK TREMOR 1 (0.5%) 0
(0.0%) 1 (0.2%) PSYCHIATRIC DISORDERS 4 (1.9%) 8 (3.9%) 12 (2.9%)
AGITATION 1 (0.5%) 0 (0.0%) 1 (0.2%) ANXIETY 0 (0.0%) 1 (0.5%) 1
(0.2%) CONFUSIONAL STATE 1 (0.5%) 4 (2.0%) 5 (1.2%) DEPRESSION 0
(0.0%) 2 (1.0%) 2 (0.5%) INSOMNIA 1 (0.5%) 0 (0.0%) 1 (0.2%) MENTAL
STATUS CHANGES 0 (0.0%) 2 (1.0%) 2 (0.5%) MOOD SWINGS 0 (0.0%) 1
(0.5%) 1 (0.2%) PERSONALITY CHANGE 1 (0.5%) 0 (0.0%) 1 (0.2%)
SUICIDE ATTEMPT 0 (0.0%) 1 (0.5%) 1 (0.2%) RESPIRATORY, THORACIC
AND 0 (0.0%) 2 (1.0%) 2 (0.5%) MEDIASTINAL DISORDERS DYSPNOEA 0
(0.0%) 1 (0.5%) 1 (0.2%) HAEMOPTYSIS 0 (0.0%) 1 (0.5%) 1 (0.2%)
SKIN AND SUBCUTANEOUS TISSUE 2 (1.0%) 2 (1.0%) 4 (1.0%) DISORDERS
HYPERHIDROSIS 0 (0.0%) 1 (0.5%) 1 (0.2%) PRURITUS 2 (1.0%) 1 (0.5%)
3 (0.7%) NOTE: DOUBLE-BLIND SAFETY POPULATION - ALL PATIENTS WHO
TAKE AT LEAST ONE DOSE OF STUDY MEDICATION IN DOUBLE-BLIND PERIOD.
[1] ADVERSE EVENT START DATE IS BETWEEN THE FIRST DOSE OF STUDY
MEDICATION IN THE DOUBLE-BLIND PERIOD THROUGH THE DATE OF
POST-TREATMENT FOLLOW-UP/STUDY TERMINATION, INCLUSIVE.
[0522] The primary efficacy endpoint for the clinical trial was a
decrease in pain intensity (AUC) between study drug BID and placebo
BID during the twelve week double-blind treatment period. Subjects
that received study drug BID demonstrated a statistically
significant decrease in their pain intensity-AUC as compared to the
subjects that received placebo BID and thus the study met its
prospectively defined primary endpoint with a p=0.007 as shown in
Table 10.
TABLE-US-00012 TABLE 10 PAIN INTENSITY - AUC 12 WEEK DOUBLE-BLIND
PERIOD ANALYSIS POPULATION: INTENT TO TREAT POPULATION PLACEBO BID
OXY BID TOTAL (N = 207) (N = 203) (N = 410) AREA UNDER CURVE (AUC)
MEAN (SD) -30.4 (140.38) -54.9 (122.44) -42.5 (132.21) MEDIAN -1.5
-27.1 -9.8 MINIMUM, -501.8, 370.7 -683.3, 382.8 -683.3, 382.8
MAXIMUM N 205 201 406 MODEL P-VALUES TREATMENT [1] 0.007 PRE-
<0.001 RANDOMIZATION PI [1] NOTE: INTENT TO TREAT POPULATION -
ALL RANDOMIZED PATIENTS WHO TAKE ANY STUDY MEDICATION AND HAVE AT
LEAST ONE POST-RANDOMIZATION PI ASSESSMENT. NOTE: THE AREA UNDER
THE CURVE (AUC) IS CALCULATED BY THE LINEAR TRAPEZOIDAL METHOD
USING CHANGE FROM PRE-RANDOMIZATION PAIN INTENSITY SCORES. [1]
P-VALUES FROM ANCOVA MODEL INCLUDING TREATMENT AS THE MAIN EFFECT
AND PRE-RANDOMIZATION PAIN INTENSITY AS A COVARIATE.
[0523] A secondary efficacy endpoint for this study was change in
pain intensity from baseline at each of the twelve weeks of the
double-blind treatment period. In general, the group that received
the study drug BID had consistently lower pain intensity scores at
each week during the twelve week double-blind treatment period as
compared to the group that received placebo BID (see, e.g., at week
twelve p=0.024). Table 11 shows the pain intensity scores at each
of the twelve weeks during the double-blind treatment period for
the treated group and the placebo group.
TABLE-US-00013 TABLE 11 PAIN INTENSITY - BY WEEK OPEN-LABEL
TITRATION AND 12-WEEK DOUBLE-BLIND PERIODS LAST OBSERVATION CARRIED
FORWARD IMPUTATION ANALYSIS POPULATION: INTENT TO TREAT POPULATION
PLACEBO BID OXY BID TOTAL (N = 207) (N = 203) (N = 410)
PRE-RANDOMIZATION MEAN (SD) 5.4 (2.11) 5.2 (2.19) 5.3 (2.15) MEDIAN
5.5 5.0 5.5 MINIMUM, MAXIMUM 0.0, 10.0 0.0, 10.0 0.0, 10.0 N 207
203 410 MODEL P-VALUES TREATMENT [1] 0.259 DOUBLE-BLIND WEEK 1 MEAN
(SD) 5.7 (2.00) 5.2 (2.00) 5.4 (2.01) MEDIAN 6.0 5.1 5.5 MINIMUM,
MAXIMUM 0.0, 10.0 0.0, 10.0 0.0, 10.0 N 207 202 409 MODEL P-VALUES
TREATMENT [1] 0.001 PRE-RANDOMIZATION <0.001 PI [1] CHANGE FROM
PRE- RANDOMIZATION TO DOUBLE-BLIND WEEK 1 MEAN (SD) 0.2 (1.14) -0.0
(1.09) 0.1 (1.13) MEDIAN 0.1 0.0 0.0 MINIMUM, MAXIMUM -3.5, 4.4
-4.6, 5.4 -4.6, 5.4 N 207 202 409 MODEL P-VALUES TREATMENT [1]
0.001 PRE-RANDOMIZATION <0.001 PI [1] DOUBLE-BLIND WEEK 2 MEAN
(SD) 5.6 (2.05) 4.9 (2.07) 5.2 (2.09) MEDIAN 5.7 4.9 5.2 MINIMUM,
MAXIMUM 0.0, 10.0 0.0, 9.9 0.0, 10.0 N 207 203 410 MODEL P-VALUES
TREATMENT [1] <0.001 PRE-RANDOMIZATION <0.001 PI [1] CHANGE
FROM PRE- RANDOMIZATION TO DOUBLE-BLIND WEEK 2 MEAN (SD) 0.1 (1.62)
-0.3 (1.61) -0.1 (1.63) MEDIAN 0.0 -0.3 -0.1 MINIMUM, MAXIMUM -4.8,
4.3 -6.9, 6.7 -6.9, 6.7 N 207 203 410 MODEL P-VALUES TREATMENT [1]
<0.001 PRE-RANDOMIZATION <0.001 PI [1] DOUBLE-BLIND WEEK 3
MEAN (SD) 5.5 (2.13) 4.6 (2.07) 5.1 (2.15) MEDIAN 5.3 4.6 5.0
MINIMUM, MAXIMUM 0.0, 10.0 0.0, 10.0 0.0, 10.0 N 207 203 410 MODEL
P-VALUES TREATMENT [1] <0.001 PRE-RANDOMIZATION [1] <0.001
CHANGE FROM PRE- RANDOMIZATION TO DOUBLE-BLIND WEEK 3 MEAN (SD) 0.1
(1.94) -0.6 (1.81) -0.2 (1.90) MEDIAN 0.0 -0.6 -0.2 MINIMUM,
MAXIMUM -6.0, 5.3 -9.5, 7.3 -9.5, 7.3 N 207 203 410 MODEL P-VALUES
TREATMENT [1] <0.001 PRE-RANDOMIZATION [1] <0.001
