U.S. patent application number 12/591343 was filed with the patent office on 2010-03-18 for topical application of adapalene for the long-term treatment of acne vulgaris.
This patent application is currently assigned to Galderma Research & Development. Invention is credited to Michael Graeber.
Application Number | 20100069495 12/591343 |
Document ID | / |
Family ID | 36120099 |
Filed Date | 2010-03-18 |
United States Patent
Application |
20100069495 |
Kind Code |
A1 |
Graeber; Michael |
March 18, 2010 |
Topical application of adapalene for the long-term treatment of
acne vulgaris
Abstract
Administration of adapalene in a 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 topically applying onto the afflicted skin
area a therapeutically effective amount of adapalene at least once
every two days for at least 6 months.
Inventors: |
Graeber; Michael;
(Lawrenceville, NJ) |
Correspondence
Address: |
BUCHANAN, INGERSOLL & ROONEY PC
POST OFFICE BOX 1404
ALEXANDRIA
VA
22313-1404
US
|
Assignee: |
Galderma Research &
Development
Biot
FR
|
Family ID: |
36120099 |
Appl. No.: |
12/591343 |
Filed: |
November 17, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11878736 |
Jul 26, 2007 |
7642288 |
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12591343 |
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PCT/EP2006/001140 |
Jan 23, 2006 |
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11878736 |
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60647306 |
Jan 26, 2005 |
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Current U.S.
Class: |
514/569 |
Current CPC
Class: |
A61P 17/00 20180101;
A61P 17/10 20180101; A61K 31/192 20130101; A61P 29/00 20180101 |
Class at
Publication: |
514/569 |
International
Class: |
A61K 31/192 20060101
A61K031/192; A61P 17/10 20060101 A61P017/10 |
Claims
1. A regimen for the treatment of acne vulgaris, comprising
topically applying onto the afflicted skin area of an individual in
need of such treatment, an anti-acne effective amount of a topical
adapalene formulation at least once every two days for a period of
time of at least six months.
2. A regimen for the treatment of acne vulgaris, comprising
topically applying onto the afflicted skin area of an individual in
need of such treatment, an anti-acne effective amount of a topical
adapalene formulation at least once every two days for a period of
time of at least six months, wherein adapalene is the only active
acne-treating agent administered during said period of time.
3. The acne vulgaris regimen as defined by claim 1, said topical
adapalene formulation comprising an aqueous gel composition.
4. The acne vulgaris regimen as defined by claim 2, said topical
adapalene formulation comprising an aqueous gel composition.
5. The acne vulgaris regimen as defined by claim 1, said topical
adapalene formulation comprising at least 0.2% adapalene by
weight.
6. A regimen for the treatment of acne vulgaris, comprising
topically applying onto the afflicted skin area of an individual in
need of such treatment, an anti-acne effective amount of a topical
adapalene formulation at least once every two days for a period of
time of at least six months; said topical adapalene formulation
comprising at least 0.2% adapalene by weight, wherein adapalene is
the only active acne-treating agent administered during said period
of time.
7. The acne vulgaris regimen as defined by claim 1, said topical
adapalene formulation comprising from 0.25% to 0.5% adapalene by
weight.
8. The acne vulgaris regimen as defined by claim 6, said topical
adapalene formulation comprising from 0.25% to 0.5% adapalene by
weight.
9. The acne vulgaris regimen as defined by claim 1, comprising
topically applying said adapalene formulation once daily onto said
afflicted skin area.
10. The acne vulgaris regimen as defined by claim 9, comprising
topically applying said adapalene formulation once daily, in the
evening after wash, onto said afflicted skin area.
11. The acne vulgaris regimen as defined by claim 1, comprising
topically applying said adapalene formulation onto said afflicted
skin area for at least nine months.
12. The acne vulgaris regimen as defined by claim 1, comprising
topically applying said adapalene formulation onto said afflicted
skin area for at least twelve months.
13. The acne vulgaris regimen as defined by claim 3, comprising
topically applying said aqueous adapalene gel composition onto said
afflicted skin area for at least nine months.
14. The acne vulgaris regimen as defined by claim 3, comprising
topically applying said aqueous adapalene gel composition onto said
afflicted skin area for at least twelve months.
15. The acne vulgaris regimen as defined by claim 1, said afflicted
skin area containing 20 to 100 non-inflammatory lesions, 20 to 50
inflammatory lesions, and no active nodules or cysts.
16. The acne vulgaris regimen as defined by claim 2, comprising
topically applying said adapalene formulation once daily onto said
afflicted skin area.
17. The acne vulgaris regimen as defined by claim 16, comprising
topically applying said adapalene formulation once daily, in the
evening after wash, onto said afflicted skin area.
18. The acne vulgaris regimen as defined by claim 2, comprising
topically applying said adapalene formulation onto said afflicted
skin area for at least nine months.
19. The acne vulgaris regimen as defined by claim 2, comprising
topically applying said adapalene formulation onto said afflicted
skin area for at least twelve months.
20. The acne vulgaris regimen as defined by claim 4, comprising
topically applying said aqueous adapalene gel composition onto said
afflicted skin area for at least nine months.
21. The acne vulgaris regimen as defined by claim 4, comprising
topically applying said aqueous adapalene gel composition onto said
afflicted skin area for at least twelve months.
22. The acne vulgaris regimen as defined by claim 2, said afflicted
skin area containing 20 to 100 non-inflammatory lesions, 20 to 50
inflammatory lesions, and no active nodules or cysts.
