Clinical trial NCT04608500
Conditions: Facial Papulopustular Rosacea
Keywords: Topical Minocycline Foam 2-Arm study Inflammatory lesion counts Investigator's Global Assessment score
Sponsor: Vyne Therapeutics Inc.
Start date: 2017-06-01; Completion date: 2018-07-31
Enrollment: 771 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are to determine the efficacy and safety of FMX103 1.5% minocycline foam applied topically once daily for 12 weeks in the treatment of rosacea.

Detailed description:
This is a randomized, multicenter, double-blind, vehicle-controlled, 2 arm study to evaluate the safety and efficacy of FMX103 topical foam containing 1.5% minocycline compared to vehicle, in the treatment of participants with moderate-to-severe facial papulopustular rosacea. Qualified participants will be randomized in a 2:1 ratio (active:vehicle) to receive 1 of the following 2 treatments:

* FMX103 minocycline foam 1.5%
* Vehicle foam

Participants will be assigned to 1 of 2 treatments according to the randomization schedule. Participants will apply (or have applied) the study drug topically once daily for 12 weeks as directed. Participants will be advised to use the study drug at approximately the same time each day. Both the Investigator and participant will be blinded to the study drug identity. Participants will return for visits at Weeks 1, 4, 6, 8, 10, and 12. Efficacy evaluations (inflammatory lesion counts and Investigator's Global Assessment \[IGA\] score) will be performed at Weeks 4, 8, and 12 during the study.

Note: Originally the two studies FX2016-11 and FX2016-12 were combinedly presented in the protocol registration form under one NCT number (NCT03142451), and later separated since results were analyzed separately.

Arms: arm 1: Participants will apply the assigned FMX103 minocycline foam 1.5% topically once daily for 12 weeks as directed. arm 2: Participants will apply the assigned vehicle foam topically once daily for 12 weeks as directed.
Interventions: intervention 1: FMX103 minocycline foam 1.5% intervention 2: Vehicle foam
Intervention descriptions: intervention 1: Dosage form description: Foam containing minocycline HCl 1.5%. Once daily application of a sufficient amount of foam to cover the entire face. Estimated maximum is 0.5 g of drug product containing 7.5 mg (1.5% active) of minocycline. Participants will apply a small amount of the drug as a thin layer over all areas of the face. Participants should apply the drug at approximately the same time each day, about 1 hour before bedtime. intervention 2: Dosage form description: Foam containing minocycline vehicle foam. Once daily application of a sufficient amount of foam to cover the entire face. Estimated maximum is 0.5 g of drug product containing 0.0 mg (vehicle) of minocycline. Participants will apply a small amount of the drug as a thin layer over all areas of the face. Participants should apply the drug at approximately the same time each day, about 1 hour before bedtime.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
A Randomized, Multicenter, Double-blind, Vehicle-controlled Study to 
Evaluate the Safety and Efficacy of FMX103 1.5% Topical Minocycline Foam 
Compared to Vehicle in the Treatment of Facial Papulopustular Rosacea 
(FX2016-12) 
 
 
 
ClinicalTrials.gov Identifier: NCT04608500  
 
 
 
Final Protocol, Version 3.0 (Amendment 2), dated 12-May-2017 
Final Protocol, Version 2.0 (Amendment 1), dated 06-Mar-2017 
Final Protocol, Version 1.0, dated 20-Jan-2017  


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Date:  12 May 2017 
CLINICAL PROTOCOL 
Title Page 
Study Title: 
A Randomized, Multicenter, Double-blind, Vehicle-
controlled Study to Evaluate the Safety and Efficacy of 
FMX103 1.5% Topical Minocycline Foam Compared to 
Vehicle in the Treatment of Facial Papulopustular Rosacea 
(FX2016-12) 
Sponsor: 
Foamix Pharmaceuticals, Inc. 
520 US Highway 22, Suite 305 
Bridgewater, NJ  08807 
Protocol Identification: 
FX2016-12 
Product: 
FMX103 1.5% minocycline foam 
Indication Studied: 
Papulopustular Rosacea 
Study Phase: 
3 
Sponsor’s Signatory: 
 
GCP Statement: 
This study will be conducted in accordance with Good 
Clinical Practice. Essential documents will be archived 
according to CPMP/ICH/135/95 
Date of Protocol: 
12 May 2017 
Version of Protocol: 
Version 3 (Amendment 2) 
Supercedes: 
Version 2, issued 06 Mar 2017 
Prepared by: 
The Write Company, LLC 
Confidentiality Statement 
This document is the property of Foamix Pharmaceuticals, Inc., and is confidential and proprietary.  The information 
contained herein is believed to be accurate and complete as of the date of preparation.  The contents may not be used, 
divulged, published or otherwise disclosed without the expressed consent of Foamix Pharmaceuticals, Inc. 
 
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Synopsis 
Name of 
Sponsor/Company: 
Foamix Pharmaceuticals, 
Inc. 
Individual Study Table Referring to 
Part of the Dossier: 
(For National Authority 
Use Only) 
Name of Finished Product: 
FMX103 
Volume: 
Name of Active 
Ingredient: 
Minocycline hydrochloride 
Page: 
Title of Study: 
A Randomized, Multicenter, Double-blind, Vehicle-controlled Study to 
Evaluate the Safety and Efficacy of FMX103 1.5% Topical 
Minocycline Foam Compared to Vehicle in the Treatment of Facial 
Papulopustular Rosacea (Study FX2016-12) 
Protocol No: 
FX2016-12 
Study Centers: 
Multicenter (approximately 40 sites in the USA) 
Publication (reference): 
None 
Phase of Development: 
3 
Objectives: 
Primary Objectives: 
•
To determine the efficacy of FMX103 1.5% minocycline foam
applied topically once daily for 12 weeks in the treatment of
rosacea.
•
To evaluate the safety of topical minocycline foam applied
once daily for 12 weeks.
Study Design and 
Methods: 
This is a randomized, multicenter, double-blind, vehicle-controlled, 
2-arm study to evaluate the safety and efficacy of FMX103 topical 
foam containing 1.5% minocycline compared to vehicle, in the 
treatment of subjects with moderate-to-severe facial papulopustular 
rosacea. Qualified subjects will be randomized in a 2:1 ratio 
(active:vehicle) to receive 1 of the following 2 treatments: 
•
FMX103 minocycline foam 1.5%
•
Vehicle foam
Subjects will be assigned to 1 of 2 treatments according to the 
randomization schedule, stratified by investigational site. Subjects will 
apply (or have applied) the study drug topically once daily for 12 weeks 
as directed. Subjects will be advised to use the study drug at 
approximately the same time each day. Both the Investigator and 
subject will be blinded to the study drug identity. 
Subjects will return for visits at Weeks 2, 4, 8, and 12. Efficacy 
evaluations (inflammatory lesion counts and Investigator’s Global 
Assessment [IGA] score) will be performed at Weeks 4, 8, and 12 
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during the study. 
Number of Subjects 
(planned): 
The planned enrollment is approximately 750 male and female subjects. 
Subjects will be randomly assigned to the two treatment groups, 
FMX103 1.5% and vehicle, in a 2:1 ratio, respectively. 
Diagnosis and Main 
Criteria for Inclusion: 
Healthy male or non-pregnant females, aged ≥18 years with a clinical 
diagnosis of moderate to severe facial papulopustular rosacea, defined 
as the presence of: 
•
At least 15 and not more than 75 inflammatory facial lesions
(ie, papules/pustules), and
•
An IGA of rosacea severity of moderate or severe using the
following scale:
Score 
Grade 
Description 
0 
Clear 
No inflammatory papules or pustules 
1 
Almost clear 
Few inflammatory papules or pustules 
2 
Mild 
Several inflammatory papules or pustules 
3 
Moderate 
Moderate number of inflammatory papules or 
pustules and no nodules 
4 
Severe 
Many inflammatory papules or pustules, and up to 
2 nodules 
•
Current or history of erythema and/or flushing
Subjects must be willing to minimize external factors that might trigger 
rosacea flare-ups (eg, spicy foods, thermally hot foods and drinks, hot 
environments, prolonged sun exposure, strong winds, and alcoholic 
beverages). 
Test Product, Dose and 
Mode of Administration: 
FMX103 minocycline foam 1.5%. Topical application, once daily to 
the face, for 12 weeks. 
Reference Therapy: 
Vehicle foam. Topical application, once daily to the face, for 12 weeks. 
Study Duration: 
Subject participation in the study will be up to 18 weeks:  up to 6 weeks 
for Screening and Day 0/Baseline, and 12 weeks of study treatment. A 
safety follow-up telephone call will be conducted 4 weeks after 
completion of study treatment for only those subjects that do not 
participate in study FX2016-13 (Open label study) and who presented 
with either new or on-going adverse events at Visit 5/Week 12 (Final 
Visit). 
Endpoints and Outcomes: 
Efficacy Evaluations 
The co-primary efficacy parameters, include inflammatory lesion 
counts and IGA, will be evaluated at Day 0/Baseline and at Weeks 4, 8, 
and 12 (Final Visit). The Subject Global Assessment will be performed 
at Weeks 2, 4, 8, and 12 (Final Visit). The subject satisfaction 
questionnaire will be assessed at Week 12 (Final Visit) only. 
Safety Evaluations 
The safety assessments will include adverse events (volunteered, 
observed, and elicited by general questioning in a non-suggestive 
manner), physical examinations, vital signs, clinical laboratory tests, 
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and local signs and symptoms assessments (including erythema, 
telangiectasia, burning/stinging, flushing/blushing, dryness/xerosis, 
itching, peeling/desquamation, and hyperpigmentation) scores. 
Statistical Methods: 
The primary population for efficacy analysis will be the intent-to-treat 
(ITT) population, using multiple imputations to impute missing values. 
Supportive efficacy analyses will be conducted on the per-protocol (PP) 
population, with no imputation for missing values. 
The co-primary efficacy endpoints will be the dichotomized IGA score 
where treatment success is defined as at least a 2-step improvement 
resulting in a 0 (clear) or 1 (almost clear) score at Week 12 compared to 
Day 0/Baseline and the absolute change in inflammatory lesion count at 
Week 12 compared to Day 0/Baseline. 
The key secondary endpoints will be analyzed hierarchically: 
•
Dichotomized IGA score where treatment success is defined as
a 2-step improvement in score at Week 12 compared to Day
0/Baseline.
•
Percent change in inflammatory lesion count at Week 12
compared to Day 0/Baseline.
Continuous efficacy endpoints will be analyzed using analysis of 
covariance (ANCOVA). Dichotomized efficacy endpoints will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) test. 
The tolerability and safety of topical minocycline foam applied daily 
for 12 weeks will be evaluated using summary statistics and individual 
subject data listings. 
The active treatment group will be tested against vehicle at the 0.05 
two-sided level of significance. No statistical tests will be performed 
for any of the safety assessments. 
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Table of Contents 
Page 
TITLE PAGE ........................................................................................................................................................ 1 
SIGNATURE PAGE ............................................................................................................................................ 2 
SYNOPSIS............................................................................................................................................................. 3 
TABLE OF CONTENTS ..................................................................................................................................... 6 
LIST OF TABLES ................................................................................................................................................ 8 
1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................... 9 
2 
STUDY ADMINISTRATIVE STRUCTURE ........................................................................................10 
3 
INTRODUCTION ....................................................................................................................................11 
4 
STUDY OBJECTIVES ............................................................................................................................12 
5 
INVESTIGATIONAL PLAN ..................................................................................................................12 
5.1 
OVERALL STUDY DESIGN ................................................................................................................12 
5.2 
RATIONALE FOR STUDY DESIGN AND DOSE SELECTION ..................................................................12 
6 
STUDY POPULATION ...........................................................................................................................13 
6.1 
INCLUSION CRITERIA .......................................................................................................................13 
6.2 
EXCLUSION CRITERIA ......................................................................................................................13 
7 
STUDY PROCEDURES ..........................................................................................................................15 
7.1 
SCREENING VISIT .............................................................................................................................17 
7.2 
VISIT 1, DAY 0/BASELINE VISIT.......................................................................................................17 
7.3 
EARLY FOLLOW-UP, WEEK 1 (±3 DAYS) .........................................................................................18 
7.4 
VISIT 2, WEEK 2 (±3 DAYS) .............................................................................................................18 
7.5 
VISIT 3, WEEK 4 (±3 DAYS) .............................................................................................................18 
7.6 
VISIT 4, WEEK 8 (±3 DAYS) .............................................................................................................19 
7.7 
VISIT 5, WEEK 12 (-3/+5 DAYS) / FINAL VISIT OR EARLY TERMINATION .........................................20 
7.8 
SAFETY FOLLOW-UP (±5 DAYS) .......................................................................................................20 
8 
STUDY TREATMENTS ..........................................................................................................................21 
8.1 
TREATMENTS ADMINISTERED ..........................................................................................................21 
8.1.1 
Dosing Instructions ........................................................................................................21 
8.1.2 
Manufacturer ..................................................................................................................21 
8.1.3 
Labeling of Study Drug ..................................................................................................21 
8.1.4 
Storage of Study Drug ....................................................................................................22 
8.2 
STUDY DRUG ACCOUNTABILITY ......................................................................................................22 
8.3 
HANDLING AND DISPOSAL OF STUDY DRUG ....................................................................................23 
8.4 
METHOD OF ASSIGNMENT OF STUDY DRUG ....................................................................................23 
8.5 
SELECTION AND TIMING OF DOSES IN THE STUDY ...........................................................................23 
8.6 
BLINDING  ........................................................................................................................................23 
8.7 
PRIOR/CONCOMITANT THERAPY ......................................................................................................24 
8.8 
USE OF CONTRACEPTION .................................................................................................................24 
8.9 
TREATMENT COMPLIANCE ...............................................................................................................25 
9 
EFFICACY ASSESSMENTS ..................................................................................................................25 
9.1 
CO-PRIMARY EFFICACY ASSESSMENTS ...........................................................................................25 
9.1.1 
Lesion Counts.................................................................................................................25 
9.1.2 
Investigator Global Assessment .....................................................................................26 
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9.2 
SECONDARY AND TERTIARY EFFICACY ASSESSMENTS ....................................................................26 
9.2.1 
Percent Change in Inflammatory Lesion Counts ............................................................26 
9.2.2 
Interim Change in Inflammatory Lesion Counts ............................................................26 
9.2.3 
Subject Global Assessment ............................................................................................26 
9.2.4 
Subject Satisfaction Questionnaire .................................................................................26 
9.3 
PHOTOGRAPHY ................................................................................................................................26 
10 
SAFETY ASSESSMENTS .......................................................................................................................27 
10.1 
MEDICAL/SURGICAL HISTORY .........................................................................................................27 
10.2 
MEDICATION HISTORY.....................................................................................................................27 
10.3 
CONCOMITANT MEDICATIONS .........................................................................................................27 
10.4 
VITAL SIGNS ....................................................................................................................................27 
10.5 
PHYSICAL EXAMINATION .................................................................................................................27 
10.6 
CLINICAL LABORATORY TESTS........................................................................................................27 
10.6.1 
Urine Pregnancy Test .....................................................................................................28 
10.6.2 
Sample Collection, Storage, and Shipping .....................................................................28 
10.7 
OTHER SAFETY MEASUREMENTS .....................................................................................................28 
10.7.1 
Local Signs and Symptoms Assessments .......................................................................28 
10.7.1.1 Erythema (Clinical Erythema Assessment Scale) .........................................29 
10.7.1.2 Telangiectasia ................................................................................................29 
10.7.1.3 Burning/Stinging ...........................................................................................29 
10.7.1.4 Flushing/Blushing .........................................................................................30 
10.7.1.5 Dryness/Xerosis ............................................................................................30 
10.7.1.6 Itching ...........................................................................................................30 
10.7.1.7 Peeling/Desquamation ...................................................................................30 
10.7.1.8 Hyperpigmentation ........................................................................................30 
10.8 
ADVERSE EVENTS ............................................................................................................................31 
10.8.1 
Method of Determining Adverse Events ........................................................................31 
10.8.2 
Adverse Event Definitions .............................................................................................31 
10.8.2.1 Adverse Events ..............................................................................................31 
10.8.2.2 Serious Adverse Events .................................................................................32 
10.8.2.3 Severity of Adverse Events ...........................................................................32 
10.8.2.4 Relationship of Adverse Events to Study Treatments ...................................33 
10.8.2.5 Adverse Events Expectedness .......................................................................33 
10.8.3 
Reporting Adverse Events ..............................................................................................33 
10.8.4 
Adverse Event Follow-up ...............................................................................................33 
10.8.4.1 Pregnancy Reporting .....................................................................................34 
10.8.5 
Clinically Significantly Abnormal Laboratory Results ..................................................34 
10.9 
APPROPRIATENESS OF SAFETY MEASUREMENT ...............................................................................34 
11 
STATISTICAL DESIGN AND ANALYSIS ..........................................................................................34 
11.1 
STATISTICAL ANALYSIS PLAN .........................................................................................................34 
11.2 
DETERMINATION OF SAMPLE SIZE ...................................................................................................35 
11.3 
ANALYSIS POPULATIONS .................................................................................................................35 
11.4 
SUBJECT ACCOUNTING, DEMOGRAPHICS, AND DAY 0/BASELINE CHARACTERISTICS ......................36 
11.5 
EFFICACY ENDPOINTS ......................................................................................................................36 
11.5.1 
Primary Efficacy Endpoints ...........................................................................................37 
11.5.2 
Secondary Efficacy Endpoints .......................................................................................37 
11.5.3 
Tertiary Efficacy Endpoints ...........................................................................................37 
11.6 
SAFETY ENDPOINTS .........................................................................................................................38 
11.6.1 
Adverse Events ...............................................................................................................38 
11.6.2 
Vital Signs and Physical Examinations ..........................................................................38 
11.6.3 
Clinical Laboratory Results ............................................................................................38 
11.7 
INTERIM ANALYSIS ..........................................................................................................................39 
12 
STUDY MANAGEMENT .......................................................................................................................39 
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12.1 
MONITORING ...................................................................................................................................39 
12.2 
PROTOCOL AMENDMENTS................................................................................................................39 
12.3 
PROTOCOL DEVIATIONS ...................................................................................................................40 
12.4 
WITHDRAWAL OF SUBJECTS ............................................................................................................40 
12.5 
TERMINATION OF THE STUDY ..........................................................................................................40 
12.6 
PUBLICATION POLICY ......................................................................................................................41 
13 
ETHICS .....................................................................................................................................................41 
13.1 
CONDUCT OF THE STUDY .................................................................................................................41 
13.2 
INSTITUTIONAL REVIEW BOARDS (IRB) ..........................................................................................41 
13.3 
WRITTEN INFORMED CONSENT ........................................................................................................41 
13.4 
SUBJECT CONFIDENTIALITY .............................................................................................................42 
13.5 
RECORDS RETENTION ......................................................................................................................42 
13.6 
FINANCING .......................................................................................................................................42 
14 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................................................43 
15 
DATA HANDLING AND RECORD KEEPING ...................................................................................43 
16 
REFERENCE LIST .................................................................................................................................43 
17 
STUDY AMENDMENTS ........................................................................................................................43 
17.1 
AMENDMENT 1, EFFECTIVE MARCH 6TH, 2017 ..................................................................................44 
17.2 
AMENDMENT 2, EFFECTIVE MAY 12TH, 2017 ....................................................................................50 
APPENDIX 1:  SUBJECT GLOBAL ASSESSMENT QUESTIONNAIRE ..................................................55 
APPENDIX 2:  SUBJECT SATISFACTION QUESTIONNAIRE .................................................................56 
APPENDIX 3: ACKNOWLEDGMENT OF RECEIPT AND REVIEW OF PROTOCOL .........................57 
List of Tables 
Table 1 
Schedule of Study Assessments and Procedures – Study FX2016-12 ........................... 16 
Table 2 
Study Drug Kits and Treatments – Study FX2016-12 ................................................... 21 
Table 3 
IGA Scale for Rosacea – Study FX2016-12 ................................................................... 26 
Table 4 
Clinical Laboratory Tests – Study FX2016-12 .............................................................. 28 
Table 5 
Sample Size Calculations Based on IGA Scores after 12 Weeks of Treatment in Phase 2 
Study FX2015-10 ........................................................................................................... 35 
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1
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation/Term 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartic acid transaminase 
BOCF 
Baseline observation carried forward 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CRO 
Contract Research Organization 
eCRF 
Electronic case report form 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IGA 
Investigator’s Global Assessment 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology System 
ITT 
Intent-to-treat (population) 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed effects model for repeated measures 
OC 
Observed cases 
OTC 
Over-the-counter 
PP 
Per-protocol (population) 
PT 
Preferred term 
RBC 
Red blood cell 
RDC 
Remote data capture 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
US 
United States 
WBC 
White blood cell 
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2
STUDY ADMINISTRATIVE STRUCTURE 
Internal 
Name 
Affiliation / Address / 
Telephone Number 
Responsibility 
Foamix Pharmaceuticals, Inc.
520 US Highway 22 
Bridgewater, NJ 08807 
Sponsor 
External – Contract Research Organization (CRO) 
Name 
Affiliation / Address / 
Telephone Number 
Responsibility 
 