DOUBLE-BLIND WEEK 4 MEAN (SD) 5.4 (2.17) 4.4 (2.07) 4.9 (2.17)
MEDIAN 5.3 4.4 4.9 MINIMUM, MAXIMUM 0.0, 10.0 0.0, 10.0 0.0, 10.0 N
207 203 410 MODEL P-VALUES TREATMENT [1] <0.001
PRE-RANDOMIZATION <0.001 PI [1] CHANGE FROM PRE- RANDOMIZATION
TO DOUBLE-BLIND WEEK 4 MEAN (SD) -0.0 (2.09) -0.8 (1.78) -0.4
(1.97) MEDIAN 0.0 -0.9 -0.3 MINIMUM, MAXIMUM -6.8, 5.0 -9.5, 4.0
-9.5, 5.0 N 207 203 410 MODEL P-VALUES TREATMENT [1] <0.001
PRE-RANDOMIZATION <0.001 PI [1] DOUBLE-BLIND WEEK 5 MEAN (SD)
5.3 (2.22) 4.4 (2.08) 4.8 (2.20) MEDIAN 5.2 4.3 4.8 MINIMUM,
MAXIMUM 0.0, 10.0 0.0, 10.0 0.0, 10.0 N 207 203 410 MODEL P-VALUES
TREATMENT [1] <0.001 PRE-RANDOMIZATION <0.001 PI [1] CHANGE
FROM PRE- RANDOMIZATION TO DOUBLE-BLIND WEEK 5 MEAN (SD) -0.1
(2.19) -0.8 (1.79) -0.5 (2.03) MEDIAN 0.0 -0.7 -0.4 MINIMUM,
MAXIMUM -6.5, 5.0 -9.5, 4.0 -9.5, 5.0 N 207 203 410 MODEL P-VALUES
TREATMENT [1] <0.001 PRE-RANDOMIZATION <0.001 PI [1]
DOUBLE-BLIND WEEK 6 MEAN (SD) 5.3 (2.32) 4.3 (2.03) 4.8 (2.22)
MEDIAN 5.1 4.2 4.7 MINIMUM, MAXIMUM 0.0, 10.0 0.0, 10.0 0.0, 10.0 N
207 203 410 MODEL P-VALUES TREATMENT [1] <0.001
PRE-RANDOMIZATION <0.001 PI [1] CHANGE FROM PRE- RANDOMIZATION
TO DOUBLE-BLIND WEEK 6 MEAN (SD) -0.2 (2.23) -0.9 (1.86) -0.5
(2.08) MEDIAN 0.0 -0.9 -0.4 MINIMUM, MAXIMUM -6.8, 5.2 -8.8, 4.8
-8.8, 5.2 N 207 203 410 MODEL P-VALUES TREATMENT [1] <0.001
PRE-RANDOMIZATION <0.001 PI [1] DOUBLE-BLIND WEEK 7 MEAN (SD)
5.2 (2.33) 4.3 (2.13) 4.8 (2.27) MEDIAN 5.0 4.2 4.7 MINIMUM,
MAXIMUM 0.0, 10.0 0.0, 10.0 0.0, 10.0 N 207 203 410 MODEL P-VALUES
TREATMENT [1] <0.001 PRE-RANDOMIZATION <0.001 PI [1] CHANGE
FROM PRE- RANDOMIZATOIN TO DOUBLE-BLIND WEEK 7 MEAN (SD) -0.2
(2.30) -0.9 (1.91) -0.6 (2.13) MEDIAN -0.1 -0.8 -0.5 MINIMUM,
MAXIMUM -6.9, 5.9 -9.5, 6.3 -9.5, 6.3 N 207 203 410 MODEL P-VALUES
TREATMENT [1] <0.001 PRE-RANDOMIZATION <0.001 PI [1]
DOUBLE-BLIND WEEK 6 MEAN (SD) 5.2 (2.33) 4.4 (2.14) 4.8 (2.26)
MEDIAN 5.1 4.4 4.8 MINIMUM, MAXIMUM 0.0, 10.0 0.0, 10.0 0.0, 10.0 N
207 203 410 MODEL P-VALUES TREATMENT [1] 0.002 PRE-RANDOMIZATION
<0.001 PI [1] CHANGE FROM PRE- RANDOMIZATION TO DOUBLE-BLIND
WEEK 8 MEAN (SD) -0.3 (2.34) -0.8 (2.01) -0.5 (2.19) MEDIAN -0.2
-0.8 -0.5 MINIMUM, MAXIMUM -7.1, 5.0 -9.5, 9.0 -9.5, 9.0 N 207 203
410 MODEL P-VALUES TREATMENT [1] 0.002 PRE-RANDOMIZATION <0.001
PI [1] DOUBLE-BLIND WEEK 9 MEAN (SD) 5.1 (2.33) 4.4 (2.15) 4.8
(2.27) MEDIAN 5.0 4.4 4.8 MINIMUM, MAXIMUM 0.0, 10.0 0.0, 10.0 0.0,
10.0 N 207 203 410 MODEL P-VALUES TREATMENT [1] 0.002
PRE-RANDOMIZATION <0.001 PI [1] CHANGE FROM PRE- RANDOMIZATION
TO DOUBLE-BLIND WEEK 9 MEAN (SD) -0.3 (2.43) -0.8 (1.95) -0.5
(2.21) MEDIAN -0.2 -0.7 -0.5 MINIMUM, MAXIMUM -8.2, 5.0 -9.5, 4.7
-9.5, 5.0 N 207 203 410 MODEL P-VALUES TREATMENT [1] 0.002
PRE-RANDOMIZATION <0.001 PI [1] DOUBLE-BLIND WEEK 10 MEAN (SD)
5.2 (2.37) 4.4 (2.16) 4.8 (2.30) MEDIAN 5.0 4.3 4.8 MINIMUM,
MAXIMUM 0.0, 10.0 0.0, 10.0 0.0, 10.0 N 207 203 410 MODEL P-VALUES
TREATMENT [1] <0.001 PRE-RANDOMIZATION <0.001 PI [1] CHANGE
FROM PRE- RANDOMIZATION TO DOUBLE-BLIND WEEK 10 MEAN (SD) -0.3
(2.45) -0.8 (2.06) -0.5 (2.28) MEDIAN 0.0 -0.7 -0.3 MINIMUM,
MAXIMUM -9.0, 5.0 -9.5, 7.8 -9.5, 7.8 N 207 203 410 MODEL P-VALUES
TREATMENT [1] <0.001 PRE-RANDOMIZATION <0.001 PI [1]
DOUBLE-BLIND WEEK 11 MEAN (SD) 5.1 (2.39) 4.4 (2.15) 4.8 (2.30)
MEDIAN 5.0 4.2 4.7 MINIMUM, MAXIMUM 0.0, 10.0 0.0, 10.0 0.0, 10.0 N
207 203 410 MODEL P-VALUES TREATMENT [1] 0.002 PRE-RANDOMIZATION
<0.001 PI [1] CHANGE FROM PRE- RANDOMIZATION TO DOUBLE-BLIND
WEEK 11 MEAN (SD) -0.3 (2.50) -0.8 (2.02) -0.6 (2.28) MEDIAN 0.0
-0.8 -0.5 MINIMUM, MAXIMUM -9.0, 4.7 -8.9, 7.0 -9.0, 7.0 N 207 203
410 MODEL P-VALUES TREATMENT [1] 0.002 PRE-RANDOMIZATION <0.001
PI [1] DOUBLE-BLIND WEEK 12 MEAN (SD) 5.1 (2.41) 4.5 (2.15) 4.8
(2.30) MEDIAN 5.0 4.3 4.8 MINIMUM, MAXIMUM 0.0, 10.0 0.0, 10.0 0.0,
10.0 N 207 203 410 MODEL P-VALUES TREATMENT [1] 0.024
PRE-RANDOMIZATION <0.001 PI [1] CHANGE FROM PRE- RANDOMIZATOIN
TO DOUBLE-BLIND WEEK 12 MEAN (SD) -0.3 (2.48) -0.7 (2.05) -0.5
(2.28) MEDIAN 0.0 -0.6 -0.2
MINIMUM, MAXIMUM -9.0, 5.0 -8.5, 6.0 -9.0, 6.0 N 207 203 410 MODEL
P-VALUES TREATMENT [1] 0.024 PRE-RANDOMIZATION <0.001 PI [1] [1]
P-VALUES FROM ANCOVA MODEL INCLUDING TREATMENT AS THE MAIN
EFFECT
[0524] Another secondary efficacy endpoint for this study was
global assessment. For global assessment, the group that received
study drug BID showed a consistently better global assessment at
each week during the twelve week double-blind treatment period as
compared to the group that received placebo BID (see, e.g., at week
twelve p=0.007). Table 12 shows the results of the global
assessment during the double-blind treatment period.