Description
CROSS-REFERENCE TO EARLIER APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/878,736, filed Jul. 26, 2007, now allowed,
which is a continuation of PCT/EP2006/001140, filed Jan. 23, 2006,
and designating the United States, published in the English
language as WO 2006/079563 A1 on Aug. 3, 2006, and which claims
benefit of U.S. Provisional Application No. 60/647,306, filed Jan.
26, 2005, each hereby expressly incorporated by reference herein in
its entirety and relied upon.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field of the Invention
[0003] The present invention relates to a regimen for the 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 accounts for up
to 20% of the visits to a dermatology facility, and affects the
majority of the teenage population. Management of acne is
challenging, especially when considering the chronicity of the
disease and its variability in response to treatment.
[0006] The management of acne often requires combination therapy
and a long-term therapeutic strategy. (See, 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(I
suppl):SI-S37). Maintenance therapy is necessary for many acne
patients, as acne lesions have been shown to recur after
discontinuing a successful treatment regimen. (See 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(I suppl):SI-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 anti-acne agents," Br. J. Dermatol., 2001;
145:19-27).
[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. (See 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. (See 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] 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.
[0010] 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).
[0011] However, adapalene and other effective retinoids were
studied in short-term (usually 12 weeks) clinical trials.
Therefore, need exists to develop a safe and effective method of
long-term treatment of acne vulgaris.
SUMMARY OF THE INVENTION
[0012] The present invention provides an effective method of
treating acne vulgaris on a long-term basis via the administration
of adapalene.
[0013] The present invention thus provides a long-term treatment of
acne vulgaris with superior efficacy and comparable tolerability by
administering higher strengths of adapalene as compared to
short-term studies.
[0014] Generally, this invention features the formulation of
adapalene in the preparation of a topical medicament for
administering to a patient to sustain its biological response in
the treatment of acne vulgaris, wherein the administration pattern
of the topical medicament comprises administering a therapeutically
effective amount of adapalene at least once every two days for at
least 6 months, preferably once daily for at least 6 months, more
preferably once daily for at least 12 months. Note: The protocol
mandated 12 month once daily treatment according to clinical
need.
[0015] Preferably, the topical medicament is applied to the
afflicted skin for at least 6 months, preferably for at least 9
months and more preferably for at least 12 months. The invention
also features a regimen for treating a patient afflicted with acne
vulgaris comprising topically applying to the afflicted skin region
of the patient a topical medicament (which is here a dermatological
preparation) which comprises a therapeutically effective amount of
adapalene at least once every two days, preferably once daily for
at least 6 months, more preferably once daily for at least 12
months.
[0016] The topical medicament, which is a dermatological
preparation, can be applied to the afflicted skin region in the
evening after wash, preferably once daily. Preferably, the
dermatological preparation is an aqueous gel composition comprising
a higher strength, i.e., at least 0.2%, more preferably 0.25% to
0.5%, most preferably 0.3% by weight of adapalene.
[0017] More specifically, the present invention features
formulation of adapalene in the preparation of 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 0.3% by weight of adapalene once daily for at least 3
months, preferably 6, more preferably 12 months. This invention
also features a regimen for the long-term treatment of acne
vulgaris comprising topically applying to the afflicted skin of a
patient a topical medicament comprising 0.3% by weight of adapalene
once daily for at least 3 months, preferably 6, more preferably 12
months.
[0018] Preferably, the topical medicament is a gel composition
comprising 0.3% by weight of adapalene and is applied to the
afflicted skin 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. For a more
complete description of the invention, its operating advantages,
and specific aspects attained by its use, reference should be had
to the drawings and descriptive matter in which there are
illustrated and described preferred embodiments of the
invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] In the drawings:
[0020] FIG. 1 is a graph showing time course of median percentage
change in lesion counts.
[0021] FIG. 2 is a graph showing time course of local cutaneous
irritation (worse than baseline, observed data, and final
score).
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED
EMBODIMENTS OF THE INVENTION
[0022] The present invention features a method for the long term
treatment of acne vulgaris by administration of a gel composition
containing 0.3% by weight of adapalene. Such product is described
in PCT/EP 03/03246. The following details a study that clearly
demonstrates the clinical benefit of long-term treatment of acne
with adapalene gel 0.3%.
[0023] In order 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 Gel
Composition Containing 0.3% by Weight of Adapalene
[0024] Methods:
[0025] Study Design and Subjects:
[0026] This was a multi-center, open-label study of the long-term
(up to 12 months) safety of Adapalene Gel, 0.3% applied once daily
in subjects aged 12 years and older with acne vulgaris. The primary
objective was to assess safety and the secondary objective was to
assess efficacy. Subjects gave written, informed consent before
undergoing any study procedure. Subjects were male and female
(demonstrably non-gravid and either infertile or using appropriate
forms of birth control), with at least 20-50 inflammatory lesions
(no active nodules or cysts) and 20-100 non-inflammatory lesions.
Qualified subjects (n=551) were enrolled at 20 independent centers
in the United States and instructed to apply Adapalene Gel, 0.3%
once daily to the face and trunk (if applicable) for a period of 12
months. Subjects were evaluated at Baseline, Week 1, and Months 1,
2, 4, 6, 8, 10 and 12 (or Early Termination Visit).