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3
INTRODUCTION 
Papulopustular rosacea is a chronic disorder affecting both the skin and the eye. It is a syndrome 
of undetermined etiology characterized by both vascular and papulopustular components 
involving the face and occasionally the neck and upper trunk. Clinical findings are usually 
limited to the sun exposed areas of the face and chest and include mid-facial erythema, 
telangiectasia, papules and pustules, and sebaceous gland hypertrophy. Rosacea is characterized 
by episodic flushing of affected areas, which may be associated with consumption of alcohol, hot 
drinks, or spicy foods. During inflammatory episodes, affected areas of the skin, primarily the 
convexities of the face, develop swelling, papules, and pustules. 
Rosacea occurs most commonly in adult life, between the ages of 30 and 60 years. It is very 
common in the United States (US) and Europe. Ocular involvement occurs in more than 50% of 
patients. 
Mainstays of treatment for papulopustular rosacea are the oral tetracyclines:  doxycycline and 
minocycline. Systemic doxycycline (Oracea®, doxycycline 40 mg capsules) is approved. Topical 
treatments for rosacea include metronidazole, azelaic acid, and brimonidine tartrate. 
Foamix has developed a topical minocycline foam product that is being evaluated for safety and 
efficacy in the treatment of rosacea. Minocycline hydrochloride is an established broad spectrum 
antibiotic that is used orally in the treatment of rosacea. The study medication FMX103 
(minocycline HCl 1.5% foam), facilitates easy application and even distribution of the agent, 
thereby improving treatment convenience. 
The efficacy and safety of FMX103 has been evaluated in a Phase 2 study at two minocycline 
concentrations, 1.5% and 3%. The study included 232 subjects (males/females, aged ≥18 years) 
with moderate-to-severe papulopustular rosacea defined by the Investigator’s Global Assessment 
(IGA) score and with ≥12 inflammatory facial lesions (papules/pustules) at Day 0/Baseline. 
Subjects were treated with FMX103 1.5%, FMX103 3%, or vehicle foam, once daily for 12 
weeks. Efficacy and safety were evaluated at Weeks 2, 4, 8, and 12, with an additional safety 
follow-up visit at Week 16. The primary efficacy end point was the absolute change in 
inflammatory lesion count at Week 12. Other assessments included IGA improvement of ≥2 
grades and reaching an IGA score of “clear” or “almost clear” (IGA 0/1), clinical assessment of 
erythema, and safety and tolerability. 
At Week 12, both the 1.5% and 3% doses of FMX103 significantly reduced the number of 
papules and pustules vs. vehicle (both p<0.001, intent-to-treat [ITT] population). The mean 
reduction in lesion count from Day 0/Baseline was 21.1 for the FMX103 1.5% dose, 19.9 for the 
FMX103 3% dose, and 7.8 for the vehicle. The corresponding percent reductions were 61.4% 
and 55.5% for the 1.5% and 3% doses, respectively, and 29.7% for the vehicle. 
Both the 1.5% and 3% doses of FMX103 were statistically significantly better than vehicle in 
improving IGA scores by ≥2 grades at week 12 (p=0.002 and p=0.032, respectively). Both doses 
were also statistically significantly better than vehicle in achieving an IGA of “clear or almost 
clear” (score 0/1) at Week 12 (p=0.001 and p=0.041, respectively). Both FMX103 1.5% and 3% 
doses appeared to be generally safe and well-tolerated. Treatment-related dermal reactions were 
reported in 1 subject from the FMX103 1.5% dose group (considered mild) and in a few subjects 
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from the FMX103 3% dose group (mild, n=1; moderate, n=2; severe, n=1). No treatment-related 
systemic adverse events (AEs) were reported and discontinuation due to AEs (eczema, n=1; 
rosacea, n=1; burning sensation, n=1) was reported in 3 subjects in the FMX103 3% dose group. 
As a consequence of the above, the FMX103 1.5% dose concentration has been selected for 
further development. This Phase 3 study will further assess the safety and efficacy of topical 
minocycline HCl foam, 1.5%, applied once daily compared with vehicle foam for the treatment 
of moderate-to-severe papulopustular rosacea. 
4
STUDY OBJECTIVES 
The primary objectives of the study are: 
•
To determine the efficacy of FMX103 1.5% minocycline foam applied topically once daily
for 12 weeks in the treatment of rosacea.
•
To evaluate the tolerability and safety of topical minocycline foam applied once daily for 12
weeks.
5
INVESTIGATIONAL PLAN 
5.1
Overall Study Design 
This is a randomized, multicenter, double-blind, vehicle-controlled, 2-arm study to evaluate the 
safety and efficacy of FMX103 topical foam containing 1.5% minocycline compared to vehicle, 
in the treatment of subjects with moderate-to-severe facial papulopustular acne rosacea. 
Qualified subjects will be randomized in a 2:1 ratio (active:vehicle) to use once daily one of the 
following two treatments: 
•
FMX103 minocycline foam 1.5%
•
Vehicle foam
Subjects will be assigned to 1 of 2 treatments according to the randomization schedule, stratified 
by investigational site. Subjects will apply (or have applied) the study drug topically once daily 
for 12 weeks as directed. Subjects will be advised to use the study drug at approximately the 
same time each day about 1 hour before bedtime. Both the Investigator and subject will be 
blinded to the study drug identity.  
Subjects will return for visits at Weeks 2, 4, 8, and 12. Efficacy evaluations (inflammatory lesion 
counts [Section 9.1.1] and IGA score [Section 9.1.2]) will be performed at Weeks 4, 8, and 12 
during the study. Other assessments will be performed as described in Section 9 and Section 10. 
5.2
Rationale for Study Design and Dose Selection 
A randomized, multicenter, double-blind, vehicle-controlled study design has been selected in 
order to assess the efficacy of the study drug. The subjects will be selected according to 
predefined entry criteria. The study treatment duration of 12 weeks is expected to be sufficient to 
show a treatment effect. 
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The concentration of minocycline in the composition was selected according to formulation 
integrity and stability considerations and based on the results of Phase 2 Study FX2015-10 
(described above in Section 3). 
Because of the mode of action of tetracycline drugs, the primary efficacy endpoints will be the 
effect on inflammatory lesion counts and IGA scores (Section 9). 
6
STUDY POPULATION 
The study will randomize approximately 750 subjects to active or vehicle treatment (in a 2:1 
ratio) at approximately 40 sites in the US. 
6.1
Inclusion Criteria 
Subjects can be included in the study if they meet all of the following inclusion criteria at the 
time of enrollment: 
1. Male or female ≥18 years-of-age.
2. Moderate-to-severe rosacea (as per the IGA score; Table 3) on the proposed facial
treatment area consisting of:
a.
At least 15 and not more than 75 facial papules and pustules, excluding lesions
involving the eyes and scalp;
b.
No more than 2 nodules on the face.
3. Presence of or history of erythema and/or flushing on the face.
4. If a female of child-bearing potential, have a negative urine pregnancy test and agree to
use an effective method of contraception (Section 8.8). A sterile sexual partner is NOT
considered an adequate form of birth control.
5. Willing to minimize external factors that might trigger rosacea flare-ups (eg, spicy foods,
thermally hot foods and drinks, hot environments, prolonged sun exposure, strong winds,
and alcoholic beverages).
6. Subjects who use make-up must have used the same brands/types of make-up for a
minimum period of 14 days prior to study entry and must agree to use the same make-up,
brand/type, or frequency of use, throughout the study.
7. Completed and signed an appropriately administered Informed Consent Form (ICF) prior
to any study-related procedures.
6.2 
Exclusion Criteria 
Subjects should be excluded from enrollment in the study for any of the following reasons: 
1. Woman who is pregnant, lactating, or planning to become pregnant during the study
period.
2. Presence of any skin condition on the face that would interfere with the diagnosis or
assessment of rosacea.
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3. Moderate or severe rhinophyma, dense telangiectasia (score 3, severe; Section 10.7.2.2), 
or plaque-like facial edema. 
4. Excessive facial hair (eg, beards, sideburns, moustaches, etc.) that would interfere with 
diagnosis or assessment of rosacea. 
5. History of hypersensitivity or allergy to minocycline, any other tetracycline, or of any 
other component of the formulation. 
6. Severe erythema, dryness, scaling, pruritus, stinging/burning, or edema. 
7. Active ocular rosacea (eg, conjunctivitis, blepharitis, or keratitis) of sufficient severity to 
require topical or systemic antibiotics. 
8. Use within 6 months prior to Day 0/Baseline of oral retinoids (eg, Accutane®) or 
therapeutic vitamin A supplements of greater than 10,000 units/day (multivitamins are 
allowed). 
9. Initiation of use of estrogens or oral contraceptives less than 3 months prior to Day 
0/Baseline. 
10. Use within 1 month prior to Day 0/Baseline of: 
a. Topical retinoids to the face. 
b. Systemic antibiotics known to have an impact on the severity of facial rosacea 
(eg, containing tetracycline and its derivatives, erythromycin and its derivatives, 
sulfamethoxazole, or trimethoprim). Subjects requiring systemic antibiotics not 
known to affect rosacea will be considered on a case-by-case basis. 
c. Systemic corticosteroids (Note: intranasal and inhalational corticosteroids do not 
require a washout and maybe used throughout the trial if the subject is on a stable 
dose). 
11. Use within 2 weeks prior to Day 0/Baseline of: 
a. Topical corticosteroids. 
b. Topical antibiotics. 
c. Topical medications for rosacea (eg, metronidazole). 
12. Use of a sauna during the 2 weeks prior to Day 0/Baseline and during the study. 
13. Had wax epilation of the face within 2 weeks prior to Day 0/Baseline. 
14. Active bacterial folliculitis. 
15. Consumption of excessive alcohol, abuse of licit or illicit drugs, or a condition that, in the 
opinion of the Investigator, could compromise the subject’s ability to comply with study 
requirements. 
16. Participation in activities that involve excessive or prolonged exposure to sunlight or 
weather extremes, such as wind or cold. 
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17. Presence of any clinically significant condition or situation, other than the condition
being studied, that in the opinion of the Investigator would interfere with the study
evaluations or optimal participation in the study.
18. Participation in an investigational drug study (ie, subject has been treated with an
investigational drug) within 30 days prior to Day 0/Baseline. Subjects who are
participating in non-treatment studies such as observational studies or registry studies can
be considered for inclusion.
19. Previously enrolled in this study.
20. Prior laser therapy (for telangiectasia or other conditions), electrodessication, or
phototherapy (eg, ClearLight®) to the facial area within 180 days prior to Day 0/Baseline.
21. Prior cosmetic procedures (eg, facials) that may affect the efficacy and safety profile of
the investigational product within 14 days prior to Day 0/Baseline.
7
STUDY PROCEDURES 
Potential subjects will be assessed for eligibility at Screening. During this visit, the purpose, 
timing, procedures, and risks of the study will be explained to the subject, including 
requirements for enrollment and participation in the study, medication restrictions during the 
study, and requirements for washout of certain medications that the subject may already be 
taking. 
The eligible subject who is willing to participate in the study will then sign an appropriately 
administered ICF prior to any study-related procedures being performed. 
Procedures at the Screening Visit will include obtaining blood and urine samples for clinical 
laboratory tests. The results of these tests must be no more than 45 days old at the time of the 
Day 0/Baseline Visit and randomization. 
If a subject who has agreed to participate in the study, has signed the ICF and is currently 
undergoing rosacea therapy identified in Exclusion Criteria 10 and 11, they must first enter a 
washout period (ie,1 month or 2 weeks, as specified in Exclusion Criteria 10 and 11, 
respectively) during the screening period.  Screening procedures are to be performed as defined 
in the Screening Visit (Section 7.1). 
The schedule of study assessments and procedures and the time point at which they will be 
performed during the study is presented in Table 1. If a subject prematurely withdraws from the 
study, the subject should return to the study site for an early termination visit during which all 
evaluations described under Final Visit 5/Week 12 must be performed. 
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Table 1 
Schedule of Study Assessments and Procedures – Study FX2016-12 
Assessment or Procedure 
Screening 
Day 0 / 
Baseline0 
Visits/Early 
Follow-up 
Final 
Visitb 
Safety 
Follow-upf 
Visit 
 
1 
EF 
2 
3 
4 
5 
 
Week 
 
 
1 
2 
4 
8 
12 
 
Informed consent 
X 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Assign subject identification 
X 
 
 
 
 
 
 
 
Medical/surgical/medication history 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Physical examination, height, weightc  
 
X 
 
 
 
 
X 
 
Blood pressure/heart rated  
 
X 
 
X 
X 
X 
X 
 
Blood and urine samples for clinical 
laboratory tests  
X 
 
 
 
 
 
X 
 
Urine pregnancy test (females of 
childbearing potential only) 
X 
X 
 
 
X 
X 
X 
 
Lesion counts 
X 
X 
 
 
X 
X 
X 
 
Investigator’s Global Assessment 
X 
X 
 
 
X 
X 
X 
 
Subject Global Assessment 
 
 
 
X 
X 
X 
X 
 
Subject Satisfaction Questionnaire 
 
 
 
 
 
 
X 
 
Local signs and symptoms 
assessmentse  
X 
X 
 
X 
X 
X 
X 
 
Photography† 
 
X 
 
 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
Perform drug accountability 
 
 
 
X 
X 
X 
X 
 
Collect used drug canister(s) 
 
 
 
