U.S. patent application number 14/337823 was filed with the patent office on 2014-11-13 for administration of adapalene and benzoyl peroxide for the long-term treatment of acne vulgaris.
The applicant listed for this patent is Galderma Research & Development. Invention is credited to Barbara GORE, Michael GRAEBER, Yin LIU.
Application Number | 20140336257 14/337823 |
Document ID | / |
Family ID | 39473958 |
Filed Date | 2014-11-13 |
United States Patent
Application |
20140336257 |
Kind Code |
A1 |
GRAEBER; Michael ; et
al. |
November 13, 2014 |
ADMINISTRATION OF ADAPALENE AND BENZOYL PEROXIDE FOR THE LONG-TERM
TREATMENT OF ACNE VULGARIS
Abstract
A regimen for the safe and effective long-term treatment of acne
vulgaris entails topically applying onto the affected skin area of
a subject afflicted therewith, for a period of time of at least
four (4) months, e.g., for at least twelve (12) months and
advantageously on a daily basis and preferably once a day, a thus
effective amount of a topical medicament containing adapalene and
benzoyl peroxide, formulated into a pharmaceutically acceptable
medium therefor.
Inventors: |
GRAEBER; Michael;
(Lawrenceville, NJ) ; LIU; Yin; (Princeton
Junction, NJ) ; GORE; Barbara; (Cranbury,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Galderma Research & Development |
Biot |
|
FR |
|
|
Family ID: |
39473958 |
Appl. No.: |
14/337823 |
Filed: |
July 22, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12458982 |
Jul 29, 2009 |
8809305 |
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14337823 |
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PCT/EP2008/051155 |
Jan 30, 2008 |
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12458982 |
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60898113 |
Jan 30, 2007 |
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Current U.S.
Class: |
514/568 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 31/192 20130101; A61K 31/327 20130101; A61P 17/00 20180101;
A61K 31/327 20130101; A61K 31/192 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61P 17/10 20180101 |
Class at
Publication: |
514/568 |
International
Class: |
A61K 31/192 20060101
A61K031/192; A61K 31/327 20060101 A61K031/327 |
Claims
1. A regimen for the safe and effective long-term treatment of acne
vulgaris, comprising topically applying onto the affected skin area
of a subject afflicted therewith, for a period of time of at least
four (4) months, a thus effective amount of a topical medicament
which comprises adapalene and benzoyl peroxide, formulated into a
pharmaceutically acceptable medium therefor.
2.-19. (canceled)
Description
CROSS-REFERENCE TO PRIORITY/PROVISIONAL APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn.120
of U.S. Provisional Application No. 60/898,113, filed Jan. 30,
2007, and is a continuation/national phase of PCT/EP 2008/051155,
filed Jan. 30, 2008 and designating the United States (published in
the English language on Aug. 7, 2008 as WO 2008/092911 A1, each
hereby expressly incorporated by reference in its entirety and each
assigned to the assignee hereof.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field of the Invention
[0003] The present invention relates to the administration of a
composition (topical medicament) comprising adapalene and benzoyl
peroxide (BPO) to a patient in need so as to provide a long-term
treatment of acne vulgaris.
[0004] 2. Description of Background and/or Related and/or Prior
Art
[0005] Acne vulgaris is a common skin disorder that makes up 20% of
the visits to a dermatology practice, and affects the majority of
the teenage population. Management of acne is challenging,
especially when considering the chronicity of the disease and the
variability in response to treatment.
[0006] The management of acne often requires combination therapy
and a long-term therapeutic strategy (for example, Thiboutot D. New
treatments and therapeutic strategies for acne. Arch Family Med
2000; 9: 179-187; Gollnick H, Cunliffe W, Berson D, et al.,
Management of acne, a report from a Global Alliance to Improve
Outcomes in Acne. J Am Acad Dermatol. 2003; 49(1 suppl):S1-S37).
Maintenance therapy is necessary for many acne patients, as acne
lesions have been shown to recur after discontinuing a successful
treatment regimen. (Gollnick H, Cunliffe W, Berson D, et al.,
Management of acne, a report from a Global Alliance to Improve
Outcomes in Acne. J Am Acad Dermatol. 2003; 49(1 suppl):S1-S37;
Thielitz A, Helmdach M, Ropke E-M, Gollnick H. Lipid analysis of
follicular casts from cyanoacrylate strips as a new method for
studying therapeutic effects of antiacne agents. Br J Dermatol.
2001; 145:19-27). Long-term therapy is necessary for many acne
patients to achieve the desired reduction of acne lesions as well
as to increase the likelihood of maintaining short-term
improvements of this commonly recurring condition (Tenaud I et al.,
In vitro modulation of TLR-2, CD1d and IL-10 by adapalene on normal
human skin and acne inflammatory lesions Exp. Dermatol. 2007 June;
16(6):500-6; and Thiboutot D M et al., Treatment considerations for
inflammatory acne: clinical evidence for adapalene 0.1% in
combination therapies, J Drugs Dermatol. 2006 September;
5(8):785-94. Review. Erratum in: J Drugs Dermatol. 2007 January;
6(1):table of contents).
[0007] Despite the variety of medications available for the
treatment of acute acne, there are few studies with respect to the
safety and efficacy of the long-term treatment of patients with
acne vulgaris.
[0008] Currently, the most effective comedolytic agents are oral
isotretinoin and topical retinoids. (Cunliffe W J, Holland D B,
Clark S M, Stables, G I. Comedogenesis: some new aetiological,
clinical and therapeutic strategies. Br J Dermatol. 2000;
142:1084-1091). Oral isotretinoin is an impractical choice for
long-term therapy due to the potential for toxicity and
teratogenicity. Topical anti-acne medication such as retinoids,
could be associated with elevated skin irritation, so careful
consideration must be given to the tolerability of a potential
maintenance therapy. Cutaneous side effects may decrease the
likelihood of treatment adherence, particularly when treating an
asymptomatic condition. (Koo J. How do you foster medication
adherence for better acne vulgaris management SKINmed. 2003;
2:229-33; and Haider A, Shaw J C. Treatment of acne vulgaris. JAMA.
2004; 292:726-735).
[0009] Available topical and systemic therapies for the treatment
of acne include retinoids, benzoyl peroxide (BPO), antibiotics, and
hormonal therapy. Since acne vulgaris involves multiple etiological
factors including follicular hyperkeratinization, increased sebum
production, P. acnes proliferation, and inflammation, (Thiboutot D
M et al., Treatment considerations for inflammatory acne: clinical
evidence for adapalene 0.1% in combination therapies, J Drugs
Dermatol. 2006 September; 5(8):785-94. Review. Erratum in: J Drugs
Dermatol. 2007 January; 6(1):table of contents; Pariser D M,
Westmoreland P, Morris A, Gold M H, Liu Y, Graeber M. Long-term
safety and efficacy of a new fixed-dose combination of adapalene
0.1% to benzoyl peroxide 2.5% for the treatment of acne vulgaris. J
Drugs Dermatol. 2007; 6(9):899-905; Thiboutot D M, Bucko A,
Eichenfield L, et al., Adapalene-benzoyl peroxide, a new fixed-dose
combination for the treatment of acne vulgaris: results of a
randomized, multi-centre, double-blind, controlled study. J Am Acad
Dermatol. doi:10.1016/j.jaad 2007.06.006. Published online Jul. 24,
2007) combination therapy utilizing agents with complementary
mechanisms, such as a topical retinoid and an antimicrobial, is
used as part of a long-term therapeutic strategy.