[0027] Expected signs and symptoms of local tolerability (cutaneous
irritation) were evaluated at each visit: erythema, scaling,
dryness, and stinging/burning (all rated on a scale ranging from 0
[none] to 3 [severe]). Adverse events and routine laboratory
parameters (hematology, chemistry, and urinalysis) were recorded
throughout the study. Efficacy data were summarized for percent
changes from Baseline (in non-inflammatory, inflammatory and total
lesion counts) and the subject's assessment of acne (i.e.,
assessment of improvement at months 6 and 12).
[0028] Of the 551 subjects enrolled, fifty point one percent of
subjects were male, mean age was 18.9 years, and 72.4% were
Caucasian, 12.5% Black, 12.5% Hispanic, 0.5% Asian, and 2.0% other
races. Most subjects had oily skin (63.9%). Skin Phototype III was
the most common (35.2%).
[0029] This study was conducted in accordance with the ethical
principles outlined in the Declaration of Helsinki and Good
Clinical Practice (GCP), and in compliance with local regulatory
requirements. All subjects in this study gave written, informed
consent to participate before any study procedures were initiated.
Subjects 18 years of age and older signed the informed consent;
subjects under 18 years signed an assent to participate and the
parent or guardian signed the informed consent.
[0030] Efficacy and Safety Variables:
[0031] Table 1 is a flow chart of assessed measurements during this
study.
TABLE-US-00001 TABLE 1 FLOW CHART OF EFFICACY AND SAFETY
MEASUREMENTS Month 12/ Early Wk Months Month Month Month
Termination Parameter Screening Baseline 1 1, 2 & 4 6 8 10
Visit Efficacy Lesion Counts X X X X X X Subject's X X Assessment
of Acne Oiliness (facial) X X X Safety Local Tolerability X X X X X
X X Adverse Events X X X X X X X X Blood and Urine X X X Sampling
Wk = Week M = Month
[0032] 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.
[0033] 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:
[0034] Non-Inflammatory Lesions:
[0035] Open Comedone: A mass of sebaceous material that is impacted
behind an open follicular orifice (blackhead).
[0036] Closed Comedone: A mass of sebaceous material that is
impacted behind a closed follicular orifice (whitehead).
[0037] Inflammatory Lesions:
[0038] Papule: A small, solid elevation less than one centimeter in
diameter.
[0039] Pustule: A small, circumscribed elevation of the skin that
contains yellow-white exudate.
[0040] Nodule/Cyst:
[0041] A circumscribed, elevated lesion generally more than 1.0 cm
in diameter.
[0042] 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-00002 TABLE 2 1 Marked Improvement 2 Moderate Improvement
3 Minimal Improvement 4 No Change 5 Worse
[0043] 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.
[0044] Erythema, scaling, dryness, and stinging/burning were rated
on the following scales:
TABLE-US-00003 TABLE 3 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-00004 TABLE 4 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-00005 TABLE 5 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-00006 TABLE 6 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
[0045] Erythema, scaling, and dryness were evaluated by the
Investigator. Stinging/burning was recorded by the Investigator
after discussion with the subject.
[0046] 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.
[0047] Adverse Events (AEs):
[0048] An AE was defined as any unfavorable and unintended sign
(e.g., including a clinically relevant abnormal laboratory
finding), 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. Pregnancy was not considered
an AE but was an important medical event.
[0049] 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).
[0050] Serious Adverse Events (SAEs):
[0051] An SAE was defined as any untoward medical occurrence that
at any dose:
[0052] Resulted in death
[0053] 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)
[0054] 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)
[0055] Resulted in persistent or significant
disability/incapacity
[0056] Was a congenital anomaly/birth defect, or
[0057] Was any other important medical event that jeopardized the
subject or required intervention to prevent one of the outcomes
listed above.
[0058] Routine Laboratory Tests:
[0059] 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, GGT, lactic
dehydrogenase (LDH), urea nitrogen, creatinine, uric acid,
cholesterol (total), triglycerides, and glucose.
[0060] 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.
[0061] 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.
[0062] Other Assessment:
[0063] Facial Oiliness, an additional measure, was rated by the
investigator on the following scale:
TABLE-US-00007 TABLE 7 None 0 No oiliness Mild 1 Slight but
definite greasiness Moderate 2 Moderate greasiness Severe 3 Marked
greasiness
[0064] Appropriateness of Measurements:
[0065] Efficacy was evaluated by lesion counting which is a current
practice to assess improvement of acne.
[0066] Safety measures were based on the known profile of retinoids
and standard procedures for reporting safety (AEs and laboratory
values) in clinical research.
[0067] Statistical Analyses:
[0068] 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.
[0069] 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).
[0070] 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.
[0071] 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.
[0072] 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.
[0073] Safety Analyses:
[0074] Local Tolerability Assessment:
[0075] 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.
[0076] 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.
[0077] Adverse Events:
[0078] All AEs recorded on the case report forms (CRFs) are
displayed in data listings.
[0079] 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.
[0080] 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.
[0081] AE summary tables are listed in the Statistical Analysis
Plan (SAP).
[0082] Laboratory Data:
[0083] Descriptive statistics for each laboratory parameter are
provided for data collected at each visit and for the changes from
Screening at each post-baseline visit. "Final" was imputed by the
last observation during the post-baseline period.
[0084] A shift table for the laboratory data at Screening versus
Final assessment was constructed for laboratory parameters for
which numeric reference ranges were available. The number of
subjects below, within, and above the laboratory reference ranges
at Screening versus the Final assessment was summarized.