X 
X 
X 
X 
 
Dispense study drug 
 
X 
 
 
X 
X 
 
 
Schedule/confirm next visit 
X 
X 
X 
X 
X 
X 
 
 
EF – Early Follow-up telephone call, no visit; † only for study centers participating in subject photography (Section 9.3) 
a. 
Day 0/Baseline must occur within 45 days of Screening. Blood test results must not show clinically significant 
abnormalities. 
b. 
If a subject prematurely withdraws from the study, all evaluations described under Visit 5/Week 12 (Final Visit) 
must be performed at an Early Termination Visit. 
c. 
Height to be measured only at Day 0/Baseline. 
d. 
Measure blood pressure and heart rate after the subject has been sitting for at least 5 minutes at rest. 
e. 
The severity of each of the following local rosacea signs/symptoms will be measured:  erythema, telangiectasia, 
burning/stinging, flushing/blushing, dryness/xerosis, itching, peeling/desquamation, and hyperpigmentation. 
f. 
A safety follow-up telephone call will be made 4 weeks after Visit 5/Week 12 (Final Visit) for only those subjects 
that do not participate in study FX2016-13 (Open label study) and presented with either new or on-going adverse 
events at Visit 5/Week 12 (Final Visit). 
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7.1 
Screening Visit 
• Obtain a signed and dated, written ICF prior to any study-related procedures. 
• Obtain demographic data. 
• Using the Interactive Response Technology System (IRT), assign the subject an identification 
number. 
• Obtain medical/surgical history (Section 10.1). 
• Obtain history of prior medication usage (including previous use of rosacea medications); 
record start and stop dates of any medications used in the last 3 months (Section 10.2). 
• Assess eligibility according to the inclusion (Section 6.1) and exclusion criteria (Section 6.2). 
• Collect a urine sample from female subjects of childbearing potential for a urine pregnancy 
test (Section 10.6.1). 
• Collect blood and urine samples for clinical laboratory tests and send to the central laboratory 
(Section 10.6.2). 
• Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
• Perform IGA (Section 9.1.2). 
• Perform local signs and symptoms assessments (Section 10.7.2). 
• Schedule/confirm the next study visit. 
7.2 
Visit 1, Day 0/Baseline Visit 
• Confirm eligibility according to the inclusion (Section 6.1) and exclusion criteria 
(Section 6.2). 
• Perform physical examination including height and weight (Section 10.5). 
• Measure blood pressure and heart rate (Section 10.4). 
• Collect a urine sample from female subjects of childbearing potential for a urine pregnancy 
test (Section 10.6.1). 
• Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
• Perform IGA (Section 9.1.2). 
• Perform photography (Section 9.3). 
• Perform local signs and symptoms assessments (Section 10.7.2). 
• Randomize the subject using the IRT when all criteria have been met. 
• Record concomitant medications (Section 8.7). 
• Record AEs (Section 10.8). 
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• Dispense one kit (2 canisters) of study drug. 
• Dispense facial cleanser and moisturizer. 
• Schedule/confirm the next study visit and remind subject to avoid overexposure to sunlight 
and to use the same make-up brand/type, or frequency of use, throughout the study as 
applicable. 
7.3 
Early Follow-up, Week 1 (±3 Days) 
An early follow-up telephone call will be made 1 week after Visit 1, Day 0/Baseline. 
• Record concomitant medications (Section 8.7). 
• Record AEs (Section 10.8). 
• Confirm that subject continues to use only the provided facial cleanser and moisturizer. 
• Review application instructions to confirm that the subject continues to use the study drug as 
directed. 
• Schedule/confirm the next study visit and remind subject to avoid overexposure to sunlight 
and to use the same make-up brand/type, or frequency of use, throughout the study as 
applicable. 
7.4 
Visit 2, Week 2 (±3 Days) 
• Measure blood pressure and heart rate (Section 10.4). 
• Have the subject complete the Subject Global Assessment (Section 9.2.3). 
• Perform local signs and symptoms assessments (Section 10.7.2). 
• Record concomitant medications (Section 8.7). 
• Record AEs (Section 10.8). 
• Confirm that subject continues to use only the provided facial cleanser and moisturizer. 
• Review application instructions to confirm that the subject continues to use the study drug as 
directed. 
• Perform drug accountability to assess compliance (Section 8.2). 
• Collect used study canister (if applicable). 
• Schedule/confirm the next study visit and remind subject to avoid overexposure to sunlight 
and to use the same make-up brand/type, or frequency of use, throughout the study as 
applicable. 
7.5 
Visit 3, Week 4 (±3 Days) 
• Measure blood pressure and heart rate (Section 10.4). 
• Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
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• Perform IGA (Section 9.1.2). 
• Have the subject complete the Subject Global Assessment (Section 9.2.3). 
• Perform photography (Section 9.3). 
• Perform local signs and symptoms assessments (Section 10.7.2). 
• Collect a urine sample from female subjects of childbearing potential for a urine pregnancy 
test (Section 10.6.1). 
• Record concomitant medications (Section 8.7). 
• Record AEs (Section 10.8). 
• Perform drug accountability to assess compliance (Section 8.2). 
• Collect used study drug canister (if applicable). 
• Dispense one kit (2 canisters) of study drug. 
• Confirm that subject continues to use only the provided facial cleanser and moisturizer and 
dispense additional quantities as required. 
• Review application instructions to confirm that the subject continues to use the study drug as 
directed. 
• Schedule/confirm the next study visit and remind subject to avoid overexposure to sunlight 
and to use the same make-up brand/type, or frequency of use, throughout the study as 
applicable. 
7.6 
Visit 4, Week 8 (±3 Days) 
• Measure blood pressure and heart rate (Section 10.4). 
• Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
• Perform IGA (Section 9.1.2). 
• Have the subject complete the Subject Global Assessment (Section 9.2.3). 
• Perform photography (Section 9.3). 
• Perform local signs and symptoms assessments (Section 10.7.2). 
• Collect a urine sample from female subjects of childbearing potential for a urine pregnancy 
test (Section 10.6.1). 
• Record concomitant medications (Section 8.7). 
• Record AEs (Section 10.8). 
• Perform drug accountability to assess compliance (Section 8.2). 
• Collect used study drug canister (if applicable). 
• Dispense one kit (2 canisters) of study drug. 
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• Confirm that subject continues to use only the provided facial cleanser and moisturizer and 
dispense additional quantities as required. 
• Review application instructions to confirm that the subject continues to use the study drug as 
directed. 
• Schedule/confirm the next study visit and remind subject to avoid overexposure to sunlight 
and to use the same make-up brand/type, or frequency of use, throughout the study as 
applicable. 
7.7 
Visit 5, Week 12 (-3/+5 days) / Final Visit or Early Termination 
• Perform physical examination including weight (Section 10.5). 
• Measure blood pressure and heart rate (Section 10.4). 
• Collect blood and urine samples for clinical laboratory tests and send to the central laboratory 
(Section 10.6.2). 
• Collect a urine sample from female subjects of childbearing potential for a urine pregnancy 
test (Section 10.6.1). 
• Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
• Perform IGA (Section 9.1.2). 
• Perform photography (Section 9.3). 
• Perform local signs and symptoms assessments (Section 10.7.2). 
• Have the subject complete the Subject Global Assessment (Section 9.2.3). 
• Have the subject complete the Subject Satisfaction Questionnaire (Section 9.2.4). 
• Record concomitant medications (Section 8.7). 
• Record AEs (Section 10.8). 
• Collect all used and full study drug canisters. 
• Perform drug accountability to assess compliance and record the date of the last dose 
(Section 8.2). 
• Schedule/confirm a safety follow-up telephone call 4 weeks from Visit 5/Week 12 (Final 
Visit) date (±5 days) only for subjects that will not participate in study FX2016-13 (Open 
label study) (Section 7.9) and presented with either new or on-going adverse events at Visit 
5/Week 12 (Final Visit). 
7.8 
Safety Follow-Up (±5 days) 
A safety follow-up telephone call will be made 4 weeks after Visit 5/Week 12 (Final Visit) for 
only those subjects that do not participate in study FX2016-13 (Open label study) and presented 
with either new or on-going adverse events at Visit 5/Week 12 (Final Visit). Follow up on these 
adverse events and any new concomitant medications will be recorded. 
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8 
STUDY TREATMENTS 
This study will include FMX103 minocycline foam 1.5% and vehicle foam. 
8.1 
Treatments Administered 
The description of study drug kits and treatments is shown below in Table 2. 
Table 2 
Study Drug Kits and Treatments – Study FX2016-12 
Dosage form description: 
Foam containing minocycline HCl 1.5% or vehicle foam 
Package description: 
Canisters, each containing 35 g of the clinical trial supply foam 
Daily dose: 
Once daily application of a sufficient amount of foam to cover the entire face. 
Estimated maximum is 0.5 g of drug product containing 7.5 mg (1.5% active) 
or 0.0 mg (vehicle) of minocycline. 
Cumulative maximal dose for 
dosing (12 weeks): 
630 mg (1.5%) minocycline 
Dispensing: 
Kits consisting of 2 canisters, each canister containing 35 g of FMX103 
minocycline formulation, 1.5%, or vehicle dispensed at Visit 1 (Day 
0/Baseline), Visit 3 (Week 4), and Visit 4 (Week 8).  
8.1.1
Dosing Instructions 
The dosing regimen will be the same for both treatment groups. 
Study drug kits containing 2 canisters of investigational drug will be dispensed at Visit 1 (Day 
0/Baseline), Visit 3 (Week 4), and Visit 4 (Week 8).  
After shaking the canister well, a small amount of study drug (about ½ gram or a cherry-sized 
amount) should be expressed from the canister onto the finger tips and then applied as a thin 
layer over all areas of the face. Additional drug may be used as needed to ensure the entire face is 
treated.  
Study drug should be applied at approximately the same time each day, about 1 hour before 
bedtime. 
8.1.2
Manufacturer 
The manufacturer of the investigational product is ASM Aerosol-Service AG, Moehlin, 
Switzerland. 
8.1.3
Labeling of Study Drug 
The Sponsor or designee will label study drug supplies according to the requirements of the 
Code of Federal Regulations (21CFR§ 210, Subpart G-Packaging & Labeling Control). 
The labels of the investigational (test) product will contain appropriate information as required 
by regional regulatory authorities and include, as needed, the following information: 
•
Name and address of the Sponsor
•
Protocol number
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• Product name/dosage form/mode of administration 
• Kit Number/Canister Number 
• Site number/Subject number 
• Name and address of manufacturer 
• Date of manufacture 
• Lot/batch number 
• Canister contents 
• Storage conditions 
• Caution statements, as follow: 
o “New Drug – Limited by Federal Law to Investigational Use” 
o “Flammable” 
o “Shake well before use” 
o “Keep out of the reach of children” 
The composition, pharmaceutical quality, batch number, and expiration date of the 
investigational (test) product will be traceable via the kit number. 
8.1.4 
Storage of Study Drug 
FMX103 1.5% and vehicle canisters must be stored at 2°C – 8°C until being dispensed to the 
subject. Subsequently, they must be stored at 20°C – 25°C (refer to USP Controlled Room 
Temperature). The Investigator will be responsible for the suitable storage of the investigational 
product in compliance with the storage instructions and must restrict access to the study 
personnel only. 
8.2 
Study Drug Accountability 
The Investigator will have overall responsibility for the use of the study drug. The Investigator or 
designee will verify the contents of the drug shipment and confirm receipt of the study drug in 
the IRT system. In addition, an accurate study drug dispensing record that specifies the date and 
amount dispensed to each subject must be kept. This inventory record must be available for 
inspection by representatives of the Sponsor and is subject to regional regulatory authority 
inspection at any time. At the conclusion of the study, the Investigator must provide a copy of 
this record to the Sponsor and each canister that has been retrieved from a subject will be 
returned to the vendor to be weighed. 
Under no circumstances will the Investigator allow the investigational drugs to be used other 
than as directed by this protocol. Qualified study personnel must use the IRT to assign and 
dispense kits to the subjects. Reasons for digression from the expected dispensing regimen must 
also be recorded. 
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8.3 
Handling and Disposal of Study Drug 
The study drug must be protected from unauthorized access (eg, in a locked storage facility). 
Any unused, partially used, or empty bottles of study drug will be returned to the Sponsor or 
designee by the time of the site’s close-out visit. Receipt, distribution, and return of the study 
drug must be properly documented on forms provided by the Sponsor or designee. 
8.4 
Method of Assignment of Study Drug 
After pretreatment, clinical evaluations and all other Screening procedures have been completed, 
authorized site personnel will acknowledge that the applicable subject met all the specified 
inclusion criteria (Section 6.1) and none of the exclusion criteria (Section 6.2). Assignment to a 
treatment group will then follow a predetermined list of randomization numbers, with each 
successive number receiving 1 of the 2 treatments in random order. Authorized site personnel 
will use the IRT system to assign a kit number that corresponds to the randomization schedule. 
The kit box with the assigned kit number will be dispensed to the subject. 
The randomization code will be provided by Premier Research, Research Triangle Park, NC. 
8.5 
Selection and Timing of Doses in the Study 
The 1.5% concentration of minocycline has been shown to be effective compared to vehicle in a 
Phase 2 study in subjects with rosacea. The once-daily dosing regimen is appropriate given the 
pharmacokinetic characteristics of minocycline. 
8.6 
Blinding 
This is a double-blind study, with limited access to the randomization code. The randomization 
code will be held in confidence until after the study database is locked and a memo documenting 
the database lock has been issued. Every effort will be made to retain the integrity of the blind. 
When issued to the sites, the study drug will be identical in appearance for all subjects, 
regardless of treatment assignment. 
The treatment each subject receives will not be disclosed to the Investigator, study site personnel, 
subjects, monitors, or the Sponsor staff except as required for the purposes of conducting this 
study. 
In the event that emergency identification of study drug is required (eg, if the Investigator 
believes that the information is necessary to properly treat a subject with an AE), the study drug 
identity can be obtained by the Investigator through the IRT system. 
Before breaking the blind for a subject, the Investigator should determine that the information is 
necessary (ie, that it will alter the subject’s immediate course of treatment and will contribute to 
the management of the AE). In many cases, particularly when the emergency is clearly not 
related to study drug, the problem may be effectively managed by assuming that the subject is 
receiving active study drug without the need for unblinding. Every effort should be made to alert 
the medical monitor before requesting that the blind be broken. If this is not possible, the medical 
monitor should be immediately notified of the breaking of the blind. The Investigator will record 
the unblinding procedures in the subject’s source documents. 
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If unblinding is necessary, the subject will be withdrawn from the study and Early Termination 
Visit (ie, Visit 5 [Week 12]) assessments will be completed. 
8.7 
Prior/Concomitant Therapy 
As necessary, subjects should use the facial cleanser Cetaphil Gentile Skin Cleanser and the 
facial moisturizer Eucerin Daily Protection Broad Spectrum SPF30 Face Lotion. Both products 
will be provided by the Sponsor. Alternative, non-medicated cleansers or moisturizers may be 
used if agreed to by the Sponsor. 
The use of or change in the dose of any and all concomitant medications, either prescription or 
over-the-counter (OTC), during the study will be recorded. The reason for use or change of dose 
of a concomitant therapy may need to be reported as an AE. Therapies (medication and non-
medication therapies) not restricted by the protocol may be used. Non-prohibited chronic 
therapies being used at Day 0/Baseline may be continued. If a female subject is using an oral 
contraceptive product, she should have been on the same product for at least 3 months and she 
should continue using the same or equivalent product for the duration of the study. 
If a subject is taking anticoagulant therapy, the subject should be advised that they may require a 
downward adjustment of their anticoagulant dosage. 
All topical or systemic medications listed in the exclusion criteria are prohibited during this 
study. Similarly, no other topical medications are permitted to be used on the face during this 
period. 
See the FMX103 Investigator’s Brochure (IB) for information about tetracyclines and possible 
drug-drug interactions. 
8.8 
Use of Contraception 
Tetracycline-class antibiotics can cause fetal harm when administered to a pregnant woman. 
Tetracycline-class antibiotics used during tooth development (last half of pregnancy, infancy, and 
childhood to the age of 8 years) may cause permanent discoloration of teeth (yellow-gray-
brown). 
Prior to study enrollment, females of childbearing potential must be advised of the importance of 
avoiding pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy. Females of childbearing potential include any female who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation/occlusion, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea 
>12 consecutive months). Females of childbearing potential must have a negative urine 
pregnancy test and, if they are sexually active or become sexually active during the study, must 
use an effective method of birth control such as those listed below during the course of the study. 
The following is not an all-inclusive list; the subject must discuss with the Investigator the most 
appropriate form of birth control: 
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• Hormonal methods 
o Oral contraceptives – (Oral antibiotics may lessen the effectiveness of oral 
contraceptives. Therefore, a second form of birth control must be utilized in 
subjects using oral contraceptives) 
o Implant 
o Injection 
o Transdermal patch 
o Intravaginal ring 
• Intrauterine device (hormonal or non-hormonal) 
• Barrier methods 
o Condom (male or female) with spermicide 
o Diaphragm with spermicide 
• Complete abstinence 
8.9 
Treatment Compliance 
Each subject is to be instructed on the importance of following the dosing schedule and returning 
all kits (empty/used/unused) at the appropriate visits. The study site personnel will question the 
subject on the history of study drug use since the last visit. A subject who deviates significantly 
from the prescribed dosage will be counseled. 
9 
EFFICACY ASSESSMENTS 
Every attempt must be made to ensure the same evaluator performs the efficacy 
evaluations for a particular subject throughout the study. 
When this is not possible, another approved evaluator may perform the evaluations. Following 
are the methods and scales that will be used to measure each of the efficacy parameters to be 
performed. 
9.1 
Co-Primary Efficacy Assessments 
The co-primary efficacy assessments will include the inflammatory lesion counts and the IGA of 
severity of disease. Lesion counts, IGA, and other efficacy evaluations will be performed by the 
Investigator/evaluator. 
9.1.1 
Lesion Counts 
The number of papules, pustules, and nodules will be counted and the numbers recorded. Facial 
area lesion counts will be made for the forehead, left and right cheeks, nose, and chin. The lesion 
counts will be performed at Screening and Visit 1 (Day 0/Baseline) to confirm eligibility, and 
again at Visit 3 (Week 4), Visit 4 (Week 8), and Visit 5 (Week 12/Final Visit). 
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9.1.2
Investigator Global Assessment 
The Investigator will also assess the global severity of rosacea using the IGA scale as described 
in Table 3. The IGA will be performed at Screening and Visit 1 (Day 0/Baseline) to confirm 
eligibility, and again at Visit 3 (Week 4), Visit 4 (Week 8), and Visit 5 (Week 12/Final Visit). 
Table 3 
IGA Scale for Rosacea – Study FX2016-12 
Score 
Grade 
Description 
0 
Clear 
No inflammatory papules or pustules 
1 
Almost clear 
Few inflammatory papules or pustules 
2 
Mild 
Several inflammatory papules or pustules 
3 
Moderate 
Moderate number of inflammatory papules or pustules and no nodules 
4 
Severe 
Many inflammatory papules or pustules, and up to 2 nodules 
9.2
Secondary 
 Efficacy Assessments 
9.2.1
Percent Change in Inflammatory Lesion Counts 
The percent change in inflammatory lesion counts at Visit 5 (Week 12/Final Visit) compared to 
Visit 1 (Day 0/Baseline) will be evaluated. 
9.2.2
Interim Change in Inflammatory Lesion Counts 
The absolute 
 change in inflammatory lesion counts at Visit 3 (Week 4) and Visit 4 
(Week 8) compared to Visit 1 (Day 0/Baseline) will be evaluated. 
9.2.3
Subject Global Assessment 
This score will be obtained from the subject at Visit 2 (Week 2), Visit 3 (Week 4), Visit 4 (Week 
8), and Visit 5 (Week 12/Final Visit) using the questionnaire in Appendix 1. 
9.2.4
Subject Satisfaction Questionnaire 
A subject satisfaction questionnaire (Appendix 2) will be administered at Visit 5 (Week 12/Final 
Visit). 
9.3
Photography 
Photography will be performed at selected study centers only. Study centers should refer to their 
specific Clinical Trial Agreement to confirm participation. 
Photography of the full face will be performed at Day 0/Baseline and at Weeks 4, 8, and 12 using 
recognized methods. The equipment and techniques for this photography and for archiving the 
images are described in the Study Manual. Photographs will be reviewed at the site and by the 
sponsor for quality. Photographs will not be used to assess the lesion counts or the IGA, but will 
be archived to be available for subsequent review, if required, by the sponsor, auditors, or the 
FDA. 
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10
SAFETY ASSESSMENTS 
The safety assessments in this study are standard safety measures in clinical studies, including 
physical examinations, the monitoring of vital signs, AEs (volunteered, observed, and elicited by 
general questioning in a non-suggestive manner), clinical laboratory tests, and local signs and 
symptoms assessments (including erythema, telangiectasia, burning/stinging, flushing/blushing, 
dryness/xerosis, itching, peeling/desquamation, and hyperpigmentation) scores. 
10.1
Medical/Surgical History 
A complete medical and surgical history will be obtained at Screening, which will include the 
following:  diseases of the head, ears, eyes, nose and throat; respiratory diseases; cardiovascular 
diseases; gastrointestinal diseases; hepatic diseases; genitourinary diseases; musculoskeletal 
diseases; endocrine diseases; neurological diseases; psychiatric diseases; skin diseases; allergies; 
hematological diseases; and other abnormalities. 
10.2
Medication History 
A history of medication usage (including previous use of rosacea medications and non-
medication therapies) will be recorded at Screening. The start and stop dates of previous use of 
medications in the last 3 months will be recorded. 
10.3
Concomitant Medications 
All topical or systemic medications listed in the exclusion criteria are prohibited. No other 
topical medications are permitted to be used on the face. All medication that the subject is 
currently taking or any change in medication or dosage since the last visit will be documented 
throughout the study. The use of or change in the dose of any and all concomitant medication, 
either prescription or OTC, during the study will be recorded. The reason for use or change of 
dose of a concomitant therapy may need to be reported as an AE. 
10.4
Vital Signs 
Heart rate and blood pressure (BP) will be measured at all post-Day 0/Baseline visits. All BP 
measurements will be made using a sphygmomanometer with an appropriate cuff size for the 
individual subject. Measurements will be taken while the subject is seated after at least 5 minutes 
at rest. 
10.5
Physical Examination 
A complete physical examination (excluding the genitourinary examination) will be performed. 
Weight will be recorded at the Visit 1 (Day 0/Baseline) and Visit 5 (Week 12/Final Visit). Height 
will be measured at Visit 1 (Day 0/Baseline) only. 
10.6
Clinical Laboratory Tests 
Serum chemistry, hematology and urinalysis will be evaluated at the Screening Visit and 
Visit 5 (Week 12/Final Visit). All clinical laboratory tests will be performed at a central 
laboratory. Table 4 presents the specific clinical laboratory tests to be evaluated. 
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Please refer to the manual from the central laboratory for detailed instructions on collecting, 
processing, and shipping of samples. 
Table 4 
Clinical Laboratory Tests – Study FX2016-12 
Hematology 
Urinalysis 
Serum chemistry 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) 
count with differential 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocytes esterase 
pH 
Protein 
Specific gravity 
 
