Multi-Center, Double-Blind, Randomized, Vehicle-Controlled, Parallel-Group Study to Compare Perrigo's Adapalene/BP Gel to Galderma's Epiduo (Adapalene/BP) Gel, and Both Treatments to a Vehicle Control in the Treatment of Acne Vulgaris
Phase: PHASE3
Conditions: Acne Vulgaris
Sponsor: Padagis LLC

 
 
NCT03393494 
 
09-28-2017 

 
A Multi-Center, Double-Blind, Randomized, Vehicle-Controlled, Parallel-Group 
Study to Compare Perrigo UK FINCO’s Limited Partnership Adapalene and Benzoyl 
Peroxide Topical Gel 0.3%/2.5% to Galderma Laboratories, L.P. Epiduo® Forte 
(Adapalene and Benzoyl Peroxide) Gel, 0.3%/2.5%, and Both Active Treatments to 
a Vehicle Control in the Treatment of Acne Vulgaris 
Protocol No.: PRG-NY-17-008 
 
 
 
Confidential 
The confidential information provided in this document is for use by parties directly involved in 
this investigation.  By accepting this document, you agree that the information contained herein 
will not be disclosed to any person not directly involved in this investigation without written 
authorization from Perrigo UK FINCO’s Limited Partnership. 
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Protocol No: PRG-NY-17-008 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................ 3 
1.
BACKGROUND ..................................................................................................................... 8 
2.
STUDY OBJECTIVES .............................................................................................................. 8 
2.1 
Endpoints ............................................................................................................................... 8 
2.2 
Safety ..................................................................................................................................... 8 
3.
STUDY DESIGN .................................................................................................................... 9 
3.1 
Type/Design of Study ............................................................................................................. 9 
3.2 
Study Population .................................................................................................................... 9 
4.
SELECTION AND WITHDRAWAL OF STUDY SUBJECTS ............................................................ 9 
4.1 
Inclusion Criteria .................................................................................................................... 9 
4.2 
Exclusion Criteria .................................................................................................................. 10 
4.3 
Prohibited Medications ........................................................................................................ 12 
4.4 
Precautions .......................................................................................................................... 14 
5.
PROCEDURES .................................................................................................................... 15 
5.1 
Subject Screening and Enrollment ....................................................................................... 15 
5.2 
Assignment of Subject Number ........................................................................................... 16 
5.3 
Demographics/Medical History ........................................................................................... 16 
5.4 
Concomitant Medications .................................................................................................... 16 
5.5 
Physical Examination............................................................................................................ 16 
5.6 
Urine Pregnancy Test ........................................................................................................... 16 
5.7 
Dermatological Assessment (Diagnosis) .............................................................................. 17 
5.8 
Investigator’s Global Assessment (IGA) ............................................................................... 17 
5.9 
Lesion Counting .................................................................................................................... 18 
5.9.1 Inflammatory Lesion Count ......................................................................................................... 18 
5.9.2  Non-inflammatory Lesion Count ................................................................................................ 18 
5.9.3 Nodulocystic Lesion Count ........................................................................................................... 18 
5.10 
Application Site Reaction Assessment ................................................................................. 19 
5.11 
Study Medication Use, Subject Instructions and Diary ........................................................ 20 
5.12 
Visit Specific Procedures ...................................................................................................... 21 
5.12.1 
Baseline Visit/ Day 1............................................................................................................. 21 
5.12.2 
Telephone Contact/Week 2/Day 14 (±4 days) ..................................................................... 22 
5.12.3 
Visit 2/Week 4/Day 28 (± 4 days) ......................................................................................... 22 
5.12.4 
Visit 3/Week 8/Day 56 (± 4 days) ......................................................................................... 22 
5.12.5 
Visit 4/Week 12/Day 84 (± 4 days) End of Treatment/Early Termination Visit ................... 23 
5.12.6 
Unscheduled Visit ................................................................................................................ 23 
5.13 
Summary of Assessments .................................................................................................... 24 
5.14 
Screen Failures ..................................................................................................................... 26 
5.15 
Protocol Deviations/Violations ............................................................................................ 26 
5.16 
Subject/Treatment Compliance ........................................................................................... 26 
5.17 
Discontinuation/Withdrawal of Study Subjects ................................................................... 27 
6.
MATERIALS AND SUPPLIES ................................................................................................. 28 
6.1 
Study Medication ................................................................................................................. 28 
6.2 
Medication Management .................................................................................................... 28 
6.2.1  
Labeling, Packaging and Distribution ................................................................................... 28 
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6.2.2 Retention Samples ....................................................................................................................... 29 
6.2.3 Storage and Test Article Accountability ....................................................................................... 29 
6.2.4 Randomization ............................................................................................................................. 30 
6.2.5 Procedure for Breaking the Blind ................................................................................................ 30 
7.
ADVERSE REACTIONS......................................................................................................... 30 
7.1 
Departure from the Protocol for Individual Subjects .......................................................... 31 
7.2 
Definitions ............................................................................................................................ 31 
7.3 
Eliciting and Reporting of Adverse Events ........................................................................... 33 
7.3.1  Expedited Reporting Responsibilities of the Study Center......................................................... 33 
7.3.2 Submitting an Expedited Safety Report to the IRB ...................................................................... 34 
7.4 
SAE & AEs Requiring Discontinuation of Study Drug, including Pregnancies ...................... 34 
7.4.1 Pregnancy .................................................................................................................................... 35 
7.5 
Post Study Adverse Events ................................................................................................... 36 
7.5.1  
Non-serious Adverse Events ................................................................................................ 36 
7.5.2 Serious Adverse Events ................................................................................................................ 36 
8.
STATISTICAL ANALYSIS ...................................................................................................... 37 
8.1 
Statistical Analysis Plan ........................................................................................................ 37 
8.1.1 Analysis Populations .................................................................................................................... 37 
8.1.2 Planned Analysis .......................................................................................................................... 38 
8.1.3 Sample Size Considerations ......................................................................................................... 38 
8.1.4 Efficacy Measures and Analysis ................................................................................................... 39 
8.1.5 Safety and Adverse Events Analysis ............................................................................................. 39 
8.2 
Comparability of Subjects at Baseline.................................................................................. 40 
9.
CONSENT/ASSENT CONSIDERATIONS AND PROCEDURES .................................................... 40 
9.1 
Subject Confidentiality ......................................................................................................... 41 
10.
CONDUCT OF STUDY .......................................................................................................... 41 
10.1 
Completion of Study ............................................................................................................ 41 
10.2 
Protocol Amendments ......................................................................................................... 42 
11.
RECORDS MANAGEMENT .................................................................................................. 42 
11.1 
Data Collection ..................................................................................................................... 42 
11.2 
Source Documents ............................................................................................................... 43 
11.3 
File Management at the Study Site ...................................................................................... 44 
11.4 
Records Retention at the Study Site .................................................................................... 44 
12.
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 44 
12.1 
Monitoring ........................................................................................................................... 44 
12.2 
Auditing ................................................................................................................................ 44 
13.
ETHICS AND RESPONSIBILITY ............................................................................................. 44 
14.
USE OF INFORMATION AND PUBLICATION ......................................................................... 45 
15.
APPENDICES ...................................................................................................................... 47 
15.1 
Appendix A: Study Personnel Contacts ................................................................................ 47 
15.2 
Appendix B:  Instructions for the Subject ............................................................................ 48 
15.3 
Appendix C:  Face Diagram .................................................................................................. 52 
16.
REFERENCES ...................................................................................................................... 53 
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STUDY SYNOPSIS 
Title: 
A Multi-Center, Double-Blind, Randomized, Vehicle-Controlled, Parallel-
Group Study to Compare Perrigo UK FINCO’s Limited Partnership Adapalene 
and Benzoyl Peroxide Topical Gel 0.3%/2.5% to Galderma Laboratories, L.P. 
Epiduo® Forte (Adapalene and Benzoyl Peroxide) Gel,0.3%/2.5%, and Both 
Active Treatments to a Vehicle Control in the Treatment of Acne Vulgaris. 
Study Period: 
12 weeks (84 Days) 
Study Medication: 
1. Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5%, Perrigo UK
FINCO 
Limited 
Partnership, 
 
 
 
2. Epiduo® Forte (Adapalene and Benzoyl Peroxide) Gel,0.3%/2.5%,
manufactured by Galderma Laboratories, L.P.
3. Vehicle of test product, Perrigo UK FINCO Limited Partnership,
Study Objectives: 
To compare the safety and efficacy profiles of Perrigo UK FINCO’s Limited 
Partnership Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% to 
Galderma Laboratories Epiduo® Forte (Adapalene and Benzoyl Peroxide) Gel, 
0.3%/2.5%, in order to prove bioequivalence between them and to 
demonstrate the superior efficacy of the two active formulations over that 
of the vehicle in the treatment of Acne Vulgaris. 
Study Design: 
Subjects in this multi-center, double-blind, randomized, vehicle-controlled, 
parallel-group study will be admitted into the study only after written 
informed consent/assent (as applicable) has been obtained and after all 
inclusion/exclusion criteria have been met.  Male and female subjects 12 
years to 40 years of age, inclusive, with acne vulgaris 
 
will be eligible for enrollment. 
Study Population: 
 healthy males and females, 12 to 40 years of age, 
inclusive, who meet the inclusion/exclusion criteria, will be enrolled to 
obtain 
 modified-Intent-To-Treat (mITT) and 
 per-
protocol (PP) subjects. 
Dosing: 
Subjects will be randomized 
 to either the test product, 
reference product or vehicle treatment group, respectively, and will apply 
 the study medication onto each area of the face 
(forehead, chin, right cheek, left cheek and nose) 
 avoiding 
contact with the eyes, lips, inside your nose/nostrils, angles of the nose, 
broken skin areas and mucous membranes at approximately the same time 
once daily for 12 weeks. 
 
