Conditions: Acne Vulgaris
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 186
Healthy volunteers: no

Brief summary:
Demonstrate that a daily treatment regimen of adapalene 0.3%/benzoyl peroxide 2.5% gel + oral Doxycycline 200 mg is effective and safe in severe inflammatory acne with 3 or fewer nodules or cysts (non-nodulocystic) during a 12-week treatment period.

Detailed description:
This Phase 4, 12-week, single-arm, open-label, multi-center investigational efficacy and safety study was conducted in subjects with severe inflammatory acne. Subjects who met the inclusion criteria and none of the exclusion criteria at the Screening visit returned to the clinic for baseline measures (Week 0) and to start treatment, which continued for up to 12 weeks.

Treatment consisted of 2 investigational study drugs:

* A/BPO 0.3%/2.5% gel applied to dry skin as directed by study staff once daily for 12 weeks, at night after washing.
* Doxycycline hyclate 200 mg: each subject was to take 2 50-mg tablets of doxycycline hyclate in the morning and 2 at night, for a total of 4 tablets (a total of 200 mg) daily for 12 weeks.

Arms:
arm 1: Topical adapalene 0.3% / benzoyl peroxide 2.5% emulsion gel (one application daily for 12 weeks)

Oral doxycycline hyclate, 200 mg per day (two 50-mg tablets twice daily for 12 weeks)

Interventions: intervention 1: Adapalene 0.3% / benzoyl peroxide 2.5% emulsion gel intervention 2: Oral doxycycline hyclate
Intervention descriptions: intervention 1: Topical acne therapy intervention 2: Tetracycline-class oral antibacterial 200 mg daily (2 tablets \[50 mg\], twice daily)

Protocol document:
Prot_000.pdf: 




Galderma Laboratories, LP 
Protocol No.:  GLI.04.SPR.US10355 
 
Final Date: 28 Jun 2016 
 
Page 3 of 102 
 
 
Investigator Agreement:   
I have read the protocol and agree to conduct the study as outlined herein. 
 
 
Signature: 
__________________________________ 
Date: ______________ 
 
Name 
(print): 
 
  
 
 
  
 


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Protocol No.:  GLI.04.SPR.US10355 
 
Final Date: 28 Jun 2016 
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TABLE OF CONTENTS 
 
TITLE PAGE .................................................................................................................................1 
SIGNATURE PAGE ......................................................................................................................2 
TABLE OF CONTENTS ..............................................................................................................4 
1.0 
PROTOCOL SYNOPSIS ..................................................................................................8 
2.0 
LIST OF ABBREVIATIONS .........................................................................................14 
3.0 
BACKGROUND AND RATIONALE ...........................................................................16 
3.1 
Medical Background and Brief Rationale for the Trial .........................................16 
4.0 
CLINICAL TRIAL OBJECTIVE AND CLINICAL HYPOTHESIS ........................17 
4.1 
Clinical Trial Objective ..........................................................................................17 
4.2 
Clinical Hypothesis ................................................................................................17 
5.0 
STUDY DESIGN ..............................................................................................................18 
5.1 
Study Duration .......................................................................................................20 
6.0 
SELECTION AND DISPOSITION OF SUBJECTS ...................................................20 
6.1 
Number of Subjects................................................................................................20 
6.2 
Clinical Trial Population Characteristics ...............................................................20 
6.2.1 
Inclusion Criteria ...................................................................................20 
6.2.2 
Exclusion Criteria..................................................................................21 
6.3 
Previous and Concomitant Therapies ....................................................................22 
6.3.1 
Definitions .............................................................................................22 
6.3.2 
Categories ..............................................................................................23 
6.3.3 
Authorized Concomitant Therapies ......................................................23 
6.3.4 
Prohibited Concomitant Therapies ........................................................23 
6.3.5 
Procedures/Reasons for Subject Discontinuation/Withdrawal .............24 
7.0 
CLINICAL SUPPLIES AND TREATMENT DESCRIPTION ..................................25 
7.1 
Description and Use of Study Medications ...........................................................25 
7.1.1 
Subject Identification Number ..............................................................26 
7.1.2 
Method of Treatment Assignment and Blinding ...................................27 
7.1.3 
Study Medication Kit Number ..............................................................27 
7.1.4 
Instructions for Use and Administration of Adapalene 0.3% / 
Benzoyl Peroxide 2.5% Gel ..................................................................27 
7.1.5 
Instructions for Use and Administration of Doxycycline Hyclate ........27 
7.1.6 
Dose Modification .................................................................................28 
7.1.7 
Other Supplies .......................................................................................28 
7.2 
Investigational Study Drug Packaging and Labeling .............................................28 


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7.3 
Supplies Management ............................................................................................28 
7.3.1 
Study Medication Accountability .........................................................28 
7.3.2 
Study Medication Storage .....................................................................29 
7.3.3 
Study Medication Dispensing and Return ............................................29 
7.4 
Treatment Compliance Management and Records ................................................30 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................30 
8.1 
Efficacy Assessments .............................................................................................30 
8.2 
Efficacy Measurements ..........................................................................................30 
8.2.1 
Investigator’s Global Assessment (IGA) ..............................................30 
8.2.2 
Lesion Counts .......................................................................................31 
8.2.3 
Oral Isotretinoin Evaluation ..................................................................31 
8.3 
Safety Assessments ................................................................................................32 
8.4 
Safety Measurements .............................................................................................32 
8.4.1 
Local Tolerability Assessment ..............................................................32 
8.4.2 
Adverse Events .....................................................................................34 
8.5 
Other Assessments .................................................................................................38 
8.5.1 
Facial Photographs (Canfield Scientific Manual of Procedures) ..........38 
8.5.2 
Subject’s Assessment of Acne Improvement ........................................38 
8.5.3 
Dermatology Life Quality Index (DLQI™), Children’s 
Dermatology Life Quality Index (cDLQI™) .......................................39 
8.5.4 
Subject Satisfaction Questionnaire .......................................................39 
8.5.5 
Acne-Specific Quality of Life Questionnaire (Acne-QoL) ...................39 
8.6 
Appropriateness of Measurements .........................................................................40 
9.0 
CLINICAL TRIAL VISITS ............................................................................................40 
9.1 
Description of Clinical Trial Visits ........................................................................40 
9.1.1 
Screening Visit ......................................................................................40 
9.1.2 
Baseline Visit ........................................................................................41 
9.1.3 
Week 4 Visit (± 3 days) ........................................................................43 
9.1.4 
Week 8 Visit (± 3 days) ........................................................................44 
9.1.5 
Week 12/Early Termination Visit (± 3 days) .........................................45 
9.2 
Additional Instructions for Subjects ......................................................................46 
10.0 
PLANNED STATISTICAL ANALYSES AND STATISTICAL 
CONSIDERATIONS .......................................................................................................46 
10.1 
Statistical Analysis Plan .........................................................................................46 
10.2 
Sample Size Determination ....................................................................................46 
10.3 
Analysis Populations ..............................................................................................47 


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10.4 
Statistical Analysis .................................................................................................47 
10.4.1 
General Methods ...................................................................................47 
10.4.2 
Demographics and Subject Disposition ................................................47 
10.4.3 
Efficacy Analysis ..................................................................................47 
10.4.4 
Safety Analysis .....................................................................................48 
11.0 
ETHICS AND GENERAL CLINICAL TRIAL CONDUCT 
CONSIDERATIONS .......................................................................................................49 
11.1 
Institutional Review Board or Independent Ethics Committee .............................49 
11.2 
Ethical Conduct of the Clinical Trial .....................................................................49 
11.3 
Informed Consent...................................................................................................49 
11.4 
Contractual Requirements ......................................................................................50 
12.0 
REGULATORY/ADMINISTRATIVE PROCEDURES AND 
DOCUMENTATION .......................................................................................................50 
12.1 
Quality Assurance and Audits/Inspections ............................................................50 
12.2 
Protocol Compliance and Protocol Deviations ......................................................50 
12.3 
Protocol Amendments ............................................................................................50 
12.4 
Data Collection and Electronic Case Report Forms (eCRFs) ................................51 
12.5 
Source Documentation ...........................................................................................51 
12.6 
Study Initiation and Personnel Training ................................................................51 
12.7 
Clinical Monitoring ................................................................................................51 
12.8 
Data Management ..................................................................................................52 
12.9 
Study Documentation and Retention of Records ...................................................52 
12.10  Insurance ................................................................................................................52 
13.0 
REFERENCES .................................................................................................................53 
14.0 
APPENDICES ..................................................................................................................56 
14.1 
PACKAGE INSERTS FOR ADAPALENE 0.3% / BENZOYL PEROXIDE 
2.5% GEL AND DOXYCYCLINE HYCLATE TABLETS .................................56 
14.2 
PROCEDURE FOR FACIAL LESION COUNTS ...............................................88 
14.3 
DERMATOLOGY LIFE QUALITY INDEX (DLQI™) ......................................90 
14.4 
CHILDREN’S DERMATOLOGY LIFE QUALITY INDEX (cDLQI™) ............92 
14.5 
SUBJECT SATISFACTION QUESTIONNAIRE ................................................94 
14.6 
ACNE-SPECIFIC QUALITY OF LIFE QUESTIONNAIRE ...............................96 
14.7 
DECLARATION OF HELSINKI..........................................................................99 
 
 


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LIST OF TABLES 
 
Table 1. ................. Schedule of Study Assessments .......................................................................19 
Table 2. ................. Exit Form Reasons for Discontinuation ...........................................................25 
Table 3. ................. Description and Dispensing of Study Medications ..........................................26 
Table 4. ................. Investigator’s Global Assessment Severity Scale ............................................31 
Table 5. ................. Local Tolerability Severity Scale .....................................................................33 
Table 6. ................. Subject’s Assessment of Acne Improvement Scale .........................................39 


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1.0 
PROTOCOL SYNOPSIS 
TITLE OF 
STUDY 
EFFICACY AND SAFETY OF ADAPALENE 0.3% / BENZOYL 
PEROXIDE 2.5% GEL PLUS DOXYCYCLINE IN SEVERE 
INFLAMMATORY ACNE (NON-NODULOCYSTIC) SUBJECTS 
STUDY 
CENTERS 
No more than 25 sites 
PHASE  
4 
STUDY 
OBJECTIVE 
Demonstrate that a daily treatment regimen of adapalene 0.3% / 
benzoyl peroxide 2.5% gel + oral Doxycycline 200 mg is an effective 
and safe alternative to oral isotretinoin in severe inflammatory acne 
with less than 3 nodules or cysts (non-nodulocystic) during a 12-week 
treatment period. 
STUDY DESIGN 
This is a Phase 4, 12-week, single-arm, open-label, multi-center 
investigational study in subjects with severe inflammatory acne. 
Male and female subjects, 12 years of age or older, presenting with 
severe inflammatory facial acne vulgaris, who have up to 2 nodules on 
the face, are evaluated with a score of 4 (severe) on the IGA scale, and 
who in the opinion of the Investigator are candidates for oral 
isotretinoin, are to be enrolled. 
Up to 25 independent study centers will participate in the study, and 
approximately 180 subjects will be enrolled. Subjects who meet the 
inclusion criteria and none of the exclusion criteria at the Screening 
visit will return to the clinic on Week 0 for baseline measures and to 
start treatment which will continue for a period of up to 12 weeks.  
Subjects who do not need to undergo a wash-out period (Section 6.2.2) 
may combine the Screening visit and Baseline visit and thus attend 4 
clinic visits. Screened subjects requiring a wash-out period (up to 4 
weeks) prior to baseline measurements and beginning treatment will 
attend a total of 5 visits. 
Following the Baseline (Week 0) visit, all subjects will report to the 
clinic for efficacy and safety evaluations at Weeks 4, 8, and 12. 
Subjects will be provided with Cetaphil Gentle Skin Cleanser and 
Cetaphil Daily Facial Moisturizer SPF15 throughout the study to help 
minimize potential irritation. 
PLANNED 
SAMPLE SIZE 
Approximately 180 subjects will be enrolled to complete 
approximately 150 subjects. 
KEY SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
1. Male or female subjects, 12 years of age or older at Screening visit.


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2. Subjects with a clinical diagnosis of severe inflammatory acne 
(IGA score of 4) who, in the opinion of the Investigator, are 
candidates for oral isotretinoin at Screening and Baseline. 
3. Subjects with ≤ 2 nodules on the face, < 1 cm in diameter. 
4. Subjects willing to be photographed at study visits. Photographs 
may be used for research, marketing, promotional, and/or scientific 
purposes. 
5. Female subjects of child-bearing potential able and willing to use a 
highly effective method of contraception associated with a barrier 
form of contraception from one month before beginning treatment 
to one month after treatment discontinuation.  
A highly effective method of contraception is defined as: bilateral 
tubal ligation; combined oral contraceptives (estrogens and 
progesterone) or implanted or injectable contraceptives with a 
stable dose for at least 1 month prior to baseline; hormonal 
intra-uterine device (IUD) inserted at least 1 month prior to 
baseline; vasectomized partner for at least 3 months prior to 
baseline and this male is the sole partner for that subject. 
Barrier forms of contraception include diaphragms, latex condoms, 
and cervical caps; each must be used with a spermicide. 
*For minors not yet sexually active, abstinence is an acceptable 
form of birth control. 
6. Subjects able to follow instructions and likely to complete all 
required visits. 
7. Subjects 18 years of age or older must read and sign the Informed 
Consent Form, which includes Photography Consent and HIPAA 
authorization, prior to any participation in the study. Consent will 
be obtained prior to any study-related procedures. 
Subjects under the age of 18 years must sign an Assent to 
Participate Form to participate in the study and must have one 
parent or guardian read and sign the Informed Consent Form prior 
to any study-related procedure. (The parent or guardian is not 
required to attend the following visits unless requested.) 
Exclusion Criteria: 
1. Subjects with nodulocystic or conglobate acne, acne fulminans, or 
secondary acne (chloracne, drug-induced acne, etc.). 
2. Subjects with ≥ 3 acne nodules or cysts on the face at Screening 
and Baseline visits. 
3. Female subjects who are pregnant, nursing, or planning a 
pregnancy during the study. 
4. Subjects who have used any systemic therapy directed at 
improving acne, including antibiotics, within 30 days prior to 


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Baseline visit. 
5. Subjects who have previously used oral isotretinoin. 
6. Subjects who have received topical treatment on the face by: 
a. Hydroquinones, peels, photodynamic therapy, laser therapy, 
microdermabrasion, deep chemical peel, or plastic surgery 
within 4 weeks prior to baseline. 
b. Corticosteroids, antibiotics, antibacterials, antiseptics, 
retinoids, azelaic acid, dapsone, other anti-inflammatory 
drugs, other acne treatments, or light therapy within 2 weeks 
prior to baseline. 
c. Zinc-containing products, or cosmetic procedures (facials, 
comedone extractions, etc.) within 1 week prior to baseline. 
7. Subjects who have received systemic treatment by corticosteroids, 
antibiotics, or spironolactone within 4 weeks prior to baseline. 
Note: No washout period is required for oral vitamin A up to the 
recommended daily dose (4000 - 5000 IU). 
8. Subjects who have started taking medications to treat a concurrent 
medical condition for which the type and dose has not been stable 
in the opinion of the Investigator for at least 90 days prior to 
signing the Informed Consent Form and/or is expected to change 
during the course of the study. 
9. Subjects with a condition or circumstance which, in the 
Investigator’s opinion, may put the subject at risk (e.g., a history 
of significant renal disease with impairment of renal function), 
confound the study results, or interfere with the subject’s 
participation in the study. 
10. Subjects who are at risk in terms of precautions, warnings, and 
contraindications for the investigational study drugs (see 
Appendix 14.1 for package inserts for adapalene 0.3% / benzoyl 
peroxide 2.5% gel and doxycycline hyclate tablets). 
11. Subjects with a known allergy to any of the components of the 
study products and/or a known hypersensitivity to adapalene, 
benzoyl peroxide, and/or tetracycline class antibiotics. 
12. Subjects with a skin condition which, in the Investigator’s opinion, 
may interfere with study assessments. 
13. Subjects who will be exposed to intensive ultraviolet (UV) 
radiation during the study (mountain sports, sunbathing, tanning 
beds, etc.). 
14. Subjects who have participated in an interventional investigational 
study within 30 days of signing the Informed Consent Form, 
participated in biologic investigational studies within 90 days of 
signing the Informed Consent Form, or who plan to participate in 
any other interventional clinical research study while participating 


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in this trial. 
15. Sponsor and study site staff, relatives of staff members, or other 
individuals who would have access to the clinical study protocol.  
TREATMENTS 
Investigational Study Drugs: 
 Topical adapalene 0.3% / benzoyl peroxide 2.5% emulsion gel (one 
application daily for 12 weeks) 
 Oral doxycycline hyclate, 200 mg per day (two 50-mg tablets twice 
daily for 12 weeks)  
Non-investigational Study Products: 
 Cetaphil Gentle Skin Cleanser (twice daily) 
 Cetaphil Daily Facial Moisturizer SPF15 (at least once daily, and 
as needed) 
EFFICACY 
PARAMETERS  
Efficacy parameters to be assessed at Weeks 4, 8, and 12: 
 Investigator’s Global Assessment (IGA) 
 Inflammatory and Non-inflammatory Lesion Counts 
EFFICACY 
ASSESSMENTS 
 Investigator Global Assessment: Evaluates acne severity on 0-4 
scale 
 Lesion Count: Enumerates inflammatory and non-inflammatory 
lesions 
 Oral Isotretinoin Evaluation: Determines if, in the opinion of the 
Investigator, the subject is a candidate for oral isotretinoin 
EFFICACY 
ENDPOINTS 
Primary efficacy endpoint: 
 Reduction in number of inflammatory lesions at Week 12 
Secondary efficacy endpoints: 
 IGA Success Rate at Weeks 4, 8, and 12 
 Percent reduction in total, inflammatory, and non-inflammatory 
lesions at Weeks 4, 8, and 12 
 Number and percent of subjects who, in the opinion of the 
Investigator, are candidates for oral isotretinoin at Weeks 0, 4, 
8, and 12 
 Reduction in number of total, inflammatory, and non-inflammatory 
lesions at Weeks 4, 8, and 12 
 Subject Assessment of Acne Improvement at Week 12 
SAFETY 
PARAMETERS 
Safety parameter to be assessed for all subjects at Baseline and at 
every subsequent visit: 
 Incidence of Adverse Events (AEs) 
SAFETY 
ASSESSMENTS 
 Adverse Events: Enumeration and details of all AEs 