 
Urine pregnancy test performed at the site 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase 
Aspartic acid transaminase (AST) 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Creatinine kinase 
Gamma glutamyl transferase (GGT) 
Globulin 
Glucose 
Phosphorus 
Potassium 
Sodium 
Total bilirubin (if elevated obtain 
direct bilirubin) 
Total protein 
Uric acid 
 
10.6.1 
Urine Pregnancy Test 
A urine pregnancy test will be performed on all females of childbearing potential at the 
Screening Visit, Visit 1 (Day 0/Baseline), Visit 3 (Week 4), Visit 4 (Week 8), and Visit 5 (Week 
12/Final Visit) or when a subject prematurely withdraws from the study. 
10.6.2 
Sample Collection, Storage, and Shipping 
Sample collection kits, requisition slips, and shipping boxes will be supplied by the central 
laboratory. Sample collection procedures and shipping instructions will be detailed in the 
laboratory manual. Study sites must be equipped to store the samples according to the laboratory 
manual procedures before shipping to the central laboratory. 
10.7 
Other Safety Measurements 
10.7.1 
Local Signs and Symptoms Assessments 
The severity of each of the following local signs and symptoms will be measured at Screening, 
Visit 1 (Day 0/Baseline), and at each study visit:  erythema, telangiectasia, burning/stinging, 
flushing/blushing, dryness/xerosis, itching, peeling/desquamation, and hyperpigmentation. The 
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score for signs will be determined by the Investigator and must represent the subject’s condition 
at the time of the evaluation; the score for symptoms (ie, burning/stinging, flushing/blushing) 
should be scored based on the subject’s symptoms reported for the previous 3 days. 
These signs/symptoms should not be included as adverse events, unless a sign/symptom is 
believed to have been related to the study medication or is the reason for discontinuation from 
the study. 
10.7.1.1 
Erythema (Clinical Erythema Assessment Scale) 
Erythema of the face will be graded according to the following scale: 
• 0 = clear skin/no signs of erythema 
• 1 = almost clear of erythema, slight redness 
• 2 = mild erythema, definite redness 
• 3 = moderate erythema, marked redness 
• 4 = severe erythema, fiery redness 
10.7.1.2 
Telangiectasia 
The severity of facial telangiectasia will be graded according to the following scale: 
• 0 = None 
• 1 = Mild:  scattered telangiectasia 
• 2 = Moderate:  numerous telangiectasia 
• 3 = Severe:  dense telangiectasia forming sprays of vessels 
10.7.1.3 
Burning/Stinging 
The severity of facial burning/stinging will be graded according to the following scale: 
• 0 = None:  no warm or burning sensation 
• 1 = Mild:  slight warm tingling/stinging sensation; not really bothersome 
• 2 = Moderate:  constant or intermittent warm tingling/stinging sensation that is somewhat 
bothersome 
• 3 = Severe:  bothersome warm to hot tingling/stinging sensation 
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10.7.1.4 
Flushing/Blushing 
The severity of facial flushing/blushing will be graded according to the following scale: 
• 0 = None 
• 1 = Mild:  sporadic episodes lasting for a few moments to several minutes 
• 2 = Moderate:  intermittent episodes lasting for greater than 30 minutes 
• 3 = Severe:  almost constant episodes lasting for several hours 
10.7.1.5 
Dryness/Xerosis 
The severity of facial dryness/xerosis will be graded according to the following scale: 
• 0 = None 
• 1 = Mild 
• 2 = Moderate 
• 3 = Severe 
10.7.1.6 
Itching 
The severity of facial itching will be graded according to the following scale: 
• 0 = None 
• 1 = Mild:  sporadic itching lasting for a few moments to several minutes 
• 2 = Moderate:  intermittent itching lasting for greater than 30 minutes 
• 3 = Severe:  almost constant, intense itching lasting for several hours 
10.7.1.7 
Peeling/Desquamation 
The severity of facial peeling/desquamation will be graded according to the following scale: 
• 0 = No peeling 
• 1 = Mild:  small, scattered areas of scaling/flaking 
• 2 = Moderate:  larger, contiguous areas of scaling/flaking 
• 3 = Severe:  pronounced flaking/shedding scales covering entire application area 
10.7.1.8 
Hyperpigmentation 
The severity of facial skin hyperpigmentation will be graded according to the following scale: 
• 0 = None 
• 1 = Mild:  few scattered, small areas of light hyperpigmentation 
• 2 = Moderate:  larger or more intense areas of hyperpigmentation 
• 3 = Severe:  intense, extensive hyperpigmentation 
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10.8 
Adverse Events 
10.8.1 
Method of Determining Adverse Events 
Safety assessments will include recording adverse events reported spontaneously by the subject 
or observed by the Investigator. AEs will be recorded at each visit on the appropriate CRF. Every 
attempt should be made to describe the AE in terms of a diagnosis. If a clear diagnosis has been 
made, individual signs and symptoms will not be recorded unless they represent atypical or 
extreme manifestations of the diagnosis, in which case they should be reported as separate 
events. If a clear diagnosis cannot be established, each sign and symptom must be recorded 
separately. 
Subjects should be asked whether, since the time of the last observation or visit, they had any of 
the following: 
• Experienced any changes in well-being 
• Used any new medications 
• Changed medication regimens (both prescription and OTC) 
• Were admitted to a hospital or had any accidents 
• Developed unusual headaches or changes in vision 
With exception to the above, all questions should be of a general nature and should not suggest 
symptoms. 
When an AE is suspected, all relevant evaluations will be performed and appropriate treatment 
provided. Additional follow-up will be done as necessary (Section 10.8.4) and recorded in the 
subject’s source documents, and the results will be provided to the Sponsor. 
For AE definitions and reporting requirements, refer to Section 10.8.2 and Section 10.8.3, 
respectively. 
10.8.2 
Adverse Event Definitions 
10.8.2.1 
Adverse Events 
An AE is any unfavorable or unintended sign, symptom, or disease that appears or worsens in a 
subject after the subject signs the ICF for a clinical study. 
Examples of what may be considered an AE include any of the following: 
• A new illness. 
• An exacerbation of a sign or symptom of an underlying condition or of a concomitant illness 
unrelated to participation in the clinical study or an effect of the study drug or comparator 
drug. 
No causal relationship with the study drug is implied by the use of the term “adverse event.” An 
exacerbation of a pre-existing condition/illness is defined as a more frequent occurrence or as an 
increase in the severity of the pre-existing condition/illness during the study. Planned or elective 
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surgical procedures for pre-existing conditions that have not worsened are not AEs. However, 
any complication that occurs during a planned or elective surgery is an AE (Note:  If the event 
meets the criteria for a serious adverse event [SAE], such as an extended hospitalization, it will 
be considered an SAE). Conditions leading to unplanned surgical procedures may also be AEs. 
10.8.2.2 
Serious Adverse Events 
A serious adverse event (SAE) is any AE that: 
• Results in death. 
• Is life-threatening. 
(Note:  The term “life-threatening” refers to any AE that, as it occurs, puts the subject at 
immediate risk of death. It does not refer to an AE that hypothetically might have caused 
death if it were more severe.) 
• Results in hospitalization or prolongation of current hospitalization (not including 
hospitalization for a pre-existing condition that has not increased in severity or frequency 
from the subject’s underlying medical condition prior to entry into the study). 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect in the offspring of a subject. 
• Is another serious (important medical events) event. 
(Note:  Important medical events may not be immediately life-threatening or result in 
death or hospitalization but may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the subject or require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; blood dyscrasias or convulsions that do not result in inpatient hospitalization; 
or development of drug dependency or drug abuse.) 
SAEs will be reported by the Sponsor to the regulatory authorities as required. 
10.8.2.3 
Severity of Adverse Events 
Severity of an AE refers to the extent to which an AE affects the subject’s daily activities and 
differs from “serious”, which is a regulatory classification. Severity will be categorized 
according to the following criteria: 
• Mild:  The symptom has a negligible effect or no impairing effect on the subject’s normal 
function. 
• Moderate:  The symptom impairs the subject’s normal function to some extent. 
• Severe:  The symptom has an obvious, significantly impairing effect on the subject’s normal 
function. 
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10.8.2.4
Relationship of Adverse Events to Study Treatments 
Causality refers to the relationship of the AE to study drug and will be categorized according to 
the following criteria: 
•
Unlikely:  There is no medical evidence to suggest that the AE may be related to study drug
usage, or there is another more probable medical explanation.
•
Possible:  There is medical evidence to suggest that there is a reasonable possibility that the
AE may be related to study drug usage. However, other medical explanations cannot be
excluded as a possible cause.
•
Probable:  There is strong medical evidence to suggest that the AE is related to study drug
usage.
10.8.2.5
Adverse Events Expectedness 
Expected AEs are defined as those described in the FMX103 IB. If an event increases in intensity 
or severity from that described in the IB, it will be considered unexpected. 
10.8.3
Reporting Adverse Events 
Adverse events that occur from the time of informed consent/assent through completion of the 
last study visit should be reported. Any AE that the Investigator becomes aware of that occurs 
within 30 days of study completion or withdrawal should also be reported. 
Any SAEs occurring in a subject receiving study drug must be reported to the Sponsor or 
designee within 24 hours of the site being informed of the event, even if the event does not 
appear to be drug-related. The report must be done by faxing the completed SAE Report Form to 
the Sponsor or designee. Any pertinent follow-up information should be provided in a similar 
manner. Contact information is provided below: 
10.8.4
Adverse Event Follow-up 
Adverse events that are ongoing when a subject withdraws from or completes the study will be 
followed until resolution or stabilization (in the opinion of the Investigator), or for 30 days, 
whichever is shorter. Investigators and the Sponsor will decide if longer follow-up is appropriate 
on a case-by-case basis. Subjects who experience any clinically significant AE will remain under 
medical supervision until the Investigator or the Sponsor’s medical monitor deems the AE to be 
resolved, stabilized, or no longer serious enough to warrant follow-up. 
Laboratory values that are abnormal and not assessed as AEs may be followed at the discretion 
of the Investigator or the Sponsor’s medical monitor until resolved or stabilized. 
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10.8.4.1 
Pregnancy Reporting 
Prior to study enrollment, females of childbearing potential must be advised of the importance of 
avoiding pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy. The ICF that the subject signs must document this discussion. 
If a subject or Investigator suspects that the subject may be pregnant prior to study drug 
administration, the study drug must be withheld until the results of laboratory pregnancy testing 
are available. If pregnancy is confirmed, the subject must not receive study drug and must not be 
enrolled in the study. 
A urine pregnancy test will be performed on all females of childbearing potential as described in 
Section 10.6.1. 
During the study, all female subjects of childbearing potential should be instructed to contact the 
Investigator immediately if they suspect they might be pregnant (eg, missed or late menstrual 
period). If a subject or Investigator suspects that the subject may be pregnant at any time before 
or during the study, the study drug must be withheld until the results of laboratory pregnancy 
testing are available. The Sponsor and site monitor must be notified and relevant information 
collected on the appropriate form. If pregnancy is confirmed, the subject must be withdrawn 
from the study and the Sponsor and site monitor notified. Additional relevant information about 
the confirmed pregnancy will be recorded on the appropriate form(s); pregnancy will not be 
captured as an AE. 
The subject should be followed until the outcome of the pregnancy is known. 
10.8.5 
Clinically Significantly Abnormal Laboratory Results  
All laboratory values that are outside of the normal range for that parameter will be so flagged 
when reported to the site. The Investigator will determine which out-of-range laboratory test 
results should be characterized as clinically significant and will so annotate the laboratory report. 
If a clinically significant laboratory abnormality requires treatment or is the reason for a subject 
being discontinued from the study, the abnormal result must also be classified as an AE. 
10.9 
Appropriateness of Safety Measurement 
The safety assessments to be utilized in this study are standard safety measures in clinical trials. 
11 
STATISTICAL DESIGN AND ANALYSIS 
11.1 
Statistical Analysis Plan 
A detailed statistical analysis plan (SAP) will be finalized prior to breaking of the study blind. 
Descriptive statistics for qualitative variables (eg, race) will include the number and percentage 
of subjects with the qualitative response. Missing responses will be enumerated, but the 
calculation of percentages will exclude missing responses. For quantitative variables (eg, age), 
descriptive statistics will include the number of subjects with non-missing data, mean, standard 
deviation, median, and minimum and maximum values. All hypothesis testing will be conducted 
using two-sided tests with a 0.05 level of significance. 
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o 
Were greater than 80% compliant with study medication where % compliance is 
defined as: 
% Compliance = 100 x (expected treatment duration in days minus # days a dose was missed) / 
(expected treatment duration in days) 
• Safety Population:  all randomized subjects who use any study product. Subjects who have 
no post-Day 0/Baseline assessments will be included in the Safety population unless all 
dispensed study drug is returned unused. 
The ITT population will be the primary population for efficacy analysis. The PP population will 
be secondary for the co-primary endpoints only. The Safety population will be used for the 
analyses of safety endpoints. 
All efficacy analyses will be conducted according to the randomized treatment assignment; all 
safety analyses will be conducted according to the treatment actually received. 
11.4 
Subject Accounting, Demographics, and Day 0/Baseline Characteristics 
Demographics, Day 0/Baseline characteristics, and prior and concomitant medications will be 
summarized by treatment. Study completion status and reasons for discontinuation will also be 
displayed by treatment. 
Medical and surgical history will only be presented in the listings. 
11.5 
Efficacy Endpoints 
The primary population for all efficacy analyses will be the ITT population. For the analyses of 
the co-primary and secondary efficacy endpoints based on the ITT population, a variety of 
methods will be used to impute missing data, including multiple imputation (MI), last-
observation-carried forward (LOCF), and Day 0/Baseline observation carried forward (BOCF). 
MI will be the primary imputation method. Sensitivity analyses using LOCF and BOCF will be 
performed only on the co-primary efficacy endpoints to assess the robustness of alternate 
imputation assumptions. For the continuous efficacy measure, a mixed effects model for repeated 
measures (MMRM) analysis will also be conducted as a sensitivity analysis. All supportive 
analyses using the PP population will use the Observed-Cases (OC) approach, that is there will 
be no imputation for missing data at any time point. No other imputations will be made unless 
otherwise specified. 
For all efficacy analyses, subjects will be analyzed according to the treatment group to which 
they were randomized. 
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11.5.1 
Primary Efficacy Endpoints 
The co-primary efficacy endpoints are: 
• The absolute change in the inflammatory lesion count at Week 12 compared to Day 
0/Baseline. 
• The dichotomized IGA score where treatment success is defined as at least a 2-step 
improvement resulting in a 0 (clear) or 1 (almost clear) score at Week 12 compared to Day 
0/Baseline. 
The null hypothesis of the equality of the FMX103 1.5% and vehicle means for absolute change 
from Day 0/Baseline to Week 12 in the inflammatory lesion count and the equality of IGA 
success rates at Week 12 will each be tested at a two-sided 0.05 level of significance. Change 
from Day 0/Baseline in inflammatory lesion count will be analyzed using an analysis of 
covariance (ANCOVA), with treatment as a main effect, Day 0/Baseline inflammatory lesion 
count as a covariate, and investigational site as a blocking factor. An investigation site-by-
treatment interaction term will be included in the ANCOVA model to test for homogeneity 
among investigational sites. 
The dichotomized IGA will be analyzed using the Cochran-Mantel-Haenszel (CMH) test, 
stratified by investigational site. For dichotomized IGA, the investigational site-by-treatment 
interaction will be assessed with the Breslow-Day test. Investigational site-by-treatment 
interaction will be tested at a two-sided 0.1 level, and if significant will be further explored 
through the examination of descriptive statistics by individual (non-pooled) investigative sites.  
For analysis purposes, all investigative sites with fewer than 8 randomized subjects will be 
combined into a single pooled site. If a resulting pooled site still has fewer than 10 randomized 
subjects, then this pooled site will be further combined with the smallest unpooled site. This 
pooling process will continue until there are at least 8 randomized subjects in each pooled site. 
11.5.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• The dichotomized IGA score where success is defined as a 2-step improvement in score at 
Week 12 compared to Day 0/Baseline. 
• The percent change in inflammatory lesion count at Week 12 compared to Day 0/Baseline. 
• The absolute change from Day 0/Baseline in the inflammatory lesion count and IGA 
treatment success at the interim visit at Week 8. 
• The absolute change from Day 0/Baseline in the inflammatory lesion count and IGA 
treatment success at the interim visit at Week 4. 
Secondary efficacy endpoints will be treated sequentially in the order listed above, at a 0.05 level 
of significance, only if the co-primary efficacy endpoints are significant. 
11.5.3 
 