. 
Study Visits: 
Clinical Evaluations will be performed at: 
1. Visit 1/Day 1 (Baseline)
2. Visit 2/Week 4/Day 28 (±4 days)(Interim)
3. Visit 3/Week 8/Day 56 (±4 days)(Interim)
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4. Visit 4/Week 12/Day 84 (±4 days)(End of treatment/End study)
Safety will be assessed by monitoring adverse events at each visit and at the 
Week 2/Day 14(±4days) Telephone Contact. 
Evaluations: 
The number of facial inflammatory and non-inflammatory lesions as well as 
the Investigator’s Global Assessment (IGA) will be recorded at baseline and 
all subsequent visits. 
Endpoints: 
The two primary efficacy endpoints will be the: 
1) Mean percent change from baseline to Week 12 (Day 84) in the
inflammatory (papules and pustules) lesion count and
2) Mean percent change from baseline to Week 12 (Day 84) in the non-
inflammatory (open and closed comedones) lesion count.
The secondary endpoint will be the proportion of subjects at Week 12 with a 
clinical response of “success”, defined as an IGA score that is at least 2 
grades less than the baseline assessment.  
Safety: 
The incidence of all adverse events reported during the study will be 
summarized by treatment group. 
 
 
 In addition, the test and reference 
treatments frequency and distribution of application site reactions of 
erythema, dryness, burning/stinging, erosion, edema, pain and itching will 
be summarized and compared descriptively. 
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ABBREVIATIONS 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
CMH 
Cochran–Mantel–Haenszel test 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practices 
ICH 
International Conference on Harmonization 
IGA 
Investigator’s Global Assessment 
IRB 
Institutional Review Board 
ITT 
Intent- to-treat (population) 
IU 
International Unit 
IUD 
Intra-Uterine Device 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat (population) 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OTC 
Over the counter 
PI 
Principal Investigator 
PP 
Per-protocol (population) 
Rx 
Prescription 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SPF 
Sun Protection Factor 
Sub-I 
Sub-Investigator 
UPT 
Urine Pregnancy Test 
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3. 
STUDY DESIGN 
 
3.1 
Type/Design of Study 
Subjects in this multi-center, double-blind, randomized, vehicle-controlled, parallel-group study will 
be assigned 
 to test product, reference product, or vehicle, respectively. 
the assigned study medication will be applied topically 
 onto each 
area of the face (forehead, chin, right cheek, left cheek and nose) avoiding contact with the eyes, 
lips, mouth, inside your nose/nostrils, angles of the nose, broken skin areas and mucous 
membranes once daily in the evening around the same time for 12 weeks.   
 
Subjects will be males and females, 12 to 40 years of age inclusive, with at least moderate facial 
acne vulgaris with an inflammatory lesion (papules and pustules) 
 and a 
non-inflammatory lesion (open and closed comedones) 
 
 nodulocystic lesions (e.g., nodules and cysts) on the face including those present on the 
nose.   Visits to the study site are scheduled at baseline (Day 1) and Days 28 (Week 4), Days 56 
(Week 8), and Day 84 (Week 12).  A telephone contact will be made at Week 2. 
 
3.2 
Study Population 
Male and female subjects, 12 to 40 years of age, inclusive, with a clinical diagnosis of at least 
moderate facial acne vulgaris with an inflammatory lesion (papules and pustules) 
 
 and a non-inflammatory lesion (open and closed comedones) 
 
 nodulocystic lesions (e.g., nodules and cysts) on the face including those 
present on the nose.   
 
4. 
SELECTION AND WITHDRAWAL OF STUDY SUBJECTS 
 
4.1 
Inclusion Criteria 
Subjects must meet all of the following criteria: 
 
1. 
Subject must sign an Institutional Review Board (IRB) approved written informed consent 
/assent for this study and must be witnessed and signed by someone (other than the person 
explaining the consent/assent form during the signing of the consent/assent before enrolling 
into the study.  
 
 
. 
2. Subjects must be male or female, 12 to 40 years of age, inclusive. 
3. Subjects must have a definite clinical diagnosis of facial acne vulgaris with an inflammatory 
lesion (papules and pustules) 
 and a non-inflammatory (open and 
closed comedones) lesion 
 and 
 nodulocystic lesions 
(e.g., nodules and cysts) including those present on the nose. 
4. 
 
 
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6. Any uncontrolled, chronic or serious disease or medical condition that would prevent
participation in a clinical trial, or, in judgment of the investigator, would put the subject at
undue risk or might confound the study assessments (such as planned hospitalizations during
the study).
7. Excessive facial hair 
 that would interfere with the
diagnosis or assessment of acne vulgaris.
8.
9.
10. History of unresponsiveness to topical adapalene and/or benzoyl peroxide therapy.
11.
12. History of hypersensitivity or allergy to adapalene, benzoyl peroxide, retinoids and/or any
ingredient in the study medication.
13. Use 
 prior to baseline or during the study of oral retinoids (e.g.
Accutane®) or therapeutic vitamin A supplements of greater than 10,000 units/day
(multivitamins are allowed).
14. Use of radiation therapy and/or anti-neoplastic agents 
 prior to Visit 1/Day 1
(Baseline).
15. Use 
 prior to baseline or during the study of therapeutic vitamin D
supplements of greater than 2,000 units/day 
16. Use of medications known to exacerbate acne 
17. Start or change 
 of Visit 1 and throughout the study of:
•
18.
19.
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20.
23. Subject consumes excessive alcohol, abuses drugs, or has a condition that could compromise
the subject’s ability to comply with study requirements.
24. Previous enrollment in this study, current enrollment in this study at another participating site
or current enrollment in another study (in parallel to this study) at another clinical research
site.
26. Participation in any clinical study involving an investigational product, agent or device (that
might influence the intended effects or mask the side effects of study medication) in the 4
weeks (30 days) prior Visit 1/Day 1 (Baseline) or throughout the study.
27. Employee (or employee’s family member) of the research center or private practice, CRO or
Sponsor, or subjects who have a conflict of interest.
28.
29.
30. Subjects who in the opinion of the investigator, are unlikely to be able to follow the restrictions
of the protocol and complete the study.
4.3 
Prohibited Medications 
The following medications/procedures are prohibited during this study: 
1. Use of any treatment for acne vulgaris of the face, other than the assigned study treatment.
2. Subjects should not apply the assigned study treatment inside their nose/nostrils, angles of the
nose, on their eyes, mouth, lips, broken skin areas or mucous membranes, or on any cuts or
open wounds.
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3. The application of medicated make-up or change in cosmetics, new or changes of medicated 
cleansers, moisturizers, creams, lotions, powders, or any other topical product (other than the 
assigned study treatment or lotion with sunscreen, and cleanser provided by the Investigator) 
to the face are prohibited during this study.  
4. 
 