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 Local Tolerability: Measures of erythema, scaling, drying, and 
stinging/burning on a 0-3 scale 
STATISTICAL 
ANALYSES 
Analysis Populations:  
The Intent-to-Treat (ITT) Population consists of the entire population 
enrolled at baseline. All efficacy data will be analyzed for the ITT 
Population.   
The Safety Population consists of the ITT Population after exclusion of 
subjects who never took the treatment with certainty, based on 
monitoring reports. All safety analyses will be summarized for the 
Safety Population. 
General Statistical Methods: 
All efficacy variables will be summarized at each visit for the ITT 
Population. Categorical variables will be summarized by counts and 
percentages for each response category (N, %). Continuous variables 
will be summarized using number of subjects, means, standard 
deviations (SD), medians, minimums, and maximums for the data 
collected at each visit. Confidence intervals (CI) will be presented as 
appropriate. All evaluations (including CIs) will be reported for 
exploratory purposes and will be interpreted as such. No formal 
statistical tests will be performed. 
Subject demographics and baseline characteristics will be summarized 
with descriptive statistics. Subject disposition will be summarized 
with the number of subjects in the Safety Population, the number and 
percentage of subjects who complete the study, and the number and 
percentage of subjects who do not complete the study for each 
discontinuation reason.  
The primary endpoint is the reduction in the number of inflammatory 
lesions at Week 12, and is the change in the lesion count from 
Baseline to Week 12. The reduction in lesion count will be 
summarized with descriptive statistics, with a 95% CI for the 
reduction in lesions.  
The IGA Success Rate is defined as the number and percent of 
subjects rated as Clear (Grade 0) or Almost Clear (Grade 1), and will 
be summarized at Weeks 4, 8, and 12 with a 95% CI for the Success 
Rate. The number and percent of subjects who are candidates for oral 
isotretinoin will be summarized at Weeks 0, 4, 8, and 12, with a 95% 
CCI


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CI. The Subject Assessment of Acne Improvement at Week 12 will be 
summarized with counts and percentages for each category.  
The data will be summarized as observed, with no imputation for 
missing values. A last observation carried forward (LOCF) approach 
will be used as a sensitivity analysis. 
Exposure to investigational study drugs and compliance will be 
summarized using descriptive statistics. AE terms will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). 
Incidence of treatment-emergent AEs will be summarized by 
MedDRA system organ class (SOC) and preferred term (PT) for the 
Safety Population. Additional summary tables will be provided for 
AEs considered related to the investigational study drug, and for AEs 
leading to discontinuation. 
The symptoms of local tolerability (erythema, scaling, dryness, and 
stinging/burning) will be summarized by frequency and percentage for 
each response category for each visit.  
Complete listings of all data represented on the electronic case report 
form (eCRF) will be provided as an appendix to the final study report 
to facilitate further investigation of tabulated values and to allow for 
clinical review of all parameters. 
FINAL DATE 
Version 1.0 
28 JUN 2016 
 
 
 
 
CCI


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2.0 
LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse Event 
BPO 
Benzoyl Peroxide (C14H10O4) 
CDMS 
Clinical Data Management System 
CI 
Confidence Interval 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
DMP 
Data Management Plan 
eCRF 
Electronic Case Report Forms 
EDC 
Electronic Data Capture 
e.g. 
For Example (Latin: exempli gratia) 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IGA 
Investigator’s Global Assessment 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IUD 
Intrauterine Device 
LOCF 
Last Observation Carried Forward 
MCID 
Minimal Clinically Important Difference 
MD 
Medical Doctor 
MedDRA 
Medical Dictionary for Regulatory Activities 
N or n 
Number 
N/A 
Not Applicable 
OTC 
Over-the-Counter 
CCI
CCI


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Abbreviation or Term 
Definition/Explanation 
PT 
Preferred Term 
PV 
Pharmacovigilance  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIN 
Subject Identification Number 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPF 
Sun Protection Factor 
UPT 
Urine Pregnancy Test 
US 
United States  
UV 
Ultraviolet 
WHO 
World Health Organization 
 


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3.0 
BACKGROUND AND RATIONALE 
3.1 
Medical Background and Brief Rationale for the Trial 
Acne vulgaris is a chronic inflammatory disease affecting approximately 80% of young adults 
and adolescents.1-4 Four main pathogenic factors are known to lead to its development: follicular 
hyperkeratosis, increased sebaceous gland activity with hyperseborrhoea, microbial 
hypercolonization with Propionibacterium acnes (P. acnes), and inflammation and 
immunological host reaction. The traditional acne treatment paradigm is directed toward these 
factors: initial treatment is with topical agents, followed by courses of antibiotics (preferably 
combined with topical agents), and hormonal treatment in women. For management of severe 
nodulocystic acne that has been proven unresponsive to these conventional therapies, including 
systemic therapy, the treatment of choice is isotretinoin.5-7 
Isotretinoin (13-cis-retinoic acid), an isomer of retinoic acid, was first introduced as a treatment 
for acne vulgaris and various other skin disorders in the 1980s. In the last decade, it is estimated 
that over 11.2 million courses of isotretinoin have been dispensed worldwide; 81 million grams 
of isotretinoin were dispensed from 2000 through 2009 (IMS Health, MIDAS Database, MAT 
Dec 2000–MAT Dec 2009).8,9 
The success of isotretinoin as a treatment for the most severe acne can be ascribed to the fact 
that it targets all four pathogenic factors. It reduces the secretion of sebum, decreases the size of 
the sebaceous glands, prevents the development of comedones, decreases the colonization with 
P. acnes, possesses anti-inflammatory properties, and reduces the levels of metalloproteinases in 
sebum.8-16  
The major limitation of isotretinoin use has been its well-documented adverse effects. 
Isotretinoin is one of the strongest known teratogens among prescription medications, with the 
overall risk of birth defects estimated to be up to 30%. In addition, by interacting with many of 
the biologic systems of the body, it produces a pattern of significant adverse effects similar to 
that seen in hypervitaminosis A. Side effects have been observed in the mucocutaneous, 
musculoskeletal, ophthalmic, and central nervous systems.14,16-20 In addition to teratogenesis, 
these side effects include headaches, elevations in triglyceride and cholesterol levels, liver 
enzyme elevations, potential skeletal abnormalities during long-term use, and depression or 
suicide. Most of the adverse effects are temporary, and resolve after the drug is discontinued. 
Therapy must be individualized for each patient based on clinical presentation, preferences and 
acceptability of adverse effects, monitoring parameters, and potential risks. However, the 
serious adverse effects are of great concern, and have led to more stringent and restrictive 
regulation regarding the use of isotretinoin.18 Despite this, a trend toward the use of isotretinoin 
for less severe forms of acne is emerging. Therefore, there is a growing need for an alternative 
safe and effective treatment for acne vulgaris.  
A medication which can help meet this need is Adapalene-Benzoyl Peroxide (C14H10O4; BPO) 
gel, a unique antibiotic-free combination of adapalene 0.3%, a well-tolerated and efficacious 
topical retinoid, and BPO 2.5%, a well-established antimicrobial agent. The complementary 
modes of action, and the positive efficacy and safety profiles of these two agents, make 
adapalene-BPO gel the most logical choice for once-daily treatment for all types of acne but the 
most severe. Adapalene possesses anticomedogenic, comedolytic, and anti-inflammatory 


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properties21-24, and BPO is the most potent bactericidal agent against P. acnes.25,26 Because 
neither retinoids nor BPO create selective pressure for resistance, this combination may be 
expected to decrease the incidence of epidermal bacterial resistance relative to antibiotics.27 
Adapalene-BPO gel has been evaluated in clinical trials as a treatment for acne, and has 
demonstrated significant efficacy in several large clinical studies.28-30 As a result, adapalene-
BPO gel has been granted marketing authorization in Canada under the trade name of Tactuo® 
(Galderma). It has also been shown that adapalene-BPO provides higher efficacy when more 
lesions are presented at baseline.31 The efficacy of adapalene-BPO gel could be explained by the 
synergistic effect of adapalene and BPO when used together.30 
Recently, a study in severe acne, following current international guidelines, showed that 
treatment with adapalene-BPO in combination with the antibiotic doxycycline resulted in a 
three-fold increase in success rate compared to treatment with oral antibiotic alone.32 
Doxycycline is a member of the tetracycline class of antibiotics, broad-spectrum bacteriostatic 
agents which are the most commonly prescribed oral antibiotics for moderate to severe 
inflammatory acne. Notably, the incidence of significant adverse effects with antibiotic use is 
low, with the main drawbacks being gastrointestinal distress and dose-dependent 
photosensitivity.15,18,32-35 
While oral isotretinoin is an excellent treatment for severe nodular acne, it may not be 
appropriate in some cases, for example, due to current or expected pregnancy or previous 
adverse reaction to this class of drugs. Combination therapy consisting of adapalene-BPO plus 
an oral antibiotic is the logical and recommended first alternative.36,37  
The gel formulation of adapalene 0.3% / benzoyl peroxide 2.5% (see Appendix 14.1 for a 
product insert) has been shown to be effective and safe, and represents a more potent 
combination product to treat severe acne vulgaris. 
The overall objective of this Phase 4 trial is to determine the extent to which daily treatment 
with adapalene 0.3% / benzoyl peroxide 2.5% gel plus oral Doxycycline 200 mg for 12 weeks 
may be an effective and safe alternative to oral isotretinoin in subjects 12 years of age and older 
having severe inflammatory acne with less than 3 nodules or cysts (non-nodulocystic/non-
conglobate). 
4.0 
CLINICAL TRIAL OBJECTIVE AND CLINICAL HYPOTHESIS 
4.1 
Clinical Trial Objective 
The clinical trial objective is to demonstrate that a daily treatment regimen of adapalene 0.3% / 
benzoyl peroxide 2.5% gel + oral Doxycycline 200 mg is an effective and safe alternative to oral 
isotretinoin in subjects 12 years of age and older having severe inflammatory acne with less than 
3 nodules or cysts (non-nodulocystic/non-conglobate) during a 12-week treatment period. 
4.2 
Clinical Hypothesis 
The proposed clinical efficacy hypothesis is based on the current Acne Treatment Guidelines for 
severe inflammatory acne from the American Academy of Dermatology/American Academy of 
Dermatology Association.37,38  


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According to these Guidelines, first-line therapy for severe inflammatory acne is an oral 
antibiotic + topical combination therapy consisting of Benzoyl Peroxide (BPO) + Antibiotic or 
Retinoid + BPO or Retinoid + BPO + Antibiotic. Thus, daily combination therapy with 
adapalene 0.3% / benzoyl peroxide 2.5% gel and Doxycycline 200 mg is a recommended first-
line therapy for severe inflammatory acne; the hypothesis of this study is that this combination is 
an effective therapy alternative for oral isotretinoin. 
5.0 
STUDY DESIGN 
This is a Phase 4, 12-week, single-arm, open-label, multi-center investigational study in subjects 
with severe inflammatory acne.  
This study will enroll male and female subjects, 12 years of age or older, presenting with severe 
inflammatory facial acne vulgaris with up to 2 nodules on the face and a score of 4 (severe) on 
the IGA scale, and who are, in the opinion of the Investigator, candidates for oral isotretinoin. If, 
at screening, the inclusion/exclusion criteria regarding the IGA score and nodule counts are not 
met, the subject should be screen-failed and will not complete a baseline evaluation. Re-
screening will not be allowed during the trial. 
Up to 25 independent study centers will participate in the study, and approximately 180 subjects 
will be enrolled. Subjects who meet the inclusion criteria and none of the exclusion criteria at 
the Screening visit will return to the clinic on Week 0 for baseline measures and to start 
treatment, which will continue for a period of up to 12 weeks. Those screened subjects who do 
not need to undergo a wash-out period (Table 1; Section 6.2.2) may combine the Screening and 
Baseline visits, and thus attend 4 clinic visits. Screened subjects requiring a wash-out period (up 
to 4 weeks) prior to baseline measurements and beginning treatment will attend a total of 
5 clinic visits. Following the Baseline (Week 0) visit, all subjects will report to the clinic for 
efficacy and safety evaluations at Week 4, Week 8, and Week 12.  
Lesion Counts and Investigator Global Assessments (IGAs) for a given subject are to be 
performed by the same Investigator throughout the study, from Week 0 through Week 12/Early 
Termination (ET) visits. 
A urine pregnancy test (UPT) will be required at the Screening, Baseline, Week 4, Week 8, and 
Week 12/ET visits for all females of childbearing potential. The decision may be made by the 
Investigator to perform additional UPTs during the course of the study. 
Subjects will be provided with Cetaphil Gentle Skin Cleanser and Cetaphil Daily Facial 
Moisturizer Sun Protection Factor SPF 15 as needed during the study. To prevent dry skin, 
subjects will be requested to use a moisturizer throughout the study. If a subject experiences 
persistent dryness or irritation, the Investigator may consider a reduced application frequency 
for the investigational study drug gel, as required for the symptomatic relief of skin dryness or 
irritation.  
A summary of the Study Schedule is provided in Table 1. 
 




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5.1 
Study Duration 
The planned clinical trial duration from the start of subject screening (i.e., Informed Consent 
Form [ICF] signature by the first subject) to last subject out (i.e., completion of the last clinical 
trial visit by the last subject) is anticipated to be approximately 8 months. The study duration for 
each subject is expected to be from 12 to 16 weeks (12-week treatment, plus a wash-out period 
of up to 4 weeks for some subjects).  
Galderma Laboratories, LP (Galderma) may decide to prematurely terminate or suspend the 
participation of a particular clinical trial center (e.g., for non-inclusion or non-compliance with 
clinical trial protocol, regulations, or Good Clinical Practice [GCP]), or to prematurely suspend 
the clinical trial (e.g., for safety, study drug quality, regulatory, efficacy, or logistical reasons) at 
any time with appropriate notification. 
6.0 
SELECTION AND DISPOSITION OF SUBJECTS 
6.1 
Number of Subjects 
It is estimated that the screen failure rate will be 20%; therefore, approximately 225 subjects 
will be screened in order to enroll approximately 180 subjects and to complete approximately 
150 subjects. 
6.2 
Clinical Trial Population Characteristics 
In order to be eligible for the clinical trial, subjects must fulfill all of the following criteria. 
Some criteria are to be checked at the Screening visit and/or at the Baseline visit, as specified.  
Male and female subjects of any race, 12 years of age or older, with acne vulgaris who meet all 
of the Inclusion criteria and none of the Exclusion criteria will be enrolled. 
6.2.1 
Inclusion Criteria 
Potential study participants must meet all of the following criteria to be eligible for inclusion in 
the study: 
1. Male or female subjects, 12 years of age or older at Screening visit. 
2. Subjects with a clinical diagnosis of severe inflammatory acne (IGA score of 4) who, in 
the opinion of the Investigator, are candidates for oral isotretinoin at Screening and 
Baseline. 
3. Subjects with ≤ 2 nodules on the face, < 1 cm in diameter. 
4. Subjects willing to be photographed at study visits. Photographs may be used for 
research, marketing, promotional, and/or scientific purposes. 
5. Female subjects of child-bearing potential able and willing to use a highly effective 
method of contraception associated with a barrier form of contraception from one month 
before beginning treatment to one month after treatment discontinuation. 
 
A highly effective method of contraception is defined as: bilateral tubal ligation; 
combined oral contraceptives (estrogens and progesterone) or implanted or injectable 


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contraceptives with a stable dose for at least 1 month prior to baseline; hormonal 
intra-uterine device (IUD) inserted at least 1 month prior to baseline; vasectomized 
partner for at least 3 months prior to baseline and this male is the sole partner for that 
subject. 
Barrier forms of contraception include diaphragms, latex condoms, and cervical caps; 
each must be used with a spermicide. 
*For minors not yet sexually active, abstinence is an acceptable form of birth control. 
6. Subjects able to follow instructions and likely to complete all required visits. 
7. Subjects 18 years of age or older must read and sign the Informed Consent Form, which 
includes Photography Consent and HIPAA authorization, prior to any participation in the 
study. Consent will be obtained prior to any study-related procedures. 
Subjects under the age of 18 years must sign an Assent to Participate Form to participate 
in the study and must have one parent or guardian read and sign the Informed Consent 
Form prior to any study-related procedure. (The parent or guardian is not required to 
attend the following visits unless requested.)  
6.2.2 
Exclusion Criteria 
Potential study participants who meet any of the following criteria must be excluded from the 
study: 
1. Subjects with nodulocystic or conglobate acne, acne fulminans, or secondary acne 
(chloracne, drug-induced acne, etc.). 
2. Subjects with ≥ 3 acne nodules or cysts on the face at Screening and Baseline visits. 
3. Female subjects who are pregnant, nursing, or planning a pregnancy during the study. 
4. Subjects who have used any systemic therapy directed at improving acne, including 
antibiotics, within 30 days prior to Baseline visit. 
5. Subjects who have previously used oral isotretinoin. 
6. Subjects who have received topical treatment on the face by: 
a. Hydroquinones, peels, photodynamic therapy, laser therapy, microdermabrasion, 
deep chemical peel, or plastic surgery within 4 weeks prior to baseline. 
b. Corticosteroids, antibiotics, antibacterials, antiseptics, retinoids, azelaic acid, 
dapsone, other anti-inflammatory drugs, other acne treatments, or light therapy 
within 2 weeks prior to baseline. 
c. Zinc-containing products, or cosmetic procedures (facials, comedone extractions, 
etc.) within 1 week prior to baseline. 
7. Subjects who have received systemic treatment by corticosteroids, antibiotics, or 
spironolactone within 4 weeks prior to baseline. 
Note: Oral vitamin A up to the recommended daily dose (4000 - 5000 IU) is 
acceptable. 
8. Subjects who have started taking medications to treat a concurrent medical condition for 
which the type and dose has not been stable in the opinion of the Investigator for at least 
90 days prior to signing the Informed Consent Form and/or is expected to change during 
the course of the study. 


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9. Subjects with a condition or circumstance which, in the Investigator’s opinion, may put 
the subject at risk (e.g., a history of significant renal disease with impairment of renal 
function), confound the study results, or interfere with the subject’s participation in the 
study. 
10. Subjects who are at risk in terms of precautions, warnings, and contraindications for the 
investigational study drugs (see Appendix 14.1 for package inserts for adapalene 0.3% / 
benzoyl peroxide 2.5% gel and doxycycline hyclate tablets). 
11. Subjects with known allergy to any of the components of the study products and/or a 
known hypersensitivity to adapalene, benzoyl peroxide, or tetracycline class antibiotics. 
12. Subjects with a skin condition which, in the Investigator’s opinion, may interfere with 
study assessments. 
13. Subjects who will be exposed to intensive ultraviolet (UV) radiation during the study 
(mountain sports, sunbathing, tanning beds, etc.). 
14. Subjects who have participated in an interventional investigational study within 30 days 
of signing the Informed Consent Form, participated in biologic investigational studies 
within 90 days of signing the Informed Consent Form, or who plan to participate in any 
other interventional clinical research study while participating in this trial. 
15. Sponsor and study site staff, relatives of staff members, or other individuals who would 
have access to the clinical study protocol.  
6.3 
Previous and Concomitant Therapies 
6.3.1 
Definitions 
Previous therapies are defined as therapies for the treatment of acne vulgaris that have been 
taken within the previous 6 months, and all other therapies or procedures that have been taken 
within the 4 weeks preceding the Screening visit. Subjects who have previously been exposed to 
oral isotretinoin will be excluded from participating in the study. 
Immunomodulators, biologics, and retinoids prescribed for indications other than acne during 
the previous 6 months must be reported.  
Concomitant therapies are defined as: 
 Any existing therapies ongoing at the time of the Screening visit. 
 Any changes to existing therapies (such as changes in dose or formulation) during the 
course of the clinical trial. 
 Any new therapies received by the subject since the Screening visit. 