 
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(normal), or above the laboratory range (high) at Day 0/Baseline with the number of subjects 
with low, normal, or high values at the Final Visit. Day 0/Baseline is defined as the last non-
missing value prior to the first dose of study drug. 
A listing of subjects with pre-treatment and treatment-emergent clinically significant abnormal 
laboratory values will be presented for each treatment group. Clinical significance is based on 
the Investigator’s judgment. 
11.7 
Interim Analysis 
No interim analysis is planned. 
12 
STUDY MANAGEMENT 
12.1 
Monitoring 
The Investigator will be responsible for preparing and maintaining adequate and accurate source 
documents (medical records, raw data collection forms, etc.) designed to record all observations 
and other pertinent data for each subject treated with the study drug. The Investigator will allow 
representatives of the Sponsor, contract designees, authorized regulatory authority inspectors, 
and the Institutional Review Board (IRB) to have direct access to all documents pertaining to the 
study. The Investigator is to immediately notify the Sponsor of any regulatory authority 
inspections. The Investigator will be informed about the outcome of any Sponsor audit. 
This study will be monitored regularly, by or under supervision of a monitor from the Sponsor. 
The frequency of monitoring visits will be agreed upon by the Sponsor’s representative and the 
study site. 
Monitoring visits will take place on a regular basis according to the enrollment rate and number 
of subjects enrolled at each investigational site. During these visits, the monitor will check the 
completion of the CRF entries, compliance with the study protocol and with GCP-ICH, and their 
agreement with the source data. The monitor will also verify the correct use of the study drug. At 
a final visit, the monitor will check all remaining material including the remaining quantities of 
the study drug and will organize their return to the Sponsor or designee. At each visit, the 
Investigator and staff will be expected to cooperate with the Sponsor’s representative(s) for the 
purposes of review and verification of protocol compliance, AE reporting, CRFs, source 
documents, clinical supplies and inventory records, and any additional records as may have been 
previously arranged between the Investigator and the Sponsor’s representative(s). 
The Investigator and/or other designated study personnel are expected to contact the Sponsor’s 
clinical research associate, as needed, regarding study concerns and/or questions. Contact 
information is provided in the Study Reference Manual for the site. 
12.2 
Protocol Amendments 
The Sponsor may propose to amend this protocol at any time. 
No change to the protocol will be implemented until the Sponsor and the IRB have reviewed and 
approved the amendment. 
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12.3 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the IRB-approved protocol 
(intentional or unintentional). All deviations are to be documented at the site and reported to the 
IRB according to the IRB’s guidelines. 
In the event of an emergency, the Investigator shall implement any medical procedures deemed 
appropriate for subject safety. All such procedures must have written documentation and be 
promptly reported to the Sponsor and IRB. 
12.4 
Withdrawal of Subjects 
Withdrawn subjects are those who do not complete all evaluations and procedures outlined in the 
protocol. Subjects who discontinue taking study drug for any reason must also be withdrawn 
from the study. Subjects may be withdrawn from the study because of any of the following: 
• Adverse Event:  An AE that, in the opinion of the Investigator or Sponsor, suggests that 
continued participation in the study is not in the subject’s best interest for safety reasons. All 
AEs that are present when the subject withdraws from the study will be followed as 
described in Section 10.8.4. 
• Abnormal Laboratory Result:  Any clinically significant laboratory abnormality that 
requires withdrawal of the subject from the study should be considered an AE leading to 
withdrawal. If possible, laboratory tests will be repeated for any results that were clinically 
significantly abnormal until the abnormality is resolved or stabilized to the satisfaction of the 
Investigator in consultation with the medical monitor. 
• Lost to Follow-up:  Confirmed at minimum by two phone calls and a traceable letter without 
answer. 
• Subject Request:  Subject requests, for any reason (eg, AE), to be withdrawn or withdraws 
his/her consent. 
• Protocol Deviation:  A subject may be withdrawn from the study at the discretion of the 
Investigator or Sponsor due to poor compliance with protocol requirements that may 
compromise the study results or subject safety. 
• Other:  Other reasons include but are not limited to, Investigator decision that it is in the 
subject’s best interest to be withdrawn, administrative reasons, relocation of subject, etc. If a 
subject becomes pregnant during the study, the subject will be withdrawn from the study and 
followed through conclusion of the pregnancy. 
If a subject is withdrawn from the study following the start of study drug, all Visit 5 
(Week 12/Final Visit) assessments should be completed. Subjects withdrawn from the study will 
not be replaced. 
12.5 
Termination of the Study 
The study may be terminated at any time at the request of the Sponsor or a regulatory authority, 
with proper and timely notification of all parties concerned. The IRB will be informed promptly 
and the Sponsor or the Investigator will supply reason(s) for the termination or suspension, as 
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specified by the applicable regulatory requirements. Otherwise, the study is considered 
terminated upon completion of all subject treatments and evaluations. 
12.6 
Publication Policy 
The data obtained in this study are the property of the Sponsor, which will make reasonable 
efforts to assure that the results are published in a peer-reviewed journal. As some of the 
information concerning the investigational product and development activities at the Sponsor 
may be of a strictly confidential nature, any manuscript or other presentation of data must first be 
reviewed by the Sponsor before its submission. 
13 
ETHICS 
13.1 
Conduct of the Study 
This study will be conducted in accordance with the ICH Harmonized Tripartite Guideline for 
GCP, 1997; the US Title 21 CFR parts 50, 56, and 312; and the ethical principles that have their 
origin in the Declaration of Helsinki. The study will not begin until all of the requirements of the 
appropriate regulatory authorities have been fulfilled. 
13.2 
Institutional Review Boards (IRB) 
This protocol (and any changes), all consent forms, and subject consent procedures must be 
reviewed and approved by a properly constituted IRB. The information presented to the IRB at 
the time initial approval is sought must include any plans for subject recruitment that involve 
advertising or other direct contact with potential subjects outside of the physician-subject 
relationship. A letter of approval issued by the IRB must be sent to the Sponsor prior to initiation 
of the study. Any changes made to the protocol must be approved by the IRB prior to 
implementation, except where needed to eliminate a potential imminent safety hazard to the 
subjects. In this case, immediate implementation may take place followed by IRB approval. 
Review and approval by the IRB for continuation of the study must take place at least once a 
year. 
13.3 
Written Informed Consent 
The Investigator or designee will explain the nature of the study, its purpose and associated 
procedures, the expected duration, and the potential benefits and risks of participation to each 
subject prior to his/her entry into the study (ie, before examinations and procedures associated 
with selection for the study are initiated). Each subject will have ample opportunity to ask 
questions and will be informed about the right to withdraw from the study at any time without 
any disadvantage and without having to provide reasons for this decision. 
Following this informative discussion, the subject will be asked if he/she is willing to sign a 
statement of informed consent. Only subjects who voluntarily sign the ICF may enter the study. 
The ICF must be reviewed and approved by the Sponsor and the IRB prior to their use. 
The original signed ICF will remain in the Investigator’s files. The Investigator or designee will 
indicate in each subject’s source documents that he/she has informed the subject about the study 
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and its procedures, the subject has signed and dated the ICF, and the subject has been given a 
copy of the documents. The Investigator or designee will inform subjects of any new information 
that may be relevant to the subject’s willingness to continue in the study. 
13.4 
Subject Confidentiality 
The Sponsor ensures that the following have permission to review all study-related documents:  
monitor, auditor, IRB, and regulatory authorities. The subject’s identity and study-related records 
will remain confidential throughout the duration of the study data collection and reporting 
process. 
The investigative site assigns a unique subject identification code to each potential study subject. 
The identification code protects the subject’s identity and is used in lieu of the subject’s name 
when reporting subject data. The data will always maintain the confidentiality of the subject. 
The Investigator or designee will review the subject data, which will be referenced using the 
subject identifier. At the conclusion of the study, the data obtained may be presented to regional 
regulatory authorities but the subject’s identity will not be revealed. In addition, if any clinical 
data obtained from the study is published in scientific journals or presented at scientific meetings 
the subject’s identity will not be revealed. 
13.5 
Records Retention 
The Investigator must maintain essential study documents (protocol and amendments, source 
documentation corresponding to all information contained in the CRFs, signed ICF and assent 
forms, relevant correspondence, and all other supporting documentation) until at least 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region, or at least 2 years after the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period if required by the applicable regulatory requirements or the 
hospital, institution, or private practice in which the study is being conducted. Subject 
identification codes (subject names and corresponding study numbers) will be retained for this 
same time period. Custody of the records may be transferred to another responsible party, 
acceptable to the Sponsor, who agrees to abide by the retention policies. Written notice of 
transfer must be submitted to the Sponsor. The Investigator must contact the Sponsor prior to 
disposing of any study records. 
13.6 
Financing 
Funding for this study will be agreed between the Investigator and the Sponsor and will be 
confirmed in writing before the study starts. 
Completion of Financial Disclosure Forms will be required before the study starts. Any additions 
to the primary site personnel will necessitate the completion of new Financial Disclosure Forms. 
This information will also be collected at site closure and 1 year after the completion of the 
study. 
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14 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor and Investigator will take all steps possible to ensure the accuracy, consistency, 
completeness, and reliability of the data, including participating in an Investigator meeting 
and/or site initiation visit, routine site monitoring, review of CRFs against source documents, and 
quality control checks. 
In addition, a representative from the Sponsor’s Clinical Quality Assurance (CQA) Department 
may conduct periodic audits of the study processes, including, but not limited to, auditing the 
clinical site, laboratories, vendors and CROs, the clinical database, and the final study report. 
15 
DATA HANDLING AND RECORD KEEPING 
This study will use web-based, electronic case report forms (eCRFs) developed through a 
validated, Electronic Records/Electronic Signatures-compliant platform (US Title 21 CFR 
Part 11). Foamix Clinical Data Management department or designee will create the eCRFs and 
corresponding clinical database based on the final protocol. 
All site personnel who will be using this system will receive formal training on the system, after 
which each person will be issued a unique username and password. Only the person who owns 
the username and password will enter the system using that username and password. For data 
security reasons and to be in compliance with regulatory guidelines, usernames and passwords 
are not transferable. 
The Investigator is responsible for all data entered via the remote data capture (RDC) system 
eCRFs and must confirm the accuracy of the data by electronically approving (signing) the 
eCRFs. This responsibility includes the timely completion and accuracy of the data entered into 
the eCRFs by their site personnel as well as the review and approval of some data entered 
directly into the database (eg, clinical laboratory results) by an external vendor. The Sponsor will 
review the database to identify data errors or inconsistencies, which will be posted in the RDC 
system as queries for resolution. In addition, the Sponsor may make obvious corrections to the 
data in the database (eg, obvious errors in dates) and so inform the Investigator without issuing a 
query to the site. 
16 
REFERENCE LIST 
Not applicable. 
17 
STUDY AMENDMENTS 
This section describes the amendment(s) that have been made to the protocol for Study 
FX2016-12. 
Section 17.1 describes the changes made to Protocol FX2016-12 Version 1 issued January 20, 
2017, via Amendment 1 effective March 6th, 2017. 
Section 17.2 describes the changes made to Protocol FX2016-12 Version 2 issued March 6th, 
2017, via Amendment 2 effective May 12th, 2017. 
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17.1 
Amendment 1, effective March 6th, 2017 
The following is the summary of the changes that were made to Protocol FX2016-12 Version 1 
issued January 20, 2017. 
Content changes:  
New or changed text is bolded. 
Section(s) 
Revision 
Rationale 
Old Text 
New Text 
Synopsis (Study 
Centers); Sect. 6 
Study Population 
…approximately 30 
sites…  
…approximately 40 sites… 
Number of study 
centers adjusted to 
account for larger study 
sample size. 
Sect. 11.2 
Determination of 
Sample Size; Table 
5 Sample Size 
Calculations Based 
on IGA Scores 
after 
 of 
Treatment in Phase 
2 Study FX2015-
10 and text  
 
…
... 
…
... 
Typographic error. 
Sect. 11.2 
Determination of 
Sample Size; Table 
5 and text  
 
New text inserted in Table 
5. 
Vehicle IGA (Score 0,1): 
; FMX103 1.5% IGA 
(Score 0,1): 
; 
Sample Size (Vehicle, 
Active): 
 
Study sample size 
calculation based on an 
assumed 
 reduction 
in effect difference 
between active and 
vehicle, relative to 
Study FX2015-10 
FMX103 1.5% IGA 
(Score 0,1) v’s Vehicle 
IGA (Score 0,1) 
observed difference. 
As above. 
Assuming a 
 dropout 
rate, 
 subjects 
receiving FMX103 and 
 subjects… 
Assuming a 
 dropout 
rate, 
 subjects receiving 
FMX103 and 
 
subjects… 
Corrected for larger 
study sample size. 
As above. 
Therefore, the sample size 
needed to provide 90% 
power for both co-primary 
endpoints is 
 and 
 
subjects… 
Therefore, the sample size 
needed to provide at least 
90% power for both co-
primary endpoints is 
 
and 
 subjects… 
Corrected for larger 
study sample size. 
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Section(s) 
Revision 
Rationale 
Old Text 
New Text 
Synopsis 
(Statistical 
Methods); Sect. 
11.5.1 Primary 
Efficacy Endpoints 
…treatment success is 
defined as a 2-step 
improvement… 
…treatment success is 
defined as at least a 2-step 
improvement… 
Clarification of 
treatment success 
criteria. 
Synopsis (Number 
of Subjects 
(planned); Sect. 6 
Study Population 
…approximately 450 
subjects… 
…approximately 600 
subjects… 
Corrected for larger 
study sample size. 
Sect. 7.2 Visit 1, 
Day 0/Baseline 
Visit 
New text. 
Dispense facial cleanser 
and moisturizer. 
Clarification of the 
need to dispense 
cleanser and 
moisturizer at Day 
0/Baseline. 
Sect. 7.4 
• Confirm that subject 
continues to use only 
the provided facial 
cleanser. 
• 
Confirm that subject 
continues to use only 
the provided facial 
cleanser and 
moisturizer. 
Reflecting the addition 
of moisturizer. 
Sect. 7.5 and 7.6 
• Confirm that subject 
continues to use only 
the provided facial 
cleanser. 
• 
Confirm that subject 
continues to use only 
the provided facial 
cleanser and 
moisturizer and 
dispense additional 
quantities as required. 
Clarification of cleanser 
and moisturizer re-
supply to subjects. 
Sect. 8.7 
Prior/Concomitant 
Therapy 
• Subjects should use 
the facial cleanser 
Cetaphil Gentle Skin 
Cleanser (which will 
be provided by the 
Sponsor). An 
alternative, non-
medicated cleanser 
may be used if agreed 
to by the Sponsor. 
• 
As necessary, subjects 
should use the facial 
cleanser Cetaphil 
Gentle Skin Cleanser 
and the facial 
moisturizer Eucerin 
Daily Protection Broad 
Spectrum SPF30 Face 
Lotion. Both products 
will be provided by 
the Sponsor. 
Alternative non-
medicated cleansers 
or moisturizers may 
be used if agreed to by 
the Sponsor. 
Addition of a SPF-
containing moisturizer 
to support a positive 
skin care regimen 
during the study. 
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Section(s) 
Revision 
Rationale 
Old Text 
New Text 
Synopsis, 
Endpoints and 
Outcomes;   
The efficacy parameters 
will include inflammatory 
lesion counts, IGA at Day 
0/Baseline and at Weeks 
4, 8, and 12 (Final Visit), 
and the subject global 
assessment and 
satisfaction questionnaire 
at the Final Visit. 
The co-primary efficacy 
parameters, include 
inflammatory lesion counts 
and IGA, will be evaluated 
at Day 0/Baseline and at 
Weeks 4, 8, and 12 (Final 
Visit). The Subject Global 
Assessment will be 
performed at Weeks 2, 4, 8, 
and 12 (Final Visit). The 
subject satisfaction 
questionnaire will be 
assessed at Week 12 (Final 
Visit) only. 
Addition of more 
frequent subject global 
assessments to be 
conducted at each post-
Day 0/Baseline visit. 
Table 1 Schedule 
of Study 
Assessments and 
Procedures – Study 
FX2016-12: 
Subject Global 
Assessment 
Subject Global 
Assessment at Week 12 
(Final Visit) only. 
Additional Subject Global 
Assessments added at 
Weeks 2, 4, and 8. 
Addition of more 
frequent subject global 
assessments to be 
conducted at each post-
Day 0/Baseline visit. 
Sect. 7.4; 7.5 and 
7.6 
New text. 
Have the subject complete 
the Subject Global 
Assessment (Section 9.2.3) 
As above. 
Sect. 9.2.3 
This score will be 
obtained from the subject 
at Visit 7 (Week 12/Final 
Visit) using the 
questionnaire in Appendix 
1. 
This score will be 
obtained from the subject 
at Visit 2 (Week 2), Visit 3 
(Week 4), Visit 4 (Week 
8), and Visit 5 (Week 
12/Final Visit) using the 
questionnaire in Appendix 
1. 
As above. 
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Section(s) 
Revision 
Rationale 
Old Text 
New Text 
Sect. 6.2 Exclusion 
Criteria 23 
Screening 
electrocardiogram (ECG) 
that reveals a QTcF >500 
msec. 
Text removed. 
A review of Solodyn® 
product labelling and 
an assessment of the 
safety and 
pharmacokinetics of 
minocycline when 
topically applied as 
FMX101 (4% 
minocycline HCl foam) 
to moderate-to-severe 
acne vulgaris subjects 
under maximum use 
conditions (4g per day 
for 21 days) warrants 
the removal of  ECG 
assessments at Day 
0/Baseline as it has 
been determined by the 
Sponsor as being an 
unnecessary procedure. 
Table 1 Schedule 
of Study 
Assessments and 
Procedures – Study 
FX2016-12 
Electrocardiogram 
Text removed. 
As above. 
Sect. 7.1 Screening 
Visit 
Perform 12-lead ECG 
(Section 10.7.1) 
Text removed. 
As above. 
Sect. 10.7.1 
Electrocardiograms 
A standard 12-lead ECG 
will be performed at 
Screening only. Subjects 
will be supine and at rest 
for at least 10 minutes 
before measurement. 
Subjects will have their 
participation discontinued 
if an ECG reveals a 
QTcF>500msec (see 
Exclusion Criterion 23). 
Text removed. 
As above. 
Global change 
Visit schedule has been 
adjusted from Visit 1 (Day 
0/Baseline); Visit 2 (Week 
1); Visit 3 (Week 4); Visit 
4 (Week 6); Visit 5 (Week 
8); Visit 6 (Week 10) and 
Visit 7 (Week 12/Final 
Visit) 
New schedule is Visit 1 
(Day 0/Baseline); Early 
Follow-up (Week 1); Visit 
2 (Week 2); Visit 3 (Week 
4); Visit 4 (Week 8) and 
Visit 5 (Week 12/Final 
Visit) 
To remove unnecessary 
study visits. 
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Section(s) 
Revision 
Rationale 
Old Text 
New Text 
Sect. 7.3 Early 
Follow-up, Week 1 
(±3 Days) 
New text. 
7.3 Early Follow-up, 
Week 1 (±3 Days) 
An early follow-up 
telephone call will be 
made 1 week after Visit 1, 
Day 0/Baseline. 
Record concomitant 
medications (Section 8.7). 
Record Aes (Section 10.8). 
Confirm that subject 
continues to use only the 
provided facial cleanser 
and moisturizer. 
Review application 
instructions to confirm 
that the subject continues 
to use the study drug as 
directed. 
Schedule/confirm the next 
study visit and remind 
subject to avoid 
overexposure to sunlight 
and to use the same make-
up brand/type, or 
frequency of use, 
throughout the study as 
applicable. 
To support early 
contact with subjects to 
address outstanding 
questions and reinforce 
study instructions. 
Sect. 7.7 Visit 5, 
Week 12 (-3/+5 
days) / Final Visit 
or Early 
Termination 
Schedule/confirm a safety 
follow-up telephone call 4 
weeks from Visit 7/Week 
12 (Final Visit) date (±5 
days) for subjects that will 
not participate in study 
FX2015-13 (Open label 
study) (Section 7.9). 
Schedule/confirm a safety 
follow-up telephone call 4 
weeks from Visit 5/Week 
12 (Final Visit) date (±5 
days) only for subjects that 
will not participate in study 
FX2015-13 (Open label 
study) (Section 7.9) and 
presented with either new 
or on-going adverse 
events at Visit 5/Week 12 
(Final Visit). 
Clarification of Safety 
Follow telephone call 
requirements. 
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Section(s) 
Revision 
Rationale 
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New Text 
Sect. 7.8 Safety 
Follow-Up ((±5 
days) 
A safety follow-up 
telephone call will be 
made 4 weeks after Visit 
7/Week 12 (Final Visit) 
for only those subjects 
that do not participate in 
study FX2015-13 (Open 
label study). Follow up on 
existing and any new 
concomitant medications 
and adverse events will be 
recorded. 
A safety follow-up 
telephone call will be made 
4 weeks after Visit 5/Week 
12 (Final Visit) for only 
those subjects that do not 
participate in study 
FX2015-13 (Open label 
study) and presented with 
either new or on-going 
adverse events at Visit 
5/Week 12 (Final Visit). 
Follow up on these adverse 
events and any new 
concomitant medications 
will be recorded. 
Clarification of AE 
reporting requirements. 
Synopsis, 
Diagnosis and 
Main Criteria for 
Inclusion 
At least 12 and not more 
than 50 inflammatory 
facial lesions (ie, 
papules/pustules),… 
At least 15 and not more 
than 75 inflammatory facial 
lesions (ie, 
papules/pustules),… 
Change inflammatory 
lesion count range in 
the inclusion criteria 
from 12-50 to 15-75. 
Sect. 6.1 Inclusion 
Criteria 
a. At least 12 and not 
more than 50 facial 
papules and pustules… 
a. At least 15 and not more 
than 75 facial papules and 
pustules… 
As above. 
Table 2 Study 
Drug Kits and 
Treatments – 
Study FX2016-12 
Additional kits of 
2 canisters may be 
dispensed at other visits if 
required. 
Text removed. 
Redundant text due to 
change in visit schedule 
Sect. 8.1.1 Dosing 
Instructions 
Additional kits will be 
available for dispensing at 
other visits (ie, Visits 4 
and 6) to ensure enough 
product is available for 
daily dosing. 
Text removed. 
As above. 
Sect. 12.2 Protocol 
Amendments 
In the event of an 
emergency, the 
Investigator shall 
implement any medical 
procedures deemed 
appropriate for subject 
safety. All such 
procedures must have 
written documentation and 
be promptly reported to 
the Sponsor 
Text removed. 
Misplaced text / 
repetition. 
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Section(s) 
Revision 
Rationale 
Old Text 
New Text 
Appendix 3 
New text. 
Addition of investigator 
acknowledgement of 
protocol review and receipt. 
Investigator 
confirmation of review 
and receipt of study 
protocol. 
17.2 
Amendment 2, effective May 12th, 2017 
The following is the summary of the changes that were made to Protocol FX2016-12 Version 2 
issued March 06, 2017. 
Content changes:  
New or changed text is bolded. 
Section(s) 
Revision 
Rationale 
Old Text 
New Text 
Synopsis, Sect. 5.1 
Overall Study 
Design 
Subjects will be assigned 
to 1 of 2 treatments 
according to the 
randomization schedule. 
Subjects will be assigned to 
1 of 2 treatments according 
to the randomization 
schedule, stratified by 
investigational site. 
Addition of clarifying 
text. 
Synopsis, Number 
of Subjects 
(planned), Sect. 6 
Study Population 
…approximately 600… 
…approximately 750… 
Adjustment in relation 
to a new sample size 
calculation. 
Sect. 6.1 Inclusion 
Criteria 
Subjects were included in 
the study if they met… 
Subjects can be included in 
the study if they meet all… 
Typographical error. 
Sect. 6.2 Exclusion 
Criteria 
Subjects were excluded 
from enrollment… 
Subjects should be 
excluded from enrollment 
As above. 
Sect. 6.2 Exclusion 
Criterion 4 
An active nodule on the 
face >5 mm in diameter. 
Text removed. 
Exclusion criterion 
inconsistent with IGA 
grade 4 inclusion 
criterion. 
Sect. 7 Study 
Procedures 
… Exclusion Criteria 11 
and 12, they must first 
enter…as specified in 
Exclusion Criteria 11 
and 12, respectively)… 
…Exclusion Criteria 10 
and 11, they must first 
enter…as specified in 
Exclusion Criteria 10 and 
11, respectively)… 
Reference changed due 
to renumbering of 
exclusion criteria due to 
the above omission. 
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Section(s) 
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Rationale 
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New Text 
Sect. 7 Study 
Procedures 
…they must first enter a 
washout period (ie,1 
month or 2 weeks, as 
specified in Exclusion 
Criteria 10 and 11, 
respectively) before 
beginning the screening 
procedures.   
…they must first enter a 
washout period (ie,1 month 
or 2 weeks, as specified in 
Exclusion Criteria 10 and 
11, respectively) during 
the screening period.  
Screening procedures are 
to be performed as 
defined in the schedule of 
events Table 1. 
Clarification that prior 
medication wash-out 
can occur during the 
screening period. 
Table 1 Schedule 
of Study 
Assessments and 
Procedures, Sect. 
7.4 Visit 2, Week 2 
(±3 Days), Sect. 
8.1.1 Dosing 
Instructions 
Procedure to dispense 
study drug at Visit 2. 
Procedure removed.  
Unnecessary dispensing 
occasion. 
Synopsis, Study 
Duration, Sect. 7.7, 
Sect. 7.8, Table 1f 
…FX2015-13… 
…FX2016-13… 
Incorrect study 
reference. 
Table 2 
…25 g… 
…35 g… 
Correction of canister 
content weight. 
Table 2 
Once daily application of 
a sufficient amount of 
foam to cover the 
involved area. 
Once daily application of a 
sufficient amount of foam 
to cover the entire face. 
Adjustment of 
application instructions 
to align with that 
conducted during Phase 
2 study (FX2015-10). 
Sect. 8.1.1 Dosing 
Instructions 
…over all involved areas 
of the face. Additional 
drug may be used as 
needed to assure the entire 
involved area… 
…over all areas of the 
face. Additional drug may 
be used as needed to ensure 
the entire face is treated… 
As above. 
Sect. 5.1 Overall 
Study Design, 
Sect. 8.1.1 Dosing 
Instructions 
Study drug should be 
applied at approximately 
the same time each day, 
preferably in the evening 
about 1 hour before 
bedtime. 
Study drug should be 
applied at approximately 
the same time each day, 
about 1 hour before 
bedtime. 
Removal of evening 
application preference 
to reflect subjects with 
different sleep patterns 
e.g. shift workers.
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New Text 
Sect. 11.2 
Determination of 
Sample Size and 
Table 5 Sample 
Size Calculations 
Based on IGA 
Scores after 
 