TABLE-US-00014 TABLE 12 GLOBAL ASSESSMENT - BY WEEK 12-WEEK
DOUBLE-BLIND PERIOD LAST OBSERVATION CARRIED FORWARD IMPUTATION
ANALYSIS POPULATION: INTENT TO TREAT POPULATION PLACEBO BID OXY BID
TOTAL (N = 207) (N = 203) (N = 410) THE DOUBLE-BLIND WEEK 1
EXCELLENT (4) 5 (2.4%) 6 (3.0%) 11 (2.7%) VERY GOOD (3) 6 (2.9%) 14
(6.9%) 20 (4.9%) GOOD (2) 62 (30.0%) 70 (34.5%) 132 (32.2%) FAIR
(1) 75 (36.2%) 66 (32.5%) 141 (34.4%) POOR (0) 29 (14.0%) 25
(12.3%) 54 (13.2%) OVERALL P-VALUE [1] 0.115 THE DOUBLE-BLIND WEEK
2 EXCELLENT (4) 1 (0.5%) 5 (2.5%) 6 (1.5%) VERY GOOD (3) 16 (7.7%)
17 (8.4%) 33 (8.0%) GOOD (2) 58 (28.0%) 79 (38.9%) 137 (33.4%) FAIR
(1) 65 (31.4%) 66 (32.5%) 131 (32.0%) POOR (0) 39 (18.8%) 23
(11.3%) 62 (15.1%) OVERALL P-VALUE [1] 0.012 THE DOUBLE-BLIND WEEK
3 EXCELLENT (4) 1 (0.5%) 9 (4.4%) 10 (2.4%) VERY GOOD (3) 16 (7.7%)
25 (12.3%) 41 (10.0%) GOOD (2) 52 (25.1%) 70 (34.5%) 122 (29.8%)
FAIR (1) 67 (32.4%) 62 (30.5%) 129 (31.5%) POOR (0) 45 (21.7%) 25
(12.3%) 70 (17.1%) OVERALL P-VALUE [1] <0.001 THE DOUBLE-BLIND
WEEK 4 EXCELLENT (4) 4 (1.9%) 5 (2.5%) 9 (2.2%) VERY GOOD (3) 22
(10.6%) 30 (14.8%) 52 (12.7%) GOOD (2) 49 (23.7%) 79 (38.9%) 128
(31.2%) FAIR (1) 55 (26.6%) 53 (26.1%) 108 (26.3%) POOR (0) 53
(25.6%) 24 (11.8%) 77 (18.8%) OVERALL P-VALUE [1] <0.001 THE
DOUBLE-BLIND WEEK 5 EXCELLENT (4) 3 (1.4%) 5 (2.5%) 8 (2.0%) VERY
GOOD (3) 13 (6.3%) 33 (16.3%) 46 (11.2%) GOOD (2) 55 (26.6%) 70
(34.5%) 125 (30.5%) FAIR (1) 63 (30.4%) 62 (30.5%) 125 (30.5%) POOR
(0) 49 (23.7%) 22 (10.8%) 71 (17.3%) OVERALL P-VALUE [1] <0.001
THE DOUBLE-BLIND WEEK 6 EXCELLENT (4) 5 (2.4%) 2 (1.0%) 7 (1.7%)
VERY GOOD (3) 18 (8.7%) 24 (11.8%) 42 (10.2%) GOOD (2) 51 (24.6%)
80 (39.4%) 131 (32.0%) FAIR (1) 57 (27.5%) 67 (33.0%) 124 (30.2%)
POOR (0) 52 (25.1%) 19 (9.4%) 71 (17.3%) OVERALL P-VALUE [1] 0.002
THE DOUBLE-BLIND WEEK 7 EXCELLENT (4) 3 (1.4%) 6 (3.0%) 9 (2.2%)
VERY GOOD (3) 22 (10.6%) 27 (13.3%) 49 (12.0%) GOOD (2) 51 (24.6%)
74 (36.5%) 125 (30.5%) FAIR (1) 53 (25.6%) 57 (28.1%) 110 (26.8%)
POOR (0) 54 (26.1%) 28 (13.8%) 82 (20.0%) OVERALL P-VALUE [1] 0.002
THE DOUBLE-BLIND WEEK 8 EXCELLENT (4) 4 (1.9%) 9 (4.4%) 13 (3.2%)
VERY GOOD (3) 19 (9.2%) 24 (11.8%) 43 (10.5%) GOOD (2) 59 (28.5%)
75 (36.9%) 134 (32.7%) FAIR (1) 46 (22.2%) 55 (27.1%) 101 (24.6%)
POOR (0) 55 (26.6%) 29 (14.3%) 84 (20.5%) OVERALL P-VALUE [1] 0.003
THE DOUBLE-BLIND WEEK 9 EXCELLENT (4) 4 (1.9%) 4 (2.0%) 8 (2.0%)
VERY GOOD (3) 19 (9.2%) 25 (12.3%) 44 (10.7%) GOOD (2) 52 (25.1%)
71 (35.0%) 123 (30.0%) FAIR (1) 53 (25.6%) 62 (30.5%) 115 (28.0%)
POOR (0) 55 (26.6%) 30 (14.8%) 85 (20.7%) OVERALL P-VALUE [1] 0.009
THE DOUBLE-BLIND WEEK 10 EXCELLENT (4) 7 (3.4%) 6 (3.0%) 13 (3.2%)
VERY GOOD (3) 15 (7.2%) 29 (14.3%) 44 (10.7%) GOOD (2) 52 (25.1%)
72 (35.5%) 124 (30.2%) FAIR (1) 52 (25.1%) 54 (26.6%) 106 (25.9%)
POOR (0) 57 (27.5%) 31 (15.3%) 88 (21.5%) OVERALL P-VALUE [1] 0.001
THE DOUBLE-BLIND WEEK 11 EXCELLENT (4) 5 (2.4%) 5 (2.5%) 10 (2.4%)
VERY GOOD (3) 19 (9.2%) 23 (11.3%) 42 (10.2%) GOOD (2) 49 (23.7%)
73 (36.0%) 122 (29.8%) FAIR (1) 57 (27.5%) 59 (29.1%) 116 (28.3%)
POOR (0) 53 (25.6%) 32 (15.8%) 85 (20.7%) OVERALL P-VALUE [1] 0.015
THE DOUBLE-BLIND WEEK 12 EXCELLENT (4) 6 (2.9%) 7 (3.4%) 13 (3.2%)
VERY GOOD (3) 19 (9.2%) 25 (12.3%) 44 (10.7%) GOOD (2) 49 (23.7%)
67 (33.0%) 116 (28.3%) FAIR (1) 52 (25.1%) 63 (31.0%) 115 (28.0%)
POOR (0) 57 (27.5%) 30 (14.8%) 87 (21.2%) OVERALL P-VALUE [1] 0.007
[1] COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST ACROSS TREATMENT
GROUPS USING EQUALLY SPACED SCORES ADJUSTING FOR BASELINE PI
(.gtoreq.7.5 AND <7.5) AND PRE-RANDOMIZATION PI (.gtoreq.5 AND
<5).
[0525] Another secondary efficacy endpoint for this study was
quality of analgesia. For quality of analgesia, the group that
received study drug BID showed a consistent and greater improvement
in the quality of analgesia at each week during the twelve week
double-blind treatment period as compared to the group that
received the placebo BID (see, e.g., at week twelve p=0.004). Table
13 shows the quality of analgesia at each of the twelve weeks
during the double-blind treatment period.