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6.3.2 
Categories 
Previous and concomitant therapies for the treatment of acne vulgaris fall into two categories: 
 Drugs/therapies including, but not limited to: prescription, OTC, birth control 
pills/patches/hormonal devices, vitamins, moisturizers, sunscreens, herbal medicines and 
supplements, and homeopathic preparations. 
 Medical and surgical procedures including, but not limited to: laser/radiation procedures, 
dermal fillers, X-rays.  
Previous and concomitant therapies are to be recorded on the form for drugs/therapies and/or on 
the form for medical/surgical procedures in the electronic case report form (eCRF). 
Concomitant therapies are to be recorded, reviewed, and updated at each visit. 
Any new concomitant therapy or modification of an existing therapy may be linked to an 
Adverse Event (AE). A corresponding AE Form must be completed to account for the change in 
therapy, except in some cases such as therapy used for prophylaxis, dose modification for a 
chronic condition, etc. 
6.3.3 
Authorized Concomitant Therapies 
Unless listed under the Exclusion Criteria (Section 6.2.2) or in Prohibited Concomitant 
Therapies (Section 6.3.4), all therapies are authorized. 
Subjects will be instructed to use Cetaphil Gentle Skin Cleanser twice daily and to apply 
Cetaphil Daily Facial Moisturizer SPF15 at least once daily; liberal application of moisturizer 
should be encouraged. Moisturizers should not be applied within 2 hours (before or after) of the 
application of study drug. The use of a moisturizer will be documented as a Concomitant 
Therapy. Use of moisturizer will not constitute an AE. Cleanser should not be used for at least 
4 hours after study drug application. 
Higher SPF sunscreens (> SPF15) are permitted when discussed with/approved by the 
Investigator, if the subject needs additional sunscreen for outdoor activities. 
6.3.4 
Prohibited Concomitant Therapies 
No topical medication treatment other than the study drug, cleanser, moisturizer, and sunscreen 
will be permitted on the face. The following therapies are prohibited because they may interfere 
with the efficacy and/or safety (e.g., interaction with the study medication metabolism) 
assessment of the study medication. Specific interfering therapies include the medications listed 
in Exclusion Criteria (Section 6.2.2) and the following: 
 Alpha hydroxyl acid products 
 Medicated shaving creams 
 Antibacterial soaps 
 Astringents 
 Preparations with alcohol 
 Drugs that are prescribed off-label for the treatment of acne vulgaris 


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If prohibited therapies become a necessary treatment for the safety or best interest of the subject, 
the medical monitor should be notified to discuss possible alternatives prior to administration of 
a prohibited therapy. 
If a subject receives prohibited therapy during the clinical trial, the medical monitor should be 
notified to discuss the pertinence and the modalities for the subject to continue in the trial. 
6.3.5 
Procedures/Reasons for Subject Discontinuation/Withdrawal 
Although the importance of completing the entire clinical trial should be explained to the subject 
by the clinical trial personnel, any subject is free to discontinue participation in this clinical trial 
at any time and for whatever reason, specified or unspecified, and without prejudice. No 
constraints are to be imposed on the subject, and when appropriate, a subject may be treated 
with other conventional therapy when clinically indicated. Any subject who does not complete 
the clinical trial will be fully assessed, if such assessment is possible. The procedures designated 
for the Week 12/ET visit should be completed for all subjects discontinuing the clinical trial and 
the appropriate eCRF page should be completed when possible. 
All discontinuations and the reasons for discontinuation are to be documented by the 
Investigator on the Exit Form in the EDC, and also on the Adverse Event Form for 
discontinuation due to an AE. 
For discontinuation due to an AE, the Investigator should ensure that the subject receives 
suitable therapy for the AE. 
An Investigator may decide to discontinue a subject from the clinical trial for safety reasons. 
Galderma may also decide to prematurely terminate or suspend a subject’s participation in the 
clinical trial. Potential reasons for discontinuation, as listed on the Exit Form, are defined in 
Table 2. 
Subjects who are discontinued or withdrawn will not be replaced. 
 


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Table 2. 
Exit Form Reasons for Discontinuation  
Reason for 
Discontinuation 
Action to be Taken at Discontinuation 
Pregnancy 
Withdraw the subject from the clinical trial, following the procedure 
described in Section 8.4.2.2.3. 
Lack of Efficacy 
Withdraw the subject from the clinical trial. This reason for 
discontinuation can be cited only by the Investigator, and is based on his 
judgment and therapeutic/disease state expectations. If only the subject 
feels there is “lack of efficacy”, mark “Subject Request” as the reason 
and document in the comment section of the eCRF Exit Form. 
Adverse Event 
Complete an AE Form. 
Subject Request
a 
Explain reason for withdrawal in the comment section of the eCRF 
Exit Form. (Reasons can include consent withdrawal, subject 
relocation, schedule conflicts, subject wants isotretinoin.) 
Protocol Violation 
Explain violation in the comment section of the eCRF Exit Form. (Major 
protocol violations, especially when subject safety is concerned, will lead
to discontinuation.) 
Lost to Follow-up 
Explain situation in the comment section of the eCRF Exit Form. (“Lost 
to Follow-up” must be confirmed with two documented phone calls and 
a certified letter [delivery receipt requested] without answer.) 
Other
a 
Explain reason for discontinuation in the comment section of the 
eCRF Exit Form. (This category is to be used for a subject who 
discontinues due to a reason other than those specified in the 
predefined categories above.) 
a If reason for discontinuation is “subject request” or “other”, the subject will be questioned to rule out the 
possibility of an AE. (This should be documented in the comment section of the eCRF Exit Form.) 
 
7.0 
CLINICAL SUPPLIES AND TREATMENT DESCRIPTION 
7.1 
Description and Use of Study Medications 
Descriptions and use of the study medications, both the investigational drugs and the non-
investigational products, are summarized in Table 3. Additional information is available in the 
package inserts for the investigational study drugs (Appendix 14.1). 
 




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7.1.2 
Method of Treatment Assignment and Blinding 
Not Applicable. This is an open-label study. All subjects will receive the same treatment. 
7.1.3 
Study Medication Kit Number 
Not Applicable. No kits will be used. 
7.1.4 
Instructions for Use and Administration of Adapalene 0.3% / Benzoyl Peroxide 
2.5% Gel 
Each subject will receive the investigational study drug adapalene 0.3% / benzoyl peroxide 
2.5% gel in 45 g pump bottles during the course of the study (Table 3).   
This study drug should be applied to dry skin once daily for 12 weeks, at night after washing 
with Cetaphil Gentle Skin Cleanser (provided by the Sponsor; Table 3). A pea-sized amount of 
adapalene 0.3% / benzoyl peroxide 2.5% gel should be put on the fingertip and applied to the 
forehead. The procedure is repeated with a pea-sized amount applied to each cheek and to the 
chin and nose, being careful to avoid application to the nostrils, mouth, lips, and eyelids. The 
objective is to cover the entire face with a thin film of the treatment, even if there are areas on 
the face that do not have acne. While there are five areas of the face to be treated (forehead, 
right cheek, left cheek, chin, and nose), four pea-sized amounts of the study drug are typically 
estimated to be enough for the entire face. Designated study personnel should demonstrate how 
to apply the study drug by using a moisturizer as a tool, to show the subject the amount of study 
drug to use daily and the method of application. The product should not be applied to cuts, 
abrasions, or eczematous or sunburned skin. 
Signs and symptoms of local tolerability are possible during treatment (erythema, scaling, 
dryness, and stinging/burning). To prevent dry skin, subjects will be requested to use a 
moisturizer (Cetaphil Daily Facial Moisturizer SPF15, provided by the Sponsor) throughout the 
study as needed. If a subject experiences persistent dryness or irritation, the Investigator may 
consider a reduced application frequency of the investigational study drug gel as required for 
the symptomatic relief of skin dryness or irritation (Section 7.1.6). 
Subjects should be instructed to store the adapalene 0.3% / benzoyl peroxide 2.5% gel at room 
temperature in a closed container, away from light, heat, and moisture. The study drug should 
not be refrigerated or frozen. 
7.1.5 
Instructions for Use and Administration of Doxycycline Hyclate 
At the Baseline/Week 0 visit, each subject will receive two 120-count bottles of the 
investigational study drug doxycycline hyclate (50 mg tablets) and will be resupplied at each 
study visit (Week 4 and 8 only) with one new bottle (Table 3). During the Baseline/Week 0 
visit, subjects will be instructed to take the first 100-mg dose of doxycycline hyclate at the same 
time as the adapalene 0.3% / benzoyl peroxide 2.5% gel treatment that evening (i.e., receiving 
only a 100-mg dose on Day 0). They will take the second 100-mg dose the next morning, 
beginning the 200 mg per day dosing regimen on Study Day 1. The subject will be instructed to 
completely use one bottle of doxycycline hyclate before starting a subsequent bottle. 


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For the 200 mg per day dosing regimen, each subject will take two 50-mg tablets of doxycycline 
hyclate in the morning and at night, for a total of four tablets (a total of 200 mg) daily for 
12 weeks. The tablets should be swallowed, not chewed, should be taken with adequate amounts 
of fluid, and may be taken with food.  
Subjects should be instructed to store doxycycline hyclate tablets at room temperature. 
7.1.6 
Dose Modification 
If a subject experiences persistent dryness or irritation despite use of the moisturizers provided 
(Section 7.1.4), the Investigator may consider dose modification; i.e., reducing the once-daily 
treatment regimen to every other day. The Investigator should attempt to return the subject to 
once-daily treatment within two weeks.  
If this dose modification occurs between Baseline Week 0 and Week 4, and lasts more than 2 
weeks after the onset date of the dryness or irritation, the signs or symptoms of local tolerability 
should be recorded as an AE. After the Week 4 visit, the signs or symptoms related to this dose 
modification should be recorded as an AE, regardless of the duration of the dose modification. 
7.1.7 
Other Supplies 
Galderma will supply the UPTs, Cetaphil® Daily Facial Moisturizer SPF15 or equivalent (Table 
3), and Cetaphil® Gentle Skin Cleanser or equivalent (Table 3). 
7.2 
Investigational Study Drug Packaging and Labeling 
Adapalene 0.3% / benzoyl peroxide 2.5% gel is packaged in a 45 g bottle with a pump. A 
representation of the package insert is provided in Appendix 14.1. 
Doxycycline Hyclate 50 mg tablets are packaged in bottles of 120 tablets per bottle. A 
representation of the package insert is provided in Appendix 14.1. 
7.3 
Supplies Management 
7.3.1 
Study Medication Accountability 
The Investigator or designee will maintain accurate records of the following: 
 Reconciliation of all study medications (investigational study drugs and non-
investigational study products; Table 3) delivered to/received at the clinical trial center 
 Overall inventory for study medications at the clinical trial center 
 Study medications dispensed to each subject 
 Study medications returned by each subject to clinical trial center 
 Used and unused investigational study drug returned to the Sponsor (or alternative 
disposal) 
Upon receipt of the study medication, the clinical trial center personnel responsible for managing 
the supplies must conduct a complete inventory of all study medication and submit a signed copy 
of the Transfer of Clinical Supply Record (a.k.a. packing slip) received with the materials to The 
Coghlan Group via fax (512) 303-1390 or email RandyD@tcgsupplies.com.  


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None of the used or unused Cetaphil® moisturizers, Cetaphil® cleansers, or UPTs will be 
returned to the Sponsor.  
All clinical investigational study drug (adapalene 0.3% / benzoyl peroxide 2.5% gel and 
doxycycline hyclate tablets) sent to the Investigator/Institution will be accounted for, and no 
unauthorized use is permitted. 
7.3.2 
Study Medication Storage 
Study medication must be stored in a safe and secure area with restricted access, under the 
storage conditions specified by Galderma (Table 3; Sections 7.1.4 and 7.1.5). 
7.3.3 
Study Medication Dispensing and Return 
Only qualified study personnel (as designated by the Principal Investigator) will be responsible 
for dispensing study medication. Upon dispensing, the designated study personnel will 
document on the medication bottles the date of dispensing, the SIN of the subject receiving the 
study medication, and the initials of the person responsible for dispensing the medication.  
Full accountability, including the date of return and initials of the study personnel responsible 
for receipt, will be performed and documented for all study medications returned to the clinical 
study center as required. 
Subjects will be instructed by study personnel on the importance of being compliant with the use 
of the study medication throughout the clinical trial, and about the importance of returning their 
investigational study drugs (used and/or unused) at each visit. Each subject will receive 
Cetaphil Gentle Skin Cleanser, Cetaphil Daily Facial Moisturizer SPF15, 45 g pumps of 
adapalene 0.3% / benzoyl peroxide 2.5% gel (to be weighed prior to dispensing and upon return) 
and 120-count bottles of 50 mg doxycycline hyclate (to be counted upon return) during the 
course of the study.  
The adapalene 0.3% / benzoyl peroxide 2.5% gel and doxycycline hyclate will each be labeled 
with the protocol number and a four-digit bottle number. Study personnel should appropriately 
document the dispensation and return of study medication on the site’s drug accountability log. 
At the appropriate visits, subjects will return their investigational study drug and will be 
dispensed new study drug; the process will be repeated throughout the subject’s participation.  
In the event of early termination/suspension of the clinical trial, a rapid recall of 
investigational study drug will be initiated. The Investigator or designee must immediately 
instruct the subjects to stop the study medication regimen and return the investigational study 
drug to the clinical trial center. 
For subjects who do not complete the entire clinical trial, all used and unused investigational 
study drug should be returned by the subjects to the clinical trial center. 
The Investigator will return the investigational study drug to The Coghlan Group at the end 
of the study when all subjects have exited the study. Coghlan will then reconcile the 
investigational study drug by counting the returned pumps and counting the number of 
tablets to create a report of all study drug accountability (pump and tablet counts); the report 
will be provided to the Sponsor. 


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7.4 
Treatment Compliance Management and Records 
Investigational study drug will be collected from subjects at Weeks 4, 8, and 12/ET visits. To 
assess subject compliance, the Study Personnel will weigh the adapalene 0.3% / benzoyl 
peroxide 2.5% gel bottle before dispensing and upon subject returning the study drug at each 
visit. The doxycycline hyclate tablets will be counted upon subject returning the study drug at 
each visit. (A count of the pumps of adapalene 0.3% / benzoyl peroxide 2.5% gel and 
doxycycline hyclate tablets will be confirmed by The Coghlan Group after receipt of the 
investigational study drugs from the site at the end of the study [Section 7.3.3].) Other than 
documentation of dispensing to the subjects, no additional accountability will be required for the 
non-investigational products (i.e., Cetaphil cleanser, Cetaphil moisturizer).  
Subjects will be questioned regarding the investigational study drug gel application technique 
and use of any additional topical or systemic medications (including OTC products, and 
sunscreen usage for outdoor activities) which will be recorded in the Concomitant Medication 
Form. Subjects will also be questioned about the number of missed gel applications (if any) 
between study visits. 
8.0 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Efficacy Assessments 
Throughout the study, the same Investigator will perform the IGA and lesion counts for a given 
individual subject (Section 8.2). The initials of the Investigator performing the assessment will 
be captured on the eCRF. In the event there is a change in the assigned Investigator for a given 
subject, the reason for change must be documented. Untrained evaluators are not allowed to 
perform these assessments. If it is not possible to use the same evaluator to follow a given 
subject, the Sponsor recommends that evaluations by the primary and subsequent Investigator 
overlap (both Investigators should examine the subject together and discuss findings) for at least 
one visit. This should be documented in the appropriate Comments section of the eCRF. 
8.2 
Efficacy Measurements 
Efficacy assessments performed by the Investigator at Baseline and Weeks 4, 8, and 12 include 
IGA, Inflammatory Lesion Counts (papules and pustules), Non-inflammatory Lesion Counts 
(open and closed comedones), and Oral Isotretinoin Evaluation. Only the subject’s face will be 
evaluated for IGA and Lesion Counts. The Subject’s Assessment of Acne Improvement is an 
efficacy-related subject survey. 
The same Investigator will evaluate a given subject at every visit throughout the study. The same 
Investigator will evaluate whether, in his opinion, the subject is suitable for an oral isotretinoin 
prescription at every study visit. 
The IGA assessment should be performed before the lesion counting. 
8.2.1 
Investigator’s Global Assessment (IGA) 
A Board Certified Dermatologist will assess the subject’s acne severity using the IGA scale at 
every visit, performing a static (“snap-shot”) evaluation of acne severity. No reference to 


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baseline or other previous visits should be made by the Investigator when evaluating the 
subject’s facial acne. 
The IGA is dichotomized, such that Success is clearly defined as 0=Clear and 1=Almost Clear. 
The IGA Severity Scale is presented in Table 4. 
Table 4. 
Investigator’s Global Assessment Severity Scale 
Severity Scale 
Description 
0 
Clear 
Clear skin with no inflammatory or non-inflammatory lesions. 
1 
Almost Clear 
A few scattered comedones and a few small papules. 
2 
Mild 
Easily recognizable; less than half the face is involved. Some 
comedones and some papules and pustules. 
3 
Moderate 
More than half of the face is involved. Many comedones, papules 
and pustules. One small nodule may be present. 
4 
Severe 
Entire face is involved. Covered with comedones, numerous 
papules and pustules. Few nodules may or may not be present. 
 
8.2.2 
Lesion Counts 
Lesion counts will be performed by the Investigator at baseline and each post-baseline visit. 
Each type of lesion will be counted separately and recorded on the appropriate eCRF page. The 
lesion counts will be taken from the forehead, right cheek, left cheek, chin, and nose (see 
Appendix 0).  
The following lesion types will be counted: 
 Inflammatory Lesions 
o Papule – a small, red, solid elevation equal to or less than 0.5 cm in diameter. 
o Pustule – a small, circumscribed elevation of the skin that contains yellow-white 
exudate. 
 Non-inflammatory Lesions 
o Open Comedone – a pigmented dilated pilosebaceous orifice (blackhead). 
o Closed Comedone – a tiny white papule (whitehead). 
Nodules/Cysts, defined as circumscribed, elevated, solid lesions generally more than 1 cm in 
diameter with palpable depth, are counted at Screening/Baseline visit only. No more than 2 
nodules/cysts will be allowed for study participation (Exclusion Criterion #2, Section 6.2.2). 
Nodules/Cysts are not counted at post-Baseline visits. 
8.2.3 
Oral Isotretinoin Evaluation 
At each study visit, subjects will be evaluated to determine if, in the opinion of the Investigator, 
they are still candidates for oral isotretinoin. Regardless of the results, subjects will not be exited 
from the study due to this evaluation, and will continue participation in the study. 