[0010] Current guidelines recommend early initiation of combination
therapy with topical retinoids and antimicrobials for all but the
most severe cases of acne, followed by topical retinoid maintenance
therapy with or without benzoyl peroxide (BPO) (Thiboutot D M et
al., J Drugs Dermatol. 2006 September; 5(8):785-94. Review. Erratum
in: J Drugs Dermatol. 2007 January; 6(1):table of contents).
Although the administration of additional agents increases the
complexity of a treatment regimen, combination therapy is effective
at addressing the multifaceted pathophysiological nature of acne.
Fixed-dose combination products may help reduce the complexity of
acne management for patients and physicians by reducing the number
of medications a patient has to remember to take on a daily basis,
thereby potentially increasing treatment adherence. Despite the
possible benefits, there are relatively few fixed-dose combination
products available for the treatment of acne. Several
BPO-antibiotic combinations are available in addition to one
product that combines a topical retinoid with a topical antibiotic
(Harkaway K S, McGinley K J, Foglia A N et al., Antibiotic
resistance patterns in coagulase-negative staphylococci after
treatment with topical erythromycin, benzoyl peroxide, and
combination therapy. Br J Dermatol. 1992; 126(6):586-90; Thielitz
A, Krautheim A, Gollnick H. Update in retinoid therapy of acne.
Dermatol Ther. 2006; 19(5):272-9; Adapalene-benzoyl peroxide, a new
once daily fixed-dose combination for the treatment of acne
vulgaris: a randomized, bilateral (split-face), dose-assessment
study of cutaneous tolerability in healthy subjects. Cutis.
Submitted).
[0011] However, there are currently no combination products with
BPO and a topical retinoid, a combination that would be consistent
with both the short-term and long-term treatment recommendations
from the acne guidelines.
[0012] Therefore, need exists for an efficient and safe drug
complying with both short term and long-term acne treatment.
SUMMARY OF THE INVENTION
[0013] The present invention features a safe and efficient
composition comprising adapalene and benzoyl peroxide used for the
long-term treatment of acne vulgaris.
[0014] Therefore, a first embodiment of the present invention is
the administration of a composition, which is in a preferred
embodiment a fixed dose combination, comprising adapalene and BPO
formulated as a topical medicament, to a patient in need so as to
provide a long-term treatment of acne vulgaris, wherein the
administration pattern of the topical medicament comprises
administering a therapeutically effective amount of the composition
for at least 4 months, preferably for at least 6 months, more
preferred for at least 9 months, preferentially for at least 12
months.
[0015] The topical medicament is administered on a daily basis and
preferably once a day. In another embodiment the topical medicament
is administered every two days and preferably once a day. In both
cases, the topical medicament is administered in the evening after
wash.
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED
EMBODIMENTS OF THE INVENTION
[0016] In a preferred embodiment, the topical medicament is a gel
composition.
[0017] The topical medicament comprises at least 0.001% of
adapalene by weight and preferentially comprises 0.01% to 2% by
weight of adapalene relative to the total weight of the
composition, preferably comprises 0.01 to 0.5% by weight, most
preferred 0.1 to 0.3%. The medicament comprises also 0.025% to 20%
by weight of BPO, preferably comprises 0.5% to 10% by weight of
BPO, most preferred 2% to 10%, preferentially 2.5 to 5% by weight
of BPO relative to the total weight of the composition.
[0018] Another embodiment of the invention is the formulation of a
composition comprising adapalene and BPO into a topical medicament
for administering to a patient so as to sustain its biological
response in the treatment of acne vulgaris, wherein the
administration pattern of the topical medicament comprises applying
to afflicted skin from 0.01% to 0.5% by weight of adapalene and
from 2% to 10% by weight of BPO relative to the total weight of the
composition for at least 4 months, preferably at least 6 months;
more preferred for at least 9 months; preferably for at least 12
months.
[0019] Particularly, one embodiment of the present invention is the
administration of a composition comprising adapalene and BPO
(topical medicament) to a patient so as to sustain its biological
response in the treatment of acne vulgaris, wherein the
administration pattern of the topical medicament comprises applying
to afflicted skin 0.1% by weight of adapalene and 2.5% by weight of
BPO once daily for at least 6 months, preferentially for at least 9
months, more preferred for at least 12 months.
[0020] According to these embodiments, the topical medicament is
applied to afflicted skin which contains preferentially from 20 to
100 non-inflammatory lesions, and/or from 20 to 50 inflammatory
lesions, and no active nodules or cysts and in preferred embodiment
the composition is a gel composition.
[0021] In another embodiment, the present invention features a
regimen of providing long-term treatment of acne vulgaris in a
patient in need thereof, comprising topically applying on afflicted
skin an effective amount of a composition comprising adapalene and
peroxide benzoyle in an acceptable pharmaceutical medium. The
composition is topically applied for at least 4 months,
prefentially applied for at least 6 months, preferably for at least
9 months, more preferred for at least 12 months.
[0022] The term "pharmaceutically acceptable medium" means a medium
that is compatible with the skin, mucous membranes and the
integuments.
[0023] The term "fixed combination" should be understood as meaning
a combination whose active principles are combined at fixed doses
in the same vehicle/medium (single formula) that delivers them
together to the point of application. Preferably, the
pharmaceutical composition in the form of a fixed combination is a
gel; in this case, the two active principles are dispersed and
intimately mixed, during the manufacture, in the same vehicle,
which delivers them together during the application of the gel.
[0024] More specifically, the present invention provides the
assessment of the long-term clinical profile of this fixed-dose
combination, in 12-month study evaluating the safety and efficacy
of the once-daily adapalene-BPO fixed-dose combination gel in the
treatment of subjects with acne vulgaris when used once daily for
up to 12 months.
[0025] The present invention also provides efficient compositions
for dermatological afflictions allowing once-daily application and
pleasant use for the patient.
[0026] However, formulation of a composition comprising BPO and
retinoids presents difficulties.
[0027] First of all, BPO efficiency is related to its decomposition
when contacted with skin. Indeed, with decomposition the oxidative
properties of free radicals provide the desirable effect. Regarding
the optimal efficiency of BPO, it is thus crucial to prevent its
decomposition while in storage.
[0028] In addition, BPO is an unstable compound that renders its
formulation difficult in formulated products.
[0029] BPO solubility and stability were studied by Chellquist et
al., in ethanol, in propylene glycol and in mixtures of
polyethylene glycol 400 (PEG 400) and water (Chellquist E. M. et
Gorman W. G., Pharm. Res., 1992, Vol. 9: 1341-1346). The authors
commented that BPO in solution is degrading more or less according
to the solvent and its concentration.
[0030] BPO degradation time in PEG 400 (0.5 mg/g), in ethanol and
in propylene glycol are respectively 14, 29 and 53 days at
40.degree. C. Such a degradation in not compatible with
commercialized products.
[0031] Another technical problem to be solved for the formulation
of a composition comprising both adapalene and BPO is the chemical
and physical compatibility of these compounds within the same
formulation provided that common retinoids are natural oxidization
sensitive, visible light and ultra violet sensitive and BPO being a
strong oxidizing agent.
[0032] Indeed, BPO triggers rapidly degradation of natural
oxidization sensitive retinoids: 50% of tretinoine is degraded
within 2 hours and 95% is degraded within 24 hours.