[0085] For each laboratory test, a complete data listing is
provided for subjects who have any laboratory results outside the
reference ranges.
[0086] Laboratory result assessments of clinical significance or
clinical non-significance by investigators recorded on the CRF page
were tabulated with a supporting data listing.
[0087] Efficacy Analyses:
[0088] Counts of the three lesion types (non-inflammatory,
inflammatory, and total) were summarized at each visit and change
and percent change from baseline at each post-baseline visit. The
observed data at each visit and at Endpoint were summarized, where
Endpoint was considered the last available data point during the
treatment period (last value carried forward), including Baseline
if no post-Baseline data were available. Subgroup summaries for the
lesion data are provided by gender (male vs. female), race
(Caucasian vs. non-Caucasian) and age group (<18, 18 to 64).
Subject's assessment of acne and facial oiliness were summarized as
categorical variables by visit and endpoint.
[0089] Results:
[0090] Subject Disposition and Baseline Characteristics:
[0091] Five hundred fifty-one (551) subjects were enrolled at 20
study centers in the United States. Table 8 provides a summary of
subject enrollment. Of the 551 subjects enrolled, 362 (65.7%) were
treated for 3 months or more, 303 (55.0%) were treated for 6 months
or more, and 166 (30.1%) were treated for at least 1 year (>353
days).
TABLE-US-00008 TABLE 8 Summary of Subject Enrollment And At Risk
Adapalene Gel, 0.3% (N = 551) Disposition n* % Baseline to
<Month 3 (1 to <83 days) 551 100.0 Month 3 to <Month 6 (83
to <173 days) 362 65.7 Month 6 to <Month 9 (173 to <263
days) 303 55.0 Month 9 to <1 Year (263 to <353 days) 174 31.6
.gtoreq.1 Year (.gtoreq.353 days) 166.sup..dagger. 30.1 *All N's
reported indicate the total number of subjects exposed to drug at
the beginning of the specified study period. .sup..dagger.One
hundred sixty-seven (167) subjects completed all study visits;
however, one subject was not included since all visits were
completed in 342 days, outside the window for the 12-month
analysis.
[0092] Of the 551 enrolled subjects, 384 (69.7%) did not complete
12 months of treatment. The two most frequent reasons for
discontinuation were administrative actions: 93 (16.9%) subjects
discontinued due to "Sponsor's decision" and 126 (22.9%) subjects
discontinued due to "site closing."
[0093] Seventy (12.7%) subjects discontinued due to "lost to
follow-up". As defined within the study protocol, this category was
to be used only after the study site personnel tried twice to reach
the subject by telephone plus a letter without answer. The number
of subjects who were lost to follow-up is consistent with the
expected attrition rate for a study population consisting of young,
healthy subjects who are treating a non-life-threatening disease
(acne vulgaris).
[0094] Fifteen (2.7%) subjects were discontinued from the study due
to an AE; 11 (2.0%) of these occurred in the first 3 months of the
study. Regardless of the reason for discontinuation, data from all
subjects were included in the data summaries.
[0095] A summary of demographic and baseline characteristics is in
Table 9. In total, 50.1% of the subjects were male, mean age was
18.9 years (age range of 11-52 years), and the majority, 72.4%,
were Caucasian. Most subjects had oily skin (63.9%). Skin Phototype
III was the most common (35.2%).
TABLE-US-00009 TABLE 9 DEMOGRAPHIC AND BASELINE CHARACTERISTICS
DEMOGRAPHICS - GENDER, RACE, SKIN TYPE, AGE, SKIN PHOTOTYPE
Adapalene Gel 0.3% (N = 551) Gender Male n (%) 276 (50.1) Female n
(%) 275 (49.9) Race White n (%) 399 (72.4) Black n (%) 69 (12.5)
Asian n (%) 3 (0.5) Hispanic n (%) 69 (12.5) Other n (%) 11 (2.0)
Skin Type Dry n (%) 10 (1.8) Normal n (%) 175 (31.8) Oily n (%) 352
(63.9) Oily + Normal n (%) 5 (0.9) Oily + Dry n (%) 9 (1.6%) Age
(years) Mean 18.9 S.D. 6.99 Median 16.0 Min, Max 11, 52 <12 n
(%) 1 (0.2) 12-17 n (%) 332 (60.3) 18-64 n (%) 218 (39.6) Skin
Phototype I n (%) 29 (5.3) II n (%) 93 (16.9) III n (%) 194 (35.2)
IV n (%) 139 (25.2) V n (%) 55 (10.0) VI n (%) 41 (7.4)
[0096] Efficacy Evaluation:
[0097] Table 10 and FIG. 1 provide a summary of the median percent
change in non-inflammatory, inflammatory, and total lesion
counts.
TABLE-US-00010 TABLE 10 SUMMARY OF LESION COUNTS Median Count at
Baseline and Median % Change at Post-Baseline ITT Population Total
Lesion Inflammatory Non-Inflammatory N count N Lesion count N
Lesion count Baseline Count 547* 70.0 551 26.0 551 40.0 Month 1
Observed 494 -23.3% 497 -28.0% 497 -20.0% Month 2 Observed 476
-45.0% 479 -52.0% 479 -42.2% Month 4 Observed 345 -56.1% 347 -63.6%
347 -51.6% Month 6 Observed 310 -60.4% 312 -63.1% 312 -58.7% Month
8 Observed 198 -72.7% 198 -75.0% 198 -71.4% Month 10 Observed 169
-74.7% 169 -74.2% 169 -76.2% Month 12 Observed 170 -76.5% 170
-77.0% 170 -78.3% Endpoint.sup..dagger. 547 -56.6% 551 -61.9% 551
-54.5% *Four subjects had missing total lesion count data at
baseline since nodule/cyst counts were not available.