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8.3 
Safety Assessments 
Safety assessments will be conducted for all subjects at Baseline and at every subsequent visit. 
8.4 
Safety Measurements 
Safety measurements include Local Tolerability Assessment and the Incidence of AEs. 
8.4.1 
Local Tolerability Assessment 
Signs and symptoms of local tolerability (erythema, scaling, dryness, and/or stinging/burning) 
will be evaluated by the Investigator at baseline and each post-baseline visit. 
The Investigator will record stinging/burning after discussion with the subject, based on the 
prior day’s application. The Investigator will ask an open-ended question such as, “Have you 
experienced any sensations immediately following dosing)?” taking care not to influence the 
subject’s answer. 
Erythema, scaling, dryness, and stinging/burning will be graded (Table 5) at Baseline and each 
post-Baseline visit (face only). 
 


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Table 5. 
Local Tolerability Severity Scale 
Severity 
Description 
Erythema – abnormal redness of the skin  
0 
None 
No erythema 
1 
Mild 
Slight pinkness present  
2 
Moderate 
Definite redness, easily recognized  
3 
Severe 
Intense redness 
Scaling – abnormal shedding of the stratum corneum 
0 
None 
No scaling 
1 
Mild 
Barely perceptible shedding, noticeable only on light scratching or 
rubbing 
2 
Moderate 
Obvious but not profuse shedding  
3 
Severe 
Heavy scale production  
Dryness – brittle and/or tight sensation  
0 
None 
No dryness  
1 
Mild 
Slight but definite roughness  
2 
Moderate 
Moderate roughness  
3 
Severe 
Marked roughness  
Stinging/Burning – prickling pain sensation immediately after (within 5 minutes) dosing  
0 
None 
No stinging/burning  
1 
Mild 
Slight warm, tingling/stinging sensation; not really bothersome  
2 
Moderate 
Definite warm, tingling/stinging sensation that is somewhat bothersome  
3 
Severe 
Hot, tingling/stinging sensation that has caused definite discomfort  
Note: Stinging/Burning at the Baseline visit is to be assessed as none (0). 
An AE will be recorded if the severity of the signs and symptoms is such that: 
 The subject’s participation in the study is interrupted at the subject’s request or at 
the Investigator’s request. 
 The subject permanently discontinues the treatment at the subject’s request or at the 
Investigator’s request. 
 The subject requires concomitant prescription or OTC therapy (other than moisturizers). 
Note: Need for increased moisturizer use does NOT constitute an AE. 
Any new sign or symptom not included in the scheduled evaluation of tolerability should be 
recorded as an AE, including those of mild intensity. 


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8.4.2 
Adverse Events  
Throughout the course of the study, all AEs will be monitored and reported on the eCRF 
Adverse Event Form, disclosing any requested and known information. When AEs occur, the 
main concern is the safety of the study subjects. 
8.4.2.1 
Definitions 
The following definitions of terms are guided by the International Conference on Harmonisation 
(ICH) and the U.S. Code of Federal Regulations (21 CFR 312.32). 
8.4.2.1.1 
Adverse Event  
An AE can be any unfavorable and/or unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal/investigational 
product, whether or not related to the medicinal/investigational products or to the study 
procedures. 
Thus any new sign, symptom or disease, or clinically significant increase in the intensity of an 
existing sign, symptom or disease, should be considered as an AE. All events that occur after 
signing of the subject ICF until the subject is off-study should be recorded.  
Notes: 
- 
Clinically significant worsening of the disease/condition being evaluated, which occurs 
during the study, is considered an AE. 
- 
Any new signs or symptoms suffered by the subject which appear after accidental or 
intentional overdose or misuse should also be reported as an AE. 
Pregnancy is not to be considered an AE, but must be reported promptly and followed up as 
described in Section 8.4.2.2.3. 
Any AE, whether or not it is related to the investigational study products or to the study 
procedures, will be reported on the eCRF Adverse Event Form along with the diagnosis 
(preferably) or description of the signs/symptoms, the date of onset, the severity, the seriousness, 
the relationship and the action taken with the investigational product, the treatment given to treat 
the AE, and the final AE outcome.  
Assessment of AE seriousness, severity, and causality will be based on specific definitions (see, 
respectively, Sections 8.4.2.1.2, 8.4.2.1.5, and 8.4.2.1.6). 
Side effects may be expected during treatment with Adapalene-BPO Gel, the characteristics of 
which are described in this protocol (e.g., erythema, scaling, dryness, and stinging/burning). The 
course of these expected events will be assessed and reported on the tolerability assessments. An 
Adverse Event Form will be completed only if the severity of the expected signs and symptoms 
is such that an interruption of the Subject’s participation in the study occurred at Investigator’s 
decision and/or if a concomitant medication (except moisturizer) is prescribed to treat the 
sign/symptom. 


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8.4.2.1.2 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening 
 Requires inpatient hospitalization or prolongation of existing 
hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered to be SAEs when, based upon appropriate medical judgment, 
they may jeopardize the safety of the subject, and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasia, or 
convulsions that do not result in hospitalization. 
Note: The term “life-threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death if 
it was more severe. 
Inpatient hospitalization is considered to have occurred if the subject has had to stay for a night 
at the hospital. The criterion for prolongation of hospitalization is also defined as an extra night 
at the hospital. Hospitalization may not constitute sufficient grounds to be considered as an SAE 
if it is solely for the purpose of a diagnostic tests (even if related to an AE), elective 
hospitalization for an intervention that was already planned before subject enrollment in the 
clinical trial, admission to a day-care facility, social admission (e.g., if the subject has no place to 
sleep), or administrative admission (e.g., for a yearly examination). 
8.4.2.1.3 
Unexpected Adverse Drug Reaction 
According to ICH E6, an unexpected adverse drug reaction is defined as an adverse reaction, the 
nature or severity of which is not consistent with the applicable study medication information 
(e.g., Investigator’s Brochure for an unapproved investigational drug or the package 
insert/summary of product characteristics for an approved product). 
8.4.2.1.4 
Adverse Event Reporting Period 
The clinical trial period during which AEs must be reported is the period from the time the 
subject (or the subject’s surrogate) signs the ICF to the end of the subject’s participation. 
The Sponsor should be informed if the Investigator becomes aware of any unusual safety 
information or any safety information that appears to be drug-related involving a subject who has 
participated in a clinical trial, even after a subject has completed the clinical trial. The 
Investigator should be diligent in looking for possible latent safety effects that may appear after 
the medication has been discontinued. 


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8.4.2.1.5 
Severity 
Severity is a clinical determination of the intensity of an AE and not of a disease. 
The Investigator is to classify the intensity of AEs using the following definitions as a guideline 
for all AEs occurring during clinical trials conducted or sponsored by Galderma. For this 
classification, the Investigator will take into account the possible range of the intensity of the 
event and report the grade of intensity which is the most appropriate according his medical 
judgment. 
Mild: Awareness of signs or symptom, but easily tolerated (acceptable) 
Moderate: Discomfort, enough to cause interference with usual activity (disturbing) 
Severe:  Incapacitating, with inability to work or perform usual activity (unacceptable) 
8.4.2.1.6 
Relationship to the study treatment 
The Investigator is to determine whether there is a reasonable causal relationship between the 
study treatment and the AE. Medical judgment should be used to determine the relationship, 
considering all relevant factors, including the pattern of reaction, temporal relationships, relevant 
medical history, and confounding factors such as co-medication or concurrent diseases. 
The expression “reasonable causal relationship” is meant to convey in general that there are facts 
or arguments to suggest a causal relationship (ICH E2A, Section IIIA 1). 
The relationship assessment for an AE is to be completed using the following definitions as a 
guideline for all AEs occurring during clinical trials conducted or sponsored by Galderma: 
 
Reasonable possibility: 
According to the reporting Investigator, there is a reasonable possibility (i.e., suggestive 
evidence or arguments) that there is a causal relationship irrespective of the dose administered 
between the study treatment (investigational product) and the AE. 
No reasonable possibility: 
No suggestive evidence or arguments can be identified regarding a causal relationship between 
the study treatment or the clinical trial protocol procedure and the AE. 
8.4.2.2 
Reporting Procedures 
8.4.2.2.1 
Procedures for reporting adverse events 
The collection of AEs will occur from the time that a subject (or the subject’s surrogate) signs 
the ICF to his final visit. Any AE occurring during the AE reporting period, whether it is related 
to the study treatment or not, will be recorded immediately in the source document, and 
described on the Adverse Event Form of the eCRF along with the date of onset, severity, 
relationship to the study treatment, and outcome, without omitting any requested and known 
information. Additional information may be requested under certain circumstances. AEs assessed 
as related to the treatment will be monitored until they are completely or satisfactorily resolved. 
Other AEs will be monitored until the last visit if they are not resolved or satisfactorily resolved. 
The Investigator will obtain and maintain in the subject’s files all pertinent medical records, 
information and medical judgment from colleagues who assisted in the treatment and follow-up 


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of the subject. If necessary, the Investigator will contact the subject’s personal physician or 
hospital staff to obtain further details. 
For SAEs (see Section 8.4.2.2.2), and pregnancies (see Section 8.4.2.2.3), the event must be 
reported by facsimile or scan and sent by e-mail within 24 hours (contact details in Section 
8.4.2.2.2). 
If the Subject discontinues due to an AE, the AE and Exit Forms must be completed. 
8.4.2.2.2 
Procedure for reporting a Serious Adverse Event 
For an SAE occurring during the period of the clinical trial, regardless of whether it is related to 
the treatment or not, and of whether it is expected or not, the Investigator must do the following: 
1. Take prompt and appropriate medical action, if necessary. The safety of the subject is the 
first priority. Additional contact details are provided in the Investigator’s site file. 
2. Complete the Adverse Event Form provided in the eCRF as fully as possible. 
3. Ensure that the event is classified as an SAE. 
4. Complete the Serious Adverse Event Form (available in the Study Reference Manual). 
Send the completed form within 24 hours to Advanced Clinical (AC) Pharmacovigilance 
(PV) by fax (847-919-4677), or scan the completed form and send within 24 hours by e-
mail (drugsafetypv@advancedclinical.com). Include any other relevant information or 
medical records (e.g., physical examination findings).  
AC PV will inform Galderma of the SAE by fax (682-831-9197) and by e-mail 
(PharmacovigilanceUS@galderma.com) within 24 hours. The minimum information that 
must be provided is identifiable coded subject, identifiable reporter, study treatment, 
description of the event (diagnosis). The demographics, medical history, previous and 
concomitant therapies, and AE pages of the eCRF must be completed and available for 
review in the Electronic Data Capture (EDC) system at the time of the report. 
5. Monitor and record the progress of the event until it resolves or reaches a clinically stable 
outcome, with or without sequelae. For all additional follow-up evaluations, complete or 
update a Serious Adverse Event Form, and then fax or scan; send by e-mail all additional 
follow-up information to the AC PV within 24 hours. SAEs will be monitored until the 
Investigator and Sponsor agree that the event is satisfactorily resolved. 
Report SAEs to: 
Advanced Clinical Pharmacovigilance 
SAE eFax:  847-919-4677 
SAE Hotline:  1-855-225-2340 
Email: drugsafetypv@advancedclinical.com 
6. Inform AC PV of the final outcome of the event. Send a revised or updated Serious 
Adverse Event Form and Adverse Event Form, if appropriate. 
7. Comply with the applicable regulatory requirement(s) related to the reporting of SAEs to 
the regulatory authority(ies), Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) and other pharmaceutical companies (as appropriate). 


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8.4.2.2.3 
Procedures for reporting pregnancies 
Pregnancies occurring during the screening period are considered screen failures and do not 
require reporting. Any pregnancy occurring during a clinical trial, in which the fetus could have 
been exposed to the study medication, must be reported in the same manner as an SAE (within 
24 hours, as described in Section 8.4.2.2.2) and monitored until its final outcome in order to 
ensure the complete collection of safety data for Galderma products. 
The Sponsor’s Pharmacovigilance Department has instituted a Pregnancy Exposure Follow-up 
program that allows for the follow-up of all exposures in pregnant women. Pregnancy exposure 
is defined as an exposure to the investigational study drug during the subject’s pregnancy.   
If a subject becomes pregnant, the Investigator is to do the following: 
1. Withdraw the subject from the clinical trial  
2. Complete appropriate final visit evaluations and eCRF pages. 
Upon the report of a pregnancy occurring during the study, the Sponsor’s Pharmacovigilance 
Department will contact the Investigator to gather additional information and provide more 
information about the Pregnancy Exposure Follow-up Program. 
If the pregnancy leads to an abortion (voluntary, spontaneous, or therapeutic), ectopic pregnancy, 
in-utero death, or congenital anomaly, the Investigator will follow the procedure for declaration 
of an SAE (see Section 8.4.2.2.2). 
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8.6 
Appropriateness of Measurements 
The measurements to be used for assessment of efficacy in this clinical trial are recommended by 
the Food and Drug Administration (FDA) in Guidance for Industry, Acne Vulgaris: Developing 
Drugs for Treatment (2005)38, and are widely accepted clinical endpoints in studies evaluating 
treatments for acne vulgaris.  
Change from Baseline in Inflammatory and Non-inflammatory Lesion Counts at Week 12 is a 
commonly used practice to assess severity of acne. All lesions will be counted, including those 
on the nose. 
An IGA will also be performed, using a 5-point scale to evaluate acne severity. As recommended 
by the Agency, IGA Success is defined as Clear (Grade 0) or Almost Clear (Grade 1) at a 
specified time point. Therefore, IGA Success Rate for this study is defined as the number and 
percent of subjects rated as Clear or Almost Clear; Success Rate will be summarized at Weeks 4, 
8, and 12. 
Collection of AEs and SAEs is a standard-of-care medical assessment for safety monitoring of 
patients participating in clinical trials. 
9.0 
CLINICAL TRIAL VISITS 
9.1 
Description of Clinical Trial Visits 
Please refer to the Schedule of Assessments (Table 1). 
A written, signed ICF ( signed Assent Form for minors) which includes Photography 
Consent and HIPAA authorization must be obtained prior to performing any clinical trial-
related evaluations and/or procedures. 
9.1.1 
Screening Visit 
The following procedures will be performed at the Screening visit. 
1. Review and explain the nature of the study to subject and parent/legal representative (as 
applicable). 
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2. Obtain the appropriate approved ICF (which contains Photography Consent and HIPAA 
authorization), and Assent form, if needed. Provide signed copies of all forms to the subject 
and parent/legal representative (as applicable). 
3. Assign a SIN to the subject after the ICF is signed. This number will be used to identify 
the subject throughout the study. 
4. Collect information regarding demographics, relevant medical history, and previous and 
ongoing medication/therapy use. 
5. Verify Inclusion/Exclusion Criteria and evaluate the subject for entry into the study. 
6. Perform a UPT on all females of child-bearing potential.  
7. Verify that the subject is not wearing makeup. In the event the subject is wearing make-up, 
the appointment may be rescheduled, or the subject can be instructed to wash the face with a 
Gentle Skin Cleanser; wait for 30 minutes prior to beginning the IGA. 
8. Evaluate acne on the face only, using IGA scale. 
9. Determine if, in the opinion of the Investigator, the subject is a candidate for oral isotretinoin. 
10. If no wash-out is required, Screening and Baseline visits can be combined.  
If Screening and Baseline visits need to occur on separate days (i.e., for subjects who have 
received, applied, or taken treatments as noted in Exclusion Criteria 6 and 7) and additional 
time for wash-out is required, schedule a return appointment for the Baseline visit according 
to the wash-out period for that medication (maximal 28 ± 3 days after Screening). Instruct the 
subject to arrive at the site for the visit without make-up. 
If Screening and Baseline visits will occur same day, complete the Baseline assessments. 
9.1.2 
Baseline Visit 
The following procedures will be performed at the Baseline visit. 
If Screening and Baseline visits occur on separate days, begin Baseline assessments at Step 1 
and complete all assessments listed. If Screening and Baseline visits occur on the same day, 
begin Baseline assessments at Step 7, after completion of Screening assessments and a UPT for 
all females of child-bearing potential (Step 3 below). 
Note: The Investigator/Evaluator for a particular subject should remain the same for the 
duration of the study. 
1. Assess concomitant medication/therapy/procedures and verify required wash-out period has 
been completed for any previous medications/therapies. 
2. Re-confirm Inclusion/Exclusion Criteria and re-evaluate the subject for entry into the study. 
If the subject no longer meets eligibility criteria, no further assessments are required. Enter 
the subject into EDC as a screen failure. 
3. Perform a UPT on all females of child-bearing potential. 
‐ Urine pregnancy testing is mandatory for all females of child-bearing potential.  
‐ For a subject with a pre-menstrual status at the previous visit, confirm that her 
childbearing potential status has not changed (began menses). If her status has changed, 
follow the pregnancy testing schedule for females of child-bearing potential correlating 
to the visit that menses began. Confirm that the subject agrees to use two effective 


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forms of birth control while in the study, until at least one month after the last study 
drug application. 
4. Verify that the subject is not wearing makeup. In the event the subject is wearing make-up, 
the appointment may be rescheduled, or the subject should be instructed to wash the face 
with a Gentle Skin Cleanser; wait for 30 minutes prior to beginning the evaluations. 
5. Evaluate acne on the face only, using IGA scale (see Section 8.2.1). 
6. Determine if, in the opinion of the Investigator, the subject is a candidate for oral 
isotretinoin (see Section 8.2.3). 
7. Conduct the facial Lesion Counts (see Section 8.2.2). 
8. Perform the Baseline Local Tolerability Assessment (erythema, dryness, scaling, 
stinging/burning; see Section 8.4.1). Note: Stinging/burning at the Baseline visit is to be 
assessed as None (0). 
9. Question the subject about AEs by asking an open-ended question, taking care not to 
influence the subject’s answer, such as: “Have you had any new symptoms, injuries, illness 
or side-effects or worsening of pre-existing conditions?” Record all events as appropriate 
on the corresponding AE eCRF pages (see Section 8.4.2). 
10. Have the subject (if 13 years of age or older at the time of Informed Consent) complete the 
Acne QoL form (see Section 8.5.5). Subjects 12 years of age at Informed Consent will not 
complete the form. Confirm that all questions have been answered prior to the subject 
leaving the office. 
12. Obtain photographs of facial acne (see Section 8.5.1).  
13. Weigh the adapalene 0.3% / benzoyl peroxide 2.5% gel and record the pre-dispensed 
weight in drug accountability record and/or source documentation.  
14. Dispense study medications as listed below to the subject:  
Product 
Quantity 
Cetaphil Daily Gentle Cleanser 
1 bottle 
Cetaphil Daily Facial Moisturizer SPF 15 
1 bottle 
Adapalene 0.3% / Benzoyl Peroxide 2.5% Gel 
1 bottle with pump 
Doxycycline Hyclate  
2 bottles 
Give verbal and written (Galderma Protocol GLI.04.SPR.US10355 Subject Instruction 
Sheet) instructions to the subject (or parent/legal representative, as appropriate) regarding 
when and how to properly apply and take the study drugs. Instructions are to include the use 
of cleansers and moisturizers, sunscreens, and other concomitant treatments or medications. 
Demonstrate how to apply the study drug gel by using moisturizer, to show the subject the 
amount of study drug gel to use daily and the method of application. 
Instruct the subject to bring the investigational study drugs to all study visits for review. 
(Subjects do not need to bring the cleanser and moisturizer to the study visits.) 
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15. Remind the subject to use a cleanser and moisturizer, throughout the duration of the study 
(e.g., Cetaphil Gentle Skin Cleanser and Cetaphil Daily Facial Moisturizer SPF15 or 
equivalent). Liberal application of moisturizers should be encouraged.  
16. Schedule a return appointment for the Week 4 Visit (a visit window of ± 3 days will be 
allowed), and remind the subject to bring the investigational study drugs to the next 
scheduled visit and to arrive at the site for the visit without make-up.  
9.1.3 
Week 4 Visit (± 3 days) 
The following procedures will be performed at the Week 4 visit. 
1. Perform a UPT on all females of child-bearing potential. 
‐ Urine pregnancy testing is mandatory for all females of child-bearing potential. 
‐ For a subject with a pre-menstrual status at the previous visit, confirm that her 
childbearing potential status has not changed (began menses). If her status has changed, 
follow the pregnancy testing schedule for females of child-bearing potential correlating 
to the visit that menses began. Confirm that the subject agrees to use an effective form 
of birth control while in the study, until at least one month after the last study drug 
application. 
2. Assess concomitant medication/therapy/procedures. 
3. Verify that the subject is not wearing makeup. In the event the subject is wearing make-up, 
the appointment may be rescheduled, or the subject should be instructed to wash the face 
with a Gentle Skin Cleanser; wait for 30 minutes prior to beginning the evaluations. 
4. Evaluate acne on the face only, using IGA scale (see Section 8.2.1). 
5. Conduct the facial Lesion Counts (see Section 8.2.2). 
6. Determine if, in the opinion of the Investigator, the subject is still a candidate for oral 
isotretinoin (see Section 8.2.3). 
7. Perform the Local Tolerability Assessment (erythema, dryness, scaling, 
stinging/burning; see Section 8.4.1). 
8. Question the subject about the occurrence of AEs and record all events as appropriate on the 
corresponding AE eCRF pages (see Section 8.4.2). 
9. Obtain photographs of facial acne (see Section 8.5.1). 
10. Collect returned Investigational Study Drugs (used and unused) and perform accountability 
evaluations as described in Section 7.4. Discuss any concerns with compliance and note 
discussion in source documentation. 
11. Obtain a new bottle of the adapalene 0.3% / benzoyl peroxide 2.5% gel, weigh, and 
document the weight in drug accountability record and/or source documentation.  
 