 
 
 
 
 
 
 
5. Initiation of or change of dose of hormonal treatment and/or drugs causing acneiform eruptions 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
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treatments or chlorine exposure (swimming, etc.) within 24 hours of study visits. Use of niacin 
 
4.4 
Precautions 
The following precautions are to be taken during this study: 
1. Subjects should avoid contact of the study medication with the eyes (upper and lower eyelids),
inside their nose/nostrils, mucous membranes, mouth and lips and or on any cuts or broken
skin. In case of accidental exposure, the eyes should be rinsed with plenty of water and a
physician should be consulted if eye irritation persists.
2.
The study medication should not be applied to cuts, abrasions, eczematous or sunburned skin,
or sites other than the treatment area.
3.
Subjects should store the study medication pump bottle upright and tightly closed at room
temperature 20°C-25°C (68°F to 77°F) in an upright position; with excursions permitted
between 15-30°C (59-86°F), away from children and heat and protected from light.
4.
Subjects should wash their hands before and immediately after applying study medication.
5.
.
6.
9.
The study medication should be spread smoothly and evenly 
 on each area of the
face (forehead, chin, and nose, left and right cheek); 
.
10. The product should not be applied more than once daily and subjects should not use more
than the recommended amount on the entire face.
11.
12. Subjects should use only the non-medicated, mild cleanser and facial lotion with sunscreen
product given to them on their face during the course of the study. Irritating topical products
such as medicated or abrasive soaps, cleansers or washes (e.g., exfoliating facial scrubs),
alcoholic toners, astringents and adhesive cleansing strips (e.g., Bioré® Pore Strips) are
prohibited throughout the study.
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Protocol No: PRG-NY-17-008 
 
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13. Subject should use protective apparel (e.g., wide-brimmed hat) when outdoors.  Weather 
extremes, such as wind or cold, may be irritating to subjects receiving treatment. 
14. Subjects should not cover the treated area with a bandage (occlusive dressing) or other types 
of dressing after applying the study medication. 
15. 
  
 
  
 
 
 
 
 
 
 
20. Subjects should consult the investigator with any questions regarding concomitant 
medications. 
21. Subjects should avoid getting the assigned treatment on their hair or on colored fabric. 
Product may bleach hair or colored fabric. 
22. 
 
23. Subjects should be informed that local skin reactions such as erythema, scaling, dryness, and 
stinging/burning as well as irritant and allergic contact dermatitis may occur and depending on 
the severity that they should report these symptoms to the study staff immediately.   
24. If a reaction suggesting sensitivity or irritation occurs, the Investigator should assess the 
subject’s condition as soon as possible (e.g., by scheduling an Unscheduled Visit, if required) 
and determine whether treatment should be discontinued. If the subject is discontinued from 
the study during an Unscheduled Visit, procedures from Visit 4 should be followed and the visit 
will be referred to as an Early Discontinuation Visit. 
 
 
5. 
PROCEDURES 
 
5.1 
Subject Screening and Enrollment 
The study personnel will review the IRB approved informed consent form and assent form, if 
applicable, with each subject and give the subject an opportunity to have all questions answered 
before proceeding.  The consent/assent form must be signed by each subject and witnessed before 
the subject is enrolled into the study.  The witness can be anyone present during the signing of the 
consent form other than the individual explaining the consent. A copy of the signed consent/assent 
will be given to every participant (or legally authorized representative) and the original will be 
maintained with the participant’s records.  Subjects under the legal age of consent must sign an IRB 
approved written informed consent/assent in addition to consent provided by a parent or legally 
authorized representative.  
 
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5.7 
Dermatological Assessment (Diagnosis) 
Investigator or sub-investigator will examine the subject to establish the clinical diagnosis of facial 
acne vulgaris.
 
 
5.8 
Investigator’s Global Assessment (IGA) 
 
 
 
 
 
 
 
.  
The following scale will be used for the Investigator’s Global Assessment: 
Grade 
Category 
Description 
0 
Clear 
Clear skin with no inflammatory or noninflammatory lesions 
1 
Almost 
Clear 
Rare non-inflammatory lesions with no more than one small 
inflammatory lesion 
2 
Mild 
Severity 
Greater than Grade 1; some noninflammatory lesions with no more 
than a few inflammatory lesions (papules/pustules only, no nodular 
lesions) 
3 
Moderate 
Severity 
Greater than Grade 2; up to many noninflammatory lesions and may 
have some inflammatory lesions, but no more than one small nodular 
lesion 
4* 
Severe 
Up to many noninflammatory lesions and may have some 
inflammatory lesions, but no more than a few nodular lesions 
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*The electronic Case Report Form (eCRF) will allow for reporting by investigators of lesion 
worsening beyond Grade 4 with post-visit 1 treatment.  Subjects who worsen beyond Grade 4 will 
be described in the safety evaluation. 
 
5.9 
Lesion Counting 
The investigator should evaluate the treatment area before a subject applies the first dose of study 
medication. Each subject’s initial condition and course of acne vulgaris will be assessed by 1) 
counting the inflammatory, non-inflammatory and nodulocystic lesions (e.g., nodules and cysts) 
including those present on the nose and documenting on the facial diagram (Appendix C) as part of 
the source documentation, 2) evaluation of the application site reaction. 
 
 
 
 
. 
 
5.9.1 Inflammatory Lesion Count (Papules and Pustules) 
The numbers of facial papules and pustules, located above the jaw line to the hairline including 
those present on the nose, are to be counted at baseline and at each subsequent visit. The type, 
location and number of each lesion is to be recorded on the source document at each visit and the 
total count recorded. 
 
Papule = solid palpable inflammatory lesion ≤ 5mm diameter 
 
Pustule = pus-filled inflammatory lesion ≤ 5mm in diameter 
 
5.9.2 Non-inflammatory Lesion Count 
The numbers of facial open comedones and closed comedones, located above the jaw line to the 
hairline including those present on the nose, are to be counted at baseline and at each subsequent 
visit.  The type, location and number of each lesion is to be recorded on the source document at 
each visit and the total count recorded. 
 
Open Comedones: blackhead, surface of the plugged sebaceous follicle has a blackish appearance  
 
Closed Comedones: whitehead, skin-colored or slightly inflamed “bump” in the skin 
 
5.9.3 Nodulocystic Lesion Count 
The numbers of facial nodules and cysts, located above the jaw line to the hairline including those 
present on the nose, are to be counted at baseline and at each subsequent visit. The total number 
of this type of lesion and location are to be recorded on the source document at each visit. 
 
 
 
 
Nodule: Palpable solid or soft lesion > 5mm in diameter. 
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Cysts: Pus filled lesion > 5mm in diameter 
5.10 
Application Site Reaction Assessment 
At baseline (Visit 1/Day 1) and each subsequent visit, application site reactions such as erythema, 
dryness, burning/stinging, erosion, edema, pain and itching are to be recorded on the source 
document. 
 
 
At Visit 1/Baseline (Day 1), the investigator should perform the application site reaction assessment 
before 
 the subject applies the first dose of the study 
medication at the site. 
The Application Site Reaction Assessment must be conducted by qualified investigators listed on 
the Form FDA 1572 who have been delegated these tasks by the PI.
 
 
 
  
Application site reactions (erythema, dryness, burning/stinging, erosion, edema, scaling/peeling, 
pain and itching) are not to be recorded as adverse events unless they result in either: 
•
The temporary discontinuation of the study medication.
•
The discontinuation of the subject from the study.
•
The use of a new concomitant medication in order to treat this event.
Any other application site reaction not listed above (such as infection) should be recorded as 
adverse events in the source document and eCRFs. 
The investigator will assess a subject’s application site reaction by rating the following symptoms 
according to the scales provided below.  Pain and itching symptoms will be assessed by discussion 
with the subject and will be reported as the severity experienced within 24 hours of the study visit. 
Site Reaction 
DESCRIPTION 
Erythema 
 
Dryness 
 
 
Scaling/Peeling 
 
Burning/Stinging 
 
Erosion 
 
Edema 
 
Pain 
 
Itching 
 
SCORE 
ASSESSMENT 
DESCRIPTION 
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0 
None 
Absent 
1 
Mild 
Slight, barely perceptible 
2 
Moderate 
Distinct presence 
3 
Severe 
Marked, intense 
5.11 
Study Medication Use, Subject Instructions and Diary 
At the baseline visit, one 
 gm pump bottle of study medication from the subject kit box will be 
dispensed by the third-party dispenser (if possible) or designee, to enrolled subjects along with a 
diary card.  Each subject will also receive a copy of written instructions, which detail the proper 
application method, and general instructions regarding the study (see Appendix B).  At Visit 
1/Baseline/Day 1, the third-party dispenser (if possible) or designee should ensure that all subjects 
met eligibility criteria and efficacy (IGA) and safety (application site reactions) assessments are 
conducted by the investigator before the subjects perform the initial application. The initial 
application on Day 1 will be demonstrated and observed by study staff when the subject applies 
the medication at the study site to ensure subject understands the instructions and is applying the 
medication appropriately. 
 
 
 
. Subsequent 
applications of study medication should be applied as instructed by the subject at home. 
 