TABLE-US-00015 TABLE 13 QUALITY OF ANALGESIA - BY WEEK 12-WEEK
DOUBLE-BLIND PERIOD LAST OBSERVATION CARRIED FORWARD IMPUTATION
ANALYSIS POPULATION: INTENT TO TREAT POPULATION PLACEBO BID OXY BID
TOTAL (N = 207) (N = 203) (N = 410) THE DOUBLE-BLIND WEEK 1
EXCELLENT 5 (2.4%) 4 (2.0%) 9 (2.2%) VERY GOOD 12 (5.8%) 23 (11.3%)
35 (8.5%) GOOD 55 (26.6%) 67 (33.0%) 122 (29.8%) FAIR 71 (34.3%) 64
(31.5%) 135 (32.9%) POOR 39 (18.8%) 30 (14.8%) 69 (16.8%) OVERALL
P-VALUE [1] 0.072 THE DOUBLE-BLIND WEEK 2 EXCELLENT 3 (1.4%) 5
(2.5%) 8 (2.0%) VERY GOOD 15 (7.2%) 28 (13.8%) 43 (10.5%) GOOD 61
(29.5%) 69 (34.0%) 130 (31.7%) FAIR 59 (28.5%) 61 (30.0%) 120
(29.3%) POOR 45 (21.7%) 27 (13.3%) 72 (17.6%) OVERALL P-VALUE [1]
0.007 THE DOUBLE-BLIND WEEK 3 EXCELLENT 4 (1.9%) 4 (2.0%) 8 (2.0%)
VERY GOOD 20 (9.7%) 32 (15.8%) 52 (12.7%) GOOD 53 (25.6%) 80
(39.4%) 133 (32.4%) FAIR 55 (26.6%) 51 (25.1%) 106 (25.9%) POOR 51
(24.6%) 24 (11.8%) 75 (18.3%) OVERALL P-VALUE [1] <0.001 THE
DOUBLE-BLIND WEEK 4 EXCELLENT 4 (1.9%) 8 (3.9%) 12 (2.9%) VERY GOOD
20 (9.7%) 35 (17.2%) 55 (13.4%) GOOD 51 (24.6%) 73 (36.0%) 124
(30.2%) FAIR 56 (27.1%) 49 (24.1%) 105 (25.6%) POOR 52 (25.1%) 26
(12.8%) 78 (19.0%) OVERALL P-VALUE [1] <0.001 THE DOUBLE-BLIND
WEEK 5 EXCELLENT 5 (2.4%) 5 (2.5%) 10 (2.4%) VERY GOOD 19 (9.2%) 36
(17.7%) 55 (13.4%) GOOD 41 (19.8%) 62 (30.5%) 103 (25.1%) FAIR 63
(30.4%) 62 (30.5%) 125 (30.5%) POOR 55 (26.6%) 27 (13.3%) 82
(20.0%) OVERALL P-VALUE [1] <0.001 THE DOUBLE-BLIND WEEK 6
EXCELLENT 5 (2.4%) 4 (2.0%) 9 (2.2%) VERY GOOD 15 (7.2%) 32 (15.8%)
47 (11.5%) GOOD 53 (25.6%) 71 (35.0%) 124 (30.2%) FAIR 49 (23.7%)
52 (25.6%) 101 (24.6%) POOR 61 (29.5%) 33 (16.3%) 94 (22.9%)
OVERALL P-VALUE [1] <0.001 THE DOUBLE-BLIND WEEK 7 EXCELLENT 5
(2.4%) 5 (2.5%) 10 (2.4%) VERY GOOD 20 (9.7%) 32 (15.8%) 52 (12.7%)
GOOD 57 (27.5%) 64 (31.5%) 121 (29.5%) FAIR 47 (22.7%) 57 (28.1%)
104 (25.4%) POOR 54 (26.1%) 34 (16.7%) 88 (21.5%) OVERALL P-VALUE
[1] 0.033 THE DOUBLE-BLIND WEEK 8 EXCELLENT 7 (3.4%) 7 (3.4%) 14
(3.4%) VERY GOOD 17 (8.2%) 31 (15.3%) 48 (11.7%) GOOD 52 (25.1%) 64
(31.5%) 116 (28.3%) FAIR 50 (24.2%) 57 (28.1%) 107 (26.1%) POOR 57
(27.5%) 33 (16.3%) 90 (22.0%) OVERALL P-VALUE [1] 0.007 THE
DOUBLE-BLIND WEEK 9 EXCELLENT 6 (2.9%) 4 (2.0%) 10 (2.4%) VERY GOOD
20 (9.7%) 32 (15.8%) 52 (12.7%) GOOD 48 (23.2%) 59 (29.1%) 107
(26.1%) FAIR 46 (22.2%) 63 (31.0%) 109 (26.6%) POOR 63 (30.4%) 34
(16.7%) 97 (23.7%) OVERALL P-VALUE [1] 0.013 THE DOUBLE-BLIND WEEK
10 EXCELLENT 8 (3.9%) 4 (2.0%) 12 (2.9%) VERY GOOD 15 (7.2%) 34
(16.7%) 49 (12.0%) GOOD 55 (26.6%) 64 (31.5%) 119 (29.0%) FAIR 43
(20.8%) 66 (32.5%) 109 (26.6%) POOR 62 (30.0%) 24 (11.8%) 86
(21.0%) OVERALL P-VALUE [1] 0.001 THE DOUBLE-BLIND WEEK 11
EXCELLENT 6 (2.9%) 6 (3.0%) 12 (2.9%) VERY GOOD 23 (11.1%) 30
(14.8%) 53 (12.9%) GOOD 49 (23.7%) 65 (32.0%) 114 (27.8%) FAIR 44
(21.3%) 58 (28.6%) 102 (24.9%) POOR 61 (29.5%) 33 (16.3%) 94
(22.9%) OVERALL P-VALUE [1] 0.015 THE DOUBLE-BLIND WEEK 12
EXCELLENT 5 (2.4%) 9 (4.4%) 14 (3.4%) VERY GOOD 25 (12.1%) 25
(12.3%) 50 (12.2%) GOOD 45 (21.7%) 67 (33.0%) 112 (27.3%) FAIR 45
(21.7%) 61 (30.0%) 106 (25.9%) POOR 63 (30.4%) 30 (14.8%) 93
(22.7%) OVERALL P-VALUE [1] 0.004 [1] COCHRAN-MANTEL-HAENSZEL (ROW
MEAN SCORES) TEST ACROSS TREATMENT GROUPS USING EQUALLY SPACED
SCORES ADJUSTING FOR BASELINE PI (.gtoreq.7.5 AND <7.5) AND
PRE-RANDOMIZATION PI (.gtoreq.5 AND <5).
[0526] Another secondary efficacy endpoint for this study was
SF-12. For SF-12, the group that received study drug BID had a
higher value for the physical component score of the SF-12 (see,
e.g., at week twelve p=0.003) and for the mental component score of
the SF-12 (see, e.g., at week twelve p=0.055) as compared to the
group administered placebo BID, wherein higher values correspond to
better health or functioning. Table 14 shows the SF-12 results at
each of the twelve weeks during the double-blind treatment
period.