 of 
Treatment in Phase 
2 Study FX2015-
10 
N/A. 
Simplification of Table 5 
and inclusion of new 
sample size calculations. 
Sponsor has elected to 
increase the sample size 
based on additional 
scenarios covering the 
Phase 2 study data 
(FX2015-10). 
Sect. 9.3 
Photography 
New text. 
Photography will be 
performed at selected 
study centers only. Study 
centers should refer to 
their specific Clinical 
Trial Agreement to 
confirm participation. 
Clarification that not all 
study centers will 
participate in subject 
photography. 
Table 1 Schedule 
of Study 
Assessments and 
Procedures 
New table footer 
† only for study centers 
participating in subject 
photography (Section 9.3). 
As above. 
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New Text 
Sect. 11.3 Analysis 
Populations 
Subjects may be excluded 
from the PP population if 
any of the following are 
met: 
Failure to meet 
inclusion/exclusion 
criteria 
Have administered any 
interfering concomitant 
medications 
Have not, in the opinion 
of the Investigator, been 
compliant with the 
treatment regimen (eg, 
reported frequent missed 
doses) 
Randomization error 
Prior to breaking the 
blind, additional criteria 
for exclusion from the PP 
population may be 
included to accommodate 
for unforeseen events that 
occurred during the 
conduct of the study. 
Subjects may be included 
in the PP population if all 
of the following are met: 
Have met all 
inclusion/exclusion 
criteria 
Have not administered 
any interfering 
concomitant medications 
Were not subject to a 
randomization error 
Completed treatment 
through Week 12 
Were greater than 80% 
compliant with study 
medication where % 
compliance is defined as: 
% Compliance = 100 x 
(expected treatment 
duration in days minus # 
days a dose was missed) / 
(expected treatment 
duration in days) 
Request by FDA to 
clarify the Per Protocol 
population. 
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Sect. 11.5.1 
Primary Efficacy 
Endpoints 
The dichotomized IGA 
will be analyzed using the 
Cochran-Mantel-Haenszel 
(CMH) test, stratified by 
investigational site. 
An investigation site-by-
treatment interaction 
term will be included in 
the ANCOVA model to 
test for homogeneity 
among investigational 
sites. 
The dichotomized IGA will 
be analyzed using the 
Cochran-Mantel-Haenszel 
(CMH) test, stratified by 
investigational site. For 
dichotomized IGA, the 
investigational site-by-
treatment interaction will 
be assessed with the 
Breslow-Day test. 
Investigational site-by-
treatment interaction will 
be tested at a two-sided 
0.1 level, and if significant 
will be further explored 
through the examination 
of descriptive statistics by 
individual (non-pooled) 
investigative sites.  
For analysis purposes, all 
investigative sites with 
fewer than 8 randomized 
subjects will be combined 
into a single pooled site. If 
a resulting pooled site still 
has fewer than 10 
randomized subjects, then 
this pooled site will be 
further combined with the 
smallest unpooled site. 
This pooling process will 
continue until there are at 
least 8 randomized 
subjects in each pooled 
site. 
Request by FDA to 
clarify the statistical 
approach for pooled 
site and site interaction 
analysis. 
 
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APPENDIX 1:  Subject Global Assessment Questionnaire 
Question:  “Considering your rosacea just before starting treatment and considering your 
condition today, indicate the change you have experienced according to the scale below”: 
 
• 5 = Much better than prior to treatment 
• 4 = Slightly better than prior to treatment 
• 3 = Same as prior to treatment 
• 2 = Slightly worse than prior to treatment 
• 1 = Much worse than prior to treatment 
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APPENDIX 2:  Subject Satisfaction Questionnaire 
The following 8 questions will be asked of the subject at Visit 5 (Week 12 / Final Visit): 
 
1. How satisfied are you with this product in treating your rosacea? 
2. How satisfied are you with how easy this product is to use? 
3. How satisfied are you with this product compared to other products you have previously 
used for rosacea, such as gels and creams? 
4. How satisfied are you with how this product feels on your skin after treatment? 
5. How satisfied are you with the odor of this product after treatment? 
6. How satisfied are you with the color of this product after treatment? 
7. Overall, how satisfied are you with this product? 
8. Overall, how likely are you to recommend this product to a friend? 
 
Answers to Questions 1 through 7 will be selected from the following: 
• 1 = Very Satisfied 
• 2 = Satisfied 
• 3 = Somewhat Satisfied 
• 4 = Dissatisfied 
• 5 = Very Dissatisfied 
 
The answer to Question 8 will be selected from the following: 
• 1 = Very Likely 
• 2 = Likely 
• 3 = Somewhat Likely 
• 4 = Unlikely 
• 5 = Very Unlikely 
 
 
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APPENDIX 3: Acknowledgment Of Receipt And Review Of 
Protocol 
 
 
Protocol Number: FX2016-12, Version 3 
 
Protocol Title: A Randomized, Multicenter, Double-blind, Vehicle-controlled Study to Evaluate 
the Safety and Efficacy of FMX103 1.5% Topical Minocycline Foam Compared to Vehicle in 
the Treatment of Facial Papulopustular Rosacea (FX2016-12) 
 
 
I hereby acknowledge receipt and review of the following Protocol: 
 
 
1. Version 3, dated May 12th, 2017 
 
 
 
 
 
 
Principal Investigator Name (Print) 
 
 
 
 
 
Principal Investigator Signature 
Date of Signature  
 
(DD MMM YYYY) 
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Date:  06 Mar 2017 
CLINICAL PROTOCOL 
Title Page 
Study Title: 
A Randomized, Multicenter, Double-blind, Vehicle-
controlled Study to Evaluate the Safety and Efficacy of 
FMX103 1.5% Topical Minocycline Foam Compared to 
Vehicle in the Treatment of Facial Papulopustular Rosacea 
(FX2016-12) 
Sponsor: 
Foamix Pharmaceuticals, Inc. 
520 US Highway 22, Suite 305 
Bridgewater, NJ  08807 
Protocol Identification: 
FX2016-12 
Product: 
FMX103 1.5% minocycline foam 
Indication Studied: 
Papulopustular Rosacea 
Study Phase: 
3 
Sponsor’s Signatory: 
 
GCP Statement: 
This study will be conducted in accordance with Good 
Clinical Practice. Essential documents will be archived 
according to CPMP/ICH/135/95 
Date of Protocol: 
06 Mar 2017 
Version of Protocol: 
Version 2 (Amendment 1) 
Supercedes: 
Version 1, issued 20 Jan 2017 
Prepared by: 
The Write Company, LLC 
 
 
Confidentiality Statement 
This document is the property of Foamix Pharmaceuticals, Inc., and is confidential and proprietary.  The information 
contained herein is believed to be accurate and complete as of the date of preparation.  The contents may not be used, 
divulged, published or otherwise disclosed without the expressed consent of Foamix Pharmaceuticals, Inc. 
 
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Synopsis 
Name of 
Sponsor/Company: 
Foamix Pharmaceuticals, 
Inc. 
Individual Study Table Referring to 
Part of the Dossier: 
(For National Authority 
Use Only) 
Name of Finished Product: 
FMX103 
Volume: 
Name of Active 
Ingredient: 
Minocycline hydrochloride 
Page: 
Title of Study: 
A Randomized, Multicenter, Double-blind, Vehicle-controlled Study to 
Evaluate the Safety and Efficacy of FMX103 1.5% Topical 
Minocycline Foam Compared to Vehicle in the Treatment of Facial 
Papulopustular Rosacea (Study FX2016-12) 
Protocol No: 
FX2016-12 
Study Centers: 
Multicenter (approximately 40 sites in the USA) 
Publication (reference): 
None 
Phase of Development: 
3 
Objectives: 
Primary Objectives: 
• 
To determine the efficacy of FMX103 1.5% minocycline foam 
applied topically once daily for 12 weeks in the treatment of 
rosacea. 
• 
To evaluate the safety of topical minocycline foam applied 
once daily for 12 weeks. 
Study Design and 
Methods: 
This is a randomized, multicenter, double-blind, vehicle-controlled, 
2-arm study to evaluate the safety and efficacy of FMX103 topical 
foam containing 1.5% minocycline compared to vehicle, in the 
treatment of subjects with moderate-to-severe facial papulopustular 
rosacea. Qualified subjects will be randomized in a 2:1 ratio 
(active:vehicle) to receive 1 of the following 2 treatments: 
• 
FMX103 minocycline foam 1.5% 
• 
Vehicle foam 
Subjects will be assigned to 1 of 2 treatments according to the 
randomization schedule. Subjects will apply (or have applied) the study 
drug topically once daily for 12 weeks as directed. Subjects will be 
advised to use the study drug at approximately the same time each day. 
Both the Investigator and subject will be blinded to the study drug 
identity. 
Subjects will return for visits at Weeks 2, 4, 8, and 12. Efficacy 
evaluations (inflammatory lesion counts and Investigator’s Global 
Assessment [IGA] score) will be performed at Weeks 4, 8, and 12 
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during the study. 
Number of Subjects 
(planned): 
The planned enrollment is approximately 600 male and female subjects. 
Subjects will be randomly assigned to the two treatment groups, 
FMX103 1.5% and vehicle, in a 2:1 ratio, respectively. 
Diagnosis and Main 
Criteria for Inclusion: 
Healthy male or non-pregnant females, aged ≥18 years with a clinical 
diagnosis of moderate to severe facial papulopustular rosacea, defined 
as the presence of: 
• 
At least 15 and not more than 75 inflammatory facial lesions 
(ie, papules/pustules), and 
• 
An IGA of rosacea severity of moderate or severe using the 
following scale: 
Score 
Grade 
Description 
0 
Clear 
No inflammatory papules or pustules 
1 
Almost clear 
Few inflammatory papules or pustules 
2 
Mild 
Several inflammatory papules or pustules 
3 
Moderate 
Moderate number of inflammatory papules or 
pustules and no nodules 
4 
Severe 
Many inflammatory papules or pustules, and up to 
2 nodules 
• 
Current or history of erythema and/or flushing 
Subjects must be willing to minimize external factors that might trigger 
rosacea flare-ups (eg, spicy foods, thermally hot foods and drinks, hot 
environments, prolonged sun exposure, strong winds, and alcoholic 
beverages). 
Test Product, Dose and 
Mode of Administration: 
FMX103 minocycline foam 1.5%. Topical application, once daily to 
the face, for 12 weeks. 
Reference Therapy: 
Vehicle foam. Topical application, once daily to the face, for 12 weeks. 
Study Duration: 
Subject participation in the study will be up to 18 weeks:  up to 6 weeks 
for Screening and Day 0/Baseline, and 12 weeks of study treatment. A 
safety follow-up telephone call will be conducted 4 weeks after 
completion of study treatment for only those subjects that do not 
participate in study FX2015-13 (Open label study) and who presented 
with either new or on-going adverse events at Visit 5/Week 12 (Final 
Visit). 
Endpoints and Outcomes: 
 
 
 