 


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12. Dispense study medications as listed below to the subject. 
Product 
Quantity 
Cetaphil Daily Facial Moisturizer SPF 15 
1 bottle 
Adapalene 0.3% / benzoyl peroxide 2.5% gel 
1 bottle with pump 
Doxycycline Hyclate - new bottle 
1 bottle 
Doxycycline Hyclate – redispense bottle 
with unused medication from previous visit 
1 bottle 
Provide verbal and/or written instructions (Galderma Protocol GLI.04.SPR.US10355 
Subject Instruction Sheet – if needed) to the subject (or parent/legal representative, as 
appropriate) on when and how to properly apply and take the study drugs.  
13. Schedule a return appointment for the Week 8 Visit (a visit window of ± 3 days will be 
allowed), and remind the subject to bring the investigational study drugs to the next 
scheduled visit and to arrive at the site for the visit without make-up.  
9.1.4 
Week 8 Visit (± 3 days) 
The following procedures will be performed at the Week 8 visit. 
1. Perform a UPT on all females of child-bearing potential. 
‐ Urine pregnancy testing is mandatory for all females of child-bearing potential. 
‐ For a subject with a pre-menstrual status at the previous visit, confirm that her 
childbearing potential status has not changed (began menses). If her status has changed, 
follow the pregnancy testing schedule for females of child-bearing potential correlating 
to the visit that menses began. Confirm that the subject agrees to use two effective forms 
of birth control while in the study, until at least one month after the last study drug 
application. 
2. Assess concomitant medication/therapy/procedures. 
3. Verify that the subject is not wearing makeup. In the event the subject is wearing make-up, 
the appointment may be rescheduled, or the subject should be instructed to wash the face 
with a Gentle Skin Cleanser; wait for 30 minutes prior to beginning the evaluations. 
4. Evaluate acne using IGA scale on the face (see Section 8.2.1) 
5. Conduct the facial Lesion Counts (see Section 8.2.2). 
6. Determine if, in the opinion of the Investigator, the subject is still a candidate for oral 
isotretinoin (see Section 8.2.3). 
7. Perform the Local Tolerability Assessment (erythema, dryness, scaling, 
stinging/burning; see Section 8.4.1). 
8. Question the subject about the occurrence of AEs and record all events as appropriate on the 
corresponding AE eCRF pages (see Section 8.4.2). 
9. Collect returned Investigational Study Drugs (used and unused) and perform accountability 
evaluations as described in Section 7.4. Discuss any concerns with compliance and note 
discussion in source documentation. 
10. Obtain a new bottle of the adapalene 0.3% / benzoyl peroxide 2.5% gel, weigh, and 


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document the weight in drug accountability record and/or source documentation.   
11. Dispense study medications as listed below to the subject:  
Product 
Quantity 
Cetaphil Daily Facial Moisturizer SPF 15 
1 bottle 
Adapalene 0.3% / Benzoyl Peroxide 2.5% Gel 
1 bottle with pump 
Doxycycline Hyclate – new bottle 
1 bottle 
Doxycycline Hyclate – redispense bottle with 
unused medication from previous visit 
1 bottle 
Again give verbal and/or written instructions (Galderma Protocol GLI.04.SPR.US10355 
Subject Instruction Sheet) to the subject (or parent/legal representative, as appropriate) on 
when and how to properly apply and take the study drugs, if needed.  
12. Schedule a return appointment for the Week 12 Visit (a visit window of ± 3 days will be 
allowed), and remind the subject to bring all study medications (both investigational study 
drugs and non-investigational study products) to the next scheduled visit and to arrive at the 
site for the visit without make-up.  
9.1.5 
Week 12/Early Termination Visit (± 3 days) 
The following procedures will be performed at the Week 12/ET visit. 
1. Perform a UPT on all females of child-bearing potential. 
‐ Urine pregnancy testing is mandatory for all females of child-bearing potential. 
‐ For a subject with a pre-menstrual status at the previous visit, confirm that her 
childbearing potential status has not changed (began menses). If her status has changed, 
follow the pregnancy testing schedule for females of child-bearing potential correlating 
to the visit that menses began. Confirm that the subject agrees to use two effective forms 
of birth control while in the study, until at least one month after the last study drug 
application. 
2. Assess concomitant medication/therapy/procedures. 
3. Verify that the subject is not wearing makeup. In the event the subject is wearing make-up, 
the appointment may be rescheduled, or the subject should be instructed to wash the face 
with a Gentle Skin Cleanser; wait for 30 minutes prior to beginning the evaluations. 
4. Evaluate acne using IGA scale on the face (see Section 8.2.1). 
5. Conduct the facial Lesion Counts (see Section 8.2.2). 
6. Determine if, in the opinion of the Investigator, the subject is still a candidate for oral 
isotretinoin (see Section 8.2.3). 
7. Perform the Local Tolerability Assessment (erythema, dryness, scaling, 
stinging/burning; see Section 8.4.1). 
8. Question subject about the occurrence of AEs and record all events as appropriate on the 
corresponding AE eCRF pages (see Section 8.4.2). 
9. Ask subject to complete the Subject Satisfaction Questionnaire (see Section 8.5.4). 


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10. Ask subject to complete the Subject Assessment of Acne Improvement form (see Section 
8.5.2). 
13. Obtain photographs of facial acne (see Section 8.5.1).  
14. Collect returned Investigational Study Medications (used and unused) and perform 
accountability evaluations as described in Section 7.4. Discuss any concerns with 
compliance and note discussion in source documentation.  
15. Complete the Study Exit Form. 
9.2 
Additional Instructions for Subjects 
There are no dietary or activity requirements; however, subjects should avoid excess sun 
exposure. Each subject will be given both oral and written instructions for use of 
investigational study drugs, cleanser, and moisturizer according to protocol. Subjects will be 
instructed to bring their study medications to each visit as noted in Sections 9.1.2 – 9.1.5. 
10.0 
PLANNED STATISTICAL ANALYSES AND STATISTICAL 
CONSIDERATIONS 
10.1 
Statistical Analysis Plan 
A Statistical Analysis Plan (SAP) will be developed and finalized prior to database lock. The 
SAP will contain detailed descriptions of data conventions and statistical procedures for 
executing the analyses that are specified in the trial protocol below.  
Any deviation(s) from the SAP will be described and justified in the clinical study report. 
CCI
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10.3 
Analysis Populations 
The Intent-to-Treat (ITT) Population consists of the entire population enrolled at baseline. All 
efficacy data will be analyzed for the ITT population. 
The Safety Population consists of the Intent-to-Treat population, after exclusion of subjects who 
never took the treatment with certainty, based on monitoring report. All safety analyses will be 
summarized for the Safety Population. 
10.4 
Statistical Analysis 
10.4.1 
General Methods 
All efficacy variables will be summarized at each visit for the ITT Population. Categorical 
variables will be summarized by counts and percentages for each response category (N, %). 
Continuous variables will be summarized using number of subjects, means, standard deviations, 
medians, minimums, and maximums for the data collected at each visit. Confidence intervals 
(CI) will be presented as appropriate. All evaluations (including CIs) will be reported for 
exploratory purposes and will be interpreted as such. No formal statistical tests will be 
performed. 
10.4.2 
Demographics and Subject Disposition 
Subject demographics and baseline characteristics will be summarized with descriptive 
statistics. Subject disposition will be summarized with the number of subjects in each 
population, the number and percentage of subjects who complete the study, along with the 
number and percentage of subjects who do not complete the study for each discontinuation 
reason as specified on the eCRFs. 
10.4.3 
Efficacy Analysis 
10.4.3.1 
Primary Efficacy Endpoint 
The primary endpoint is the reduction in the number of inflammatory lesions at Week 12, and is 
the change in the inflammatory lesion count from Baseline to Week 12. The reduction in lesion 
count will be summarized with descriptive statistics. A 95% CI for the reduction in lesions will 
be presented.  
The data will be summarized as observed, with no imputation for missing values. A last 
observation carried forward (LOCF) approach will be used as a sensitivity analysis. 
10.4.3.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints are: 
 IGA Success Rate at Weeks 4, 8, and 12 
 Percent reduction in total, inflammatory, and non-inflammatory lesions at Weeks 4, 8, 
and 12 
 Number and percent of subjects who, in the opinion of the Investigator, are candidates 
for oral isotretinoin at Weeks 0, 4, 8, and 12 


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 Reduction in number of total, inflammatory, and non-inflammatory lesions at Weeks 4, 8, 
and 12 
 Subject Assessment of Acne Improvement at Week 12 
The IGA Success Rate is defined as the number and percent of subjects rated as Clear (Grade 0) 
or Almost Clear (Grade 1). It will be summarized at Weeks 4, 8, and 12 with a 95% CI for the 
Success Rate.  
The reduction in lesion count (both percent and number of lesions) at Weeks 4, 8, and 12 will be 
summarized with descriptive statistics and a 95% CI for the reduction in lesions. 
The number and percent of subjects who are candidates for oral isotretinoin will be summarized 
at Weeks 0, 4, 8, and 12, and a 95% CI will be provided. 
The Subject Assessment of Acne Improvement at Week 12 will be summarized with counts and 
percentages for each category (ranging from 0 = Complete Improvement to 5 = Worse).   
All data will be summarized as observed with no imputation for missing values. LOCF will be 
performed as a sensitivity analysis. 
A pharmaco-economic analysis will be performed. 
10.4.4 
Safety Analysis 
10.4.4.1 
Study Drug Exposure 
Exposure to investigational study drugs and compliance will be summarized using descriptive 
statistics.  
10.4.4.2 
Adverse Events 
AE terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs are defined as any AE with onset or (worsening of a pre-existing 
condition) after the first dose of study drug through the end of participation in the study. AEs 
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with partial dates will be assessed using the available date information to determine if treatment-
emergent. AEs with completely missing dates will be assumed to be treatment-emergent.  
Incidence of treatment-emergent AEs will be summarized by MedDRA system organ class 
(SOC) and preferred term (PT) for the Safety Population. If a subject has more than one AE 
with same PT, the subject will be counted only once for that PT. Additional summary tables will 
be provided for AEs considered related to the study drug, and AEs leading to discontinuation. 
All AEs will be displayed in data listings.  
10.4.4.3 
Local Tolerability 
The symptoms of local tolerability (erythema, scaling, dryness and stinging/burning) will be 
summarized by frequency and percentage for each response category for each visit. Scores range 
from 0 = None to 3 = Severe. 
10.4.4.4 
Previous and Concomitant Medications, Therapies, and Procedures 
Previous and concomitant medications will be coded according to the World Health 
Organization (WHO) Drug Dictionary. Prior medications are defined as those ending prior to 
the first dose of investigational study drug. Concomitant medications are defined as those 
ongoing at the time of the first dose of study drug or started after the first dose.  
11.0 
ETHICS AND GENERAL CLINICAL TRIAL CONDUCT CONSIDERATIONS 
11.1 
Institutional Review Board or Independent Ethics Committee 
This clinical trial protocol and all amendments will be reviewed and approved by the appropriate 
IRBs/IECs. 
11.2 
Ethical Conduct of the Clinical Trial 
This clinical trial will be conducted according to the protocol, and the ethical principles that have 
their origin in the Declaration of Helsinki (1964; Appendix 14.7) and subsequent amendments, 
U.S. and international standards of GCP (FDA regulations 21 CFR 312 for Investigational New 
Drug (IND) studies and FDA Guidance E6), and applicable regulatory requirements. To ensure 
ethical conduct of this clinical study, Investigators will be expected to adhere to the basic 
principles in recognized guidelines such the Belmont Report and the International Ethical 
Guidelines for Biomedical Research Involving Human Subjects.  
11.3 
Informed Consent 
All subjects who participate in this clinical trial are required to be fully informed about the 
clinical trial in accordance with GCP guidelines, federal regulations, and HIPAA, and in 
accordance with local requirements. 
The ICF (which contains Photography Consent and HIPAA authorization) and the Assent 
approved by an IRB/IEC will be fully explained to the subject (or parent/legal representative, if 
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Prior to enrollment into the clinical trial, the subject, and as applicable, the subject’s parent/legal 
representative when the subject is a minor, will sign and date the consent form(s). The 
Investigator is responsible for maintaining each subject’s consent form(s) in the Investigator’s 
site file and providing each subject, or the subject’s parent or legal representative (for minors), 
with a copy of the signed and dated consent form(s). 
11.4 
Contractual Requirements 
A contractual agreement will be signed between the Sponsor/Contract Research Organization 
(CRO) and each Investigator/Institution. This document will contain supplementary information, 
including financial terms, confidentiality, the clinical trial schedule, third party responsibility, 
and publication rights. 
12.0 
REGULATORY/ADMINISTRATIVE PROCEDURES AND DOCUMENTATION 
12.1 
Quality Assurance and Audits/Inspections 
The study will be conducted under the sponsorship of Galderma in compliance with all 
applicable international and local regulatory requirements and applicable ICH guidelines, and in 
accordance with the SOPs for clinical trial conduct and monitoring from Galderma and/or the 
CRO. 
Audits of clinical trial centers may be conducted by the Sponsor/CRO representatives, and 
inspection may be performed by Regulatory Authority inspectorates or IRBs/IECs before, 
during, or after the clinical trial.  
The Investigator will allow and assist the CRO/Sponsor’s representatives, IRBs/IECs, and any 
regulatory agency to have direct access to all requested clinical trial-related records. 
For the audits performed by, or on behalf of, Galderma auditors, audit certificate(s) will be 
provided by Quality Assurance. 
12.2 
Protocol Compliance and Protocol Deviations 
With the exception of eliminating an immediate hazard to a subject, the Investigator should not 
deviate from the clinical trial protocol or implement any changes without written approval from 
the Sponsor and prior review and documented approval/favorable opinion from the IRB/IEC of a 
protocol amendment. 
Changes that involve only logistical or administrative changes to the clinical trial protocol are 
authorized. The Investigator should document and explain any deviation from the clinical trial 
protocol. 
12.3 
Protocol Amendments 
The Sponsor may modify the clinical trial protocol at any time for ethical, medical, or scientific 
reasons. 
No amendment can be implemented at clinical trial centers, unless to eliminate an immediate 
hazard to the subjects, without having been submitted to the FDA or any appropriate Regulatory 


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Authority for its review and having obtained approval from the IRB/EC with responsibility for 
review and approval of the clinical trial. 
12.4 
Data Collection and Electronic Case Report Forms (eCRFs) 
The Investigator must maintain all required records for all subjects. Data for this clinical trial 
will be recorded in the subject’s source documents and on the eCRFs provided by the Sponsor. 
All data should be recorded on the eCRFs completely and promptly. 
12.5 
Source Documentation 
The Investigator must keep accurate separate records (other than the CRFs) of all subject visits, 
being sure to include all pertinent clinical trial-related information. A statement should be made 
indicating that the subjects have been included in this clinical trial and have provided signed 
written Informed Consent and Assent to Participate as applicable. All AEs must be thoroughly 
documented. 
Results of any diagnostic tests conducted during the clinical trial should also be included in the 
source documentation. 
12.6 
Study Initiation and Personnel Training 
An Investigator’s Meeting will be conducted. It is recommended that all Investigators, other 
Evaluators, study coordinators, or other applicable personnel attend. During this meeting, 
participants will be trained on the protocol, ICH-GCP, study-specific procedures, and eCRF 
completion. Site personnel are expected to attend the Investigator Meeting and receive on-site 
training prior to participating in the procedures and evaluations in this study. Each study center 
will have a training record as part of the site file and Trial Master File. 
Study initiation will be conducted for each study center prior to the enrollment of any subjects.  
The Investigator Meeting may serve as the initiation visit. In the event the Primary Investigator 
does not attend the Investigator Meeting but site personnel attend, the Investigator may be 
initiated and trained via telephone/WebEx. If a site is not represented at the Investigator Meeting 
and no personnel are present, an on-site initiation visit will be required. 
Clinical Research Associates (CRAs) and other applicable personnel will be trained prior to 
study initiation to familiarize the CRAs with the disease, the Standard Operating Procedures 
(SOPs)/study procedures, the protocol, and other study-specific items. Team organization, 
communication, and operational issues will also be discussed. 
An Investigator’s Site File will be provided to each study center. 
12.7 
Clinical Monitoring 
The conduct of the clinical trial will be closely monitored by representatives of Advanced 
Clinical to verify adherence to the clinical trial protocol, ICH-GCP guidelines, and applicable 
SOPs/study procedures. 
The Investigator will allow the CRO/Sponsor’s representatives, to have direct access to all 
clinical trial records, eCRFs, corresponding subject medical records, study medication 


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dispensing records, study medication storage area, clinical trial facilities, and any other 
documents considered source documentation. 
12.8 
Data Management 
All data management procedures will be detailed in a Data Management Plan (DMP). 
The DMP will describe the Clinical Data Management System (CDMS) that will be used to 
collect data via EDC, and whether the data management activities are performed internally or 
outsourced. Computerized edit checks and review processes will be performed on an ongoing 
basis as outlined in the DMP until all data clarifications are resolved. The data will be exported 
to be stored in SAS datasets. After all data clarifications are resolved, coding is approved, and 
subject’s evaluability is determined, the database will be locked. 
12.9 
Study Documentation and Retention of Records 
All pertinent data, samples, photographs, correspondence, and reports, the original or amended 
clinical trial protocol, and all other material relating to the clinical trial will be maintained 
securely in Sponsor/CRO/Investigator/Institution archives for the legally required duration for 
archiving. 
The Investigator/Institution should maintain the essential clinical trial documents as specified in 
Section 8 of ICH-GCP, and according to the applicable regulatory requirements. 
The Investigator/Institution should take measures to prevent accidental or premature destruction 
of these documents. 
If the Principal Investigator retires, relocates, or withdraws from the responsibility of keeping the 
clinical trial records for any other reasons, custody must be transferred to a person who will 
accept the responsibility. The Sponsor/CRO must be notified in writing of the name and address 
of the new custodian. 
12.10 Insurance 
A certificate attesting Third Party coverage of Sponsor/CRO will be provided upon request. 
 