[0033] Contrary thereto, in view of the composition of the
invention where adapalene is the retinoid, no adapalene degradation
had appeared within 24 hours.
[0034] In the context of the present invention, BPO can be used in
the free or encapsulated form, for instance adsorbed BPO form or
absorbed BPO form within any porous support. It might be for
instance encapsulated BPO within polymeric system constituted by
porous microspheres like microsponges marketed under the
trademark--Microsponges P009A Benzoyle peroxyde by Cardinal Health
company.
[0035] Adapalene (6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic
acid) is a naphthoic acid derivative with potent retinoid and
anti-inflammatory properties. Adapalene was developed for the
topical treatment of acne vulgaris and other retinoid-sensitive
dermatoses including various disorders of keratinization,
proliferation and differentiation. Adapalene acts mainly by
regulating differentiation of keratinocytes (comedolytic effect and
preventing new comedones), but also has anti-inflammatory activity.
In particular, adapalene is a well-tolerated topical retinoid.
[0036] Adapalene is marketed under the brand name Differin.RTM. at
a weight concentration of 0.1%, in the form of an "alcoholic
lotion" solution, an aqueous gel and a cream. These compositions
are useful for treating acne.
[0037] The present invention encompasses also the salts of
adapalene. By salts of adapalene are meant the salts formed with a
pharmaceutically acceptable base, especially mineral bases such as
sodium hydroxide, potassium hydroxide and ammonia or organic bases
such as lysine, arginine or N-methylglucamine. The term "adapalene
salts" also means the salts formed with fatty amines such as
dioctylamine and stearylamine.
[0038] WO 03/055472 moreover describes stable pharmaceutical
compositions comprising adapalene and benzoyl peroxide (BPO).
[0039] Reported non-serious adverse reactions associated with
adapalene include common signs and symptoms of local irritative
reactions (erythema, peeling, dry skin, pruritus, burning and
stinging), rare cases of local allergic reactions (edema at the
application site, contact eczema or dermatitis), or other skin and
appendage disorders (very rare cases of hypopigmentation and
hyperpigmentation, photosensitivity reactions, hair thinning, hair
growth, skin erosion following facial waxing).
[0040] However, adapalene and other effective retinoids were
studied only in short-term (12 weeks) clinical trials. Therefore,
there is a need to develop a safe and effective method of long-term
treatment of acne vulgaris moreover without inducing bacterial
resistance.
[0041] BPO is a well established antimicrobial agent, is more
effective than topical antibiotics on P acnes suppression, with no
evidence of microorganism resistance..sup.2. Because retinoids do
not create selective pressure for resistance, this combination is
expected to decrease the incidence of epidermal bacterial
resistance relative to an antibiotic.
[0042] In addition, as shown in example below, the composition of
the present invention which is a fixed-dose combination of
adapalene and benzoyle peroxide (BPO) was well tolerated in the
current long-term study, with a similar safety and tolerability
profile as adapalene monotherapy.
[0043] Advantageously, the present compositions comprise from
0.0001 and 20% by weight of BPO and from 0.0001 and 20% by weight
of adapalene relative to the total weight of the composition;
preferentially respectively from 0.025 and 10% by weight of BPO and
from 0.01% to 2% by weight of adapalene relative to the total
weight of the composition.
[0044] Preferably and as an example, in compositions for treating
acne, BPO is used with concentrations from 2% to 10% by weight and
preferentially from 2.5% to 5% by weight relative to the total
weight of the composition. Adapalene is used in this kind of
composition in concentration from 0.01% to 1% by weight and
preferentially from 0.01% to 0.5%, most preferred 0.1% to 0.3% by
weight relative to the total weight of the composition.
[0045] Advantageously, adapalene and BPO particles are sized such
that at least 80% of particles and preferably at least 90% of
particles have a diameter of less than 25 .mu.m and at least 99% of
particles have a diameter of less than 100 .mu.m.
[0046] One aspect of the present invention is to provide an
effective method of treating acne vulgaris on a long-term basis by
using a composition combining adapalene and BPO.
[0047] Another aspect of the present invention is to provide a
long-term treatment of acne vulgaris with superior efficacy and
comparable tolerability by using higher strengths of adapalene and
BPO as compared to short-term studies.
[0048] The present invention also features a method for treating a
patient afflicted with acne vulgaris comprising topically applying
to afflicted skin region of the patient a topical medicament (which
is here a dermatological preparation) comprising a therapeutically
effective amount of a composition comprising adapalene and BPO at
least every two days, preferably at least once every two days. More
preferably, the composition is administered on a daily basis,
preferably once daily for at least 6 months, more preferably once
daily for at least 12 months.
[0049] The topical medicament, which is a dermatological
preparation, can be applied to the afflicted skin region in the
evening after wash, preferably once daily.
[0050] More specifically, the present invention provides the
formulation of adapalene and BPO into a topical medicament for
administering to a patient so as to sustain its biological response
in the treatment of acne vulgaris, wherein the administration
pattern of the topical medicament comprises administering 0.1% by
weight of adapalene and 2.5% by weight of BPO once daily for more
than 3 months, preferably for at least 4 months, more preferably
for at least 6 months, more preferred for at least 9 months, most
preferred for at least 12 months.
[0051] This invention also features a method of long-term treatment
of acne vulgaris comprising topically applying to afflicted skin of
a patient a topical medicament comprising 0.1% by weight of
adapalene and 2.5% by weight of BPO once daily for more than 3
months, preferably for at least 4 months, more preferably for at
least 6 months, more preferred for at least 9 months, most
preferred for at least 12 months.
[0052] The topical medicament is in a form compatible with topical
administration and particularly is a form of gel, cream, lotion,
emulsion, suspension.
[0053] Preferably, the topical medicament is a gel composition and
more preferred is an aqueous gel composition comprising 0.1% by
weight of adapalene and 2.5% by weight of BPO and is applied to the
afflicted skin for at least 4 months, more preferably for at least
6 months, most preferred for at least 9 months, preferably for at
least 12 months. The topical medicament is particularly efficient
when the afflicted skin contains 20 to 100 non-inflammatory
lesions, 20 to 50 inflammatory lesions, and no active nodules or
cysts.
[0054] For a better understanding of the invention, its operating
advantages, and specific objects attained by its use, reference
should be had to the drawing and descriptive matter in which there
are illustrated and described preferred embodiments of the
invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0055] FIG. 1 shows a time course of median percentage change in
lesion counts.
[0056] Median Percent Change in Lesion Counts (ITT Population,
Observed Data, and Month 12 LOCF)
[0057] Endpoint: the last available data observed during the study.
Baseline value was used if no post-Baseline data were
available.
[0058] FIG. 2 shows time course of local cutaneous irritation
(worse than baseline, observed data, and final score). Percentages
of subjects with scores worse than baseline at each time point with
endpoint.
[0059] FIG. 3 shows the local Tolerability with representation of
the Final Score and Worst Score (Safety Population).
[0060] "Final" means the last available data observed during the
post-baseline period.
[0061] "Worst" means the data observed with the highest severity
during the post-baseline period.
[0062] The present invention provides a regimen for the long-term
treatment of acne vulgaris by the use of a gel composition
containing 0.1% by weight of adapalene and 2.5% by weight of
Benzoyle Peroxide. Such product is described in WO 03/055472. The
following details a study that clearly demonstrates the clinical
benefit of long-term treatment of acne with the above mentioned
composition.