TABLE-US-00016 TABLE 14 SF-12 HEALTH SURVEY - CHANGE AND PERCENT
CHANGE FROM PRE-RANDOMIZATION 12-WEEK DOUBLE-BLIND PERIOD OBSERVED
CASES ANALYSIS POPULATION: INTENT TO TREAT POPULATION NORM-BASED
STANDARDIZED MENTAL COMPONENT SUMMARY (MCS) PLACEBO BID OXY BID
TOTAL (N = 207) (N = 203) (N = 410) PRE-RANDOMIZATION MEAN (SD)
52.2 (10.35) 53.8 (10.48) 53.0 (10.43) MEDIAN 54.0 56.1 55.2 MIN,
MAX 26.3, 72.9 18.6, 72.3 18.6, 72.9 N 206 198 404 MODEL P-VALUES
TREATMENT [1] 0.128 DOUBLE-BLIND WEEK 12/ET MEAN (SD) 52.2 (11.42)
50.6 (12.22) 51.4 (11.84) MEDIAN 54.7 53.9 54.3 MIN, MAX 16.0, 73.8
16.9, 71.0 16.0, 73.8 N 167 164 331 MODEL P-VALUES TREATMENT [1]
0.055 PRE-RANDOMIZATION <0.001 SCORE [1] CHANGE FROM PRE-
RANDOMIZATION TO DOUBLE-BLIND WEEK 12/ET MEAN (SD) -0.5 (10.49)
-3.4 (12.40) -1.9 (11.55) MEDIAN -0.1 -1.8 -0.8 MIN, MAX -33.8,
30.7 -36.9, 28.4 -36.9, 30.7 N 167 162 329 MODEL P-VALUES TREATMENT
[1] 0.055 PRE-RANDOMIZATION <0.001 SCORE [1] PRE-RANDOMIZATION
MEAN (SD) 35.2 (8.75) 34.8 (8.48) 35.0 (8.61) MEDIAN 35.2 34.8 350
MIN, MAX 12.0, 56.7 7.2, 56.5 7.2, 56.7 N 206 198 404 MODEL
P-VALUES TREATMENT [1] 0.585 DOUBLE-BLIND WEEK 12/ET MEAN (SD) 34.9
(9.36) 37.3 (9.31) 36.1 (9.40) MEDIAN 34.2 37.1 35.9 MIN, MAX 13.4,
67.9 9.7, 60.2 9.7, 67.9 N 167 164 331 MODEL P-VALUES TREATMENT [1]
0.003 PRE-RANDOMIZATION <0.001 SCORE [1] CHANGE FROM PRE-
RANDOMIZATION TO DOUBLE-BLIND WEEK 12/ET MEAN (SD) -0.4 (7.93) 2.2
(7.98) 0.9 (8.04) MEDIAN -0.6 2.0 0.7 MIN, MAX -23.7, 29.2 -20.8,
23.6 -23.7, 29.2 N 167 162 329 MODEL P-VALUES TREATMENT [1] 0.003
PRE-RANDOMIZATION <0.001 SCORE [1] NOTE: INTENT TO TREAT
POPULATION - ALL RANDOMIZED PATIENTS WHO TAKE ANY STUDY MEDICATION
AND HAVE AT LEAST ONE POST-RANDOMIZATION PI ASSESSMENT. NOTE: LOWER
VALUES CORRESPOND TO BETTER HEALTH OR FUNCTIONING. [1] P-VALUES
FROM ANOVA MODEL INCLUDING TREATMENT AS THE MAIN EFFECT.
[0527] Another secondary efficacy endpoint for this study was a
functional assessment using WOMAC, including its three subscales
for pain, stiffness and physical function. For the stiffness
(Tables 15C-D) and physical function (Tables 15E-F) subscales of
the WOMAC, although the values were lower in the group administered
study drug BID as compared to the group administered placebo BID,
as expected, the differences were not significant (stiffness
subscale p=0.366 at week twelve and physical function subscale
p=0.221 at week twelve). For the pain subscale of the WOMAC, the
values (% change from baseline to week twelve) were significantly
lower in the group administered study drug BID as compared to the
group administered placebo BID (p=0.023 at week twelve), wherein
lower values correspond to better health or functioning (Tables
15A-B). Total scores are shown in Tables 15G-H.
TABLE-US-00017 TABLE 15A WOMAC OSTEOARTHRITIS INDEX CHANGE AND
PERCENT CHANGE FROM PRE-RANDOMIZATION 12-WEEK DOUBLE-BLIND PERIOD
OBSERVED CASES ANALYSIS POPULATION: INTENT TO TREAT POPULATION PAIN
SUBSCALE PLACEBO BID OXY BID TOTAL (N = 207) (N = 203) (N = 410)
PRE- RANDOMIZATION MEAN (SD) 230.1 (117.83) 229.0 (125.07) 229.6
(121.27) MEDIAN 234.5 232.0 234.0 MIN, MAX 3.0, 494.0 0.0, 497.0
0.0, 497.0 N 206 197 403 MODEL P-VALUES TREATMENT [1] 0.928 NOTE:
LOWER VALUES CORRESPOND TO BETTER HEALTH OR FUNCTIONING. [1]
P-VALUES FROM ANCOVA MODEL INCLUDING TREATMENT AS THE MAIN
EFFECT.
TABLE-US-00018 TABLE 15B WOMAC OSTEOARTHRITIS INDEX CHANGE AND
PERCENT CHANGE FROM PRE-RANDOMIZATION 12-WEEK DOUBLE-BLIND PERIOD
OBSERVED CASES ANALYSIS POPULATION: INTENT TO TREAT POPULATION PAIN
SUBSCALE PLACEBO BID OXY BID TOTAL (N = 207) (N = 203) (N = 410)
DOUBLE-BLIND WEEK 12/ET MEAN (SD) 232.7 (126.08) 199.7 (122.09)
216.4 (125.04) MEDIAN 258.0 195.0 214.0 MIN, MAX 3.0, 488.0 12.0,
486.0 3.0, 488.0 N 168 163 331 MODEL P-VALUES TREATMENT [1] 0.023
PRE-RANDOMIZATION <0.001 SCORE [1] CHANGE FROM PRE-
RANDOMIZATION TO DOUBLE-BLIND WEEK 12/ET MEAN (SD) .sup. -2.3
(118.49) -22.5 (117.61) -12.2 (118.32) MEDIAN -2.0 -8.0 -5.5 MIN,
MAX -296.0, 377.0 -437.0, 305.0 -437.0, 377.0 N 168 162 330 MODEL
P-VALUES TREATMENT [1] 0.023 PRE-RANDOMIZATION <0.001 SCORE [1]
NOTE: LOWER VALUES CORRESPOND TO BETTER HEALTH OR FUNCTIONING. [1]
P-VALUES FROM ANCOVA MODEL INCLUDING TREATMENT AS THE MAIN
EFFECT.
TABLE-US-00019 TABLE 15C WOMAC OSTEOARTHRITIS INDEX CHANGE AND
PERCENT CHANGE FROM PRE-RANDOMIZATION 12-WEEK DOUBLE-BLIND PERIOD
OBSERVED CASES ANALYSIS POPULATION: INTENT TO TREAT POPULATION
STIFFNESS SUBSCALE PLACEBO BID OXY BID TOTAL (N = 207) (N = 203) (N
= 410) PRE- RANDOMIZATION MEAN (SD) 111.7(51.46) 106.3(51.95)
109.0(51.71) MEDIAN 122.0 113.0 118.0 MIN, MAX 5.0, 197.0 0.0,
198.0 0.0, 198.0 N 206 197 403 MODEL P-VALUES TREATMENT [1] 0.295
NOTE: LOWER VALUES CORRESPOND TO BETTER HEALTH OR FUNCTIONING. [1]
P-VALUES FROM ANCOVA MODEL INCLUDING TREATMENT AS THE MAIN
EFFECT.
TABLE-US-00020 TABLE 15D WOMAC OSTEOARTHRITIS INDEX CHANGE AND
PERCENT CHANGE FROM PRE-RANDOMIZATION 12-WEEK DOUBLE-BLIND PERIOD
OBSERVED CASES ANALYSIS POPULATION: INTENT TO TREAT POPULATION
STIFFNESS SUBSCALE PLACEBO BID OXY BID TOTAL (N = 207) (N = 203) (N
= 410) DOUBLE-BLIND WEEK 12/ET MEAN (SD) 107.7(54.58) 97.6(55.16)
102.7(55.02) MEDIAN 119.0 101.0 110.0 MIN, MAX 2.0, 195.0 4.0,
195.0 2.0, 195.0 N 168 163 331 MODEL P-VALUES TREATMENT [1] 0.366
PRE-RANDOMIZATION <0.001 SCORE [1] CHANGE FROM PRE-
RANDOMIZATION TO DOUBLE-BLIND WEEK 12/ET MEAN (SD) .sup.
-5.8(49.64) -5.8(54.44) .sup. -5.8(51.97) MEDIAN -8.5 0.5 -3.5 MIN,
MAX -128.0, 133.0 -174.0, 147.0 -174.0, 147.0 N 168 162 330 MODEL
P-VALUES TREATMENT [1] 0.366 PRE-RANDOMIZATION <0.001 SCORE [1]
NOTE: LOWER VALUES CORRESPOND TO BETTER HEALTH OR FUNCTIONING. [1]
P-VALUES FROM ANCOVA MODEL INCLUDING TREATMENT AS THE MAIN
EFFECT.