. The study staff 
should instruct the subject to apply all subsequent doses of the study medication once daily 
(starting on the evening of Day 2 of the study treatment period) as demonstrated. At all 
subsequent study visits, the study medication and diary will be collected to visually inspect the 
pumps and diary completion.  Empty pump bottles will be collected and kept by the site.  Pump 
bottles with remaining medication will be redispensed to the subject.  In addition to the re-
dispensed pump bottle, the subject will receive a new pump bottle each at Visit 2/Week 4/Day 28 
(±4days) and Visit 3/Week 8/Day 56 (±4days).   
The dispenser will write the dispensing dates on the label of the study medication when it is 
dispensed to the subject.  The study medication kits must be stored at room temperature at 20°C 
to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) in a secure limited 
area at the investigator site. Subjects will be instructed to store the pump bottles at room 
temperature 20°C to 25°C (68°F to 77°F) in an upright position, away from children and heat, and 
should be protected from light.  
A non-medicated, mild cleanser and a facial lotion with sunscreen will be dispensed to the subjects 
at the Visit 1/Day 1 (Baseline).  Subjects will cleanse their face with the study provided non-
medicated, mild cleanser using only the hands and pat dry with a soft clean towel and then wait an 
additional 15 minutes before applying the study medication. 
 
 the study medication onto each area of the face (forehead, chin, 
right cheek, left cheek, and nose) avoiding contact with the eyes, lips, angles of the nose, inside 
your nose/nostrils, broken skin and mucous membranes at approximately the same time once daily 
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Protocol No: PRG-NY-17-008 
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in for 12 weeks.
 
Subjects will be instructed to wash hands immediately after applying the study 
medication.  Subjects should continue to use the mild cleanser and facial lotion with sunscreen 
provided by the sponsor to wash the face for the duration of the study. Subjects will be instructed 
to not use any other topical treatments or products other than the study medication and sponsor 
provided non-medicated, mild cleanser and facial lotion with sunscreen.  
A diary card will be dispensed to each enrolled subject at Visits 1, 2 & 3.  The subjects will be 
instructed to complete the diary card after applying each daily dose of study medication.  At each 
subsequent visit, study personnel will review and collect the diary card, determine whether the 
subject requires counseling for dosage compliance, confirm and record use of any prohibited 
medications, assess AEs, dispense additional study medication, cleanser or lotion and a new diary 
as required.  In addition, each study subject will be reminded to bring with them all previously 
dispensed pump bottles (regardless of content) and the completed diary card at the next visit. 
Study personnel will schedule the subject’s next visit prior to the subject’s departure. 
5.12 
Visit Specific Procedures 
The following sections outline the procedures required at each visit. 
5.12.1 Baseline Visit/ Day 1 
Prospective subjects will visit the study center and be examined by the study physician who will 
perform the procedures below at this visit.  
 
 
 
 
 
 
 
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5.12.2 Telephone Contact/Week 2/Day 14 (±4 days) 
 
 
 
 
 
 
 
 
 
 
 
5.12.3 Visit 2/Week 4/Day 28 (± 4 days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.12.4 Visit 3/Week 8/Day 56 (± 4 days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.12.5 Visit 4/Week 12/Day 84 (± 4 days) End of Treatment/Early Termination Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.12.6 Unscheduled Visit 
An unscheduled visit is allowed at any time if in the investigator’s opinion it is warranted.  If the 
investigator assesses the subject’s condition and determines that the subject’s condition has 
worsened to the degree that it is unsafe for the subject to continue in the study, the subject may 
be discontinued from the study as a treatment failure, an Early Termination Visit conducted, and a 
standard of care treatment may be advised at the investigator’s discretion. The following 
procedures may be performed at the Unscheduled Visit if required. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
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5.13 
Summary of Assessments 
The schedule of visits and procedures to be conducted at each visit are summarized in the Schedule 
of Study Procedures. 
 
The 
following 
procedures: 
Informed 
Consent, 
Inclusion/Exclusion 
Criteria, 
Medical 
History/Demographics, collection and review of Concomitant medications, Physical exam, Vital 
signs, dermatological assessment (diagnosis), lesion counting, IGA, and Urine pregnancy test must 
be completed and documented on the source document before a subject is randomized on the 
study. 
 
 
. 
 
 
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missed. On Week 2 Day 14/ (±4 days), compliance will be assessed via telephone contact. The study 
coordinator, or designee, will review the Subject Instruction Sheet and Diary with the subject on 
the phone. The total number of study medication doses applied and/or missed will be determined 
based upon the first dose applied through and including the last dose applied. The first and last 
dates of treatment should be recorded in the source documents and eCRFs. The total of applied 
and missed study medication applications should also be recorded.  By definition there are no 
missed applications before the first date of treatment or after the last date of treatment. 
 
 
 
 All used and unused pump bottles of study 
medication will be collected by the study site at appropriate visits or early termination. 
 
5.17 
Discontinuation/Withdrawal of Study Subjects 
Subjects may be removed from the study for any of the following reasons: 
• The subject withdraws his or her consent for any reason. 
• The subject’s condition has worsened to the degree that the investigator feels it is unsafe for 
the subject to continue in the study or requires an alternative therapy. 
• The subject’s medication code is unblinded. 
• Subject did not meet or no longer meets the entry criteria. 
• An adverse event including intercurrent illness, occurs for which the subject desires to 
discontinue treatment or the investigator determines that it is in the subject’s best interest to 
be discontinued. 
• The subject is lost to follow-up.  The investigator will document efforts to attempt to reach the 
subject twice by telephone and will send a certified follow-up letter before considering that 
subject lost to follow-up. All attempts must be thoroughly recorded. 
• The subject becomes pregnant during the course of the trial. 
• 
 
 
• Investigator discretion (e.g., non-compliant to study protocol requirements). 
 
After a subject has been discontinued, he/she will not be allowed to re-enroll in the study at any 
facility.  
 
The reasons for a subject being discontinued will be documented in the eCRFs and the enrollment 
log. 
 
If a subject is discontinued from the study for any reason, the Visit 4 (Day 84)/End of Study 
Visit/Early Termination Visit procedures should be completed and any outstanding data and study 
medication should be collected.  Data, in addition to the reason for discontinuation and the date of 
removal, will be recorded on the Source Document and End of Study eCRF. 
 
In the event that a subject discontinues from the study at any time due to an adverse event, the 
reason for discontinuation, the nature of the event and its clinical course must be fully 
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documented.  For such a subject, the investigator must strive to follow the subject until the 
adverse event has resolved, become clinically insignificant, is stabilized, or the subject is lost to 
follow-up. 
 
 
 
 
.  
 
6. 
MATERIALS AND SUPPLIES 
 
6.1 
Study Medication 
The study medication supplied by Perrigo will consist of: 
 
Test Product:  Adapalene and Benzoyl Peroxide Topical Gel 0.3%/2.5%,  
Perrigo UK FINCO Limited Partnership 
 
 
Reference Product:  Epiduo® Forte (Adapalene and Benzoyl Peroxide) Gel, 0.3%/2.5%, 
Marketed by Galderma Laboratories, L.P. 
 
Vehicle:  Vehicle of test product  
Perrigo UK FINCO Limited Partnership (
 
 
 
 
 
 
6.2 
Medication Management 
 
6.2.1 Labeling, Packaging and Distribution 
The study medication assigned to each subject number will be determined by a computer-
generated randomization schedule.  Study medication is labeled and packaged, according to the 
randomization code, so that neither the subject nor the investigator can identify the treatment. 
 
 
 
 
 
 
 
 
 
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The investigator or sub-investigator performing the clinical evaluations will not dispense or collect 
study medication.  
 
6.2.2 Retention Samples 
Each investigational site where study medication is dispensed to at least one subject will be 
required to randomly select 
 study medication (
 subject treatment 
units) to be maintained as retain samples.  The investigator will maintain 
 selected 
block of study medication from each shipment of study medication received.  As per the Code of 
Federal Regulations Part 21, Section 320.38(e), “Each reserve sample shall be stored under 
conditions consistent with product labeling and in an area segregated from the area where testing 
is conducted and with access limited to authorized personnel (in an upright position away from 
children and heat and protected from light at room temperature, 20-25°C (68-77°F); with 
excursions permitted between 15°C to 30°C (59°F and 86°F), even after the study has concluded. 
Each reserve sample shall be retained for a period of at least 5 years following the date on which 
the application or supplemental application is approved, or, if such application or supplemental 
application is not approved, at least 5 years following the date of completion of the bioavailability 
study in which the sample from which the reserve sample was obtained or was used.” The 
investigator will store the retain sample study medication until such time as notification is received 
from Perrigo that the samples are no longer required. 
 
 
6.2.3 Storage and Test Article Accountability 
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Study articles used to conduct this study will be maintained under adequate security by the 
investigator or designee. Each investigator site will ensure that the temperature of study 
medication is monitored and recorded throughout the study. The study medication should be 
stored at room temperature in a secured area with limited access, 20-25°C (68-77°F); with 
excursions permitted between 15°C to 30°C (59°F to 86°F) and pumps must be kept in an upright 
position and tightly closed. The medication may bleach hair and colored fabric, should not be 
frozen, should be protected from light, kept away from children, heat and kept tightly closed.  The 
investigator will not supply study medication to any person not enrolled in this study, or to any 
physician or scientist except those named as sub-investigators. 
 