.sup..dagger.Endpoint = Last observation carried forward, including
Baseline.
[0098] Treatment with Adapalene Gel, 0.3% for up to 12 months
showed continuing improvement in lesion counts (non-inflammatory,
inflammatory and total) starting at Month 1, the second
post-Baseline visit at which lesion count was performed, until the
end of the 12-month treatment. The greatest reductions in lesion
counts were seen after 12 months of treatment and reached at least
75% reduction from baseline.
[0099] A summary of subject's assessment of acne is in Table 11.
Overall improvement was observed in the subject's assessment of
acne. The median assessment was "Moderate Improvement" at Month 6,
and "Marked Improvement" at Month 12.
TABLE-US-00011 TABLE 11 SUBJECT'S ASSESSMENT OF ACNE Improvements
Moderate Marked Time point Median assessment (%) (%) Month 6 (n =
313) Moderate Improvement 59.7 21.4 Month 12 (n = 167*) Marked
Improvement 34.1 55.7 Endpoint (n = 462) Moderate Improvement 45.5
31.0 *Includes that subject who completed all the visits in 342
days. Endpoint = Last observation carried forward, including
baseline.
[0100] Ratings of facial oiliness were improved from Baseline at
both Months 6 and 12. At Baseline, 69 (12.6%) subjects had no
oiliness, versus 130 (41.7%) at Month 6 and 111 (66.1%) at Month
12.
[0101] Therefore, the following points were observed from this
study:
[0102] Continuous reductions in non-inflammatory, inflammatory, and
total lesion counts occurred over time.
[0103] Median reductions from baseline were greater than 75% for
all lesion types by Month 12.
[0104] Safety Evaluation:
[0105] Extent of Exposure:
[0106] A total of 551 subjects received adapalene gel, 0.3%
treatment in this study. The mean treatment duration was 190.2
days. The mean total amount of medication used was 141.24 grams
(Range: 1.5-639.4 grams) per subject. The mean daily medication
usage was 0.7 grams/day (Range: 0.02-6.7 grams/day) per subject. As
used herein, daily medication usage (g/day)=total medication usage
(g) divided by treatment duration (day).
[0107] Local Tolerability:
[0108] Expected signs and symptoms of skin irritation (erythema,
scaling, dryness and stinging/burning) were evaluated on a scale of
0 (none) to 3 (severe) at each visit. Table 12 and FIG. 2 present
the percent of subjects with expected signs and symptoms of skin
irritation worse than baseline.
TABLE-US-00012 TABLE 12 LOCAL CUTANEOUS IRRITATION* (WORSE THAN
BASELINE) N Erythema N Scaling N Dryness N Stinging/Burning Week 1
(Observed) 469 30.1% 469 47.1% 468 53.8% 469 29.6% Month 1
(Observed) 504 20.4% 503 29.0% 503 34.2% 504 11.7% Month 2
(Observed) 479 16.3% 479 19.2% 478 22.2% 478 4.2% Month 4
(Observed) 347 11.8% 347 11.8% 345 20.0% 347 4.6% Month 6
(Observed) 312 8.3% 312 10.6% 311 17.0% 312 3.5% Month 8 (Observed)
198 8.1% 198 19.2% 197 20.8% 198 6.1% Month 10 (Observed) 169 13.6%
169 21.9% 168 19.6% 169 5.3% Month 12 (Observed) 170 9.4% 170 11.8%
169 17.8% 170 2.4% Final (Last score).dagger. 537 11.0% 537 12.3%
536 15.9% 537 4.8% Worst (Highest score).dagger. 537 45.4% 537
60.7% 536 67.5% 537 38.4% *Local Cutaneous Irritation was reported
as Local Cutaneous Tolerance; these terms are used interchangeably
.dagger.During the post-baseline period. Percentages shown are
subjects at each visit with scores worse than baseline. Final: Last
observation during post-Baseline period. N = Number of subjects in
the study with data available at Baseline and the specified
timepoint (based on erythema) Note: Slight data point variations
(.+-.0.1%) in FIG. 2 are due to rounding rule effect.
[0109] The proportion of subjects for which there was a worsening
from baseline in erythema, scaling, dryness and stinging/burning
was greatest at Week 1 and declined continuously thereafter.
[0110] Expected signs and symptoms of local cutaneous irritation
were mild to moderate in severity. Very few subjects had severe
scores (Table 13).
TABLE-US-00013 TABLE 13 LOCAL CUTANEOUS IRRITATION* SCORES BY
SEVERITY (HIGHEST SCORES WORSE THAN BASELINE) Severity N (%) Mild
Moderate Severe Variable N = 537.sup..dagger. n (%) n (%) n (%)
Erythema 244 (45.4) 170 (31.7) 71 (13.2) 3 (0.6) Scaling 326 (60.7)
239 (44.5) 84 (15.6) 3 (0.6) Dryness 362 (67.5) 277 (51.7) 79
(14.7) 6 (1.1) Stinging/burning 206 (38.4) 155 (28.9) 41 (7.6) 10
(1.9) *Local Cutaneous Irritation was reported as Local Cutaneous
Tolerance; these terms are used interchangeably .sup..dagger.N =
536 for dryness.