 
Efficacy Evaluations 
The co-primary efficacy parameters, include inflammatory lesion 
counts and IGA, will be evaluated at Day 0/Baseline and at Weeks 4, 8, 
and 12 (Final Visit). The Subject Global Assessment will be performed 
at Weeks 2, 4, 8, and 12 (Final Visit). The subject satisfaction 
questionnaire will be assessed at Week 12 (Final Visit) only. 
Safety Evaluations 
The safety assessments will include adverse events (volunteered, 
observed, and elicited by general questioning in a non-suggestive 
manner), physical examinations, vital signs, clinical laboratory tests, 
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 and local signs and symptoms assessments (including erythema, 
telangiectasia, burning/stinging, flushing/blushing, dryness/xerosis, 
itching, peeling/desquamation, and hyperpigmentation) scores. 
Statistical Methods: 
The primary population for efficacy analysis will be the intent-to-treat 
(ITT) population, using multiple imputations to impute missing values. 
Supportive efficacy analyses will be conducted on the per-protocol (PP) 
population, with no imputation for missing values. 
The co-primary efficacy endpoints will be the dichotomized IGA score 
where treatment success is defined as at least a 2-step improvement 
resulting in a 0 (clear) or 1 (almost clear) score at Week 12 compared to 
Day 0/Baseline and the absolute change in inflammatory lesion count at 
Week 12 compared to Day 0/Baseline. 
The key secondary endpoints will be analyzed hierarchically: 
• 
Dichotomized IGA score where treatment success is defined as 
a 2-step improvement in score at Week 12 compared to Day 
0/Baseline. 
• 
Percent change in inflammatory lesion count at Week 12 
compared to Day 0/Baseline. 
Continuous efficacy endpoints will be analyzed using analysis of 
covariance (ANCOVA). Dichotomized efficacy endpoints will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) test. 
The tolerability and safety of topical minocycline foam applied daily 
for 12 weeks will be evaluated using summary statistics and individual 
subject data listings. 
The active treatment group will be tested against vehicle at the 0.05 
two-sided level of significance. No statistical tests will be performed 
for any of the safety assessments. 
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Table of Contents 
Page 
TITLE PAGE ........................................................................................................................................................ 1 
SIGNATURE PAGE ............................................................................................................................................ 2 
SYNOPSIS............................................................................................................................................................. 3 
TABLE OF CONTENTS ..................................................................................................................................... 6 
LIST OF TABLES ................................................................................................................................................ 8 
1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................... 9 
2 
STUDY ADMINISTRATIVE STRUCTURE ........................................................................................10 
3 
INTRODUCTION ....................................................................................................................................11 
4 
STUDY OBJECTIVES ............................................................................................................................12 
5 
INVESTIGATIONAL PLAN ..................................................................................................................12 
5.1 
OVERALL STUDY DESIGN ................................................................................................................12 
5.2 
RATIONALE FOR STUDY DESIGN AND DOSE SELECTION ..................................................................12 
6 
STUDY POPULATION ...........................................................................................................................13 
6.1 
INCLUSION CRITERIA .......................................................................................................................13 
6.2 
EXCLUSION CRITERIA ......................................................................................................................13 
7 
STUDY PROCEDURES ..........................................................................................................................15 
7.1 
SCREENING VISIT .............................................................................................................................17 
7.2 
VISIT 1, DAY 0/BASELINE VISIT.......................................................................................................17 
7.3 
EARLY FOLLOW-UP, WEEK 1 (±3 DAYS) .........................................................................................18 
7.4 
VISIT 2, WEEK 2 (±3 DAYS) .............................................................................................................18 
7.5 
VISIT 3, WEEK 4 (±3 DAYS) .............................................................................................................18 
7.6 
VISIT 4, WEEK 8 (±3 DAYS) .............................................................................................................19 
7.7 
VISIT 5, WEEK 12 (-3/+5 DAYS) / FINAL VISIT OR EARLY TERMINATION .........................................20 
7.8 
SAFETY FOLLOW-UP (±5 DAYS) .......................................................................................................20 
8 
STUDY TREATMENTS ..........................................................................................................................21 
8.1 
TREATMENTS ADMINISTERED ..........................................................................................................21 
8.1.1 
Dosing Instructions ........................................................................................................21 
8.1.2 
Manufacturer ..................................................................................................................21 
8.1.3 
Labeling of Study Drug ..................................................................................................21 
8.1.4 
Storage of Study Drug ....................................................................................................22 
8.2 
STUDY DRUG ACCOUNTABILITY ......................................................................................................22 
8.3 
HANDLING AND DISPOSAL OF STUDY DRUG ....................................................................................23 
8.4 
METHOD OF ASSIGNMENT OF STUDY DRUG ....................................................................................23 
8.5 
SELECTION AND TIMING OF DOSES IN THE STUDY ...........................................................................23 
8.6 
BLINDING  ........................................................................................................................................23 
8.7 
PRIOR/CONCOMITANT THERAPY ......................................................................................................24 
8.8 
USE OF CONTRACEPTION .................................................................................................................24 
8.9 
TREATMENT COMPLIANCE ...............................................................................................................25 
9 
EFFICACY ASSESSMENTS ..................................................................................................................25 
9.1 
CO-PRIMARY EFFICACY ASSESSMENTS ...........................................................................................25 
9.1.1 
Lesion Counts.................................................................................................................25 
9.1.2 
Investigator Global Assessment .....................................................................................26 
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9.2 
SECONDARY AND TERTIARY EFFICACY ASSESSMENTS ....................................................................26 
9.2.1 
Percent Change in Inflammatory Lesion Counts ............................................................26 
9.2.2 
Interim Change in Inflammatory Lesion Counts ............................................................26 
9.2.3 
Subject Global Assessment ............................................................................................26 
9.2.4 
Subject Satisfaction Questionnaire .................................................................................26 
9.3 
PHOTOGRAPHY ................................................................................................................................26 
10 
SAFETY ASSESSMENTS .......................................................................................................................27 
10.1 
MEDICAL/SURGICAL HISTORY .........................................................................................................27 
10.2 
MEDICATION HISTORY.....................................................................................................................27 
10.3 
CONCOMITANT MEDICATIONS .........................................................................................................27 
10.4 
VITAL SIGNS ....................................................................................................................................27 
10.5 
PHYSICAL EXAMINATION .................................................................................................................27 
10.6 
CLINICAL LABORATORY TESTS........................................................................................................27 
10.6.1 
Urine Pregnancy Test .....................................................................................................28 
10.6.2 
Sample Collection, Storage, and Shipping .....................................................................28 
10.7 
OTHER SAFETY MEASUREMENTS .....................................................................................................28 
10.7.1 
Local Signs and Symptoms Assessments .......................................................................28 
10.7.1.1 Erythema (Clinical Erythema Assessment Scale) .........................................29 
10.7.1.2 Telangiectasia ................................................................................................29 
10.7.1.3 Burning/Stinging ...........................................................................................29 
10.7.1.4 Flushing/Blushing .........................................................................................30 
10.7.1.5 Dryness/Xerosis ............................................................................................30 
10.7.1.6 Itching ...........................................................................................................30 
10.7.1.7 Peeling/Desquamation ...................................................................................30 
10.7.1.8 Hyperpigmentation ........................................................................................30 
10.8 
ADVERSE EVENTS ............................................................................................................................31 
10.8.1 
Method of Determining Adverse Events ........................................................................31 
10.8.2 
Adverse Event Definitions .............................................................................................31 
10.8.2.1 Adverse Events ..............................................................................................31 
10.8.2.2 Serious Adverse Events .................................................................................32 
10.8.2.3 Severity of Adverse Events ...........................................................................32 
10.8.2.4 Relationship of Adverse Events to Study Treatments ...................................32 
10.8.2.5 Adverse Events Expectedness .......................................................................33 
10.8.3 
Reporting Adverse Events ..............................................................................................33 
10.8.4 
Adverse Event Follow-up ...............................................................................................33 
10.8.4.1 Pregnancy Reporting .....................................................................................34 
10.8.5 
Clinically Significantly Abnormal Laboratory Results ..................................................34 
10.9 
APPROPRIATENESS OF SAFETY MEASUREMENT ...............................................................................34 
11 
STATISTICAL DESIGN AND ANALYSIS ..........................................................................................34 
11.1 
STATISTICAL ANALYSIS PLAN .........................................................................................................34 
11.2 
DETERMINATION OF SAMPLE SIZE ...................................................................................................35 
11.3 
ANALYSIS POPULATIONS .................................................................................................................35 
11.4 
SUBJECT ACCOUNTING, DEMOGRAPHICS, AND DAY 0/BASELINE CHARACTERISTICS ......................36 
11.5 
EFFICACY ENDPOINTS ......................................................................................................................36 
11.5.1 
Primary Efficacy Endpoints ...........................................................................................37 
11.5.2 
Secondary Efficacy Endpoints .......................................................................................37 
11.5.3 
Tertiary Efficacy Endpoints ...........................................................................................37 
11.6 
SAFETY ENDPOINTS .........................................................................................................................37 
11.6.1 
Adverse Events ...............................................................................................................38 
11.6.2 
Vital Signs and Physical Examinations ..........................................................................38 
11.6.3 
Clinical Laboratory Results ............................................................................................38 
11.7 
INTERIM ANALYSIS ..........................................................................................................................38 
12 
STUDY MANAGEMENT .......................................................................................................................39 
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12.1 
MONITORING ...................................................................................................................................39 
12.2 
PROTOCOL AMENDMENTS................................................................................................................39 
12.3 
PROTOCOL DEVIATIONS ...................................................................................................................39 
12.4 
WITHDRAWAL OF SUBJECTS ............................................................................................................40 
12.5 
TERMINATION OF THE STUDY ..........................................................................................................40 
12.6 
PUBLICATION POLICY ......................................................................................................................40 
13 
ETHICS .....................................................................................................................................................41 
13.1 
CONDUCT OF THE STUDY .................................................................................................................41 
13.2 
INSTITUTIONAL REVIEW BOARDS (IRB) ..........................................................................................41 
13.3 
WRITTEN INFORMED CONSENT ........................................................................................................41 
13.4 
SUBJECT CONFIDENTIALITY .............................................................................................................41 
13.5 
RECORDS RETENTION ......................................................................................................................42 
13.6 
FINANCING .......................................................................................................................................42 
14 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................................................42 
15 
DATA HANDLING AND RECORD KEEPING ...................................................................................43 
16 
REFERENCE LIST .................................................................................................................................43 
17 
STUDY AMENDMENTS ........................................................................................................................43 
17.1 
AMENDMENT 1, EFFECTIVE MARCH 6TH, 2017 ................................................................................43 
APPENDIX 1:  SUBJECT GLOBAL ASSESSMENT QUESTIONNAIRE ..................................................51 
APPENDIX 2:  SUBJECT SATISFACTION QUESTIONNAIRE .................................................................52 
APPENDIX 3: ACKNOWLEDGMENT OF RECEIPT AND REVIEW OF PROTOCOL .........................53 
 
List of Tables 
Table 1 
Schedule of Study Assessments and Procedures – Study FX2016-12 ........................... 16 
Table 2 
Study Drug Kits and Treatments – Study FX2016-12 ................................................... 21 
Table 3 
IGA Scale for Rosacea – Study FX2016-12 ................................................................... 26 
Table 4 
Clinical Laboratory Tests – Study FX2016-12 .............................................................. 28 
Table 5 
Sample Size Calculations Based on IGA Scores after 12 Weeks of Treatment in Phase 2 
Study FX2015-10 ........................................................................................................... 35 
 
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1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation/Term 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartic acid transaminase 
BOCF 
Baseline observation carried forward 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CRO 
Contract Research Organization 
eCRF 
Electronic case report form 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IGA 
Investigator’s Global Assessment 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology System 
ITT 
Intent-to-treat (population) 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed effects model for repeated measures 
OC 
Observed cases 
OTC 
Over-the-counter 
PP 
Per-protocol (population) 
PT 
Preferred term 
RBC 
Red blood cell 
RDC 
Remote data capture 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
US 
United States 
WBC 
White blood cell 
2 
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2 
STUDY ADMINISTRATIVE STRUCTURE 
 
 
Internal 
 
Name 
Affiliation / Address / 
Telephone Number 
Responsibility 
Foamix Pharmaceuticals, Inc. 
520 US Highway 22 
Bridgewater, NJ 08807 
Sponsor 
 
 
External – Contract Research Organization (CRO) 
 