TABLE-US-00021 TABLE 15E WOMAC OSTEOARTHRITIS INDEX CHANGE AND
PERCENT CHANGE FROM PRE-RANDOMIZATION 12-WEEK DOUBLE-BLIND PERIOD
OBSERVED CASES ANALYSIS POPULATION: INTENT TO TREAT POPULATION
PHYSICAL FUNCTION SUBSCALE PLACEBO BID OXY BID TOTAL (N = 207) (N =
203) (N = 410) PRE- RANDOMIZATION MEAN (SD) 853.0(399.35)
834.5(403.94) 844.0(401.20) MEDIAN 906.5 877.5 895.0 MIN, MAX 10.0,
1606.0 0.0, 1654.0 0.0, 1654.0 N 206 196 402 MODEL P-VALUES
TREATMENT [1] 0.644 NOTE: LOWER VALUES CORRESPOND TO BETTER HEALTH
OR FUNCTIONING. [1] P-VALUES FROM ANCOVA MODEL INCLUDING TREATMENT
AS THE MAIN EFFECT.
TABLE-US-00022 TABLE 15F WOMAC OSTEOARTHRITIS INDEX CHANGE AND
PERCENT CHANGE FROM PRE-RANDOMIZATION 12-WEEK DOUBLE-BLIND PERIOD
OBSERVED CASES ANALYSIS POPULATION: INTENT TO TREAT POPULATION
PHYSICAL FUNCTION SUBSCALE PLACEBO BID OXY BID TOTAL (N = 207) (N =
203) (N = 410) DOUBLE-BLIND WEEK 12/ET MEAN (SD) 819.5(439.81)
738.3(425.43) 779.6(434.06) MEDIAN 841.5 753.5 800.0 MIN, MAX 7.0,
1616.0 33.0, 1647.0 7.0, 1647.0 N 168 162 330 MODEL P-VALUES
TREATMENT [1] 0.221 PRE-RANDOMIZATION <0.001 SCORE [1] CHANGE
FROM PRE- RANDOMIZATION TO DOUBLE-CLIND WEEK 12/ET MEAN (SD)
-41.2(406.39) -68.3(382.61) -54.4(394.60) MEDIAN -26.5 -38.0 -31.5
MIN, MAX -1008.0, 1122.0 -1347.0, 868.0 -1347.0, 1122.0 N 168 160
328 MODEL P-VALUES TREATMENT [1] 0.221 PRE-RANDOMIZATION <0.001
SCORE [1] NOTE: LOWER VALUES CORRESPOND TO BETTER HEALTH OR
FUNCTIONING. [1] P-VALUES FROM ANCOVA MODEL INCLUDING TREATMENT AS
THE MAIN EFFECT.
TABLE-US-00023 TABLE 15G WOMAC OSTEOARTHRITIS INDEX CHANGE AND
PERCENT CHANGE FROM PRE-RANDOMIZATION 12-WEEK DOUBLE-BLIND PERIOD
OBSERVED CASES ANALYSIS POPULATION: INTENT TO TREAT POPULATION
TOTAL SCORE PLACEBO BID OXY BID TOTAL (N = 207) (N = 203) (N = 410)
PRE- RANDOMIZATION MEAN (SD) 1194.8(553.78) 1170.2(566.69)
1182.8(559.55) MEDIAN 1255.5 1211.5 1240.0 MIN, MAX 33.0, 2342.0
0.0, 2341.0 0.0, 2342.0 N 206 196 402 MODEL P-VALUES TREATMENT [1]
0.660 NOTE: LOWER VALUES CORRESPOND TO BETTER HEALTH OR
FUNCTIONING. [1] P-VALUES FROM ANCOVA MODEL INCLUDING TREATMENT AS
THE MAIN EFFECT.
TABLE-US-00024 TABLE 15H WOMAC OSTEOARTHRITIS INDEX CHANGE AND
PERCENT CHANGE FROM PRE-RANDOMIZATION 12-WEEK DOUBLE-BLIND PERIOD
OBSERVED CASES ANALYSIS POPULATION: INTENT TO TREAT POPULATION
TOTAL SCORE PLACEBO BID OXY BID TOTAL (N = 207) (N = 203) (N = 410)
DOUBLE-BLIND WEEK 12/ET MEAN (SD) 1159.9(605.96) 1035.3(586.35)
1098.8(598.77) MEDIAN 1191.0 1042.5 1144.0 MIN, MAX 12.0, 2260.0
49.0, 2317.0 12.0, 2317.0 N 168 162 330 MODEL P-VALUES TREATMENT
[1] 0.147 PRE-RANDOMIZATION <0.001 SCORE [1] CHANGE FROM PRE-
RANDOMIZATION TO DOUBLE-BLIND WEEK 12/ET MEAN (SD) -492(552.69)
.sup. -97.9(532.83) .sup. -73.0(542.81) MEDIAN -17.5 -56.0 -24.0
MIN, MAX -1327.0, 1624.0 -1924.0, 1108.0 -1924.0, 1624.0 N 168 160
328 MODEL P-VALUES TREATMENT [1] 0.147 PRE-RANDOMIZATION 0.001
SCORE [1] NOTE: LOWER VALUES CORRESPOND TO BETTER HEALTH OR
FUNCTIONING. [1] P-VALUES FROM ANCOVA MODEL INCLUDING TREATMENT AS
THE MAIN EFFECT.
[0528] No drug related safety issues were noted in this study.
Example 2
Preparation of Opioid Formulations
[0529] Exemplary opioid dosage forms comprising oxycodone are
prepared as described herein. For clinical studies as described in
Example 1, capsules having different amounts of oxycodone are
produced.
[0530] Capsule formulations containing oxycodone at various dose
levels (5.0, 10.0, 20.0, 30.0 and 40.0 mg/capsule) and matching
placebo capsules are prepared.
[0531] The components, pharmaceutical grade, and function of each
component used to make oxycodone capsules are provided in Table 16
below.
TABLE-US-00025 TABLE 16 Components for Oxycodone Capsules Component
Function Oxycodone base (micronized) Active pharmaceutical
ingredient Sucrose acetate isobutyrate Liquid carrier material
Triacetin, USP Solvent Isopropyl myristate, NF Rheology modifier
Cellulose acetate butyrate, Network former NF/EP, ethanol washed
(grade 381-20 BP) Hydroxyethyl cellulose, NF Hydrophilic agent
Colloidal silicon dioxide, NF Viscosity enhancing agent Butylated
hydroxytoluene, NF Antioxidant Hard gelatin capsule Dosage form
[0532] The following steps were used to prepare capsules comprising
oxycodone. These steps as well as in-process controls (IPC) are
summarized in the flowchart below.
[0533] The following raw materials were used to create the
formulations: Oxycodone base, micronized; Isopropyl Myristate, NF
("IPM"); Colloidal silicon dioxide (CABOSIL.TM., Cabot Corp)
(SiO.sub.2"); Butylated hydroxyl toluene, NF ("BHT"); Hydroxyethyl
cellulose, NF ("HEC"); Sucrose Acetate Isobutyrate (Eastman),
("SAIB"); Triacetin USP ("TA"); Cellulose Acetate Butyrate, grade
381-20 BP, ethanol washed (Eastman) ("CAB"); Sodium Lauryl Sulfate
NF ("SDS"); and Labrafil M2125 CS ("LAB").
[0534] Two different processes were developed for opioid dosage
forms as shown in the flowchart above. In process one, compounding
was carried out at a 45 kg scale. In process two, compounding was
carried out at 150 kg scale. The same materials were used in both
processes but there were some differences. One difference was the
order in which ingredients were added during the manufacture in
order to enhance mixing and efficiency during the compounding
process. For example, in process two, IPM and SiO.sub.2 were added
earlier in the process and CAB was added later in the process to
lower fluid viscosity during the first part of the compounding
process. Another difference in the oral dosage forms used in some
of the clinical studies was that the capsules filled from process
one were not sealed, while capsules filled from process two were
sealed using a liquid encapsulation microspray sealing (LEMS)
process from Capsugel.
[0535] Table 17 shows a manufacturing process and equipment
comparison.