 
 
 
The clinic personnel at each investigator site will keep a running inventory of study medication 
dispensed that will include subject numbers assigned and the date each pump of study medication 
is dispensed, and returned.  A study medication accountability form will be provided to the 
investigator to document all medications received, dispensed by and used by each subject.  At the 
conclusion of the study all unused, partially used, and empty pumps must be inventoried by the 
monitor and returned to Perrigo, or designee, for destruction, with the exception of retention 
samples which shall remain at the Investigator site. 
 
6.2.4 Randomization 
Randomization will be performed according to a computer-generated randomization scheme 
where the treatment group designation has been assigned to the subject number.  The treatment 
designation will remain blinded until the final database is closed.  An independent third party will 
hold the randomization code throughout the study.  The randomization scheme will be a block 
randomization, with 
 subjects assigned to Test: Reference: Vehicle 
. 
 
6.2.5 Procedure for Breaking the Blind 
The investigator, staff at the study site, study monitors, and data analysis/management personnel 
are blinded to the subject assignment. In the event of an emergency, the specific subject treatment 
may be identified by removing the overlay of the blinded label for each subject at each investigator 
site, which is attached to the study medication log; however, every effort should be made to 
maintain the blind.  The investigator must not scratch off the occluding layer of the label unless 
absolutely necessary to provide medical treatment to a subject in an emergency situation only 
and should seek prior authorization by Perrigo or designee when possible. The reason for 
breaking the blind must be clearly documented in the source documentation and eCRF and the 
subject must be discontinued from the study. Perrigo must be notified immediately upon all 
unblinding situations.  
 
 
 
7. 
ADVERSE REACTIONS 
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The potential adverse reactions of generic Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5%, 
are anticipated to be similar to those observed in EPIDUO® Forte (adapalene – benzoyl Peroxide 
Topical) Gel 0.3%/2.5%.   
 
The following adverse reactions occurred in greater than 1% of patients treated with Epiduo ®Forte 
Gel include local cutaneous irritation (erythema, scaling, dryness and stinging/burning,) skin 
irritation, eczema, atopic dermatitis and skin burning sensation.  Irritant and allergic contact 
dermatitis may occur.  
 
There is no post marketing experience with Epiduo Forte gel. The following adverse reactions have 
been identified during post-approval use of EPIDUO gel, a similar drug containing 0.1% adapalene 
and 2.5% benzoyl peroxide as the active ingredients: eyelid edema, sunburn, blister, pain of skin, 
pruritus, swelling face, conjunctivitis, skin discoloration, rash, eczema, throat tightness and allergic 
contact dermatitis. 
 
7.1 
Departure from the Protocol for Individual Subjects 
When an emergency occurs requiring a departure from the protocol for a subject, departure will be 
only for that subject.  In such circumstances, the investigator or other physician in attendance will 
contact the Medical Monitor or Perrigo by telephone and follow up with a written description as 
soon as possible.  The overseeing IRB should also be notified. 
 
7.2 
Definitions 
An adverse event (AE) is defined as any untoward medical occurrence in a subject administered a 
medicinal product and which does not necessarily have to have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (for example, 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to this medicinal product. 
 
A serious adverse event (SAE) is an adverse event that results in any of the following outcomes: 
• Death 
• Life-threatening event (e.g., the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred.  It does not include an event that, had it occurred 
in a more severe form, might have caused death) 
• Requires in-subject hospitalization or prolongs hospitalization 
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Congenital anomaly/birth defect 
• Other adverse events that may be considered serious based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
 
Immediately Reportable Adverse Events (IRAE): Any serious AE or any AE that necessitates 
discontinuation of study medication, including pregnancy. 
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Unexpected Adverse Event:  An unexpected event is any adverse drug experience, the specificity or 
severity of which is not consistent with the current approved product labeling (package insert) for 
the study medication, the Investigator’s Brochure, or as described in the clinical protocol and 
consent materials.    
Intensity of Adverse Events:  The maximum intensity of an AE during a day should be recorded on 
the CRF. If the intensity of an AE changes over a number of days, then separate entries should be 
made having distinct onset dates for the changes in severity. 
Mild - AEs are usually transient, requiring no special treatment, and do not interfere with 
subject’s daily activities. 
Moderate - AEs typically introduce a low level of inconvenience or concern to the subject and 
may interfere with daily activities, but are usually ameliorated by simple therapeutic 
measures. 
Severe - AEs interrupt a subject’s usual daily activity and traditionally require systemic drug 
therapy or other treatment. 
Causal Relationship to Study Medication: The following criteria should be used in assessing the 
apparent causal relationship of an AE to study medication.  
Definitely - The AE: 
•
follows a reasonable temporal sequence from study medication administration
•
abates upon discontinuation of the study medication (dechallenge)
•
is confirmed by reappearance of the reaction on repeat exposure
Probably - The AE: 
•
follows a reasonable temporal sequence from study medication administration
•
abates upon discontinuation of the study medication (dechallenge)
•
cannot be reasonably explained by the known characteristics of the subject’s state.
Possible - The AE: 
•
follows a reasonable temporal sequence from study medication administration
•
but that could readily be produced by a number of other factors.
Unlikely - The AE: 
•
follows a reasonable temporal sequence from study medication administration.
•
could have been produced by either the subject’s clinical state or by study medication
administration.
Not related - The AE: 
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• does not have a reasonable temporal association with the administration of study 
medication  
• has some other obvious explanation for the event. 
 
7.3 
Eliciting and Reporting of Adverse Events 
The investigator will periodically assess subjects for the occurrence of adverse events.  In order to 
avoid bias in eliciting adverse events, the subject or parent/legally authorized representative 
should be asked a non-specific question (e.g., “How have you been feeling since your last visit?”) to 
assess whether any AE has been experienced since the last visit.  All adverse events (as defined in 
Section 7.2), either observed by the Investigator or one of his/her medical collaborators, or 
reported by the participant spontaneously, or in response to direct questioning, will be reported 
and documented in the source document and the study reporting forms. When reporting an 
adverse event, the Investigator must assign a severity grade to each event and declare an opinion 
on the relatedness of the event to the study medication or procedure.  Serious or unexpected 
adverse events must be reported to Perrigo within 24 hours of when the Investigator first learns of 
the occurrence of the event.  
 
Adverse events will be documented in the source document and recorded in a timely manner on 
the eCRFs.  Adverse events (e.g., worsening of acne*) that are identified at the last assessment visit 
(or the early termination visit) must be recorded on the AE eCRF with the status of the AE noted.  
 
 
Adverse event reporting begins from the signing of informed consent/assent. Adverse events 
should be followed until resolved or 30 days after the final study treatment.  In any case, serious 
adverse events that are not resolved or considered to be chronic within 30 days of the final study 
treatment must be followed by the investigator until they become resolved or are considered to be 
chronic (stabilized for at least 30 days).  All events that are ongoing at this time will be recorded as 
ongoing on the eCRF. 
 
7.3.1 Expedited Reporting Responsibilities of the Study Center 
For any serious or unexpected adverse event, the sponsor must be notified within 24 hours of 
when the Investigator first learns of the occurrence of the event. Expedited reporting requirements 
for serious adverse events are described below. Adequate information must be collected with 
supporting documentation to complete a standard report for submission to Perrigo. The adverse 
event term on the AE eCRF and the SAE report should agree exactly. Special attention should be 
given to recording hospitalizations and concomitant medications.   
 