[0063] To further illustrate the present invention and the
advantages thereof, the following specific examples are given, it
being understood that same are intended only as illustrative and in
nowise limitative. In said examples to follow, all parts and
percentages are given by weight, unless otherwise indicated.
EXAMPLE
Clinical Test of Long-Term Treatment of Acne Vulgaris with a
Fixed-Dose Combination Gel Containing Adapalene 0.1% to BPO 2.5% by
Weight/Total Composition Weight
Study Design and Subjects
[0064] The long-term safety and efficacy of a fixed combination gel
of adapalene-BPO were evaluated in a multicenter, open-label,
single-arm study conducted at 28 centers in the United States.
Subjects with acne vulgaris applied once-daily adapalene-BPO to the
face for up to 12 months. Safety and efficacy evaluations were
performed at baseline, week 1, week 2, and at months 1, 2, 4, 6, 8,
10, and 12. A urine pregnancy test was required at baseline and at
the final study visit for all females of childbearing potential.
Subjects were free to withdraw from the study at any time and for
any reason. Subjects not completing the entire study were to be
fully evaluated when possible.
[0065] A total of 452 subjects enrolled in 28 study centers in the
United States. All 452 subjects applied study medication at least
once, and were analyzed in both the Safety and Efficacy (ITT)
populations. Male and female subjects, 12 years of age or older,
with 30 to 100 non-inflammatory facial lesions, 20 to 50
inflammatory facial lesions, and no active nodules or cysts were
enrolled in the study. Specified washout periods were required for
subjects taking certain topical and systemic treatments. Exclusion
criteria prohibited enrollment of subjects with severe acne
requiring isotretinoin therapy or other dermatologic conditions
requiring interfering treatment. Women were excluded if they were
pregnant, nursing, or planning a pregnancy as were men with facial
hair that would interfere with the assessments.
TABLE-US-00001 TABLE 1 Summary of Subject Demographics and Baseline
Characteristics (ITT Population): Variable Total (N = 452) Gender
Male 222 (49.1%) Female 230 (50.9%) Total 452 (100.0%) Age (Years)
N 452 Mean 18.3 S.D. 6.62 Median 16.0 Min, Max 12, 50 Age Category
(Years) 12 to 17 299 (66.2%) 18 to 64 153 (33.8%) 65 and Above 0
Total 452 (100.0%) Race Caucasian 345 (76.3%) Black 53 (11.7%)
Asian 10 (2.2%) Hispanic 31 (6.9%) Other 13 (2.9%) Total 452
(100.0%) Skin Photo Type I 12 (2.7%) II 105 (23.2%) III 162 (35.8%)
IV 87 (19.2%) V 61 (13.5%) VI 25 (5.5%) Total 452 (100.0%)
Safety and Efficacy Assessments
[0066] Safety and tolerability were assessed through evaluations of
local facial tolerability and adverse events. At each visit, the
investigator rated erythema, scaling, dryness, stinging/burning on
a scale ranging from 0 (none) to 3 (severe). Adverse events were
evaluated at each visit. Routine laboratory data (hematology, blood
chemistry, and urinalysis) were collected at screening, month 6,
and month 12.
[0067] The efficacy variables were percent lesion count reduction
from baseline (total, inflammatory, and non-inflammatory) and
subject's assessment of acne (on a scale from 0 [complete
improvement] to 5 [worse]). Lesion counts were assessed on the face
only, excluding the nose.
Efficacy and Safety Variables
[0068] Table 2 is a flow chart of assessed measurements during this
study.
TABLE-US-00002 TABLE 2 Flow Chart of Efficacy and Safety
Measurements: Month 12/ Early Wk Months Month Month Month
Termination Parameter Screening Baseline 1 & 2 1, 2 & 4 6 8
10 Visit Efficacy Lesion Counts X X X X X X X X Subject's X X
Assessment of Acne Safety Local X X X X X X X Tolerability Adverse
Events X X X X X X X Blood & Urine X X X Sampling Wk = Week M =
Month
[0069] The Investigator (or responsible designee) conducted
efficacy evaluations consisting of non-inflammatory lesion counts
(open and closed comedones) and inflammatory lesion counts (papules
and pustules) and nodules/cysts. Lesion counts were taken from the
face only. Subject's assessment of acne was also documented.
[0070] Non-inflammatory and inflammatory lesions were counted on
the forehead, left and right cheeks, and chin above the jaw line
(excluding the nose). Total lesion counts were calculated by the
Sponsor. The following definitions were used:
Non-Inflammatory Lesions
[0071] Open Comedone: A mass of sebaceous material that is impacted
behind an open follicular orifice (blackhead). [0072] Closed
Comedone: A mass of sebaceous material that is impacted behind a
closed follicular orifice (whitehead).
Inflammatory Lesions
[0072] [0073] Papule: A small, solid elevation less than one
centimeter in diameter. [0074] Pustule: A small, circumscribed
elevation of the skin that contains yellow-white exudate.
[0075] Nodule/Cyst: A circumscribed, elevated lesion generally more
than 1.0 cm in diameter.
[0076] Subjects evaluated their facial acne at the Month 6 and
Month 12/Early Termination Visit, as compared to the Baseline
Visit, according to the following scale:
TABLE-US-00003 TABLE 3 1 Marked Improvement 2 Moderate Improvement
3 Minimal Improvement 4 No Change 5 Worse
[0077] The safety variables evaluated were: local tolerability
(erythema, scaling, dryness, and stinging/burning), Adverse Events
(AEs), and routine laboratory data (hematology, blood chemistry,
and urinalysis). Side effects expected during treatment with
topical retinoids include erythema, scaling, dryness, and
stinging/burning. During the study, the course of these expected
events was assessed as local tolerability.
[0078] Erythema, scaling, dryness, and stinging/burning were rated
on the following scales:
TABLE-US-00004 TABLE 4 Erythema: abnormal redness of the skin: None
0 No erythema Mild 1 Slight pinkness present Moderate 2 Definite
redness, easily recognized Severe 3 Intense redness
TABLE-US-00005 TABLE 5 Scaling: abnormal shedding of the stratum
corneum: None 0 No scaling Mild 1 Barely perceptible shedding,
noticeable only on light scratching or rubbing Moderate 2 Obvious
but not profuse shedding Severe 3 Heavy scale production
TABLE-US-00006 TABLE 6 Dryness: brittle and/or tight sensation:
None 0 No dryness Mild 1 Slight but definite roughness Moderate 2
Moderate roughness Severe 3 Marked roughness
TABLE-US-00007 TABLE 7 Stinging/Burning: prickling pain sensation
immediately after (within 5 minutes of) dosing: None 0 No
stinging/burning Mild 1 Slight warm, tingling/stinging sensation;
not really bothersome Moderate 2 Definite warm, tingling/stinging
sensation that is somewhat bothersome Severe 3 Hot,
tingling/stinging sensation that has caused definite discomfort
[0079] Erythema, scaling, and dryness were evaluated by the
Investigator. Stinging/burning was recorded by the Investigator
after discussion with the subject.
[0080] Local tolerability measures of the signs and symptoms of
skin irritation were considered adverse effects only if the
severity of the expected signs and symptoms was such that an
interruption of the subject's participation in the study, at
his/her request or at the Investigator's discretion, had occurred.
Altered dosing regimens (such as every other day dosing) to manage
irritation were not considered to be an interruption of the
subject's participation in the study.