TABLE-US-00026 TABLE 17 Manufacturing Process and Equipment
Comparison Process and Equipment Information Process Description
Process 1 Process 2 API Milling 8-20 kg scale 28-36 Kg scale
(micronization) Spiral Jet Mill Spiral Jet Mill Hosokawa Alpine
model Hosokawa Alpine Model 50AS 50AS Compounding 45 kg scale 150
kg scale Multishaft mixer Multishaft mixer including including low
shear anchor low shear anchor agitator agitator high speed
disperser high speed disperser high shear high shear rotor-stator
rotor-stator Charles Ross mixer Charles Ross mixer model VMC 10
model PVM 40 Encapsulation Hard gelatin capsule Hard gelatin
capsule filling machine filling machine Shionogi encapsulator
Zanasi encapsulator model F-40 model 40E Capsule None- capsules
were Capsules sealed with Sealing not sealed LEMS technology
Capsugel sealing machine model LEMS30
[0536] Compounding for process one was carried out using a Ross
VMC-10 Mixer with SLIM. Accordingly, all references to a specific
rpm numeric throughout this compounding process correspond to this
model. In a first step, sucrose acetate isobutyrate (SAIB) was
preheated to 50-65.degree. C. and then added into a compounding
vessel with an anchor speed of at 20-40 rpm. The temperature of the
product was maintained at 50-60.degree. C. In a second step,
triacetin was added into the compounding vessel and mixed at anchor
speed of 20-40 rpm and a disperser speed of 700-2000 rpm. The
vessel contents were mixed to achieve a uniform solution of SAIB in
triacetin. Again, the product temperature was maintained at
50-60.degree. C. In a third step, pre-sieved, cellulose acetate
butyrate (CAB) was inducted into the vessel using high shear
dispersion during the addition to prevent formation of
agglomerates. The vessel contents were mixed with an anchor speed
of 20-50 rpm, a rotor stator speed of 700-4500 rpm and a disperser
speed of 700-3500 rpm until the CAB was completely dissolved and a
clear gel formed. After formation of the clear-gel the vessel
contents were mixed for an additional thirty minutes with the same
anchor, rotor stator and disperser speeds. In a fourth step, in a
separate container, a solution was prepared containing butylated
hydroxytoluene (BHT) and approximately 15% portion of isopropyl
myristate (IPM). A 10% portion of the IPM may be set aside to be
used as a rinse solvent later in the process. The remaining
quantity of the IPM-BHT solution was subsequently added to the
compounding vessel and mixed to achieve uniformity with an anchor
speed of 20-50 rpm and disperser speed of 700-3500 rpm. After
formation of a uniform mixture, the vessel contents were mixed for
an additional five minutes with the same anchor and disperser
speeds. During the additional mixing, the stator was jogged as
necessary at 700-1200 rpm. Again, the product temperature was
maintained at 50-60.degree. C. In a fifth step, oxycodone was
inducted into the compounding vessel and mixed to achieve
uniformity with an anchor speed of 20-50 rpm, disperser speed of
700-3500 rpm and a rotor stator speed of 800-4500 rpm. The product
temperature was maintained at 55-65.degree. C. The vessel contents
were mixed for a minimum of an additional two minutes with the same
anchor, disperser and rotor stator speeds. In a sixth step,
hydroxyethyl cellulose (HEC) was inducted into the vessel using
high shear dispersion during the addition and mixed to achieve a
uniform dispersion with an anchor speed of 20-50 rpm, disperser
speed of 700-3500 rpm and a rotor stator speed of 800-4500 rpm. The
vessel contents were mixed for an additional two minutes with the
same anchor, disperser and rotor stator speeds. Again, the product
temperature was maintained at 55-65.degree. C. In a seventh step,
colloidal silicon dioxide (SiO.sub.2) was inducted with to the
vessel using high shear dispersion during the addition and mixed
with an anchor speed of 20-50 rpm, disperser speed of 700-3500 rpm
and a rotor stator speed of 800-4500 rpm. The vessel contents were
mixed for a minimum of an additional two minutes with the same
anchor, disperser and rotor stator speeds. Again, the product
temperature was maintained at 55-65.degree. C. In an eighth step,
IPM was inducted into the vessel and mixed with an anchor speed of
20-50 rpm, disperser speed of 700-2000 rpm and rotor stator speed
of 1500-3000 rpm. The vessel contents were continuously mixed with
anchor and maintained at 50-60.degree. C. The final compounded mass
was de-aerated by vacuum and flushed with nitrogen at 4-5 psig for
at least five minutes. The compounded, controlled-release mass was
filled into hard gelatin capsules and packaged into unit dose
blisters or multidose plastic bottles with child-resistant closures
for clinical supply.
[0537] Compounding for process two was carried out with a Ross
PVM-40 Mixer with SLIM. Accordingly, all references to a specific
rpm numeric throughout this compounding procedure correspond to
this model. In a first step, sucrose acetate isobutyrate (SAIB) was
preheated to 50-65.degree. C. and added to a compounding vessel. In
a second step, triacetin was added to the compounding vessel. In a
third step, a butylated hydroxytoluene/isopropyl myristate solution
was prepared by dispensing a portion of isopropyl myristate
(balance of IPM is added in next step) into a separate stainless
steel container. Butylated hydroxytoluene was added to the
container and the solution was mixed for at least ten minutes until
BHT was dissolved. The BHT hydroxytoluene/isopropyl myristate
solution was then added to the compounding vessel. In a fourth
step, isopropyl myristate was added to the compounding vessel and
mixed to homogeneity with an anchor speed of 10-50 rpm and a
disperser speed of 1-2550 rpm. The product temperature was
maintained at 35-50.degree. C. In a fifth step, colloidal silicon
dioxide (SiO.sub.2) was inducted into the compounding vessel and
mixed to achieve uniform dispersion with an anchor speed of 10-50
rpm (e.g., 20 rpm), a disperser speed of 1-2550 rpm (e.g., 1000
rpm) and an rotor stator speed of 1-3600 rpm (e.g. 2500 rpm). Again
the product temperature was maintained at 35-50.degree. C. The
vessel contents were mixed for an additional two to four minutes
with the same anchor, disperser and rotor stator speeds. In a sixth
step, cellulose acetate butyrate (CAB) was inducted into to the
compounding vessel and mixed with an anchor speed of 10-50 rpm
(e.g., 20 rpm), a disperser speed of 1-2550 rpm (e.g., 1500 rpm)
and a rotor stator speed of 1-3600 rpm (e.g., 3000 rpm). The
product temperature was maintained at 40-60.degree. C. The vessel
contents were mixed for an additional two to four minutes with the
same anchor, disperser and rotor stator speeds. In a seventh step,
oxycodone is inducted into the compounding vessel and mixed to
achieve a uniform dispersion with an anchor speed of 10-50 rpm
(e.g., 20 rpm), a disperser speed of 1-2550 rpm (e.g., 1500 rpm),
and an speed of 1-3600 rpm (e.g., 3000 rpm). Again the product
temperature was maintained at 40-60.degree. C. The vessel contents
were mixed for an additional two to four minutes with the same
anchor, disperser and rotor stator speeds. In an eighth step,
hydroxyethyl cellulose (HEC) was inducted into the compounding
vessel and mixed with an anchor speed of 10-50 rpm (e.g., 20 rpm),
a disperser speed of 1-2550 rpm (e.g., 1500 rpm), and a rotor
stator speed of 1-3600 rpm (e.g., 3000 rpm). Again the product
temperature was maintained at 40-60.degree. C. The vessel contents
were mixed for an additional two to four minutes with the same
anchor, disperser and rotor stator speeds. The final compounded
mass was de-aerated by vacuum at no less than 14 mm Hg for no less
than two hours with anchor speed of 10-50 rpm (e.g., 20 rpm) and
dispersion speed of 1-2250 rpm (e.g., 1250 rpm). The compounded,
controlled-release mass was filled into hard gelatin capsules.
Filled capsules were sealed using LEMS (liquid encapsulation
microspray sealing) from Capsugel and packaged into unit dose
blisters or multidose plastic bottles with child-resistant
closures.
[0538] The compounded mass prepared by process 2 is encapsulated
using a Zanasi Liqui-Fill Encapsulator and sealed using a LEMS30
Capsule Sealer. Initially, the compounded mass is transferred from
the Ross PVM-40 Mixer to a Zanasi Hopper. The transfer lines are
heated with a heated hose controller to a temperature of
55-65.degree. C. Then, a Zansai Liqui-Fill Encapsulator is readied
by adjusting the Stroke Scale until the proper fill weight is
obtained and the temperature of the compounded mass for filling is
maintained at 60-65.degree. C. Depending on the size of the dosage
form capsule, a variety of filling nozzles were designed with
varying nozzle diameters (e.g., 1.2-2.0 mm) for use on the
Encapsulator. For a 5 mg, 10 mg or 20 mg capsule dosage form, a 1.2
mm diameter nozzle is used. For a 30 mg or 40 mg capsule dosage
form, a 1.5 mm diameter nozzle is used. Next, capsules are removed
from the Zansai Liqui-Fill Encapsulator into a collection container
and sealed using the LEMS30 Capsule Sealer.