Subjects with unresolved adverse event(s) or serious adverse event(s) should be followed by the 
investigator until the events are resolved, events determined to be chronic or the subject is lost to 
follow-up.  Resolution means the subject has returned to the baseline state of health, or the 
investigator does not expect any further improvement or worsening of the adverse event. The 
investigator should continue to report any significant follow-up information to the sponsor up to 
the point that the event has resolved.  Any serious adverse event reported by the subject to the 
investigator that occurs within 30 days after the last assessment, and are determined by the 
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investigator to be reasonably associated with the use of the study medication, should be reported 
to the sponsor within 24 hours of when the Investigator first learns of the occurrence of the event.   
When reporting a serious adverse event (SAE) the Investigator (or the Study Coordinator) will 
promptly report any serious adverse event or pregnancy by telephone to 
 
 
 immediately after the investigator becomes 
aware of the event.  An SAE form should be completed and sent by fax, email, or overnight courier 
to 
 within 24 hours of knowledge of the event by the site.  In many cases, only preliminary 
information will be available. Appropriate follow up information should be sought (hospital 
discharge summaries, operative reports etc.) and a follow up SAE report form submitted.  A 
designation of causality from the study medication should always be included with a follow up 
report.  Assess and report the causality of the event. 
7.3.2 Submitting an Expedited Safety Report to the IRB 
Once 
 receives all supporting documentation for the reported event, the Medical Monitor, 
in conjunction with Perrigo, will determine if the safety report is eligible for expedited review. 
 will log the initial event and will notify the sponsor that an event has been reported within 
1 business day after initial receipt. 
 will complete the review of the event, enter information 
into their safety database and generate the report. This form, as well as other supporting 
documentation, will be forwarded to 
 Medical Monitor for review.  
 will finalize the 
report and distribute it to the sponsor within 1 day (one) after initial receipt. When expedited 
safety reporting to regulatory authorities is indeed required, the Investigator should review and 
update any newly available materials at once.  Follow-up queries may be sent to the study center 
to further clarify the event. 
Each expedited safety report will routinely include a brief cover memorandum, the completed 
report, and any additional pertinent information recommended by 
 Perrigo, or study 
Medical Monitor. Once the report is assembled, the Principal Investigator must submit the 
expedited safety report to the IRB within the required reporting timeframe. Follow-up reports 
should be submitted when requested or when pertinent information becomes available.  
When a Principal Investigator receives an expedited safety report from 
 or the sponsor 
detailing adverse events occurring at other study centers under this protocol, it must be promptly 
submitted to the study center’s IRB.  The Principal Investigator must retain a copy of such reports 
as submitted to their IRB in the site’s study Regulatory Binder. 
7.4 
SAE & AEs Requiring Discontinuation of Study Drug, including Pregnancies 
ANY SAE, WHICH OCCURS AFTER A SUBJECT HAS ENTERED THE STUDY, WHETHER OR NOT RELATED 
TO STUDY MEDICATION, MUST BE REPORTED TO 
 AND PERRIGO IMMEDIATELY (WITHIN 24 
HOURS) VIA TELEPHONE OR FACSIMILE. IF INITIALLY REPORTED VIA TELEPHONE, THIS MUST BE 
FOLLOWED-UP BY A FACSIMILE OF THE WRITTEN SAE REPORT WITHIN 24 HOURS OF THE CALL TO 
 
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Non-serious events that require discontinuation of study medication (including laboratory 
abnormalities) should be reported to Perrigo immediately and within 1 working day. 
 
Subjects who discontinue due to experiencing adverse events should be followed clinically until 
their health has returned to baseline status, or until all parameters have returned to normal.  It is 
expected that the investigator will provide or arrange appropriate supportive care for the subject. 
 
A subject who experiences a severe adverse event related to study drug will be discontinued from 
the study. 
 
The notification about any serious adverse event should be directed to: 
 
 
 
 
 
 
 
 
  
  
 
 
7.4.1 Pregnancy 
At the time a Principal Investigator or site personnel becomes aware that a study participant 
became pregnant following study participation, the Principal Investigator or designee will report 
the pregnancy immediately by phone and/or by faxing a completed Pregnancy Report to 
 
within one working day of being notified of the pregnancy report. 
 
The report will include the following elements: 
• Participant (mother’s) coded study identifier; 
• Date of participant’s last menstrual period; 
• Total accumulated dose of study treatment administered to date; 
• Date of study medication administration. 
 
The investigator will follow the subject until completion of the pregnancy and must assess the 
outcome in the shortest possible time but not more than 30 days within completion of the 
pregnancy. 
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Upon delivery, miscarriage or abortion, the Principal Investigator or designee must forward a 
follow-up Pregnancy Report with any relevant information on the present condition of the fetus to 
the 
 including: 
•
Mother’s coded study identifier(s);
•
Gestational age at delivery, miscarriage or abortion;
•
Birth weight, gender, length and head circumference, if available;
•
Apgar scores recorded after birth, if available;
•
Any abnormalities.
If the outcome of the pregnancy meets the criteria for immediate classification of an SAE (e.g., 
spontaneous or therapeutic abortion [any congenital anomaly detected in an aborted fetus is to be 
documented], stillbirth, neonatal death, or congenital anomaly), the investigator will report the 
event by phone and by faxing a completed SAE report form to 
 within one working day of 
being notified of the pregnancy report. 
If the trial is completed before the outcome of the pregnancy is known, 
 will assume the 
responsibility for following up on the pregnancy.  
 will contact the Investigator or Study 
coordinator on or around the potential expected date of delivery to follow-up on the outcome of 
pregnancy and will also check on the status of the infant 8 weeks post-delivery.  Upon awareness of 
the pregnancy outcome and known status of the infant following 8 weeks of delivery, the 
investigator will complete the applicable pregnancy report forms and fax to 
 within 1 day of 
being notified. 
7.5 
Post Study Adverse Events 
7.5.1 Non-serious Adverse Events 
Adverse events that are identified at the last assessment visit (or the early termination visit) must 
be recorded on the AE eCRF with the status of the AE noted.  These adverse events must be 
followed by the investigator until the events are resolved, events determined to be chronic or the 
subject is lost to follow-up.  Resolution means the subject has returned to the baseline state of 
health, or the investigator does not expect any further improvement or worsening of the adverse 
event. 
7.5.2 Serious Adverse Events 
Serious adverse events that are identified on the last assessment visit (or the early termination 
visit) must be recorded on the AE eCRF page and reported to Perrigo according to the procedures 
outlined above. Subjects with unresolved previously reported serious adverse events, or any new 
serious adverse events identified on the last assessment visit, should be followed by the 
investigator until the events are resolved, or the subject is lost to follow-up.  Resolution means the 
subject has returned to the baseline state of health, or the investigator does not expect any further 
improvement or worsening of the adverse event.  The investigator should continue to report any 
significant follow-up information to Perrigo up to the point that the event has resolved.  Any 
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serious adverse event reported by the subject to the investigator that occurs after the last 
assessment, and are determined by the investigator to be reasonably associated with the use of 
the study drug, should be reported to Perrigo. 
8.
STATISTICAL ANALYSIS
The sections that follow highlight sample size determination and the planned analyses for this
study.  A statistical analysis plan (SAP) will be prepared separately from this protocol which gives
descriptions of the statistical methods, models, hypotheses and subject populations to be analyzed.
The SAP will be completed and approved before locking the database and unblinding the study and
will serve as a companion to the protocol and the de facto documentation of the proposed
statistical evaluation.  The SAP will be completed and finalized prior to breaking the blind.
8.1 
Statistical Analysis Plan 
8.1.1 Analysis Populations 
The following populations are defined for the purpose of analyses: 
•
Intent-to-Treat (ITT) (safety population):  Any subject that was randomized, received and
used study medication. 
•
Modified Intent-to-Treat (mITT):  Any subject, who met the inclusion/exclusion criteria, was
randomized, received and used the study medication, and returned for at least one post-
baseline efficacy assessment.
•
Per Protocol (PP):  Any subject who:
•
met inclusion/exclusion criteria,
•
was randomized, received and used study medication,
•
met the protocol criteria for compliance 
and
•
completed Visit 4/Week 12/Day 84 (End of Treatment/Early Termination Visit) efficacy
evaluations within the designated window (±4 days) OR was discontinued from the
study due to treatment failure and
•
had no significant protocol violations that could have interfered with the administration
of the treatment or the precise evaluation of treatment efficacy.
 
 
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. 
 
8.1.2 Planned Analysis 
The safety analysis will be performed for the ITT subjects. The efficacy analysis will be conducted 
on both the PP and the mITT subject populations.  Two-sided hypothesis testing will be conducted.  
Resulting p-values less than 0.05 will be considered statistically significant.  No adjustments of 
p-values for multiple comparisons will be made.  No interim analyses are planned.  SAS software 
will be used for all data analyses and tabulations. 
 
The treatment response will be summarized by treatment group for the end-of-treatment 
evaluation.  
 
The two primary efficacy endpoints will be the mean percent change from baseline to Visit 4/day 
84/Week 12 in the inflammatory (papules and pustules) lesion counts AND the mean percent 
change from baseline to Visit 4/Day 84/Week 12 in the non-inflammatory (open and closed) 
lesions. 
 
 
 
 
8.1.3 Sample Size Considerations 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.1.4 Efficacy Measures and Analysis 
Clinical endpoints 
The primary efficacy measure will be the mean percent change from baseline to Visit 4/Day 
84/Week 12 in the inflammatory (papules and pustules) lesion counts AND the mean percent 
change from baseline to Visit 4/Day 84/Week 12 in the non-inflammatory (open and closed) lesion 
counts. The secondary efficacy measure will be the proportion of subjects with clinical success on 
the Investigator’s Global Assessment (IGA) at Visit 4/Day 84/Week 12.  Success is defined as an IGA 
score that is at least 2 grades less than the baseline assessment. 
 