Adverse Events (AEs)
[0081] An AE was defined as any unfavorable and unintended sign,
symptom, or disease temporally associated with the use of a
medicinal (investigational) product, whether or not related to the
investigational product. Any new sign, symptom or disease, or
clinically significant increase in the intensity of an existing
sign, symptom or disease, was considered an AE. This included any
new signs or symptoms suffered by the subject after accidental or
intentional overdose or misuse. Lack of efficacy of the study drug
was not considered an AE unless it led to other unfavorable medical
occurrences. However, clinically significant worsening of the
treated disease was considered an AE.
[0082] Pregnancy was not considered an AE but was an important
medical event.
[0083] Severity of an AE was rated as mild, moderate, or severe.
Relationship of an AE to study drug was rated as: related
(possibly, probably or definitely related) or unrelated (unlikely
or definitely unrelated).
Serious Adverse Events (SAEs)
[0084] An SAE was defined as any untoward medical occurrence that
at any dose: [0085] Resulted in death [0086] Was life-threatening
(i.e., the subject was at risk of death at the time of the event,
but not an event which hypothetically might have caused death if it
were more severe) [0087] Required inpatient hospitalization or
prolongation of an existing hospitalization (hospitalization solely
for diagnostic tests, even if related to an adverse event, elective
hospitalization for any intervention planned before subject entered
the study, or admission to a day-care facility did not themselves
constitute an SAE) [0088] Resulted in persistent or significant
disability/incapacity or [0089] Resulted in a congenital
anomaly/birth defect, or [0090] other important medical events that
jeopardized the subject or required intervention to prevent one of
the outcomes listed above.
Routine Laboratory Tests
[0091] Blood and urine samples were obtained according to the
schedule specified in the study flow chart of Table 1. The
following blood chemistries were evaluated: protein, albumin,
globulin, A/G ratio, bilirubin (total), alanine transaminase (ALT),
aspartate transaminase (AST), alkaline phosphate, gamma-glutamyl
transferase GGT, lactic dehydrogenase (LDH), blood urea nitrogen
(BUN), creatinine, uric acid, cholesterol (total), triglycerides,
and glucose.
[0092] The following hematology parameters were evaluated:
hematocrit, hemoglobin, red cell count, mean corpuscular volume
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular
hemoglobin concentration (MCHC), white cell count, and platelet
count.
[0093] A routine urinalysis for the following was performed: color,
appearance, specific gravity, urine reaction pH, glucose, protein
(qualitative.), ketones, occult blood, bilirubin, nitrite, and
leukocytes.
Statistical Analyses
[0094] As this was an open-label study, only descriptive data
presentations were made. No formal statistical hypotheses were
tested. Descriptive statistics were used to summarize all data. For
continuous variables, the number of subjects (N), mean, standard
deviation (SD), median, minimum and maximum are provided for the
data collected at each visit and the changes/percent changes from
baseline at each post-baseline visit. For categorical variables,
frequencies and percentages for each category are provided.
[0095] All summaries for subject characteristics and efficacy data
were based on the Intent to Treat (ITT) population (this population
consisted of all subjects enrolled, to whom study medication was
dispensed). All safety data is based on the safety population (all
subjects who applied study drug at least once).
[0096] Analysis visits were imputed according to an algorithm to
summarize data by the treatment duration. If multiple measurements
were present within the same interval, the measurement closest to
the target study day was used for analysis. If two measurements
were taken with equal differences in timing compared with the
target day, data from the nominal visit number (recorded on the
case report form) was used for analysis. For example, if
measurements were collected on Day 360 and Day 367, the data
collected at Day 360 was used for analysis at Month 12 while data
collected at Day 367 was used in analysis for endpoint. Although
all data were used in imputing the visits for analysis, some data
were not used for analysis due to multiple observations within a
visit window.
[0097] Subject data for all treated subjects were summarized by
four quarters of the study: "Baseline to <3 months", "3 months
to <6 months", "6 months to <9 months", and "9 months to 1
year." The number of subjects at risk for each period (i.e.,
subjects available at beginning of each period) was tabulated. The
number of subjects at risk is determined based on each subject's
treatment duration. Each month was considered to be 30 days for
these calculations, and a 7-day visit window was used. Thus,
"Baseline to <3 months" is Day 1 through Day 82, "3 months to
<6 months" is Day 83 through Day 172, "6 months to <9 months"
is Day 173 through Day 262, "9 months to <1 year" is Day 263
through Day 352, and "1 year and above" is Day 353 and above.
[0098] By the same principle, subject completion/discontinuation
was summarized by subjects and by four quarters. The
discontinuation rate for each quarter was calculated by the number
of subjects who discontinued within the period divided by the
number of subjects at risk for the given period.
[0099] The planned safety variables to be analyzed were as follows:
[0100] 1. Local Tolerability Assessment (Erythema, Scaling,
Dryness, Stinging/Burning) was to be evaluated at Baseline and each
post-Baseline visit on a "0" (=None) to "3" (=Severe) scale. [0101]
2. AEs were to be assessed at each visit. [0102] 3. Routine
laboratory data (haematology, blood chemistry, urinalysis) were to
be collected at Screening, Month 6 and Month 12/Early Termination
Visit.
[0103] The planned efficacy variables to be analyzed were: [0104]
1. Percent change from Baseline in facial Inflammatory,
Non-inflammatory, and Total Lesion Counts at scheduled
post-Baseline visits. [0105] 2. Subject's Assessment of Acne on a
"5" (Worse) to "0" (Complete Improvement) scale at Month 6 and
Month 12/Early Termination Visit.
[0106] The Non-inflammatory Lesion Count was the sum of open
comedones and closed comedones. The Inflammatory Lesion Count was
the sum of papules and pustules. The other Lesion Count was the sum
of nodules and cysts. The Total Lesion Count was the sum of
Inflammatory, Non-inflammatory, and other Lesions. Subject's
Assessment of Acne was evaluated on a 5 (Worse) to 0 (Complete
Improvement) scale.
[0107] The intent-to-treat (ITT) population was defined as all
subjects enrolled, to whom medication was dispensed. The safety
population was defined as all subjects enrolled who had applied
study medication at least once. Subjects with major protocol
deviations were to be tabulated. No per-protocol (PP) population
was defined for this study.
[0108] All data analyses were carried out according to a
pre-established analysis plan. The sample size of 450 was selected
to ensure approximately 300 subjects would be exposed to
adapalene-BPO for at least 6 months and 100 subjects would be
exposed for up to 1 year. All safety data were summarized based on
the safety population. Adverse events were tabulated in frequency
tables and summarized by quarters to evaluate the adverse event
profile over time. Tolerability variables (erythema, scaling,
dryness, stinging/burning) were summarized by severity score. A
shift table for the laboratory data at screening versus last
post-baseline visit was tabulated for each laboratory parameter.
All efficacy data were summarized based on the ITT population.
Lesion count data collected at each visit and the changes and
percent changes from baseline at post-baseline visits were
summarized. Subject's assessment of acne was tabulated. Descriptive
statistics were used to summarize the data. No formal statistical
hypotheses were tested.
[0109] The safety population was defined as all patients randomized
and treated at least once. The intent-to-treat (ITT) population
included all randomized subjects who were dispensed study
medication. At each time point, efficacy assessments were evaluated
using observed data as well as using last observation carried
forward methodology (LOCF). Subjects with major protocol deviations
were to be tabulated. No per-protocol (PP) population was defined
for this study.