 


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13.0 
REFERENCES 
1. Kraining KK, Odland GF, eds. Prevalence, morbidity, and cost of dermatologic diseases. J 
Invest Dermatol 1979;73(5 Pt 2):395-513. 
2. Cunliffe WJ, Gould DJ. Prevalence of facial acne vulgaris in late adolescence and in adults. 
Br Med J 1979;1(6171):1109- 1110. 
3. Usatine RP, Quan MA, Strick R. Acne vulgaris: a treatment update. Hosp Pract 
(1995)1998;33(2):111-117, 121-124, 127. Review. 
4. Leyden JJ. New understandings of the pathogenesis of acne. J Am Acad Dermatol 1995;32(5 
Pt 3):S15-S25. Review. 
5. Thiboutot D. Regulation of human sebaceous glands. J Invest Dermatol 2004;123(1):1-12. 
6. Pawin H, Beylot C, Chivot M et al. Physiopathology of acne vulgaris: recent data, new 
understanding of the treatments. Eur J Dermatol 2004;14(1):4-12. Review. 
7. Leyden JJ. A review of the use of combination therapies for the treatment of acne vulgaris. J 
Am Acad Dermatol 2003;49(3 suppl):S200-S210. 
8. Rademaker M. Adverse effects of isotretinoin: A retrospective review of 1743 patients 
started on isotretinoin. Australas J Dermatol 2010;51(4):248-253. 
11. Lester RS, Schachter GD, Light MJ. Isotretinoin and tetracycline in the management of 
severe nodulocystic acne. Int J Dermatol 1985;24(4):252-257. 
12. Gollnick HP, Graupe K, Zaumseil RP. Comparison of combined azelaic acid cream plus oral 
minocycline with oral isotretinoin in severe acne. Eur J Dermatol 2001;11(6):538-544. 
13. Oprica C, Emtestam L, Hagströmer L, Nord CE. Clinical and microbiological comparisons of 
isotretinoin vs. tetracycline in acne vulgaris. Acta Derm Venereol 2007;87(3):246-254. 
14. Rumsfield JA, West DP, Tse CS et al Isotretinoin in severe, recalcitrant cystic acne: a 
review. Drug Intell Clin Pharm 1983;17(5):329-333. Review. 
15. Strauss JS, Leyden JJ, Lucky AW et al. A randomized trial of the efficacy of a new 
micronized formulation versus a standard formulation of isotretinoin in patients with severe 
recalcitrant nodular acne. J Am Acad Dermatol 2001;45(2):187-195. 
16. Akman A, Durusoy C, Senturk M et al. Treatment of acne with intermittent and conventional 
isotretinoin: a randomized, controlled multicenter study. Arch Dermatol Res 
2007;299(10):467-473. 
17. Newman MD, Bowe WP, Heughebaert C et al. Therapeutic considerations for severe nodular 
acne. Am J Clin Dermatol 2011;12(1):7-14. 
18. Goldsmith LA, Bolognia JL, Callen JP et al. American Academy of Dermatology Consensus 
Conference on the safe optimal use of isotretinoin: summary and recommendations. J Am 
Acad Dermatol 2004;50(6):900-906. 
19. Strauss JS, Rapini RP, Shalita JR et al. Isotretinoin therapy for acne: results of a multicenter 
dose-response study. J Am Acad Dermatol 1984;10(3):490-496. 


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20. Strauss JS, Krowchuk DP, Leyden JJ et al. Guidelines of care for acne vulgaris management. 
J Am Acad Dermatol 2007;56(4):651-663. 
21. Karadag AS, Ertugrul DT, Tutal E et al. Isotretinoin influences pituitary hormone levels in 
acne patients. Acta Derm Venereol 2011;91(1):31-34. 
22. Madden WS, Landells ID, Poulin Y et al. Treatment of acne vulgaris and prevention of acne 
scarring: Canadian consensus guidelines. J Cutan Med Surg 2000;(4 Supp 1):S2 to S13. 
21. Gollnick H, Schramm M. Topical drug treatment in acne. Dermatol 1998;196(1):119-125. 
22. Brogden RN, Goa KE. Adapalene: A review of its pharmacological properties and clinical 
potential in the management of mild to moderate acne. Drugs 1997;53(3):511-519. 
23. Michel S, Jomard A, Demarchez M. Pharmacology of adapalene. Br J Dermatol 
1998;139(Suppl 52):3-7. 
24. Shroot B, Michel S. Pharmacology and chemistry of adapalene. J Am Acad Dermatol 1997; 
36(6 Pt 2): S96-S103. Review. 
25. Leyden JJ. Current issues in antimicrobial therapy for the treatment of acne. J Eur Acad 
Dermatol Venereol 2001;15 Suppl 3:51-55. Review. 
26. Pariser DM, Westmoreland P, Morris A et al. Long-term safety and efficacy of a unique 
fixed-dose combination gel of adapalene 0.1% and benzoyl peroxide 2.5% for the treatment 
of acne vulgaris. J Drugs Dermatol 2007;6(9):899- 905. 
27. Tan J, Gollnick HP, Loesche C et al. Synergistic efficacy of adapalene 0.1%-benzoyl 
peroxide 2.5% in the treatment of 3855 acne vulgaris patients. J Dermatolog Treat 
2011;22(4)197-205. Epub 2010 Jul 28.  
28. Thiboutot DM, Weiss J, Bucko A et al. Adapalene-BPO Study Group. Adapalene-benzoyl 
peroxide, a fixed-dose combination for the treatment of acne vulgaris: results of a 
multicenter, randomized double-blind, controlled study. J Am Acad Dermatol 
2007;57(5):791-799. 
29. Gollnick HP, Draelos Z, Glenn MJ et al. Adapalene-BPO Study Group. Adapalene-benzoyl 
peroxide, a unique fixed-dose combination topical gel for the treatment of acne vulgaris: a 
transatlantic, randomized, double-blind, controlled study in 1670 patients. Br J Dermatol 
2009; 161(5):1180-1189. 
30. Gold LS, Tan J, Cruz-Santana A et al. Adapalene-BPO Study Group. A North American 
study of adapalene-benzoyl peroxide combination gel in the treatment of acne. Cutis 2009; 
84(2):110-116. 
31. Feldman SR, Tan J, Poulin Y et al. The efficacy of adapalene- benzoyl peroxide combination 
increases with number of acne lesions J Am Acad Dermatol 2011;64(6):1085-1091. 
32. Gold LS, Cruz A, Eichenfield L et al. Effective and safe combination therapy for severe acne 
vulgaris: a randomized, vehicle-controlled, double blind study of adapalene 0.1%-benzoyl 
peroxide 2.5% fixed-dose combination gel with doxycycline hyclate 100 mg. Cutis 
2010;85(2):94-104. 
33. Plewig G, Kligman AM. Acne and Rosacea, 3rd ed. New York:Springer-Verlag; 2000. 


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34. Webster GF, Leyden JJ. Suppression of polymorphonuclear leukocyte chemotactic factor 
production in Propionibacterium acnes by subminimal inhibitory concentrations of 
tetracycline, ampicillin, minocycline, and erythromycin. Antimicrob Agents Chemother 
1982;21(5):770-772. 
35. Melski JW, Arndt KA. Current concepts: topical therapy for acne. N Engl J Med 
1980;302(9):503-506. 
36. 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. 
37. Hanifin JM, Cooper KD, Ho VC et al. Guidelines of care for atopic dermatitis, developed in 
accordance with the American Academy of Dermatology (AAD)/American Academy of 
Dermatology Association “Administrative Regulations for Evidence-Based Clinical Practice 
Guidelines.” J Am Acad Dermatol 2004;50(3):391-404. Erratum in: J Am Acad Dermatol 
2005;52(1):156. 
38. U.S. Department of Health and Human Services Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER). Guidance for Industry, Acne Vulgaris: Developing 
Drugs for Treatment. September 2005. 


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14.0 
APPENDICES 
14.1 
PACKAGE INSERTS FOR ADAPALENE 0.3% / BENZOYL PEROXIDE 2.5% 
GEL AND DOXYCYCLINE HYCLATE TABLETS 
 
 


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Package Insert for ADAPALENE 0.3% / BENZOYL PEROXIDE 2.5% GEL 
 
 


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Package Insert for DOXYCYCLINE HYCLATE TABLETS  
 
 


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14.2 
PROCEDURE FOR FACIAL LESION COUNTS 
1. If the skin is very greasy, blot off the sebum with a paper towel before counting lesions. 
2. Instruct subjects to attend with a clean face and no make-up (foundation, powder, concealer, blush), or remove 
makeup completely with Cetaphil® Gentle Skin Cleanser as soon as they arrive, and wait for 30 minutes prior to 
beginning assessments. Let the skin color return to normal before counting. 
3. Always use a lamp (and glasses, if needed), but do not routinely use a magnifying lens. Use the same room and 
constant lighting conditions for every evaluation. Avoid shadows. 
4. Position the subject in the same place every time. Make sure the subject is comfortable. The subject’s seat 
should be fairly high, so that the evaluator can view the facial skin comfortably (without excessive bending). 
5. Each subject should be assessed at all visits by the same evaluator (Investigator or designee): 
• 
Practice: count-recount (minimizes intra-rater variability). 
• 
Make your decision promptly - hesitation leads to confusion. 
• 
Evaluate the subject after visual inspection and palpation of the skin. Use palpation to assess the depth of 
the spots and to locate ones that are not obvious. 
• 
Do not stretch the skin; this alters the profile of the spots. 
• 
Where many lesions are present, stroke the skin from left to right or from top to bottom to avoid counting 
some spots more than once and others not at all. 
• 
Count the different types of lesions separately. Spots of any size should be counted, however small. 
• 
If it appears difficult to count accurately in a particular area, make a note and exclude this region every 
time for a given subject. If stubble is very obvious, it is best to avoid counting in the beard area. 
• 
Record any problems and how they were dealt with in the subject’s notes. 
6. Lesions should routinely be counted on the whole face, area by area:  
• 
The face is defined by the hairline and edge of the jaw (mandibular lines). 
• 
Use the following template to divide the face into five areas to be evaluated: forehead, right cheek, left 
cheek, chin, and nose (see CRF). 
• 
Nodules/cysts are counted only at Screening/Baseline visit. 
 
 


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7. The exact number of each lesion should be recorded on the appropriate CRF page. The lesion counts will be 
electronically added together to obtain a total lesion count. 
 
The following definitions describe the lesions to be counted: 
 
Non-inflammatory lesions 
- Open Comedone - A mass of sebaceous material that is impacted behind an open follicular orifice 
(blackhead). 
- Closed Comedone - A mass of sebaceous material that is impacted behind a closed follicular orifice 
(white head). 
 
Inflammatory lesions 
- Papules - A small, solid, red elevation less than 5 mm in diameter. Most of the lesion is above the surface 
of the skin. 
- Pustules - A small, circumscribed red elevation of the skin which contains yellow-white exudates. 
Nodules/Cysts, defined as circumscribed, elevated, solid lesions generally more than 1 cm in diameter with 
palpable depth, are counted at the Screening/Baseline visit only. No more than 2 nodules/cysts will be allowed 
for study participation (Exclusion Criterion #2, Section 6.2.2). Nodules/Cysts are not counted at post-Baseline 
visits. 
 
 
 






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14.5 
SUBJECT SATISFACTION QUESTIONNAIRE 
INSTRUCTIONS: 
Please complete this questionnaire regarding the study treatments you have been using in this study.  
Your answers will help us to better understand your needs and expectations.  
This questionnaire has been designed so that it can be completed quickly and easily. Please use black pen to 
complete this questionnaire. Please give only ONE answer per question. 
There are no “Right” or “Wrong” answers.  
If you are unsure how to answer a question, please give the best answer you can.  
If you need to make a change, draw a line through the answer you would like to change, record your new response 
with a checkmark, and put your initials and today’s date next to your correction. 
Your answers will not affect your participation in the study and no prejudice will be shown towards you for 
completing this document. 
1. How bothered were you by the treatment side effects? 
[  ]1 
Not bothered at all 
[  ]2 
Bothered somewhat 
[  ]3 
Bothered 
[  ]4 
Bothered a great deal 
2. How satisfied were you with the time it took for treatment to work? 
[  ]1 
Very satisfied 
[  ]2 
Satisfied 
[  ]3 
Somewhat satisfied 
[  ]4 
Not satisfied 
3. How satisfied were you with the effectiveness of the treatment? 
[  ]1 
Very satisfied 
[  ]2 
Satisfied 
[  ]3 
Somewhat satisfied 
[  ]4 
Not satisfied 
 


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4. How do you feel about yourself, since starting your treatment? 
[  ]1 
Very much better 
[  ]2 
A lot better 
[  ]3 
A little better 
[  ]4 
Worse 
5. Overall, are you satisfied with the treatment? 
[  ]1 
Very satisfied 
[  ]2 
Satisfied 
[  ]3 
Somewhat satisfied 
[  ]4 
Not satisfied 
6. Would you consider using this treatment again? 
[  ]1 
Yes 
[  ]2 
No 
7. Did you use the provided moisturizing lotion? 
[  ]1 
Yes 
[  ]2 
No 
a. If yes, would you say (check as many answers as you wish) 
[  ]1 
The moisturizer helps to reduce irritation 
[  ]2 
The moisturizer helps you to be adherent to study 
treatments 
[  ]3 
The moisturizer was pleasant to use 
[  ]4 
None of the above 
 
 
 


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14.7 
DECLARATION OF HELSINKI 
 
 
 


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SAP_001.pdf: 




  
 
 
 
 
 
                                 
 
 
 
  
 
Galderma Laboratories, LP 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol Number GLI.04.SPR.US10355 
 
 
EFFICACY AND SAFETY OF ADAPALENE 0.3% / BENZOYL 
PEROXIDE 2.5% GEL PLUS DOXYCYCLINE IN SEVERE 
INFLAMMATORY ACNE (NON-NODULOCYSTIC) SUBJECTS 
 
SPONSOR 
 
Galderma Laboratories, LP 
14501 North Freeway 
Fort Worth TX 76177 
 
Final 
30NOV016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prepared By: Advanced Clinical LLC
CCI


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Statistical Analysis Plan for GLI.04.SPR.US10355 
30NOV2016  
 
 
Page 2 of 29 
 
 
Table of Contents  
List of Abbreviations and Definition of Terms................................................................... 4 
1 
Introduction .......................................................................................................... 5 
2 
Overall Study Design and Objectives .................................................................. 5 
2.1.1 
Study Objectives .................................................................................................. 5 
2.1.2 
Clinical Hypothesis .............................................................................................. 5 
2.2 
Trial Design and Study Procedures...................................................................... 5 
2.3 
Treatments and Assignment to Treatments.......................................................... 8 
2.3.1 
Dose Modification ............................................................................................... 9 
2.4 
Determination of Sample Size ........................................................................... 10 
3 
General Analysis Conventions ........................................................................... 10 
3.1 
Study Periods ..................................................................................................... 11 
3.2 
Visit Windows ................................................................................................... 11 
4 
Analysis Populations .......................................................................................... 11 
4.1 
Intent-to-Treat Population .................................................................................. 11 
4.2 
Safety Population ............................................................................................... 11 
5 
Subject Disposition ............................................................................................ 11 
6 
Protocol Deviations ............................................................................................ 11 
7 
Demographic and Baseline Characteristics ....................................................... 12 
7.1 
Demographic Characteristics ............................................................................. 12 
7.2 
Medical History ................................................................................................. 12 
8 
Efficacy Assessments......................................................................................... 13 
8.1 
Lesion Counts .................................................................................................... 13 
8.2 
Investigator’s Global Assessment (IGA) ........................................................... 13 
8.3 
Oral Isotretinoin Evaluation ............................................................................... 14 
8.4 
Subject’s Assessment of Acne Improvement .................................................... 14 
8.5 
Subject Satisfaction Questionnaire .................................................................... 14 
8.6 
Acne-Specific Quality of Life Questionnaire (Acne-QoL) ............................... 14 
9 
Efficacy Analysis ............................................................................................... 16 
9.1 
Primary Efficacy Analysis ................................................................................. 16 
9.2 
Secondary Efficacy Analysis ............................................................................. 17 
10 
Statistical/Analytical Issues ............................................................................... 18 
10.1 
Handling of Dropouts or Missing Data .............................................................. 18 
10.2 
Pooling of Centers in Multi-Center Studies ....................................................... 18 
10.3 
Multiple Comparisons/Multiplicity ................................................................... 18 
10.4 
Examination of Subgroups ................................................................................. 19 
10.5 
Interim Analysis and Data Monitoring .............................................................. 19 
11 
Safety Analysis .................................................................................................. 19 
11.1 
Study Drug Exposure ......................................................................................... 19 
11.2 
Adverse Events .................................................................................................. 20 
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11.2.1 
Overview of Treatment-Emergent Adverse Events ........................................... 20 
11.2.2 
Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
20 
11.3 
Local Tolerability............................................................................................... 21 
11.4 
Prior and Concomitant Medications .................................................................. 22 
12 
Quality Control .................................................................................................. 22 
13 
Tables and Listings Conventions ....................................................................... 23 
14 
Preliminary List of Statistical Tables, Listings, and Figures to Be Programmed
 
25 
14.1 
Statistical Tables ................................................................................................ 25 
14.2 
Data Listings ...................................................................................................... 27 
14.3 
Figures................................................................................................................ 29 
 
Tables 
Table 1: Schedule of Assessments ...................................................................................... 7 
Table 2: Description and Dispensing of Study Medications .............................................. 9 
Table 3: Investigator’s Global Assessment Severity Scale............................................... 13 
Table 4: Subject’s Assessment of Acne Improvement Scale............................................ 14 
Table 5: Local Tolerability Severity Scale ....................................................................... 21 


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List of Abbreviations and Definition of Terms  
 
Abbreviation 
Description 
AE 
Adverse Event 
ATC-2 
Anatomical Therapeutic Chemical 2nd level 
ATC-3 
Anatomical Therapeutic Chemical 3rd level 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BPO 
Benzoyl Peroxide (C14H10O4) 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
eCRF 
Electronic Case Report Form 
e.g. 
For Example (Latin: exempli gratia) 
eCTD 
Electronic Common Technical Document 
ET 
Early Termination 
ICH 
International Conference on Harmonization 
IGA 
Investigator’s Global Assessment 
ITT 
Intent-To-Treat 
LOCF 
Last Observation Carried Forward 
MCID 
Minimal Clinically Important Difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SPF 
Sun Protection Factor 
UPT 
Urine Pregnancy Test 
US 
United States  
TEAE 
Treatment-Emergent Adverse Event 
WHO 
World Health Organization 
 
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1 Introduction 
This statistical analysis plan (SAP) describes the efficacy and safety summaries and 
analyses that will be performed for Study GLI.04.SPR.US10355 (ALAMO), based on the 
study protocol Amendment 1 dated 14SEP2016. 
A pharmaco-economic analysis will be described in a separate plan. 
2 Overall Study Design and Objectives 
2.1.1 Study Objectives  
The clinical trial objective is to demonstrate that a daily treatment regimen of adapalene 
0.3% / benzoyl peroxide 2.5% gel + oral doxycycline 200 mg is an effective and safe 
alternative to oral isotretinoin in subjects 12 years of age and older having severe 
inflammatory acne with ≤ 4 nodules/cysts > 1 cm in diameter (non-nodulocystic) during 
a 12-week treatment period. 
2.1.2 Clinical Hypothesis 
The proposed clinical efficacy hypothesis is based on the current Acne Treatment 
Guidelines for severe inflammatory acne from the American Academy of 
Dermatology/American Academy of Dermatology Association. 
 