Equivalent efficacy 
For the mean percent reduction from baseline in the inflammatory and non-inflammatory lesion 
counts, the Test treatment will be considered to be therapeutically equivalent to the Reference 
treatment if the 90% confidence interval on the Test-to-Reference ratio of means, calculated by 
Fieller’s Method, falls within the interval 0.80 to 1.25. The treatment means and estimate of 
residual variance for the confidence interval calculation will come from an Analysis of Variance of 
the Test and Reference results using a statistical model containing terms for Treatment and Site. 
 
For the proportion of subjects with clinical success, the Test treatment will be considered to be 
therapeutically equivalent to the Reference treatment if the 90% confidence interval on the 
difference between Test and the Reference proportions is contained within the interval –20% to 
+20%. The confidence interval will be constructed using Wald’s method with Yates’ continuity 
correction.  
 
 
 
 
Superiority 
For the percent reductions from baseline in the inflammatory and non-inflammatory lesion counts, 
each active treatment will be evaluated to determine if it has superior efficacy to that of the 
Vehicle at Visit 4/Week 12/Day 84 via an Analysis of Variance using a statistical model containing 
terms for Treatment and Site.  
 
The proportion of subjects with clinical success for each active treatment will be compared to that 
of the Vehicle using a Z-test with Yates’ continuity correction. 
 
 
 
All hypothesis tests will be two-sided at a significance level of α = 0.05, except confidence intervals 
which will be based on α = 0.1 (e.g., 90% coverage). 
 
8.1.5 Safety and Adverse Events Analysis 
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The frequency and percent of subjects with adverse events will be summarized by MedDRA system 
organ class and preferred term and by severity and relationship to study drug for all three 
treatment groups.  The adverse events reported by at least five percent of the subjects in any 
treatment group will also be tabulated. The comparable safety of the Test and Reference 
treatments will be evaluated by statistical comparison of the proportion of subjects who reported 
any adverse events.  The frequency and distribution of application site reactions of erythema, 
dryness, scaling/peeling, burning/stinging, erosion, edema, pain and itching will be summarized 
and compared descriptively.  Safety comparisons will be performed only for the safety intent-to-
treat population. 
 
8.2 
Comparability of Subjects at Baseline 
Descriptive statistics will be presented, by treatment group, for subject baseline characteristics. 
The significance of any obvious treatment group differences will be discussed in the CSR. 
 
9. 
CONSENT/ASSENT CONSIDERATIONS AND PROCEDURES 
It will be made clear to the subject that, for the purposes of the study, they are consenting only for 
topical application of medication or vehicle.  Investigators may discuss the availability of the study 
and the possibility for entry with a potential subject without first obtaining consent/assent. 
However, informed consent/assent must be obtained and documented prior to initiation of any 
procedures that are performed solely for the purpose of determining eligibility for research, 
including withdrawal from current medication(s).  When this is done in anticipation of, or in 
preparation for, the research, it is considered to be part of the research. 
 
The study must be approved in writing by an appropriate IRB as defined by FDA regulations.  A copy 
of the Letter of Approval from the IRB, which also contains specific identification of the documents 
approved, must be received by Perrigo, prior to study commencement. 
 
Periodic status reports must be submitted to the IRB at least annually as required by the site’s IRB, 
as well as notification of completion of the study and a final report within three months of study 
completion or termination.  A copy of all reports submitted to the IRB must be sent to Perrigo. 
 
The investigator(s) has both ethical and legal responsibility to ensure that each subject being 
considered for inclusion in this study is given a full explanation of the protocol.  This shall be 
documented on a written informed consent/assent form, which shall be approved by the same 
Institutional Review Board (IRB) responsible for approval of this protocol. Each informed 
consent/assent form shall include the elements required by FDA regulations in 21 CFR Part 50.  The 
investigator agrees to obtain approval from Perrigo of any written informed consent/assent form 
used in the study, preferably prior to submission to the IRB. 
 
Once the appropriate essential information has been provided to the subject and fully explained by 
the investigators (or a qualified designee) and it is felt that the subject understands the 
implications of participating, the IRB-approved written informed consent/assent form shall be 
signed by the subject (or their parent/legally authorized representative) and the person obtaining 
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Protocol No: PRG-NY-17-008 
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consent/assent (investigator or designee).  The subject shall be given a copy of the signed informed 
consent/assent form and the investigator shall keep the original on file. 
If the subject fails to meet the inclusion/exclusion criteria at the conclusion of the screening phase, 
the subject will be withdrawn from screening.  In the event that the subject is re-screened for study 
participation, a new informed consent/assent form must be signed. 
9.1 
Subject Confidentiality 
All participants are concerned for the individual subject’s privacy and, therefore, all subject data 
will be identified only by a subject identification number and subject initials. However, in 
compliance with federal guidelines regarding the monitoring of clinical studies and in fulfillment of 
his/her obligations to Perrigo, it is required that the investigator permit the study monitor, any 
Perrigo authorized representative, and/or FDA representative to review that portion of the 
subject’s medical record that is directly related to the study.  This shall include all study relevant 
documentation including subject medical histories to verify eligibility, laboratory test result reports 
to verify transcription accuracy, admission/discharge summaries for hospital stays occurring while 
the subject is enrolled in the study and autopsy reports for deaths occurring during the study. 
As part of the required content of informed consent, the subject must be informed that his/her 
medical chart may be reviewed by Perrigo or their authorized representative, or a representative of 
the FDA.  Should access to the medical record require a separate waiver or authorization, it is the 
investigator’s responsibility to obtain such permission from the subject in writing before the 
subject is entered into the study. 
To preserve the subject's confidentiality, the data collected will be available only to the 
investigators of the study, their support staff, Perrigo or their authorized representative and 
possibly the FDA. 
All reports and communications relating to the subject in the study will identify each subject only 
by the subject’s initials and by the subject number. The investigator agrees to furnish Perrigo with 
complete subject identification, if necessary on a confidential follow-up form, which will be used 
for the purpose of a long-term follow-up, if needed.  This will be treated with strict adherence to 
professional standards of confidentiality and will be filed at Perrigo under adequate security and 
restricted accessibility. 
10.
CONDUCT OF STUDY
The investigational site is to maintain complete documentation of all events and the times at which
they occur.
10.1 
Completion of Study 
The investigational site will complete the study and complete all documentation required, in 
satisfactory compliance with the protocol, within 3.5 months of enrollment of the last subject and 
extending beyond as needed to complete necessary data queries. 
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Protocol No: PRG-NY-17-008 
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It is agreed that, for reasonable cause, either the investigator or Perrigo may terminate this study 
before completion provided written notice is submitted at a reasonable time in advance of 
intended termination.  Any extension of this study must be mutually agreed upon in writing by 
both the investigator and Perrigo. 
10.2 
Protocol Amendments 
The Investigator will not make any changes to this protocol without prior written consent from 
Perrigo and subsequent approval by the IRB.  Any permanent change to the protocol, whether it is 
an overall change or a change for specific study center(s), must be handled as a protocol 
amendment. Any amendment to the protocol that appears indicated as the study progresses will 
be fully discussed between 
 
and Perrigo. If agreement is reached regarding the need for 
an amendment, the amendment will be written by Perrigo. The written amendment must be 
submitted to the chairman of the IRB identified with this responsibility.  Except for ‘administrative 
amendments’, investigators must await IRB approval of protocol amendments before 
implementing the change(s). Administrative amendments are defined to have no effect on the 
safety of the research subjects, scope of the investigation, or quality of the trial.  However, a 
protocol change intended to eliminate an apparent immediate hazard to subjects should be 
implemented immediately, and the IRB notified within five days.  Perrigo will submit protocol 
amendments to the FDA or other regulatory agencies. 
When, in the judgment of the reviewing IRB, the investigators and/or Perrigo, the amendment to 
the protocol substantially alters the study design and/or increases the potential risk to the subject, 
the currently approved written informed consent form will require similar modification.  In such 
cases, repeat informed consent will be obtained from subjects enrolled in the study before 
expecting continued participation. 
11.
RECORDS MANAGEMENT
11.1 
Data Collection 
Database set-up will be performed by 
 in collaboration with the Electronic Data Capture 
(EDC) vendor, using an appropriate fully validated, 21 CFR Part 11 compliant EDC system. eCRFs will 
be provided to each site via a secured web link. All applicable study data collected on each subject 
will be recorded by approved site personnel into the eCRF.  Only authorized site personnel will be 
able to enter/modify/correct data to the eCRF. 
Approved staff at 
 will verify all data entered into eCRFs for completeness and accuracy with 
reference to the source documents and records and will issue manual data queries to correct 
missing data or discrepancies found against the source within the EDC system. 
Data validation will consist of automated and manual edit checks that are created directly into EDC. 
Automated edit checks will be executed on all data points defined and documented by the study 
team and data management. Study metrics will be reported from the EDC system. 
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Protocol No: PRG-NY-17-008 
 
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After all data have been verified by approved staff at 
 an Investigator or Sub-Investigator 
(listed on Form FDA 1572) is required to review and approve all eCRFs prior to database lock and 
breaking of the blind.  
 