Results
Subject Disposition and Baseline Characteristics
[0110] A total of 452 subjects were enrolled in the study (table
1). All 452 subjects applied study medication at least once and
were analyzed in the ITT and safety populations. A total of 397
(87.8%) subjects were evaluated for 3 months or more, 366 (81.0%)
were evaluated for 6 months or more, and 334 (73.9%) were evaluated
for 9 months or more. Overall, 327 (72.3%) of subjects completed
the 12-month study. The mean (.+-.SD) extent of exposure was 294.6
days (.+-.117.7). No subjects discontinued due to lack of efficacy
and discontinuations due to adverse events were low (2.0%). The
baseline characteristics of the ITT population are summarized in
Table I.
Efficacy Evaluation
[0111] The results for percent change in lesion counts in the ITT
Population are shown in FIG. 1 and table 8.
TABLE-US-00008 TABLE 8 Summary of Inflammatory, Non-inflammatory,
and Total Lesion Counts: Median Counts at Baseline and Median
Percent Change from Baseline at Each Visit and at Month 12 LOCF
(ITT Population): Inflammatory Non-inflammatory Total Time-point N
Lesion Count N Lesion Count N Lesion Count Baseline 452 27.0 452
42.0 452 72.0 Count Week 1 423 -21.9% 423 -19.3% 423 -19.4% Week 2
429 -32.1% 429 -31.7% 429 -31.0% Month 1 415 -42.5% 415 -43.3% 415
-43.2% Month 2 426 -53.7% 426 -54.0% 426 -53.7% Month 4 390 -69.3%
390 -64.8% 390 -65.4% Month 6 361 -69.4% 361 -61.9% 361 -64.8%
Month 8 341 -74.1% 341 -70.6% 341 -70.1% Month 10 329 -74.4% 329
-68.8% 329 -69.4% Month 12 327 -76.0% 327 -70.0% 327 -70.8% Month
12 452 -69.5% 452 -65.7% 452 -64.9% LOCF
[0112] For the 327 subjects who remained in the study until Month
12 visit (observed data), the percent reductions in total,
inflammatory and non-inflammatory lesion counts were 70.8%, 76% to
70% respectively. When ITT LOCF data are considered, the median
percent reductions from baseline in total, inflammatory, and
non-inflammatory lesion counts were 64.9%, 69.5%, and 65.7% at
Month 12, respectively. Reductions in inflammatory,
non-inflammatory, and total lesions were observed starting as early
as Week 1. For patients remaining in the study, lesion counts
continued to decrease through the initial 4 months of the study and
the reductions were maintained for the duration of the study.
[0113] The subject assessment demonstrated a clinical improvement
with 12 months of adapalene-BPO treatment. At the end of the study,
330 subjects (330/411, 80.3%) reported a moderate, marked, or
complete improvement, 45 subjects (45/411, 10.9%) reported a
minimal improvement, and 36 subjects (36/411, 8.8%) reported no
change or worsening. The results were similar regardless of age,
gender, or race.
[0114] FIG. 1 illustrates the effect of adapalene-BPO combination
therapy on facial acne during the course of the 12-month study.
TABLE-US-00009 TABLE 9 Summary of Subject's Assessment of Acne (ITT
Population, Month 12 Observed Data, and Month 12 LOCF): Subjects
Assessment Month 12 of Acne Month 6 Month 12 LOCF 0 = Complete 17
(4.7%) 40 (12.2%) 43 (10.5%) Improvement 1 = Marked 149 (41.5%) 164
(50.2%) 193 (47.0%) Improvement 2 = Moderate 147 (40.9%) 77 (23.5%)
94 (22.9%) Improvement 3 = Minimal 31 (8.6%) 37 (11.3%) 45 (10.9%)
Improvement 4 = No Change 11 (3.1%) 6 (1.8%) 20 (4.9%) 5 = Worse 4
(1.1%) 3 (0.9%) 16 (3.9%) Total 359 (100.0%) 327 (100.0%) 411
(100.0%) Month 12 LOCF: the last available data observed during the
study carried forward. Baseline value was used if no post-Baseline
data were available.
Safety Evaluation
Local Tolerability Assessment
[0115] Local tolerability variables (erythema, scaling, dryness,
and stinging/burning) were summarized by a severity score on a
4-point scale at each visit (0=none to 3=severe). Each subject's
"Worst" score and the "Final" score were summarized where "Worst"
was the highest score and "Final" was the last observation during
the post-baseline period.
[0116] The number of subjects whose local tolerability data were
worse (higher score) than their Baseline score was tabulated at
each post-baseline visit. The "Worst" and "Final" scores for each
subject, if higher than Baseline were tabulated.
[0117] Overall, treatment with adapalene-BPO was safe and
well-tolerated when used for up to 12 months in subjects with acne
vulgaris. The scores for the severity of erythema, scaling,
dryness, and stinging/burning after study treatment are summarized
in FIG. 2. Local cutaneous tolerability of the study treatment was
good throughout the study, with mean tolerability scores for
erythema, dryness, scaling, and burning/stinging all less than 1
(mild) at each study visit. The mean worst scores of all subjects
were consistent with mild irritation. The highest mean cutaneous
tolerability scores were recorded in the first post-baseline study
visit (week 1) and then decreased to levels similar to baseline
scores.
[0118] Erythema, Scaling, Dryness, and Stinging/Burning were graded
at Baseline and each post-Baseline visit on a scale of "0" (=None)
to "3" (=Severe) scale. The results were similar for each of the
signs and symptoms. The worst severity scores were generally mild
or moderate, and rarely severe.
[0119] A summary of the worst severity scores in the subjects with
Local Tolerability Assessments worse than baseline is provided in
Table 10. Incidences for severe Local Tolerability scores ranged
from 0.4% to 3.3% overall signs and symptoms.
TABLE-US-00010 TABLE 10 Summary of Local Tolerability Assessment -
Percentages of Subjects with Scores Worse than Baseline (Safety
Population): Stinging/ Timepoint N Erythema N Scaling N Dryness N
Burning Week 1 423 29.3% 423 40.2% 423 45.2% 423 50.8% (observed)
Week 2 429 19.8% 429 29.4% 429 31.5% 429 24.0% (observed) Month 1
415 16.1% 415 20.5% 415 25.5% 415 19.3% (observed) Month 2 426
13.4% 426 16.4% 426 21.6% 426 11.5% (observed) Month 4 389 4.6% 389
8.0% 389 11.8% 389 5.9% (observed) Month 6 361 7.8% 361 7.8% 361
9.1% 361 6.4% (observed) Month 8 341 7.9% 341 10.0% 341 13.8% 341
8.2% (observed) Month 10 329 7.0% 329 9.1% 329 11.9% 329 7.3%
(observed) Month 12 327 5.5% 327 4.6% 327 9.2% 327 5.8% (observed)
Final 448 7.4% 448 9.4% 448 14.1% 448 8.5% Worst 448 48.0% 448
61.8% 448 65.2% 448 66.1% Final: The last available data observed
during the post-Baseline period. Worst: The data observed with the
highest severity during the post-Baseline period.