[0111] Adverse Events:
[0112] Of the 551 subjects enrolled, 244 (44.3%) had one or more
AEs. Overall, 142 (25.8%) subjects reported one or more
dermatologic AEs and 155 (28.1%) subjects reported one or more
non-dermatologic AEs.
[0113] Serious AEs were reported by six subjects; all were
non-related to study drug. There were no deaths in this study.
[0114] Discontinuation due to AEs occurred for 15 subjects (2.7%);
all had dermatologic AEs and one had an additional non-dermatologic
AE.
[0115] Drug-related AEs were reported by 119 subjects (21.6%); 117
subjects (21.2%) reported dermatologic, drug-related AEs.
[0116] The percent of subjects with severe AEs was 1.8% (10
subjects with 13 AEs). All were non-related to study drug. Only one
event was dermatologic (one subject had an infected ingrown
toenail).
[0117] The incidence of dermatologic AEs was highest in the first
quarter [111 (20.1%) incidents] and decreased substantially by the
second quarter [23 (6.4%) incidents] and remained low throughout
the remainder of the study [18 (5.9%) and 10 (5.7%) for the third
and fourth quarters, respectively]. Most of the dermatologic AEs
were related to study drug and therefore the profile for AEs
related to study drug followed the same profile for dermatologic
AEs. Similarly, the majority of dermatologic AEs leading to
discontinuation occurred in the first quarter.
[0118] The percent of subjects with non-dermatologic AEs was
comparable between the first two quarters (first quarter: 13.1% and
second quarter: 11.0%) and second two quarters (third quarter:
12.5% and fourth quarter: 17.2%). Drug-related non-dermatologic AEs
were reported by four (0.7%) subjects (two with pain eye, one with
headache and one with increased liver enzymes).
[0119] An overall summary of adverse events, most frequently
reported adverse events, adverse events related to study drug, and
incidence of adverse events coded as sunburn are displayed in
Tables 14-17.
TABLE-US-00014 TABLE 14 Overall Summary Of Adverse Events Bsl to
<3 Mo Mo 3 to <Mo 6 Mo 6 to <Mo 9 Mo 9 to 1 Year Total (N
= 551) (N = 362) (N = 303) (N = 174) (N = 551) Total Number of
Adverse Events 303 72 64 42 505 Subjects who had any AE n (%) 161
(29.2) 57 (15.7) 48 (15.8) 37 (21.3) 244 (44.3) Dermatologic n (%)
111 (20.1) 23 (6.4) 18 (5.9) 10 (5.7) 142 (25.8) Non-dermatologic n
(%) 72 (13.1) 40 (11.0) 38 (12.5) 30 (17.2) 155 (28.1) Subjects
with AE related to study n (%) 98 (17.8) 12 (3.3) 13 (4.3) 6 (3.4)
119 (21.6) drug Dermatologic n (%) 98 (17.8) 10 (2.8) 12 (4.0) 6
(3.4) 117 (21.2) Non-dermatologic n (%) 1 (0.2) 2 (0.6) 1 (0.3) 0
(0.0) 4 (0.7) Subjects with SAE n (%) 3 (0.5) 1 (0.3) 1 (0.3) 1
(0.6) 6 (1.1) Dermatologic n (%) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0
(0.0) Non-dermatologic n (%) 3 (0.5) 1 (0.3) 1 (0.3) 1 (0.6) 6
(1.1) Subjects with AE leading to n (%) 11 (2.0) 3 (0.8) 1 (0.3) 0
(0.0) 15 (2.7) discontinuation Dermatologic n (%) 11 (2.0) 3 (0.8)
1 (0.3) 0 (0.0) 15 (2.7) Non-dermatologic n (%) 1 (0.2) 0 (0.0) 0
(0.0) 0 (0.0) 1 (0.2) Bsl = baseline Mo = month Note: N's reflect
the number of subjects at risk at the beginning of the time period.
Each subject was counted only once per AE row or body system row,
regardless of the number of occurrences of the individual event or
the number of AEs within the body system.
TABLE-US-00015 TABLE 15 MOST FREQUENTLY REPORTED (.gtoreq.1%)
ADVERSE EVENTS Adapalene Gel, 0.3% (N = 551) Total No. of Subjects
with Any AE n (%) 244 (44.3) Skin and Appendages n (%) 142 (25.8)
Skin dry n (%) 59 (10.7) Discomfort - skin n (%) 48 (8.7) Sunburn n
(%) 28 (5.1) Desquamation n (%) 19 (3.4) Erythema n (%) 16 (2.9)
Irritant Dermatitis n (%) 10 (1.8) Pruritis n (%) 10 (1.8)
Dermatitis - contact n (%) 8 (1.5) Body as a Whole n (%) 87 (15.8)
Flu syndrome n (%) 28 (5.1) Injury - accidental n (%) 22 (4.0) Lab
test abnormal n (%) 14 (2.5) Headache n (%) 12 (2.2) Infection n
(%) 6 (11) Allergic Reaction n (%) 6 (1.1) Respiratory System n (%)
48 (8.7) Pharyngitis n (%) 28 (5.1) Rhinitis n (%) 7 (1.3)
Sinusitis n (%) 6 (1.1) Digestive System n (%) 25 (4.5) Vomiting n
(%) 6 (1.1) Gastroenteritis n (%) 6 (1.1) Special Senses n (%) 14
(2.5) Otitis Media n (%) 7 (1.3) Urogenital System n (%) 14 (2.5)
Nervous System n (%) 7 (13) Note: N's reflect the number of
subjects at risk throughout the study. Each subject was counted
only once per AE row or body system row, regardless of the number
of occurrences of the individual or the number of AEs within the
body system.