After database lock, each site will be provided with a password protected CD that will include the 
eCRF data from their site for local archival purposes. 
 
Quality assurance verification via a 10% database audit of eCRF data will be conducted before the 
treatment assignment code is broken. 
 
During each subject’s visit to the clinic, a designee participating in the study will record progress 
notes to document all significant observations.  At a minimum, these notes will contain: 
 
a) Documentation of the informed consent process; 
b) The date of the visit and the corresponding Visit or Week in the study schedule; 
c) General subject status remarks, including any significant medical findings.  The severity, 
frequency, and duration of any adverse events and the investigator's assessment of 
relationship to study medication must also be recorded. 
d) Any changes in concomitant medications or dosages; 
e) A general reference to the procedures completed; and 
f) The signature (or initials) and date of all clinicians who made an entry in the progress notes. 
 
In addition, any contact with the subject via telephone or other means that provides significant 
clinical information will also be documented in the progress notes as described above. 
 
Any changes to information in the study progress notes and other source documents, will be 
entered in black or blue ink, initialed and dated by the authorized person making the 
correction/addition.  Changes will be made by striking a single line through erroneous data, and 
clearly entering the correct data.  (e.g., wrong data right data).  Entries may not be erased or 
masked with white-out fluid.  If the reason for the change is not apparent, a brief explanation for 
the change will be written adjacent to the change by the clinician. 
 
For transmission to Perrigo, information from the study progress notes and other source 
documents will be promptly entered into the database.  The database also contains a complete 
audit trail to capture all regulatory components of data corrections (e.g. initial entry, new value, 
initials and date of the change). 
 
11.2 
Source Documents 
Source documents are defined as the results of original observations and activities of a clinical 
investigation.  Source documents will include, but are not limited to, progress notes and screening 
logs.  All source documents pertaining to this study will be maintained by the investigators and 
made available for inspection by authorized persons.  The original signed informed consent form 
for each participating subject shall be filed with records kept by the investigators and a copy given 
to the subject. 
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Protocol No: PRG-NY-17-008 
 
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11.3 
File Management at the Study Site 
It is the responsibility of the investigator to ensure that the study center file is maintained in 
accordance with Section 8 of the International Conference on Harmonization (ICH) Guideline for 
Good Clinical Practices (GCP). 
 
11.4 
Records Retention at the Study Site 
FDA regulations 21 CFR§312.57 require all investigators participating in clinical drug studies to 
maintain detailed clinical data for one of the following periods: 
 
a) A period of at least two years following the date on which a New Drug Application is 
approved by the FDA; 
b) A period of two years after Perrigo notifies the investigator that no further application is to 
be filed with the FDA. 
 
The investigator must not dispose of any records relevant to this study without either (1) written 
permission from Perrigo or (2) providing an opportunity for Perrigo to collect such records.  The 
investigator shall take responsibility for maintaining adequate and accurate electronic or hard copy 
source documents of all observations and data generated during this study.  Such documentation is 
subject to inspection by Perrigo and the FDA. 
 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
12.1 
Monitoring 
Perrigo has ethical, legal and scientific obligations to carefully follow this study in a detailed and 
orderly manner in accordance with established research principles and FDA regulations.  All 
medical records (source documents) of the subjects participating in this study must be presented 
for review and verification of eCRFs. 
 
12.2 
Auditing 
Perrigo (or representative) may conduct audits at the study center(s).  Audits will include, but are 
not be limited to, drug supply, presence of required documents, the informed consent process, and 
comparison of electronic case report forms with source documents.  The investigator agrees to 
participate with audits conducted at a reasonable time in a reasonable manner. 
 
Regulatory authorities worldwide may also audit the investigator during or after the study. The 
investigator should contact Perrigo immediately if notified of such an audit, and must fully 
cooperate with the audits conducted at a reasonable time in a reasonable manner. 
 
 
13. 
ETHICS AND RESPONSIBILITY 
This study must be conducted in compliance with the protocol, the United States Food and Drug 
Administration (FDA) regulations, any other countries regulations, and ICH GCP Guidelines. 
 
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Protocol No: PRG-NY-17-008 
 
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14. 
USE OF INFORMATION AND PUBLICATION 
All information supplied by Perrigo in connection with this study and not previously published, is 
considered confidential information.  This information includes, but is not limited to, data, 
materials (e.g., the clinical protocol, eCRFs), equipment, experience (whether of a scientific, 
technical, engineering, operational, or commercial nature), designs, specifications, know-how, 
product uses, processes, formulae, costs, financial data, marketing plans and direct selling systems, 
customer lists and technical and commercial information relating to customers or business 
projections used by Perrigo in its business. Any data, inventions, or discoveries collected or 
developed, as a result of this study is considered confidential. This confidential information shall 
remain the sole property of Perrigo, shall not be disclosed to any unauthorized person or used in 
any unauthorized manner without written consent of Perrigo, and shall not be used except in the 
performance of the study.  As such, confidential study-related information should not be included 
on the curriculum vitae of any participating investigator or study staff. 
 
The information developed during the course of this clinical study is also considered confidential, 
and will be used by Perrigo in connection with the development of the drug.  The information may 
be disclosed as deemed necessary by Perrigo to allow the use of the information derived from this 
clinical study, the investigator is obliged to provide Perrigo with complete test results and all data 
developed in the study. The information obtained during this study may be made available to other 
investigators who are conducting similar studies. 
 
The investigator shall not make any publication related to this study without the express written 
permission of Perrigo. 
 
 
 
 
 
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Protocol No: PRG-NY-17-008 
 
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INVESTIGATOR AGREEMENT 
 
PROTOCOL NUMBER:  PRG-NY-17-008 
 
PROTOCOL TITLE: 
 
 
A Multi-Center, Double-Blind, Randomized, Vehicle-Controlled, Parallel-
Group Study to Compare Perrigo UK FINCO’s Limited Partnership 
Adapalene and Benzoyl Peroxide Topical Gel 0.3%/2.5% to Galderma 
Laboratories, L.P. Epiduo® Forte (Adapalene and Benzoyl Peroxide) Gel 
0.3%/2.5%, and Both Active Treatments to a Vehicle Control in the 
Treatment of Acne Vulgaris 
 
 
I have carefully read the foregoing protocol and agree that it contains all the necessary information 
for conducting this study safely.  I will conduct this study in strict accordance with this protocol, ICH 
Guidelines for Good Clinical Practices, the Code of Federal Regulations, the Health Insurance 
Portability and Accountability Act (HIPAA) and any local regulatory requirements and will attempt 
to complete the study within the time designated.  I will provide access to copies of the protocol 
and all other information relating to pre-clinical and prior clinical experience submitted by Perrigo 
to all personnel responsible to me who participate in the study.  I will discuss this information with 
them to assure that they are adequately informed regarding the drug and conduct of the study.  I 
agree to keep records on all subject information in accordance with FDA regulations. 
 
 
 
 
 
 
 
 
   Principal Investigator’s Printed Name 
 
 
 
 
 
 
 
 
   Principal Investigator’s Signature 
 
 
 
 
 
 
 
   Date 
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Protocol No: PRG-NY-17-008 
 
Page 50 of 53 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
. 
 
 
Your study coordinator will call you in about 2 weeks to see how you are doing and to answer any 
questions you may have: 
 
Your call is scheduled for:   _____________________ (Week 2)  
 
 
 
 
          (Date) 
You are scheduled to return at: 
 
__________________on ________________ (Visit 2, Study Week 4)    
(Time) 
(Date) 
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Protocol No: PRG-NY-17-008 
 
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__________________on ________________ (Visit 3, Study Week 8)  
(Time)   
 
 
(Date) 
 
 
__________________on ________________ (Visit 4, Study Week 12)  
(Time)  
 
 
(Date)  
 
ALL APPOINTMENTS ARE IMPORTANT! IF YOU NEED TO RE-SCHEDULE YOUR APPOINTMENT, PLEASE 
CALL YOUR STUDY DOCTOR’S OFFICE IMMEDIATELY. 
 
______________________________________________________________________  
Name and Telephone Number of Study Coordinator/Study Site 
 
 
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Protocol No: PRG-NY-17-008 
 
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16. 
REFERENCES 
 
1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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