[0120] The majority of Local Tolerability Assessment scores which
were worse than the baseline scores were reported during the first
week of treatment with Adapalene/Benzoyl Peroxide Gel for 29.3% of
subjects for Erythema, 40.2% for Scaling, 45.2% for Dryness, and
50.8% for Stinging/Burning (Table 10). However, the incidence of
Erythema, Scaling and Stinging/Burning decreased rapidly, and were
reported by 10% or less subjects by Month 4. Incidences of Dryness
were less than 12% by Month 4, and following Month 4 fluctuated
from 9% to 14% for the remainder of the study.
[0121] Expected signs and symptoms of local cutaneous irritation
were mild to moderate in severity. Very few subjects had severe
scores. (Table 11).
TABLE-US-00011 TABLE 11 Summary of Local Tolerability Assessment
Worse than Baseline - Worst Scores (Safety Population): Local
Tolerability Worse than Baseline - Worst Score.sup.a (N =
448).sup.b Worst Severity Score in these Subjects Number of Mild
Moderate Severe Variable Subjects N (%) N (%) N (%) Erythema 215
(48.0%) 151 (33.7%) 61 (13.6%) 3 (0.7%) Scaling 277 (61.8%) 225
(50.2%) 50 (11.2%) 2 (0.4%) Dryness 292 (65.2%) 230 (51.3%) 57
(12.7%) 5 (1.1%) Stinging/ 296 (66.1%) 185 (41.3%) 96 (21.4%) 15
(3.3%) Burning .sup.aThe data observed with the highest severity
during the post-Baseline period for the subjects with data worse
than Baseline. .sup.bN = 448 is the number of subjects with local
tolerability data available at Baseline and at least one
post-baseline data point.
Adverse Events
[0122] All AEs recorded on the case report forms (CRFs) are
displayed in data listings. [0123] AEs were also summarized for all
subjects. A subject was counted only once per body system, even if
more than one event was reported, and only once per COSTART (Coding
Symbols for Thesaurus of Adverse Reaction Terms), even if more than
one occurrence was reported. [0124] The AE incidence by quarter was
summarized for "Baseline to <3 months", "3 months to <6
months", "6 months to <9 months", and "9 months to 1 year." The
AE incidence for each period was calculated as the number of
subjects with AE onset dates within the period divided by the
number of subjects at risk per period. [0125] AE summary tables are
listed in the Statistical Analysis Plan (SAP).
[0126] A summary of adverse events over the course of the study is
shown in Table 12. Overall, 288 subjects (63.7%) experienced
adverse events during the study. A total of 147 subjects (32.5%)
had treatment-related adverse events (i.e., adverse event
relationship to study drug assessed as "possible", "probable" or
"definitely related"). The most common treatment-related adverse
event was dry skin (17.3%) (table 13). The majority of adverse
events were mild or moderate in severity. Most adverse events
occurred within the first 3 months of therapy and the incidence
dropped at subsequent visits. Only 19 subjects (4.2%) had severe
adverse events and, of these, 10 subjects (2.2%) had severe adverse
events deemed at least possibly related to study treatment. During
the 12-month course of the study, only 9 subjects had 10 adverse
events leading to discontinuation. Out of these 10 adverse events,
7 were related to study treatment.
TABLE-US-00012 TABLE 12 Overall Summary of Adverse Events (Safety
Population): Baseline Month 3 Month 6 Month 9 to <Month 3 to
<Month 6 to <Month 9 to Year Total Category (N+ = 452) (N+ =
397) (N+ = 366) (N+ = 334) (N = 452) Subjects With At Least One AE
195 (43.1%) 79 (19.9%) 83 (22.7%) 82 (24.6%) 288 (63.7%)
Dermatological AE 104 (23.0%) 13 (3.3%) 12 (3.3%) 11 (3.3%) 131
(29.0%) Non-Dermatological AE 139 (30.8%) 72 (18.1%) 77 (21.0%) 78
(23.4%) 243 (53.8%) Subjects With At Least One AE 127 (28.1%) 16
(4.0%) 11 (3.0%) 5 (1.5%) 147 (32.5%) Related To Study Drug
Dermatological AE 94 (20.8%) 8 (2.0%) 8 (2.2%) 4 (1.2%) 110 (24.3%)
Non-Dermatological AE 66 (14.6%) 8 (2.0%) 4 (1.1%) 2 (0.6%) 78
(17.3%) Subjects With At Least One SAE 1 (0.2%) 2 (0.5%) 1 (0.3%) 1
(0.3%) 5 (1.1%) Dermatological AE 0 0 0 0 0 Non-Dermatological AE 1
(0.2%) 2 (0.5%) 1 (0.3%) 1 (0.3%) 5 (1.1%) Subjects With At Least
One AE 7 (1.5%) 1 (0.3%) 0 1 (0.3%) 9 (2.0%) Leading to Disc.
Dermatological AE 6 (1.3%) 1 (0.3%) 0 0 7 (1.5%) Non-Dermatological
AE 1 (0.2%) 0 0 1 (0.3%) 2 (0.4%) indicates data missing or
illegible when filed
[0127] Subjects may be counted twice, once in Dermatological
category and once in Non-dermatological category for having more
than one AE.
[0128] Related to study drug means that AE relationship to study
drug was assessed as `possible`, `probable` or `definitely
related`.
[0129] Subjects may be counted in more than one period due to
multiple AEs.
[0130] AE(s) with incomplete onset date(s) or onset date(s) prior
to the first application are only included in the Total column.
[0131] N+=N at risk, the number of subjects at the beginning of
each period.