TABLE-US-00016 TABLE 16 DRUG RELATED ADVERSE EVENTS (BASE-<M0 3)
(Mo 3-<Mo 6) (Mo 6-<Mo 9) (Mo 9-1 Year) Total (N = 551) (N =
362) (N = 303) (N = 174) (N = 551) Total Number of AE(s) 170 14 14
6 208 Total Number (%) of n (%) 98 (17.8%) 12 (3.3%) 13 (4.3%) 6
(3.4%) 119 (21.6%) Subjects with AE(s) Skin and Appendages n (%) 98
(17.8%) 10 (2.8%) 12 (4.0%) 6 (3.4%) 117 (21.2%) Skin Dry n (%) 45
(8.2%) 6 (1.7%) 8 (2.6%) 4 (2.3%) 58 (10.5%) Discomfort Skin n (%)
42 (7.6%) 2 (0.6%) 2 (0.7%) 0 (0.0%) 46 (8.3%) Desquamation n (%)
14 (2.5%) 2 (0.6%) 1 (0.3%) 0 (0.0%) 18 (3.3%) Sunburn n (%) 15
(2.7%) 1 (0.3%) 0 (0.0%) 1 (0.6%) 17 (3.1%) Erythema n (%) 13
(2.4%) 1 (0.3%) 0 (0.0%) 0 (0.0%) 14 (2.5%) Pruritus n (%) 8 (1.5%)
0 (0.0%) 0 (0.0%) 1 (0.6%) 10 (1.8%) Irritant Dermatitis n (%) 9
(1.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 9 (1.6%) Seborrhea n (%) 1 (0.2%)
0 (0.0%) 1 (0.3%) 0 (0.0%) 2 (0.4%) Dermatitis n (%) 1 (0.2%) 0
(0.0%) 1 (0.3%) 0 (0.0%) 2 (0.4%) Edema Skin n (%) 2 (0.4%) 0
(0.0%) 0 (0.0%) 0 (0.0%) 2 (0.4%) Skin Color n (%) 1 (0.2%) 0
(0.0%) 0 (0.0%) 0 (0.0%) 1 (0.2%) Atopic Dermatitis n (%) 1 (0.2%)
0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.2%) Hirsutism n (%) 1 (0.2%) 0
(0.0%) 0 (0.0%) 0 (0.0%) 1 (0.2%) Derm Contact n (%) 1 (0.2%) 0
(0.0%) 0 (0.0%) 0 (0.0%) 1 (0.2%) Body as a Whole n (%) 0 (0.0%) 1
(0.3%) 1 (0.3%) 0 (0.0%) 2 (0.4%) Lab Test Abnormality n (%) 0
(0.0%) 0 (0.0%) 1 (0.3%) 0 (0.0%) 1 (0.2%) Headache n (%) 0 (0.0%)
1 (0.3%) 0 (0.0%) 0 (0.0%) 1 (0.2%) Special Senses n (%) 1 (0.2%) 1
(0.3%) 0 (0.0%) 0 (0.0%) 2 (0.4%) Pain Eye n (%) 1 (0.2%) 1 (0.3%)
0 (0.0%) 0 (0.0%) 2 (0.4%) *Each subject was counted only once per
AE row or body system row, regardless of the number of occurences
of the individual AE or the number of AEs within the body system.
Note: N's reflect the number of subjects at the beginning of the
time period described.
TABLE-US-00017 TABLE 17 INCIDENCE OF ADVERSE EVENTS CODED AS
SUNBURN (PERCENT OF SUBJECTS WITH AE) RD.06.SRE.18082 First Quarter
12-month Adapelene Gel, 0.3% Sunburn, All 3.8% 5.1% Sunburn,
Related to Study Drug 2.7% 3.1% Note: The time period for study
18082 first quarter was March though August (spring and summer
months).
[0120] In sum, in this study, Adapalene Gel 0.3% was well-tolerated
in long-term (one-year) treatment of acne vulgaris:
[0121] Expected signs and symptoms of skin irritation (erythema,
scaling, dryness and stinging/burning) were mostly mild or moderate
and were transient.
[0122] Most of the AEs occurred in the first quarter, were
dermatologic, and were mild or moderate in severity.
[0123] Clinical laboratory evaluations did not provide any evidence
of systemic toxicity.
DISCUSSION AND OVERALL CONCLUSION
[0124] This was a multi-center, open-label study of the long-term
(up to 12 months) safety of Adapalene Gel, 0.3% applied once daily
in subjects with acne vulgaris. The primary objective was to assess
safety and the secondary objective was to assess efficacy. Subjects
were male and female (demonstrably non-gravid and either infertile
or using appropriate forms of birth control), aged 12 years or
older, with at least 20 to 50 inflammatory lesions (no nodules or
cysts) and 20 to 100 non-inflammatory lesions. Qualified subjects
(N=551) were enrolled at 20 independent centers in the United
States and instructed to apply Adapalene Gel, 0.3% once daily to
the face and trunk (if applicable) for a period of 12 months.
Subjects were evaluated at Baseline, Week 1 and Months 1, 2, 4, 6,
8, 10 and 12 (or Early Termination Visit).