[0539] In some cases, the oxycodone used in process one or process
two was micronized. Micronization of the oxycodone was conducted
using a Hosokawa Alpine Spiral Jet Mill. In operation, a feed
material comprising a non-micronized opioid is injected into a flat
cylindrical grinding chamber, the chamber having nozzles arranged
tangentially on a peripheral wall, in the presence of a propellant
air pressure and grinding air pressure appropriate for providing
the desired flow dynamics within the chamber needed to effect
collision of the opioid particles with each other. An appropriate
speed and pressure of the propellant air pressure (such as an
injector air pressure of 6.8 Bar) and the grinding air pressure
(such as 6.2 Bar) is applied such that a particle on particle
collision and interaction with the chamber wall results. The
injector gas pressure was always approximately 0.3 to 0.7 Bar
higher than grinding pressure to obtain constant flow of oxycodone
into the spiral jet mill. A micronized particle thus occurs,
providing an opioid preparation having a reduced particle size, the
particle size being less than about 10.mu.. The larger particles
are held in the mill by centrifugal (mass) force, while the fine,
micronized particles leave the mill in an air stream and are
collected (drag force). One set of processing parameters that may
be used in the methods for preparing a micronized opioid
preparation within a jet gas mill, includes, a batch size of 4 kg;
injector clearance default of +3 mm; a feed rate of 40 to 50 g/min;
a grinding gas pressure of 6.8 Bar and an injector gas pressure of
6.2 Bar.
[0540] Immediately following micronization, the micronized
oxycodone is packaged in plastic bags with dessicant and then
stored in plastic drums to preserve the integrity of the micronized
particles. This is necessary to maintain stabilized micronized
opioid particle preparations. The micronized opioids, particularly
the salt forms such as oxycodone HCl or hydromorphone HCl, are
hydroscopic. The immediate packaging with dessication is required
to prevent agglomeration and/or fused particles. For example, the
micronized oxydocone is placed into a labeled anti-static bag and
secured with a cable or twist tie at the open end of the bag. The
anti-static bag is placed into a poly bag with a layer of
eight-unit, silica gel, printer, Natrasorb.RTM. S Tyvek.RTM.
four-side seal bag desiccant separating the anti-static bag from
the poly bag. The label on the anti-static bag is checked to ensure
that it is visible through the poly bag and the poly bag is sealed
at its open end. The poly bag is placed in a HDPE (high density
polyethylene) drum with a layer of eight-unit, silica gel, printer,
Natrasorb.RTM. S Tyvek.RTM. four-side seal bag desiccant separating
the poly bag from the drum. A lid is placed on the open end of the
drum and secured using a uniquely numbered security locking tag
through a side lever-lock (SSL). Such dessicant packaged and stored
micronized opioid preparations may be used in the manufacturing
processes, including the compounding processes described
herein.
[0541] All of the raw materials were used as obtained from the
various manufacturers with the following exceptions. The active
ingredient (Oxycodone) was subject to a jet milling process to
micronize the solid material into a substantially homogenous
particle size. After collection from the jet mill apparatus, the
micronized oxycodone was passed through a 20-mesh stainless steel
screen and weighed. The CAB raw material was washed using ethanol
(EtOH) to remove possible contaminants.
[0542] The amounts of active ingredients and excipients in various
capsules of different strengths are set forth in Tables 18 through
22.
[0543] Table 18 sets forth the composition of exemplary 5.0 mg
strength capsules (capsules comprising 5.0 mg oxycodone).
TABLE-US-00027 TABLE 18 Quantity per Quantity per Capsule (mg)
Capsul (mg) Component (Study Drug) (Placebo) Oxycodone base
(micronized) 5.0 0.0 Sucrose acetate isobutyrate 40.0 42.1
Triacetin, USP 26.6 28.1 Isopropyl myristate, NF 13.9 14.6
Cellulose acetate butyrate, 4.6 4.9 NF/EP, ethanol washed (grade
381-20 BP) Hydroxyethyl cellulose, NF 5.5 5.9 Colloidal silicon
dioxide, NF 1.8 2.0 Butylated hydroxytoluene, NF 0.02 0.02 Total
97.5 97.5
[0544] Table 19 sets forth the composition of exemplary 10.0 mg
strength capsules (capsules comprising 10.0 mg oxycodone).
TABLE-US-00028 TABLE 19 Quantity per Quantity per Capsule (mg)
Capsul (mg) Component (Study Drug) (Placebo) Oxycodone base
(micronized) 10.0 0.0 Sucrose acetate isobutyrate 79.9 84.2
Triacetin, USP 53.3 56.1 Isopropyl myristate, NF 27.7 29.3
Cellulose acetate butyrate, 9.2 9.8 NF/EP, ethanol washed (grade
381-20 BP) Hydroxyethyl cellulose, NF 11.1 11.7 Colloidal silicon
dioxide, NF 3.7 3.9 Butylated hydroxytoluene, NF 0.04 0.04 Total
195.0 195.0
[0545] Table 20 sets forth the composition of exemplary 20.0 mg
strength capsules (capsules comprising 20.0 mg oxycodone).
TABLE-US-00029 TABLE 20 Quantity per Quantity per Capsule (mg)
Capsul (mg) Component (Study Drug) (Placebo) Oxycodone base
(micronized) 20.0 0.0 Sucrose acetate isobutyrate 159.8 168.4
Triacetin, USP 106.5 112.3 Isopropyl myristate, NF 55.5 58.5
Cellulose acetate butyrate, 18.5 19.5 NF/EP, ethanol washed (grade
381-20 BP) Hydroxyethyl cellulose, NF 22.2 23.4 Colloidal silicon
dioxide, NF 7.4 7.8 Butylated hydroxytoluene, NF 0.08 0.08 Total
390.0 390.0
[0546] Table 21 sets forth the composition of exemplary 30.0 mg
strength capsules (capsules comprising 30.0 mg oxycodone).
TABLE-US-00030 TABLE 21 Quantity per Quantity per Capsule (mg)
Capsul (mg) Component (Study Drug) (Placebo) Oxycodone base
(micronized) 30.0 0.0 Sucrose acetate isobutyrate 239.7 42.1
Triacetin, USP 159.8 28.1 Isopropyl myristate, NF 83.2 14.6
Cellulose acetate butyrate, 27.8 4.9 NF/EP, ethanol washed (grade
381-20 BP) Hydroxyethyl cellulose, NF 33.3 5.9 Colloidal silicon
dioxide, NF 11.1 2.0 Butylated hydroxytoluene, NF 0.12 0.02 Total
585.0
[0547] Table 22 sets forth the composition of exemplary 40.0 mg
strength capsules (capsules comprising 40.0 mg oxycodone).
TABLE-US-00031 TABLE 22 Quantity per Quantity per Capsule (mg)
Capsul (mg) Component (Study Drug) (Placebo) Oxycodone base
(micronized) 40.0 0.0 Sucrose acetate isobutyrate 319.6 336.9
Triacetin, USP 213.1 224.6 Isopropyl myristate, NF 111.0 117.0
Cellulose acetate butyrate, 37.0 39.0 NF/EP, ethanol washed (grade
381-20 BP) Hydroxyethyl cellulose, NF 44.4 46.8 Colloidal silicon
dioxide, NF 14.8 15.6 Butylated hydroxytoluene, NF 0.16 0.16 Total
780.0 780.0
[0548] Clinical supplies of oxycodone capsules or placebo capsules
were packaged in plastic film blister packs with foil backing. The
blister packs were placed inside a foil/foil pouch with a silica
gel desiccant to assure that products conform to specifications
while in use.
[0549] While the invention will be described in connection with one
or more embodiments, it will be understood that the invention is
not limited to those embodiments. On the contrary, the invention
includes all alternatives, modification, and equivalents as may be
included within the spirit and scope of the appended claims.
* * * * *
References