According to these Guidelines, first-line therapy for severe inflammatory acne is an oral 
antibiotic + topical combination therapy consisting of Benzoyl Peroxide (BPO) + 
Antibiotic or Retinoid + BPO or Retinoid + BPO + Antibiotic. Thus, daily combination 
therapy with adapalene 0.3% / benzoyl peroxide 2.5% gel and doxycycline 200 mg is a 
recommended first-line therapy for severe inflammatory acne; the hypothesis of this 
study is that this combination is an effective therapy alternative for oral isotretinoin. 
2.2 Trial Design and Study Procedures 
This is a Phase 4, 12-week, single-arm, open-label, multi-center investigational study in 
subjects with severe inflammatory acne. 
 
This study will enroll male and female subjects, 12 years of age or older, presenting with 
severe inflammatory facial acne vulgaris with up to 4 nodules/cysts > 1cm in diameter on 
the face and a score of 4 (severe) on the Investigator’s Global Assessment (IGA) scale, 
and who are, in the opinion of the Investigator, candidates for oral isotretinoin. If, at 
screening, the inclusion/exclusion criteria regarding the IGA score and nodule counts are 
not met, the subject should be screen-failed and will not complete a baseline evaluation. 
Rescreening will not be allowed during the trial. 
 
Up to 40 independent study centers will participate in the study, and approximately 180 
subjects will be enrolled. Subjects who meet the inclusion criteria and none of the 
exclusion criteria at the Screening visit will return to the clinic on Week 0 for baseline 


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measures and to start treatment, which will continue for a period of up to 12 weeks. 
Those screened subjects who do not need to undergo a wash-out period may combine the 
Screening and Baseline visits, and thus attend 4 clinic visits. Screened subjects requiring 
a wash-out period (up to 4 weeks) prior to baseline measurements and beginning 
treatment will attend a total of 5 clinic visits. Following the Baseline (Week 0) visit, all 
subjects will report to the clinic for efficacy and safety evaluations at Week 4, Week 8, 
and Week 12/ET. 
 
Investigator Global Assessments (IGAs), Oral Isotretinoin Evaluations, and Local 
Tolerability Evaluations for a given subject are to be performed by the same Investigator 
(a Board-Certified Dermatologist) at all visits throughout the study, from Week 0 through 
Week 12/Early Termination (ET). Lesion Counts may be performed by a Board-Certified 
Dermatologist or a licensed Sub-Investigator (i.e., PA, NP, or RN) trained in the protocol, 
with the same evaluator performing the counts for a given subject at all visits throughout 
the study.  
 
A urine pregnancy test (UPT) will be required at the Screening, Baseline, Week 4, Week 
8, and Week 12/ET visits for all females of childbearing potential. The decision may be 
made by the Investigator to perform additional UPTs during the course of the study. 
 
Subjects will be provided with Cetaphil Gentle Skin Cleanser and Cetaphil Daily Facial 
Moisturizer SPF 15 as needed during the study. To prevent dry skin, subjects will be 
requested to use a moisturizer throughout the study. If a subject experiences persistent 
dryness or irritation, the Investigator may consider a reduced application frequency for 
the investigational study drug gel, as required for the symptomatic relief of skin dryness 
or irritation. 
 
A summary of the Study Schedule is provided in Table 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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2.3 Treatments and Assignment to Treatments 
This is an open-label study. All subjects will receive the investigational study drug 
adapalene 0.3% / benzoyl peroxide 2.5% gel in 45 g pump bottles plus oral doxycycline 
200 mg tablets in 120-count bottles during the course of the study. 
 
The study drug gel should be applied to dry skin once daily for 12 weeks, at night after 
washing with Cetaphil Gentle Skin Cleanser (provided by the Sponsor). A pea-sized 
amount of adapalene 0.3% / benzoyl peroxide 2.5% gel should be put on the fingertip and 
applied to the forehead. The procedure is repeated with a pea-sized amount applied to 
each cheek and to the chin and nose, being careful to avoid application to the nostrils, 
mouth, lips, and eyelids. The objective is to cover the entire face with a thin film of the 
treatment, even if there are areas on the face that do not have acne. While there are five 
areas of the face to be treated (forehead, right cheek, left cheek, chin, and nose), four pea-
sized amounts of the study drug are typically estimated to be enough for the entire face. 
The product should not be applied to cuts, abrasions, or eczematous or sunburned skin. 
 
At the Baseline/Week 0 visit, each subject will receive two 120-count bottles of the 
investigational study drug doxycycline hyclate (50 mg tablets) and will be resupplied at 
each study visit (Week 4 and 8 only) with one new bottle. During the Baseline/Week 0 
visit, subjects will be instructed to take the first 100-mg dose of doxycycline hyclate at 
the same time as the adapalene 0.3% / benzoyl peroxide 2.5% gel treatment that evening.  
They will take the second 100-mg dose the next morning. The subject will be instructed 
to completely use one bottle of doxycycline hyclate before starting a subsequent bottle. 
For the 200 mg per day dosing regimen, each subject will take two 50-mg tablets of 
doxycycline hyclate in the morning and at night, for a total of four tablets (a total of 200 
mg) daily for 12 weeks. The tablets should be swallowed, not chewed, should be taken 
with adequate amounts of fluid, and may be taken with food.  
 
Signs and symptoms of local tolerability are possible during treatment (erythema, scaling, 
dryness, and stinging/burning). To prevent dry skin, subjects will be requested to use a 
moisturizer (Cetaphil Daily Facial Moisturizer SPF15, provided by the Sponsor) 
throughout the study as needed. If a subject experiences persistent dryness or irritation, 
the Investigator may consider a reduced application frequency of the investigational 
study drug gel as required for the symptomatic relief of skin dryness or irritation. 
 
Descriptions and use of the study medications, both the investigational drugs and the non-
investigational products, are summarized in Table 2. 
 
 
 
 
 
 




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If this dose modification occurs between Baseline Week 0 and Week 4, and lasts more 
than 2 weeks after the onset date of the dryness or irritation, the signs or symptoms of 
local tolerability should be recorded as an AE. After the Week 4 visit, the signs or 
symptoms related to this dose modification should be recorded as an AE, regardless of 
the duration of the dose modification. 
3 General Analysis Conventions 
Data collected in this study will be documented using summary tables and subject data 
listings.  Continuous variables will be summarized using descriptive statistics (number of 
subjects, mean, median, standard deviation [SD], minimum, and maximum).  Categorical 
variables will be summarized using counts and percentages for each response category.  
Confidence intervals (CI) will be presented as appropriate.  All evaluations (including 
CIs) will be reported for explorative purposes and will be interpreted as such.  
Study days will be calculated relative to the first dose of study drug.  Day 1 will be the 
first day of study drug administration in the study, and the day prior to the first dose of 
study drug administration will be Day -1.  There will be no Day 0.  
Baseline will be the last assessment prior to the first dose of study drug unless otherwise 
indicated. 
No formal statistical tests will be performed.  
Adverse events will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA), Version 19.0.  Prior and concomitant medications as well as prior and 
concomitant medical and surgical procedures will be coded using the World Health 
Organization (WHO) Drug Dictionary (March 2015).   
Data for all subjects in the clinical database will be included in the data listings.  
Calculated (derived) variables will be listed as appropriate.  Tables, listings, and figures 
will be programmed using SAS Version 9.3 or higher. 
A list of proposed statistical tables and data listings is provided in Section 14. 
Any changes from the SAP will be detailed in the clinical study report. 
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3.1 Study Periods 
The study consists of a Screening wash-out period and a treatment period. Screened 
subjects visit the clinic on Week 0 for baseline measures and to start treatment. Those 
screened subjects who do not need to undergo a wash-out period may combine the 
Screening and Baseline visits, and thus attend 4 clinic visits. Screened subjects requiring 
a wash-out period (up to 4 weeks) prior to baseline measurements and beginning 
treatment will attend a total of 5 clinic visits. Following the Baseline (Week 0) visit, all 
subjects will report to the clinic for efficacy and safety evaluations at Week 4, Week 8, 
and Week 12/ET.  
3.2 Visit Windows 
Study visits are expected to occur according to the schedule outlined in the protocol.  All 
data will be summarized based on the actual visit as recorded on the eCRF.  
4 Analysis Populations 
4.1 Intent-to-Treat Population 
The Intent-to-Treat (ITT) Population consists of the entire population enrolled at 
baseline. All efficacy data will be analyzed for the ITT population. 
4.2 Safety Population 
The Safety Population consists of the Intent-to-Treat population, after exclusion of 
subjects who never took the treatment with certainty, based on drug accountability data. 
All safety analyses will be summarized for the Safety Population. 
5 Subject Disposition 
Subject disposition will be summarized overall.  The number of subjects in intent-to-treat 
and safety population will be summarized.  The number and percentage of subjects in the 
ITT population who complete the study will be summarized, along with the number and 
percentage of subjects who do not complete the study for each discontinuation reason as 
specified on the eCRFs.  Inclusion/exclusion data will be presented by subject in a data 
listing. 
6 Protocol Deviations 
Protocol deviations will be presented by subject in a data listing. 
 
 
 


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7 Demographic and Baseline Characteristics 
7.1 Demographic Characteristics 
 
Demographic and baseline characteristics at study entry will be summarized overall for 
the safety population.  Variables to be summarized are:  
• Continuous variables 
- Age (years) 
- Time since Acne Onset (months) 
- Inflammatory Lesion Count 
- Non-inflammatory Lesion Count 
- Total Lesion Count 
 
• Categorical variables 
- Sex 
- Race 
- Ethnicity 
- Wash-Out Status (Yes, No) 
- Age Category (≤ 17, 18 – 24, >= 25 years)  
- Age at Acne Onset (≤ 11, 12 – 14, 15 – 17, >= 18 years)  
- Time since Acne Onset Category (based on quartiles in months) 
Time since acne onset will be calculated as the informed consent date minus the onset 
date of acne vulgaris collected on medical history CRF expressed in months. If the day of 
acne onset date is missing, 15 will be imputed for calculations. If the acne onset month is 
missing the month and day of the informed consent date will be used for calculations. 
Similarly, age at acne onset will be calculated based on the onset date of acne vulgaris 
and the date of birth. 
Continuous variables will be summarized with descriptive statistics (number of subjects, 
mean, SD, median, minimum, and maximum).  Categorical variables will be summarized 
using counts and percentages. 
Demographic and baseline characteristics will be presented by subject in data listings. 
7.2 Medical History 
 
Medical history information will be presented by subject in a data listing.   


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8 Efficacy Assessments  
8.1 Lesion Counts 
The primary efficacy endpoint is the reduction in the number of inflammatory lesions at 
Week 12/ET. Lesion counts will be performed by the Investigator at baseline and each 
post-baseline visit. Each type of lesion will be counted separately and recorded on the 
appropriate eCRF page. The lesion counts will be taken from the forehead, right cheek, 
left cheek, chin, and nose. 
 
The following lesion types will be counted: 
• Inflammatory Lesions 
o Papule – a small, red, solid elevation equal to or less than 0.5 cm in 
diameter. 
o Pustule – a small, circumscribed elevation of the skin that contains yellow-
white exudate. 
• Non-inflammatory Lesions 
o Open Comedone – a pigmented dilated pilosebaceous orifice (blackhead). 
o Closed Comedone – a tiny white papule (whitehead). 
 
The inflammatory lesion count is the sum of the number of papules and pustules over all 
regions of the face, and the non-inflammatory lesion count is the sum of the open and 
closed comedones over all regions of the face. 
8.2 Investigator’s Global Assessment (IGA) 
A Board Certified Dermatologist will assess the subject’s acne severity using the IGA 
scale at every visit, performing a static (“snap-shot”) evaluation of acne severity. No 
reference to baseline or other previous visits should be made by the Investigator when 
evaluating the subject’s facial acne. The IGA is dichotomized, such that Success is 
clearly defined as 0=Clear and 1=Almost Clear. 
 
The IGA Severity Scale is presented in Table 3. 
 
Table 3: Investigator’s Global Assessment Severity Scale 
 
Severity Scale 
Description 
0 
Clear 
Clear skin with no inflammatory or non-inflammatory lesions. 
1 
Almost Clear 
A few scattered comedones and a few small papules. 
2 
Mild 
Easily recognizable; less than half the face is involved. Some 
comedones and some papules and pustules. 
3 
Moderate 
More than half of the face is involved. Many comedones, papules and 
pustules. One small nodule may be present. 
4 
Severe 
Entire face is involved. Covered with comedones, numerous 
papules and pustules. Few nodules may or may not be present. 


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8.3 Oral Isotretinoin Evaluation 
At each study visit, subjects will be evaluated to determine if, in the opinion of the 
Investigator, they are still candidates for oral isotretinoin. Regardless of the results, 
subjects will not be exited from the study due to this evaluation, and will continue 
participation in the study. 
8.4 Subject’s Assessment of Acne Improvement 
The Subject’s Assessment of Acne Improvement on a 0 to 5 scale, as given in Table 4, 
will be documented at the Week 12/ET visit, based on a comparison to the subject’s 
facial acne condition at Baseline. 
 
Table 4: Subject’s Assessment of Acne Improvement Scale 
 
8.5 Subject Satisfaction Questionnaire  
The Subject Satisfaction Questionnaire will be completed by the subject at Week 12/ET. 
The questionnaire has seven questions, most with four possible responses to assess the 
subject’s satisfaction with study treatment, where a lower score represents higher 
satisfaction.  
8.6 Acne-Specific Quality of Life Questionnaire (Acne-QoL)  
The Acne-QoL will be collected at Baseline and the Week 12/ET visit. The Investigator 
or designee provides the subjects who are ages 13 and older at Informed Consent, with 
the Acne-QoL form and instruct the subject to read and answer all questions. Subjects 
who are 12 years of age at the time of Informed Consent will not complete this 
questionnaire. 
 
The questionnaire will measure the impact of facial acne on health-related quality of life. 
There are 19 questions, with multiple-choice responses on a 0-6 scale, where higher 
scores represent a higher quality of life.  
 
Questions are separated into 4 domains:  
i) 
Self-perception (5 questions - total score range from 0 to 30) 
ii) 
Role-emotional (5 questions - total score range from 0 to 30) 
iii) 
Role-social (4 questions - total score range from 0 to 24) 
iv) 
Acne symptoms (5 questions - total score range from 0 to 30) 
Severity Scale 
Description 
0 
Complete Improvement 
1 
Marked Improvement 
2 
Moderate Improvement 
3 
Minimal Improvement 
4 
No Change 
5 
Worse 


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The score for each domain is calculated by summing the score for the questions 
pertaining to the domain. At least 3 items must be answered within each domain in order 
to calculate the domain scores. If the minimum numbers of items have been answered but 
1-2 questions have missing responses, the mean value is calculated within the domain for 
the answered items and missing values are replaced with the mean value. If fewer than 
the minimum number of items have been answered, the domain score should not be 
calculated. 
 
Content areas for each domain (i.e., questions contributing to each domain) are given 
below: 
 
Self Perception 
Role-emotional 
1 
Feel unattractive 
5 
Spending time treating face 
3 
Feel self-conscious 
9 
Need to have meds or cover-up available 
10 
Self-confidence affected 
8 
Meds won’t clear face fast enough 
2 
Feel embarrassed 
7 
Not looking your best 
6 
Dissatisfied with self-appearance 
4 
Feel upset 
Role-Social 
Acne Symptoms 
12 
Going out in public 
15 
Bumps on face 
11 
Meeting new people 
16 
Bumps full of pus 
14 
Interacting with opposite sex (or 
same sex if gay) a problem 
17 Scabbing from acne 
13 
Socializing with people a problem 
18 
Concerned with scarring 
19 
Oily skin 
 
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9 Efficacy Analysis 
All efficacy variables will be summarized at each scheduled visit for the ITT Population. 
Categorical variables will be summarized by counts and percentages for each response 
category (N, %). Continuous variables will be summarized using number of subjects, 
mean, SD, median, minimum, and maximum for the data collected at each visit, and for 
change from baseline to each visit where appropriate. CIs will be presented as 
appropriate. All evaluations (including CIs) will be reported for exploratory purposes and 
will be interpreted as such. No formal confirmatory statistical testing is planned in this 
trial. 
9.1 Primary Efficacy Analysis 
The primary endpoint is the reduction in the number of inflammatory lesions at Week 
12/ET. The reduction in lesion count will be summarized with descriptive statistics. A 
95% CI for the reduction in lesions will be presented. The data will be summarized as 
CCI
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observed, with no imputation for missing values. A last observation carried forward 
(LOCF) approach will be used as a sensitivity analysis. 
9.2 Secondary Efficacy Analysis 
Secondary efficacy endpoints are: 
 
• IGA Success Rate at Weeks 4, 8, and 12/ET 
• Percent reduction in total, inflammatory, and non-inflammatory lesions at Weeks 
4, 8, and 12/ET 
• Number and percent of subjects who, in the opinion of the Investigator, are 
candidates for oral isotretinoin at Weeks 0, 4, 8, and 12/ET 
• Reduction in number of total, inflammatory, and non-inflammatory lesions at 
Weeks 4, 8, and 12/ET 
• Subject Assessment of Acne Improvement at Week 12/ET 
 
The IGA Success Rate is defined as the number and percent of subjects rated as Clear 
(Grade 0) or Almost Clear (Grade 1). It will be summarized at Weeks 4, 8, and 12/ET 
with a 95% CI for the Success Rate using Wilson’s score method. 
 