[0125] Expected signs and symptoms of local cutaneous irritation
were evaluated at each visit: erythema, scaling, dryness, and
stinging/burning (all rated on a scale ranging from 0 [none] to 3
[severe]). Adverse events and routine laboratory parameters
(hematology, chemistry, and urinalysis) were recorded throughout
the study. Efficacy data were summarized for percent changes from
Baseline (in non-inflammatory, inflammatory and total lesion
counts) and the Subject's assessment of acne.
[0126] Of the 551 subjects enrolled, 362 (65.7%) were treated for 3
months or more, 303 (55.0%) for 6 months or more, and 166 (30.1%)
for 1 year or more. The two most frequent reasons for
discontinuation were administrative actions: 93 (16.9%) subjects
discontinued due to "Sponsor's decision" and 126 (22.9%) subjects
discontinued due to "site closing". Fifteen (2.7%) subjects were
withdrawn from the study due to an AE; 11 (2.0%) of these occurred
in the first 3 months of the study. Regardless of the reason for
discontinuation, data from all subjects were included in the data
summaries.
[0127] Fifty point one percent of subjects were male, mean age was
18.9 years, and 72.4% were Caucasian (12.5% Black, 12.5% Hispanic,
0.5% Asian, and 2.0% Other). Most subjects had oily skin (63.9%).
Skin Phototype III was the most common (35.2%).
[0128] In conclusion, Adapalene Gel, 0.3% was well-tolerated and
effective in long term treatment in acne vulgaris patients. Signs
and symptoms of skin irritation (erythema, dryness, scaling, and
stinging/burning) were mostly mild or moderate and were transient.
There were very few SAEs and none were related to study treatment.
Most AEs reported in this study were of mild to moderate severity.
The AE incidence by quarter showed that most AEs (including related
AEs, dermatological AEs, SAEs, and AEs leading to discontinuation)
occurred in the first quarter and the incidence of study
drug-related AEs generally decreased over time. Nearly all of the
related AEs were dermatologic.
[0129] Dry skin, skin discomfort, desquamation, erythema, pruritus
and irritant dermatitis are all expected signs of irritation
related to treatment with retinoids such as adapalene. The
observation of drug-related sunburn was not considered clinically
significant. The percentage of subjects with any sunburn during the
first quarter and twelve months was low (4% and 5%, respectively)
and similar to that observed during the twelve-week study about
safety and efficacy of adapalene gel, 0.3% as compared to adapalene
gel, 0.1% and adapalene gel, vehicle in the treatment of acne
vulgaris (3% and 4% for subjects in the Adapalene Gel, 0.3% and Gel
Vehicle groups, respectively). The time period for the quoted
twelve-week study and the first quarter of the present study was
March through August coinciding with the summer season when sunburn
is expected.
[0130] All subjects contributed safety data for the treatment
period with the highest incidence of adverse events and local
cutaneous irritation (the first three months) including those
discontinued due to the administrative actions of "Sponsor's
decision" and "site closure."
[0131] Routine laboratory parameters (clinical chemistry,
hematology and urinalysis) showed no evidence of systemic toxicity.
No unexpected laboratory AEs occurred during the study. One subject
had an AE of elevated liver enzymes considered possibly related to
study drug by the Investigator. However, the subject was receiving
four oral concomitant medications (citalopram, venlafaxine,
alprazolam, and acetaminophen) which are metabolized via the liver.
Furthermore, two of these concomitant medications (venlafaxine and
acetaminophen) are known to cause increased liver function
values.
[0132] Safety findings were consistent with the known profile of
retinoids. No unexpected AEs, either. systemic or dermatological,
or evidence of cumulative toxicity were observed over time.
Consequently, extending treatment beyond 12 weeks does not suggest
substantial additional risk for the subjects treated with Adapalene
Gel, 0.3%.
[0133] The efficacy of Adapalene Gel, 0.3% was demonstrated for
non-inflammatory, inflammatory and total lesions. Adapalene Gel,
0.3% showed continuing reductions greater than 75% in all lesion
counts for subjects treated for 12 months.
[0134] In conclusion, Adapalene Gel, 0.3% was well-tolerated and
effective in long-term (one-year) treatment of acne vulgaris.
[0135] Expected signs and symptoms of skin irritation (erythema,
scaling, dryness and stinging/burning) were mostly mild or moderate
and were transient.
[0136] Most of the AEs occurred in the first quarter, were
dermatologic, and were mild or moderate in severity.
[0137] Clinical laboratory evaluations did not provide any evidence
of systemic toxicity.
[0138] Continuous reductions in non-inflammatory, inflammatory, and
total lesion counts occurred over time. Median reductions from
baseline were greater than 75% for all lesion types by Month
12.
[0139] Thus, while there have shown and described and pointed out
fundamental novel features of the invention as applied to a
preferred embodiment thereof, it will be understood that various
omissions and substitutions and changes in the form and details of
the devices illustrated, and in their operation, may be made by
those skilled in the art without departing from the spirit of the
invention. For example, it is expressly intended that all
combinations of those elements and/or method steps which perform
substantially the same function in substantially the same way to
achieve the same results are within the scope of the invention.
Moreover, it should be recognized that structures and/or elements
and/or method steps shown and/or described in connection with any
disclosed form or embodiment of the invention may be incorporated
in any other disclosed or described or suggested form or embodiment
as a general matter of design choice.
[0140] Each patent, patent application, publication, text and
literature article/report cited or indicated herein is hereby
expressly incorporated by reference.
[0141] 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.
* * * * *