TABLE-US-00013 TABLE 13 Most Frequent Adverse Events, Reported by
at Least 1% of Total Subjects by System Organ Class and Preferred
Term (Safety Population): Baseline Month 3 Month 6 Month 9 System
Organ Class/Preferred to <Month 3 to <Month 6 to <Month 9
to 1 Year Total Term* (N+ = 452) (N+ = 397) (N+ = 366) (N+ = 334)
(N = 452) Total Number of AE(s) 405 113 125 108 766 Total Number
(%) of Subjects 195 (43.1%) 79 (19.9%) 83 (22.7%) 82 (24.6%) 288
(63.7%) with AE(s) Infections and Infestations 48 (10.6%) 33 (8.3%)
39 (10.7%) 49 (14.7%) 135 (29.9%) Nasopharyngitis 14 (3.1%) 7
(1.8%) 9 (2.5%) 8 (2.4%) 30 (6.6%) Upper Respiratory Tract 7 (1.5%)
0 11 (3.0%) 9 (2.7%) 26 (5.8%) Infection Influenza 4 (0.9%) 2
(0.5%) 2 (0.5%) 10 (3.0%) 18 (4.0%) Sinusitis 6 (1.3%) 3 (0.8%) 3
(0.8%) 5 (1.5%) 15 (3.3%) Pharyngitis Streptococcal 5 (1.1%) 2
(0.5%) 3 (0.8%) 3 (0.9%) 13 (2.9%) Urinary Tract Infection 1 (0.2%)
3 (0.8%) 0 4 (1.2%) 8 (1.8%) Gastroenteritis Viral 2 (0.4%) 1
(0.3%) 2 (0.5%) 3 (0.9%) 7 (1.5%) Bronchitis 0 3 (0.8%) 1 (0.3%) 3
(0.9%) 7 (1.5%) Skin and Subcutaneous Tissue 104 (23.0%) 13 (3.3%)
12 (3.3%) 11 (3.3%) 131 (29.0%) Disorders Dry Skin 71 (15.7%) 5
(1.3%) 6 (1.6%) 3 (0.9%) 80 (17.7%) Erythema 22 (4.9%) 1 (0.3%) 2
(0.5%) 1 (0.3%) 25 (5.5%) Skin Desquamation 22 (4.9%) 0 1 (0.3%) 0
23 (5.1%) Contact Dermatitis 12 (2.7%) 1 (0.3%) 2 (0.5%) 2 (0.6%)
17 (3.8%) Pruritus 4 (0.9%) 0 2 (0.5%) 1 (0.3%) 7 (1.5%) Acne 3
(0.7%) 2 (0.5%) 0 0 5 (1.1%) Swelling Face 4 (0.9%) 0 1 (0.3%) 1
(0.3%) 5 (1.1%) Skin Discomfort 5 (1.1%) 0 0 0 5 (1.1%) General
Disorders and 63 (13.9%) 5 (1.3%) 7 (1.9%) 2 (0.6%) 74 (16.4%)
Administration Site Conditions Application Site Burning 57 (12.6%)
3 (0.8%) 4 (1.1%) 1 (0.3%) 64 (14.2%) Application Site Irritation
16 (3.5%) 1 (0.3%) 0 1 (0.3%) 18 (4.0%) Injury, Poisoning and 21
(4.6%) 18 (4.5%) 5 (1.4%) 4 (1.2%) 47 (10.4%) Procedural
Complications Sunburn 11 (2.4%) 8 (2.0%) 1 (0.3%) 2 (0.6%) 21
(4.6%) Joint Sprain 2 (0.4%) 1 (0.3%) 0 1 (0.3%) 5 (1.1%)
Respiratory, Thoracic and 9 (2.0%) 6 (1.5%) 13 (3.6%) 3 (0.9%) 29
(6.4%) Mediastinal Disorders Pharolaryngeal Pain 4 (0.9%) 4 (1.0%)
5 (1.4%) 1 (0.3%) 14 (3.1%) Nasal Congestion 1 (0.2%) 1 (0.3%) 2
(0.5%) 1 (0.3%) 5 (1.1%) Gastrointestinal Disorders 14 (3.1%) 8
(2.0%) 6 (1.6%) 4 (1.2%) 28 (6.2%) Vomiting 4 (0.9%) 1 (0.3%) 2
(0.5%) 0 6 (1.3%) Nausea 1 (0.2%) 1 (0.3%) 3 (0.8%) 1 (0.3%) 6
(1.3%) Nervous System Disorders 16 (3.5%) 5 (1.3%) 1 (0.3%) 5
(1.5%) 25 (5.5%) Headache 16 (3.5%) 4 (1.0%) 1 (0.3%) 3 (0.9%) 21
(4.6%) *Multiple occurrences within a System Organ Class (SOC) by a
subject were counted once per SOC. Multiple occurrences of a
Preferred Term by a subject were counted once per Preferred Term. A
subject was counted once even if the subject experienced more than
one AE during the study. Subjects may be counted in more than one
period due to multiple AEs. AE(s) with incomplete onset date(s) or
onset date(s) prior to the first application are only included in
the Total column. N+ = N at risk, the number of subjects at the
beginning of each period.
[0132] Five subjects (5/452, 1.1%) had a total of 6 serious adverse
events (depression, staphylococcal infection, clavicle fracture,
syncope, bipolar disorder and drug abuse), all of which were
non-dermatologic and unrelated to the study drug. There were no
deaths during the study and no confirmed cases of sensitization
occurred in the study. Over the course of the one year, no
clinically relevant drug-related changes in routine laboratory
parameters (clinical chemistry, hematology and urinalysis) were
observed. Ten subjects (10/452, 2.2%) had clinically significant
post-baseline laboratory assessments reported as adverse events,
although these were not considered treatment-related.
[0133] This study is the first long-term clinical evaluation of the
safety and efficacy of a unique fixed-dose combination of a
retinoid (adapalene 0.1%) and BPO 2.5%. This once-daily combination
addresses multiple pathogenic factors of acne, providing prompt and
sustained efficacy with no risk for antibiotic resistance. Overall,
the results of the study support the safe and effective use of the
fixed-dose combination gel of adapalene and BPO for the long-term
management of subjects with acne vulgaris. In terms of safety, most
adverse events and symptoms of skin irritation were
mild-to-moderate, occurred early in the study, and were transient.
The use of a daily moisturizer when starting therapy may help to
avoid the most common adverse events, like dry skin. Importantly,
there was a low rate of discontinuation due to adverse events
(2.0%) and no subjects discontinued due to lack of efficacy.
Clinically significant inflammatory and non-inflammatory lesion
count reductions were observed as early as week 1 and were
sustained for up to 1 year. Eighty percent (80%) of subjects
reported moderate, marked, or complete improvement of their acne.
Results of this study are consistent with a previous 12-week,
double-blind controlled study, which showed the adapalene-BPO
combination produced significantly greater lesion reductions and
had a quicker onset of action relative to corresponding
monotherapies, with a comparable safety profile to adapalene.
[0134] Since acne is a chronic disease, its management often
requires a long-term therapeutic strategy to control acne and
maintain improvements. For all but the most severe acne,
combination therapy with agents with complementary mechanisms of
action should be utilized as early as possible and then followed
with a maintenance therapy. As observed in this study, the use of
the adapalene-BPO fixed-dose combination can be use for both
initiation and long-term therapy for moderate to severe acne.
[0135] Previous studies have shown that the use of combination
therapy with adapalene gel 0.1% may be more tolerable and
associated with a lower rate of adverse events relative to the
other topical retinoids..sup.25-29 Consistent with these prior
experiences, adapalene when combined with BPO in a fixed-dose
formulation was well tolerated in pre-clinical studies, a large
double-blind controlled clinical study, and in the current
long-term study, with a similar safety and tolerability profile as
adapalene monotherapy. Furthermore, a well-tolerated fixed-dose
combination therapy may also be more convenient and simplify a acne
treatment regimen, thereby potentially improving treatment
adherence.
[0136] The results of this study are compatible with those reported
in recently published acne maintenance studies. Acne lesions have
been shown to return after discontinuing a combination treatment
regimen and therefore long-term therapy is necessary for many acne
patients. In this study, acne lesions continued to decrease from
baseline to approximately month 4 and the therapeutic effect was
sustained throughout the year. There are several published studies
demonstrating the value of long-term treatment following successful
initial therapy to help limit the development of subclinical
microcomedones and thereby prevent the recurrence of the disease
after initial improvement. For example, Thiboutot et al assessed
the maintenance effect of adapalene 0.1% gel relative to gel
vehicle in 253 subjects successfully treated in a previous
adapalene-doxycycline combination therapy study. This 16-week study
demonstrated a significant clinical benefit of continued treatment
with adapalene 0.1% gel relative to vehicle. Although future
studies will be needed to properly evaluate adapalene-BPO as a
maintenance therapy, the long-term safety and efficacy results of
the current study suggest that expanding the armamentarium
available for acne management with this fixed-dose combination will
provide greater flexibility for customizing both short- and
long-term care.
[0137] Each patent, patent application, publication, text and
literature article/report cited or indicated herein is hereby
expressly incorporated by reference in its entirety.
[0138] While the invention has been described in terms of various
specific and preferred embodiments, the skilled artisan will
appreciate that various modifications, substitutions, omissions,
and changes may be made without departing from the spirit thereof.
Accordingly, it is intended that the scope of the present invention
be limited solely by the scope of the following claims, including
equivalents thereof.
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