The reduction in lesion count (both percent and number of lesions) at Weeks 4, 8, and 
12/ET will be summarized with descriptive statistics and a 95% CI for the reduction in 
lesions. The % reduction is calculated as 100% multiplied by (the lesion count at baseline 
minus the lesion count at each week divided by the lesion count at baseline). 
 
The number and percent of subjects who are candidates for oral isotretinoin will be 
summarized at Weeks 0, 4, 8, and 12/ET, and a 95% CI will be provided using Wilson’s 
score method. Subgroup analyses for the number and percent of subjects who are 
candidates for oral isotretinoin are described in Section 10.4. 
 
The Subject Assessment of Acne Improvement at Week 12/ET will be summarized with 
counts and percentages for each category (ranging from 0 = Complete Improvement to 5 
= Worse). 
 
All data will be summarized as observed with no imputation for missing values. LOCF 
will be performed as a sensitivity analysis for IGA Success Rate, number of subjects 
eligible for oral isotretinoin, and lesion counts.   
 
All efficacy data will be presented by subject in data listings.   
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10  Statistical/Analytical Issues 
10.1 Handling of Dropouts or Missing Data 
For analyses of the observed data, no imputation will be performed for missing values, 
except where specified. If any items of the Acne-QoL questionnaire are not answered, 
Section 8.6 describes rules how to replace the missing value and calculate domain score. 
A sensitivity analysis of the efficacy variables will be performed by applying 
lastobservation carried forward (LOCF) approach for the ITT population. For LOCF, the 
last post-baseline assessment will be carried forward. Early termination records will be 
summarized at Week 12 for subjects who prematurely discontinue.  
10.2 Pooling of Centers in Multi-Center Studies 
There will be no pooling of centers.  
10.3 Multiple Comparisons/Multiplicity 
No adjustments for multiple comparisons or multiplicity will be made since no formal 
statistical testing will be performed.  
 
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10.4 Examination of Subgroups 
The number and percent of subjects who are candidates for oral isotretinoin at Week 
12/ET will be summarized by applying both observed and LOCF approach for the ITT 
population for the following subgroups: 
• Time since acne onset (based on quartiles in months) by gender 
• Age of acne onset (≤ 11, 12 – 14, 15 – 17, >= 18 years) by gender   
10.5 Interim Analysis and Data Monitoring 
An interim analysis is planned for this study which will summarize data for all subjects 
who have completed the study by February of 2017 as outlined in the Interim Analyses 
Plan.  All analyses described in this SAP will be provided for the interim analysis. 
11 Safety Analysis 
The safety endpoints include study drug exposure, adverse events, and local tolerability.   
All safety data will be included in the data listings.  All safety data will be summarized as 
observed with descriptive statistics for the safety population. 
11.1 Study Drug Exposure  
The following variables will be summarized for both the Adapalene 0.3% / benzoyl 
peroxide 2.5% gel and doxycycline hyclate tablets using descriptive statistics: 
• Duration of study drug exposure 
• Adapalene 0.3% / benzoyl peroxide 2.5% average daily use (g/day) 
• Compliance with doxycycline hyclate 
Study drug exposure will be calculated as the duration from the date of first dose to the 
date of last dose as: 
        Exposure (days) = Last Dose Date – First Dose Date +1. 
The average daily use for Adapalene 0.3% / benzoyl peroxide 2.5% gel will be based on 
the weight of the returned gel and will be calculated as amount of product used (in grams) 
divided by the exposure. Compliance for doxycycline will be based on the number of 
tablets dispensed and returned and will be calculated as number of tablets consumed (i.e. 
total number dispensed – total number returned) divided by the expected number of 
tablets taken.  The expected number of tables taken is 4 x (last dose date – first dose date) 
+ 2 (subjects are supposed to take 2 tablets the evening of their baseline visit, and 4 
tablets daily during the rest of the treatment period). 


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Study drug administration and accountability data will be presented by subject in data 
listings. 
11.2 Adverse Events 
Adverse events (AEs) will be summarized for the safety population.  All AEs will be 
coded using MedDRA and presented by MedDRA system organ class (SOC) and 
preferred term (PT). Any AE with onset or worsening of a pre-existing condition on or 
after the first dose of study drug through the end of participation in the study will be 
considered a treatment-emergent adverse event (TEAE). 
  
Adverse events with partial dates will be assessed using the available date information to 
determine if treatment-emergent. Adverse events with a missing start date will be 
considered treatment-emergent unless the event has a stop date prior to the date of the 
first dose of study drug. 
11.2.1 Overview of Treatment-Emergent Adverse Events 
An overview summary of TEAEs will include the number and percentage of subjects in 
each of the following categories: 
• Subjects reporting at least one TEAE 
• Subjects reporting at least one treatment-related TEAE 
• Subjects reporting at least one serious AE (SAE) 
• Subjects reporting at least one TEAE leading to discontinuation of study drug 
• Subjects with at least one AE resulting in death  
11.2.2 Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
The number and percentage of subjects with the following categories of TEAEs will be 
summarized by SOC and PT: 
• Any TEAE 
• Any TEAE by severity 
• Any TEAE by relationship to study drug 
• Any treatment-emergent SAE 
• Any TEAE leading to discontinuation of study drug 
The number and percentage of subjects who experienced at least one TEAE will be 
summarized overall and for each SOC and each PT.  The percentage will be based on the 
number of subjects in the safety population.  Each subject will contribute at most one 
count per summarization category.  In other words, if a subject has more than one TEAE 
with same PT, the subject will be counted only once for that PT.  Similarly, if a subject 


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has more than one TEAE for a SOC, the subject will be counted only once in that SOC 
and PT.  
Adverse event severity is classified as mild, moderate, or severe. If a subject has multiple 
occurrences of the same system organ class or preferred term, then only the most severe 
event will be summarized in the tables for that system organ class and preferred term.  
Missing severity will be considered severe. 
The relationship of the AE is classified into 2 categories of “Reasonable Possibility” and 
“No Reasonable Possibility".  If a subject has multiple occurrences of the same system 
organ class or preferred term, then only the most related event will be summarized in the 
tables for that system organ class and preferred term.  Missing relationships will be 
considered “Reasonable Possibility”. 
All reported AEs will be listed in data listings.  By-subject listings also will be provided 
for all subjects (safety population) for the following: treatment-related AEs, AEs 
resulting in discontinuation of study drug, and serious AEs. 
All AEs will be presented by subject in data listings. 
11.3 Local Tolerability  
Signs and symptoms of local tolerability (erythema, scaling, dryness, and/or 
stinging/burning) will be summarized for the safety population by frequency and 
percentage for each response category for baseline and each post-baseline visit. The local 
tolerability scores for each category, and the change from Baseline to each post-baseline 
visit, will also be summarized using descriptive statistics (number of subjects, means, 
medians, SDs, minimums, and maximums).  A shift table will be prepared showing shift 
from baseline to worst on-treatment value for each symptom. Scores range from 0 = 
None to 3 = Severe, according to Table 5. 
 
Table 5: Local Tolerability Severity Scale 
 
Severity 
Description 
Erythema – abnormal redness of the skin 
0 
None 
No erythema 
1 
Mild 
Slight pinkness present 
2 
Moderate 
Definite redness, easily recognized 
3 
Severe 
Intense redness 
Scaling – abnormal shedding of the stratum corneum 
0 
None 
No scaling 
1 
Mild 
Barely perceptible shedding, noticeable only on light scratching or rubbing 
2 
Moderate 
Obvious but not profuse shedding 
3 
Severe 
Heavy scale production 
Dryness – brittle and/or tight sensation 
0 
None 
No dryness 
1 
Mild 
Slight but definite roughness 
2 
Moderate 
Moderate roughness 


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3 
Severe 
Marked roughness 
Stinging/Burning – prickling pain sensation immediately after (within 5 minutes) dosing 
0 
None 
No stinging/burning 
1 
Mild 
Slight warm, tingling/stinging sensation; not really bothersome 
2 
Moderate 
Definite warm, tingling/stinging sensation that is somewhat bothersome 
3 
Severe 
Hot, tingling/stinging sensation that has caused definite discomfort 
Note: Stinging/Burning at the Baseline visit is to be assessed as none (0). 
 
Local tolerability results will be presented by subject in a data listing. 
11.4 Prior and Concomitant Medications    
The number and percentage of the subjects who took each medication will be tabulated 
by WHO Drug Dictionary Anatomical Therapeutic Chemical 3rd level (ATC-3) and 
preferred name for concomitant medications.  If the 3rd level term is not available, the 
next available level (e.g., ATC-2) will be used. A subject will only be counted once 
within each ATC-3 code and within each preferred name. 
 
Medications will be included in the concomitant medication summary if they were taken 
on or after the first day of the study drug administration, regardless of when the 
medication started. Medications with partial dates will be assessed using the available 
date information to determine if they will be categorized as concomitant medications. If 
an end date is missing or the medication is ongoing, the medication will be included as 
concomitant. 
 
Prior medications are defined as those ending prior to the first dose of investigational 
study drug.  
 
All prior and concomitant medication data will be presented by subject in a data listing.  
All prior and concomitant medical and surgical procedures will be presented by subject in 
a data listing. 
12 Quality Control 
All data displays and analyses will adhere to the International Conference on 
Harmonisation (ICH) Harmonized Tripartite Guideline: Structure and Content of 
Clinical Study Reports (ICH Topic E3). 
All analyses will be performed using SAS® Version 9.3 (or later).  Advanced Clinical 
will follow its standard operating procedures in the creation and quality control of all 
tables, listings, figures, and analyses.  Galderma or its designee will review all tables, 
listings, and figures prior to final database lock.  All final SAS programs and associated 
output files will be transferred to Galderma in agreed-upon format at project completion. 




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Statistical Table Conventions 
Mock-ups for statistical tables will include headers, title numbers, titles, column headers 
and footers, and a proposed layout for the display of data.  The final decision on the 
precision (i.e., number of decimal places) for presentation of descriptive statistics will be 
made by Galderma after review of draft statistical tables and before database freeze.   
Data Listing Conventions 
Mock-ups for data listings will include headers, title numbers, titles, column headers, and 
footers.  Data listings will provide all data either collected on the corresponding eCRF 
page or loaded directly into the database, unless otherwise indicated.  If there are too 
many fields to be fit into a single page, data should be grouped logically and the listings 
will be generated as Part I, Part II, etc. 
In general, data listings should include all subjects with data.  However, if only subjects 
who meet a certain condition are listed (e.g., subjects with SAEs) and no subjects meet 
the condition, the data listing will so indicate. 
Data presented in data listings will be sorted by subject number, unless otherwise 
requested by Galderma.  Within a subject, data will be listed in chronological order.  
Whenever possible, formatted values will be displayed (i.e., decoded).  Where applicable, 
calendar date and study day of evaluations/events will be provided in the data listings. 
 
 


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14 Preliminary List of Statistical Tables, Listings, and Figures 
to Be Programmed 
14.1 Statistical Tables 
 
Table 
Number  
Table Title  
Analysis Population  
(U)nique/ 
(P)roduction 
14.1 Demographic Data 
14.1.1 
Subject Enrollment and Disposition 
 
U 
14.1.2 
Demographic and Baseline 
Characteristics 
 Safety   
U 
14.2  Efficacy Data    
14.2.1.1 
Reduction in Lesion Counts at Each 
Scheduled Visit (Observed) 
ITT 
U 
14.2.1.2 
Reduction in Lesion Counts at Each 
Scheduled Visit (LOCF) 
ITT 
P 
14.2.2.1 
Percent Reduction in Lesion Counts at 
Each Scheduled Visit (Observed) 
ITT 
U 
14.2.2.2 
Percent Reduction in Lesion Counts at 
Each Scheduled Visit (LOCF) 
ITT 
P 
14.2.3.1 
Summary of IGA Success Rate at Each 
Visit (Observed) 
ITT 
U 
14.2.3.2 
Summary of IGA Success Rate at Each 
Visit (LOCF) 
ITT 
P 
14.2.4.1.1 
Summary of Number and Percent of 
Subjects Who Are Candidates for Oral 
Isotretinoin at Each Visit (Observed) 
ITT 
U 
14.2.4.1.2 
Summary of Number and Percent of 
Subjects Who Are Candidates for Oral 
Isotretinoin at Each Visit (LOCF) 
ITT 
P 
14.2.4.2.1 
Summary of Number and Percent of 
Subjects Who Are Candidates for Oral 
Isotretinoin at Week 12/ET by Time 
Since Acne Onset and Gender (Observed) 
ITT 
U 
14.2.4.2.2 
Summary of Number and Percent of 
Subjects Who Are Candidates for Oral 
Isotretinoin at Week 12/ET by Time 
Since Acne Onset and Gender (LOCF) 
ITT 
P 
14.2.4.3.1 
Summary of Number and Percent of 
Subjects Who Are Candidates for Oral 
Isotretinoin at Week 12/ET by Age of 
Acne Onset and Gender (Observed) 
ITT 
U 


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Table 
Number  
Table Title  
Analysis Population  
(U)nique/ 
(P)roduction 
14.2.4.3.2 
Summary of Number and Percent of 
Subjects Who Are Candidates for Oral 
Isotretinoin at Week 12/ET by Age of 
Acne Onset and Gender (LOCF) 
ITT 
P 
14.2.5 
Summary of Subject Assessment of Acne 
Improvement at Week 12/ET  
 
ITT 
U 
14.2.6 
Summary of Subject Satisfaction 
Questionnaire at Week 12/ET  
ITT 
U 
14.2.7.1 
Summary of Number and Percent of 
Acne-QoL Item Score at Baseline and 
Week 12/ET  
ITT 
U 
14.2.7.2 
Summary of Acne-QoL Item Score and 
Change from Baseline to Week 12/ET 
ITT 
U 
14.2.7.3 
Summary of Acne-QoL Domain Score 
and Change from Baseline to Week 
12/ET 
ITT 
U 
14.3 Safety Data 
14.3.1 Exposure and Adverse Events 
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Table 
Number  
Table Title  
Analysis Population  
(U)nique/ 
(P)roduction 
14.3.1.1 
Exposure to Study Drug  
Safety   
U 
14.3.1.2 
Overall Summary of Treatment-Emergent 
Adverse Events 
Safety   
U 
14.3.1.3 
Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and 
Preferred Term 
Safety   
U 
14.3.1.4 
Treatment-Emergent Adverse Events by 
Relationship to Study Drug by MedDRA 
System Organ Class and Preferred Term 
Safety   
U 
14.3.1.5 
Treatment-Emergent Adverse Events by 
Severity by MedDRA System Organ 
Class and Preferred Term 
Safety   
U 
14.3.2.1 
Serious Treatment-Emergent Adverse 
Events by MedDRA System Organ Class 
and Preferred Term 
Safety   
P 
14.3.2.2 
Treatment-Emergent Adverse Events 
Leading to Discontinuation of Study 
Drug by MedDRA System Organ Class 
and Preferred Term 
Safety 
P 
Other Safety 
14.3.4.1 
Summary of Local Tolerability at Each 
Visit 
Safety   
U 
14.3.4.2 
Shifts from Baseline to Worst On-
Treatment Value for Each Local 
Tolerability Symptom  
Safety 
U 
14.3.4.3 
Summary of Local Tolerability and 
Change from Baseline to Each Visit 
Safety 
U 
14.3.5 
Concomitant Medications by WHO Drug 
Dictionary ATC-3 Code and Preferred 
Name 
 Safety   
U 
 
14.2 Data Listings 
 
Number  
Title  
(U)nique/ 
(P)roduction 
16.2.1.1 
Study Completion and Discontinuation Information 
U 
16.2.1.2 
Screen Failures 
U 
16.2.1.3 
Study Visits 
U 
16.2.2 Protocol Deviations  
 


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Number  
Title  
(U)nique/ 
(P)roduction 
16.2.2.1 
Inclusion and Exclusion Criteria Not Met 
U 
16.2.2.2 
Protocol Deviations 
U 
16.2.4 Demographic Data  
 
16.2.4.1  
Demographics and Baseline Characteristics 
U 
16.2.4.2 
Medical History  
U 
16.2.4.3 
Childbearing Potential 
U 
16.2.5 Study Drug Administration  
 
16.2.5.1 
Study Drug Accountability - Adapalene 0.3% / Benzoyl 
Peroxide 2.5% Gel 
U 
16.2.5.2 
Study Drug Accountability - Doxycycline Hyclate 
U 
16.2.6 Individual Efficacy Response Data  
 
16.2.6.1 
Lesion Counts 
U 
16.2.6.2 
Investigator's Global Assessment 
U 
16.2.6.3 
Oral Isotretinoin Evaluation 
U 
16.2.6.4 
Subject Assessment of Acne Improvement 
U 
16.2.6.5 
Subject Satisfaction Questionnaire  
U 
16.2.6.6.1 
Acne-Specific Quality of Life Questionnaire – Part 1 
U 
16.2.6.6.2 
Acne-Specific Quality of Life Questionnaire – Part 2 
P 
16.2.6.7.1 
Dermatology Life Quality Index (DLQI) – Part 1 
U 
16.2.6.7.2 
Dermatology Life Quality Index (DLQI) – Part 2 
P 
16.2.6.8.1 
Childrens Dermatology Life Quality Index (cDLQI) – Part 1 
U 
16.2.6.8.2 
Childrens Dermatology Life Quality Index (cDLQI) – Part 2 
P 
16.2.6.9 
Photographs 
U 
16.2.7 Adverse Event Listings  
 
16.2.7.1  
Adverse Events  
U 
16.2.7.2 
Serious Adverse Events 
P 
16.2.7.3 
Adverse Events Leading Discontinuation of Study Drug 
P 
16.2.8 Listings of Individual Laboratory Measurements  
 
16.2.8.1 
Local Tolerability 
U 
16.2.8.2 
Urine Pregnancy Test 
U 
16.2.8.3 
Prior and Concomitant Medications/Therapies 
U 
16.2.8.4 
Prior and Concomitant Medical/Surgical Procedures 
U 
16.2.8.5 
Comments 
U 
 


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14.3 Figures 
 
Figure 
Number  
Figure Title  
Analysis 
Population  
(U)nique/ 
(P)roduction 
Figure 1 
Reasons for Discontinuation from Study (Bar 
Chart) 
ITT 
U 
Figure 2 
Median Percent Reduction from Baseline in 
Total, Inflammatory, and Non-inflammatory  
Lesion Counts (LOCF) (Line Chart) 
ITT 
U 
Figure 3 
IGA Success Rate at Each Visit (LOCF) 
(Line Chart) 
ITT 
U 
Figure 4 
Oral Isotretinoin Evaluation at Each Visit 
(Line Chart) 
ITT 
U 
Figure 5 
Subject Satisfaction Questionnaire (Bar 
Chart) 
ITT 
U 
Figure 6 
Mean Change from Baseline in Acne-QoL 
Domain Scores   Over Time (Observed) (Line 
Chart) 
ITT 
U 
Figure 7 
Mean Change from Baseline in Local 
Tolerability Category Scores (Line Chart) 
Safety 
U