Name 
Affiliation / Address / 
Telephone Number 
Responsibility 
 
 
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3 
INTRODUCTION 
Papulopustular rosacea is a chronic disorder affecting both the skin and the eye. It is a syndrome 
of undetermined etiology characterized by both vascular and papulopustular components 
involving the face and occasionally the neck and upper trunk. Clinical findings are usually 
limited to the sun exposed areas of the face and chest and include mid-facial erythema, 
telangiectasia, papules and pustules, and sebaceous gland hypertrophy. Rosacea is characterized 
by episodic flushing of affected areas, which may be associated with consumption of alcohol, hot 
drinks, or spicy foods. During inflammatory episodes, affected areas of the skin, primarily the 
convexities of the face, develop swelling, papules, and pustules. 
Rosacea occurs most commonly in adult life, between the ages of 30 and 60 years. It is very 
common in the United States (US) and Europe. Ocular involvement occurs in more than 50% of 
patients. 
Mainstays of treatment for papulopustular rosacea are the oral tetracyclines:  doxycycline and 
minocycline. Systemic doxycycline (Oracea®, doxycycline 40 mg capsules) is approved. Topical 
treatments for rosacea include metronidazole, azelaic acid, and brimonidine tartrate. 
Foamix has developed a topical minocycline foam product that is being evaluated for safety and 
efficacy in the treatment of rosacea. Minocycline hydrochloride is an established broad spectrum 
antibiotic that is used orally in the treatment of rosacea. The study medication FMX103 
(minocycline HCl 1.5% foam), facilitates easy application and even distribution of the agent, 
thereby improving treatment convenience. 
The efficacy and safety of FMX103 has been evaluated in a Phase 2 study at two minocycline 
concentrations, 1.5% and 3%. The study included 232 subjects (males/females, aged ≥18 years) 
with moderate-to-severe papulopustular rosacea defined by the Investigator’s Global Assessment 
(IGA) score and with ≥12 inflammatory facial lesions (papules/pustules) at Day 0/Baseline. 
Subjects were treated with FMX103 1.5%, FMX103 3%, or vehicle foam, once daily for 12 
weeks. Efficacy and safety were evaluated at Weeks 2, 4, 8, and 12, with an additional safety 
follow-up visit at Week 16. The primary efficacy end point was the absolute change in 
inflammatory lesion count at Week 12. Other assessments included IGA improvement of ≥2 
grades and reaching an IGA score of “clear” or “almost clear” (IGA 0/1), clinical assessment of 
erythema, and safety and tolerability. 
At Week 12, both the 1.5% and 3% doses of FMX103 significantly reduced the number of 
papules and pustules vs. vehicle (both p<0.001, intent-to-treat [ITT] population). The mean 
reduction in lesion count from Day 0/Baseline was 21.1 for the FMX103 1.5% dose, 19.9 for the 
FMX103 3% dose, and 7.8 for the vehicle. The corresponding percent reductions were 61.4% 
and 55.5% for the 1.5% and 3% doses, respectively, and 29.7% for the vehicle. 
Both the 1.5% and 3% doses of FMX103 were statistically significantly better than vehicle in 
improving IGA scores by ≥2 grades at week 12 (p=0.002 and p=0.032, respectively). Both doses 
were also statistically significantly better than vehicle in achieving an IGA of “clear or almost 
clear” (score 0/1) at Week 12 (p=0.001 and p=0.041, respectively). Both FMX103 1.5% and 3% 
doses appeared to be generally safe and well-tolerated. Treatment-related dermal reactions were 
reported in 1 subject from the FMX103 1.5% dose group (considered mild) and in a few subjects 
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from the FMX103 3% dose group (mild, n=1; moderate, n=2; severe, n=1). No treatment-related 
systemic adverse events (AEs) were reported and discontinuation due to AEs (eczema, n=1; 
rosacea, n=1; burning sensation, n=1) was reported in 3 subjects in the FMX103 3% dose group. 
As a consequence of the above, the FMX103 1.5% dose concentration has been selected for 
further development. This Phase 3 study will further assess the safety and efficacy of topical 
minocycline HCl foam, 1.5%, applied once daily compared with vehicle foam for the treatment 
of moderate-to-severe papulopustular rosacea. 
4 
STUDY OBJECTIVES 
The primary objectives of the study are: 
• To determine the efficacy of FMX103 1.5% minocycline foam applied topically once daily 
for 12 weeks in the treatment of rosacea. 
• To evaluate the tolerability and safety of topical minocycline foam applied once daily for 12 
weeks. 
5 
INVESTIGATIONAL PLAN 
5.1 
Overall Study Design 
This is a randomized, multicenter, double-blind, vehicle-controlled, 2-arm study to evaluate the 
safety and efficacy of FMX103 topical foam containing 1.5% minocycline compared to vehicle, 
in the treatment of subjects with moderate-to-severe facial papulopustular acne rosacea. 
Qualified subjects will be randomized in a 2:1 ratio (active:vehicle) to use once daily one of the 
following two treatments: 
• FMX103 minocycline foam 1.5% 
• Vehicle foam 
Subjects will be assigned to 1 of 2 treatments according to the randomization schedule. Subjects 
will apply (or have applied) the study drug topically once daily for 12 weeks as directed. 
Subjects will be advised to use the study drug at approximately the same time each day, 
preferably in the evening about 1 hour before bedtime. Both the Investigator and subject will be 
blinded to the study drug identity.  
Subjects will return for visits at Weeks 2, 4, 8, and 12. Efficacy evaluations (inflammatory lesion 
counts [Section 9.1.1] and IGA score [Section 9.1.2]) will be performed at Weeks 4, 8, and 12 
during the study. Other assessments will be performed as described in Section 9 and Section 10. 
5.2 
Rationale for Study Design and Dose Selection 
A randomized, multicenter, double-blind, vehicle-controlled study design has been selected in 
order to assess the efficacy of the study drug. The subjects will be selected according to 
predefined entry criteria. The study treatment duration of 12 weeks is expected to be sufficient to 
show a treatment effect. 
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The concentration of minocycline in the composition was selected according to formulation 
integrity and stability considerations and based on the results of Phase 2 Study FX2015-10 
(described above in Section 3). 
Because of the mode of action of tetracycline drugs, the primary efficacy endpoints will be the 
effect on inflammatory lesion counts and IGA scores (Section 9). 
6
STUDY POPULATION 
The study will randomize approximately 600 subjects to active or vehicle treatment (in a 2:1 
ratio) at approximately 40 sites in the US. 
6.1
Inclusion Criteria 
Subjects were included in the study if they met all of the following inclusion criteria at the time 
of enrollment: 
1. Male or female ≥18 years-of-age.
2. Moderate-to-severe rosacea (as per the IGA score; Table 3) on the proposed facial 
treatment area consisting of:
a.
At least 15 and not more than 75 facial papules and pustules, excluding lesions 
involving the eyes and scalp;
b.
No more than 2 nodules on the face.
3. Presence of or history of erythema and/or flushing on the face.
4. If a female of child-bearing potential, have a negative urine pregnancy test and agree to 
use an effective method of contraception (Section 8.8). A sterile sexual partner is NOT 
considered an adequate form of birth control.
5. Willing to minimize external factors that might trigger rosacea flare-ups (eg, spicy foods, 
thermally hot foods and drinks, hot environments, prolonged sun exposure, strong winds, 
and alcoholic beverages).
6. Subjects who use make-up must have used the same brands/types of make-up for a 
minimum period of 14 days prior to study entry and must agree to use the same make-up, 
brand/type, or frequency of use, throughout the study.
7. Completed and signed an appropriately administered Informed Consent Form (ICF) prior 
to any study-related procedures. 
6.2 
Exclusion Criteria 
Subjects were excluded from enrollment in the study for any of the following reasons: 
1. Woman who is pregnant, lactating, or planning to become pregnant during the study
period.
2. Presence of any skin condition on the face that would interfere with the diagnosis or
assessment of rosacea.
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3. Moderate or severe rhinophyma, dense telangiectasia (score 3, severe; Section 10.7.2.2), 
or plaque-like facial edema. 
4. An active nodule on the face >5 mm in diameter. 
5. Excessive facial hair (eg, beards, sideburns, moustaches, etc.) that would interfere with 
diagnosis or assessment of rosacea. 
6. History of hypersensitivity or allergy to minocycline, any other tetracycline, or of any 
other component of the formulation. 
7. Severe erythema, dryness, scaling, pruritus, stinging/burning, or edema. 
8. Active ocular rosacea (eg, conjunctivitis, blepharitis, or keratitis) of sufficient severity to 
require topical or systemic antibiotics. 
9. Use within 6 months prior to Day 0/Baseline of oral retinoids (eg, Accutane®) or 
therapeutic vitamin A supplements of greater than 10,000 units/day (multivitamins are 
allowed). 
10. Initiation of use of estrogens or oral contraceptives less than 3 months prior to Day 
0/Baseline. 
11. Use within 1 month prior to Day 0/Baseline of: 
a. Topical retinoids to the face. 
b. Systemic antibiotics known to have an impact on the severity of facial rosacea 
(eg, containing tetracycline and its derivatives, erythromycin and its derivatives, 
sulfamethoxazole, or trimethoprim). Subjects requiring systemic antibiotics not 
known to affect rosacea will be considered on a case-by-case basis. 
c. Systemic corticosteroids (Note: intranasal and inhalational corticosteroids do not 
require a washout and maybe used throughout the trial if the subject is on a stable 
dose). 
12. Use within 2 weeks prior to Day 0/Baseline of: 
a. Topical corticosteroids. 
b. Topical antibiotics. 
c. Topical medications for rosacea (eg, metronidazole). 
13. Use of a sauna during the 2 weeks prior to Day 0/Baseline and during the study. 
14. Had wax epilation of the face within 2 weeks prior to Day 0/Baseline. 
15. Active bacterial folliculitis. 
16. Consumption of excessive alcohol, abuse of licit or illicit drugs, or a condition that, in the 
opinion of the Investigator, could compromise the subject’s ability to comply with study 
requirements. 
17. Participation in activities that involve excessive or prolonged exposure to sunlight or 
weather extremes, such as wind or cold. 
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18. Presence of any clinically significant condition or situation, other than the condition
being studied, that in the opinion of the Investigator would interfere with the study
evaluations or optimal participation in the study.
19. Participation in an investigational drug study (ie, subject has been treated with an
investigational drug) within 30 days prior to Day 0/Baseline. Subjects who are
participating in non-treatment studies such as observational studies or registry studies can
be considered for inclusion.
20. Previously enrolled in this study.
21. Prior laser therapy (for telangiectasia or other conditions), electrodessication, or
phototherapy (eg, ClearLight®) to the facial area within 180 days prior to Day 0/Baseline.
22. Prior cosmetic procedures (eg, facials) that may affect the efficacy and safety profile of
the investigational product within 14 days prior to Day 0/Baseline.
7
STUDY PROCEDURES 
Potential subjects will be assessed for eligibility at Screening. During this visit, the purpose, 
timing, procedures, and risks of the study will be explained to the subject, including 
requirements for enrollment and participation in the study, medication restrictions during the 
study, and requirements for washout of certain medications that the subject may already be 
taking. 
The eligible subject who is willing to participate in the study will then sign an appropriately 
administered ICF prior to any study-related procedures being performed. 
Procedures at the Screening Visit will include obtaining blood and urine samples for clinical 
laboratory tests. The results of these tests must be no more than 45 days old at the time of the 
Day 0/Baseline Visit and randomization. 
If a subject who has agreed to participate in the study and signed the ICF is currently undergoing 
rosacea therapy identified in Exclusion Criteria 11 and 12, they must first enter a washout period 
(ie,1 month or 2 weeks, as specified in Exclusion Criteria 11 and 12, respectively) before 
beginning the screening procedures. 
The schedule of study assessments and procedures and the time point at which they will be 
performed during the study is presented in Table 1. If a subject prematurely withdraws from the 
study, the subject should return to the study site for an early termination visit during which all 
evaluations described under Final Visit 5/Week 12 must be performed. 
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Table 1 
Schedule of Study Assessments and Procedures – Study FX2016-12 
Assessment or Procedure 
Screening 
Day 0 / 
Baseline0 
Visits/Early 
Follow-up 
Final 
Visitb 
Safety 
Follow-upf 
Visit 
1 
EF 
2 
3 
4 
5 
Week 
1 
2 
4 
8 
12 
Informed consent 
X 
Demographic data 
X 
Assign subject identification 
X 
Medical/surgical/medication history 
X 
Inclusion/exclusion criteria 
X 
X 
Physical examination, height, weightc 
X 
X 
Blood pressure/heart rated 
X 
X 
X 
X 
X 
Blood and urine samples for clinical 
laboratory tests  
X 
X 
Urine pregnancy test (females of 
childbearing potential only) 
X 
X 
X 
X 
X 
Lesion counts 
X 
X 
X 
X 
X 
Investigator’s Global Assessment 
X 
X 
X 
X 
X 
Subject Global Assessment 
X 
X 
X 
X 
Subject Satisfaction Questionnaire 
X 
Local signs and symptoms 
assessmentse  
X 
X 
X 
X 
X 
X 
Photography 
X 
X 
X 
X 
Randomization 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Perform drug accountability 
X 
X 
X 
X 
Collect used drug canister(s) 
X 
X 
X 
X 
Dispense study drug 
X 
X 
X 
X 
Schedule/confirm next visit 
X 
X 
X 
X 
X 
X 
EF – Early Follow-up telephone call, no visit 
a.
Day 0/Baseline must occur within 45 days of Screening. Blood test results must not show clinically significant
abnormalities.
b.
If a subject prematurely withdraws from the study, all evaluations described under Visit 5/Week 12 (Final Visit)
must be performed at an Early Termination Visit.
c.
Height to be measured only at Day 0/Baseline.
d.
Measure blood pressure and heart rate after the subject has been sitting for at least 5 minutes at rest.
e.
The severity of each of the following local rosacea signs/symptoms will be measured:  erythema, telangiectasia,
burning/stinging, flushing/blushing, dryness/xerosis, itching, peeling/desquamation, and hyperpigmentation.
f.
A safety follow-up telephone call will be made 4 weeks after Visit 5/Week 12 (Final Visit) for only those subjects
that do not participate in study FX2015-13 (Open label study) and presented with either new or on-going adverse
events at Visit 5/Week 12 (Final Visit).
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7.1 
Screening Visit 
• Obtain a signed and dated, written ICF prior to any study-related procedures. 
• Obtain demographic data. 
• Using the Interactive Response Technology System (IRT), assign the subject an identification 
number. 
• Obtain medical/surgical history (Section 10.1). 
• Obtain history of prior medication usage (including previous use of rosacea medications); 
record start and stop dates of any medications used in the last 3 months (Section 10.2). 
• Assess eligibility according to the inclusion (Section 6.1) and exclusion criteria (Section 6.2). 
• Collect a urine sample from female subjects of childbearing potential for a urine pregnancy 
test (Section 10.6.1). 
• Collect blood and urine samples for clinical laboratory tests and send to the central laboratory 
(Section 10.6.2). 
• Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
• Perform IGA (Section 9.1.2). 
• Perform local signs and symptoms assessments (Section 10.7.2). 
• Schedule/confirm the next study visit. 
7.2 
Visit 1, Day 0/Baseline Visit 
• Confirm eligibility according to the inclusion (Section 6.1) and exclusion criteria 
(Section 6.2). 
• Perform physical examination including height and weight (Section 10.5). 
• Measure blood pressure and heart rate (Section 10.4). 
• Collect a urine sample from female subjects of childbearing potential for a urine pregnancy 
test (Section 10.6.1). 
• Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
• Perform IGA (Section 9.1.2). 
• Perform photography (Section 9.3). 
• Perform local signs and symptoms assessments (Section 10.7.2). 
• Randomize the subject using the IRT when all criteria have been met. 
• Record concomitant medications (Section 8.7). 
• Record AEs (Section 10.8). 
• Dispense one kit (2 canisters) of study drug. 
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• Dispense facial cleanser and moisturizer. 
• Schedule/confirm the next study visit and remind subject to avoid overexposure to sunlight 
and to use the same make-up brand/type, or frequency of use, throughout the study as 
applicable. 
7.3 
Early Follow-up, Week 1 (±3 Days) 
An early follow-up telephone call will be made 1 week after Visit 1, Day 0/Baseline. 
• Record concomitant medications (Section 8.7). 
• Record AEs (Section 10.8). 
• Confirm that subject continues to use only the provided facial cleanser and moisturizer. 
• Review application instructions to confirm that the subject continues to use the study drug as 
directed. 
• Schedule/confirm the next study visit and remind subject to avoid overexposure to sunlight 
and to use the same make-up brand/type, or frequency of use, throughout the study as 
applicable. 
7.4 
Visit 2, Week 2 (±3 Days) 
• Measure blood pressure and heart rate (Section 10.4). 
• Have the subject complete the Subject Global Assessment (Section 9.2.3). 
• Perform local signs and symptoms assessments (Section 10.7.2). 
• Record concomitant medications (Section 8.7). 
• Record AEs (Section 10.8). 
• Confirm that subject continues to use only the provided facial cleanser and moisturizer. 
• Review application instructions to confirm that the subject continues to use the study drug as 
directed. 
• Perform drug accountability to assess compliance (Section 8.2). 
• Collect used study canister (if applicable). 
• Dispense one kit (2 canisters) of study drug. 
• Schedule/confirm the next study visit and remind subject to avoid overexposure to sunlight 
and to use the same make-up brand/type, or frequency of use, throughout the study as 
applicable. 
7.5 
Visit 3, Week 4 (±3 Days) 
• Measure blood pressure and heart rate (Section 10.4). 
• Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
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• Perform IGA (Section 9.1.2). 
• Have the subject complete the Subject Global Assessment (Section 9.2.3). 
• Perform photography (Section 9.3). 
• Perform local signs and symptoms assessments (Section 10.7.2). 
• Collect a urine sample from female subjects of childbearing potential for a urine pregnancy 
test (Section 10.6.1). 
• Record concomitant medications (Section 8.7). 
• Record AEs (Section 10.8). 
• Perform drug accountability to assess compliance (Section 8.2). 
• Collect used study drug canister (if applicable). 
• Dispense one kit (2 canisters) of study drug. 
• Confirm that subject continues to use only the provided facial cleanser and moisturizer and 
dispense additional quantities as required. 
• Review application instructions to confirm that the subject continues to use the study drug as 
directed. 
• Schedule/confirm the next study visit and remind subject to avoid overexposure to sunlight 
and to use the same make-up brand/type, or frequency of use, throughout the study as 
applicable. 
7.6 
Visit 4, Week 8 (±3 Days) 
• Measure blood pressure and heart rate (Section 10.4). 
• Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
• Perform IGA (Section 9.1.2). 
• Have the subject complete the Subject Global Assessment (Section 9.2.3). 
• Perform photography (Section 9.3). 
• Perform local signs and symptoms assessments (Section 10.7.2). 
• Collect a urine sample from female subjects of childbearing potential for a urine pregnancy 
test (Section 10.6.1). 
• Record concomitant medications (Section 8.7). 
• Record AEs (Section 10.8). 
• Perform drug accountability to assess compliance (Section 8.2). 
• Collect used study drug canister (if applicable). 
• Dispense one kit (2 canisters) of study drug. 
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• Confirm that subject continues to use only the provided facial cleanser and moisturizer and 
dispense additional quantities as required. 
• Review application instructions to confirm that the subject continues to use the study drug as 
directed. 
• Schedule/confirm the next study visit and remind subject to avoid overexposure to sunlight 
and to use the same make-up brand/type, or frequency of use, throughout the study as 
applicable. 
7.7 
Visit 5, Week 12 (-3/+5 days) / Final Visit or Early Termination 
• Perform physical examination including weight (Section 10.5). 
• Measure blood pressure and heart rate (Section 10.4). 
• Collect blood and urine samples for clinical laboratory tests and send to the central laboratory 
(Section 10.6.2). 
• Collect a urine sample from female subjects of childbearing potential for a urine pregnancy 
test (Section 10.6.1). 
• Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
• Perform IGA (Section 9.1.2). 
• Perform photography (Section 9.3). 
• Perform local signs and symptoms assessments (Section 10.7.2). 
• Have the subject complete the Subject Global Assessment (Section 9.2.3). 
• Have the subject complete the Subject Satisfaction Questionnaire (Section 9.2.4). 
• Record concomitant medications (Section 8.7). 
• Record AEs (Section 10.8). 
• Collect all used and full study drug canisters. 
• Perform drug accountability to assess compliance and record the date of the last dose 
(Section 8.2). 
• Schedule/confirm a safety follow-up telephone call 4 weeks from Visit 5/Week 12 (Final 
Visit) date (±5 days) only for subjects that will not participate in study FX2015-13 (Open 
label study) (Section 7.9) and presented with either new or on-going adverse events at Visit 
5/Week 12 (Final Visit). 
7.8 
Safety Follow-Up (±5 days) 
A safety follow-up telephone call will be made 4 weeks after Visit 5/Week 12 (Final Visit) for 
only those subjects that do not participate in study FX2015-13 (Open label study) and presented 
with either new or on-going adverse events at Visit 5/Week 12 (Final Visit). Follow up on these 
adverse events and any new concomitant medications will be recorded. 
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8 
STUDY TREATMENTS 
This study will include FMX103 minocycline foam 1.5% and vehicle foam. 
8.1 
Treatments Administered 
The description of study drug kits and treatments is shown below in Table 2. 
Table 2 
Study Drug Kits and Treatments – Study FX2016-12 
Dosage form description: 
Foam containing minocycline HCl 1.5% or vehicle foam 
Package description: 
Canisters, each containing 25 g of the clinical trial supply foam 
Daily dose: 
Once daily application of a sufficient amount of foam to cover the involved 
area. Estimated maximum is 0.5 g of drug product containing 7.5 mg (1.5% 
active) or 0.0 mg (vehicle) of minocycline. 
Cumulative maximal dose for 
dosing (12 weeks): 
630 mg (1.5%) minocycline 
Dispensing: 
Kits consisting of 2 canisters, each canister containing 25 g of FMX103 
minocycline formulation, 1.5%, or vehicle dispensed at Visit 1 (Day 
0/Baseline), Visit 2 (Week 2), Visit 3 (Week 4), and Visit 4 (Week 8).  
8.1.1
Dosing Instructions 
The dosing regimen will be the same for both treatment groups. 
Study drug kits containing 2 canisters of investigational drug will be dispensed at Visit 1 (Day 
0/Baseline), Visit 2 (Week 2), Visit 3 (Week 4), and Visit 4 (Week 8).  
After shaking the canister well, a small amount of study drug (about ½ gram or a cherry-sized 
amount) should be expressed from the canister onto the finger tips and then applied as a thin 
layer over all involved areas of the face. Additional drug may be used as needed to assure the 
entire involved area is treated.  
Study drug should be applied at approximately the same time each day, preferably in the evening 
about 1 hour before bedtime. 
8.1.2
Manufacturer 
The manufacturer of the investigational product is ASM Aerosol-Service AG, Moehlin, 
Switzerland. 
8.1.3
Labeling of Study Drug 
The Sponsor or designee will label study drug supplies according to the requirements of the 
Code of Federal Regulations (21CFR§ 210, Subpart G-Packaging & Labeling Control). 
The labels of the investigational (test) product will contain appropriate information as required 
by regional regulatory authorities and include, as needed, the following information: 
•
Name and address of the Sponsor
•
Protocol number
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• Product name/dosage form/mode of administration 
• Kit Number/Canister Number 
• Site number/Subject number 
• Name and address of manufacturer 
• Date of manufacture 
• Lot/batch number 
• Canister contents 
• Storage conditions 
• Caution statements, as follow: 
o “New Drug – Limited by Federal Law to Investigational Use” 
o “Flammable” 
o “Shake well before use” 
o “Keep out of the reach of children” 
The composition, pharmaceutical quality, batch number, and expiration date of the 
investigational (test) product will be traceable via the kit number. 
8.1.4 
Storage of Study Drug 
FMX103 1.5% and vehicle canisters must be stored at 2°C – 8°C until being dispensed to the 
subject. Subsequently, they must be stored at 20°C – 25°C (refer to USP Controlled Room 
Temperature). The Investigator will be responsible for the suitable storage of the investigational 
product in compliance with the storage instructions and must restrict access to the study 
personnel only. 
8.2 
Study Drug Accountability 
The Investigator will have overall responsibility for the use of the study drug. The Investigator or 
designee will verify the contents of the drug shipment and confirm receipt of the study drug in 
the IRT system. In addition, an accurate study drug dispensing record that specifies the date and 
amount dispensed to each subject must be kept. This inventory record must be available for 
inspection by representatives of the Sponsor and is subject to regional regulatory authority 
inspection at any time. At the conclusion of the study, the Investigator must provide a copy of 
this record to the Sponsor and each canister that has been retrieved from a subject will be 
returned to the vendor to be weighed. 
Under no circumstances will the Investigator allow the investigational drugs to be used other 
than as directed by this protocol. Qualified study personnel must use the IRT to assign and 
dispense kits to the subjects. Reasons for digression from the expected dispensing regimen must 
also be recorded. 
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8.3 
Handling and Disposal of Study Drug 
The study drug must be protected from unauthorized access (eg, in a locked storage facility). 
Any unused, partially used, or empty bottles of study drug will be returned to the Sponsor or 
designee by the time of the site’s close-out visit. Receipt, distribution, and return of the study 
drug must be properly documented on forms provided by the Sponsor or designee. 
8.4 
Method of Assignment of Study Drug 
After pretreatment clinical evaluations and all other Screening procedures have been completed, 
authorized site personnel will acknowledge that the applicable subject met all the specified 
inclusion criteria (Section 6.1) and none of the exclusion criteria (Section 6.2). Assignment to a 
treatment group will then follow a predetermined list of randomization numbers, with each 
successive number receiving 1 of the 2 treatments in random order. Authorized site personnel 
will use the IRT system to assign a kit number that corresponds to the randomization schedule. 
The kit box with the assigned kit number will be dispensed to the subject. 
The randomization code will be provided by Premier Research, Research Triangle Park, NC. 
8.5 
Selection and Timing of Doses in the Study 
The 1.5% concentration of minocycline has been shown to be effective compared to vehicle in a 
Phase 2 study in subjects with rosacea. The once-daily dosing regimen is appropriate given the 
pharmacokinetic characteristics of minocycline. 
8.6 
Blinding 
This is a double-blind study, with limited access to the randomization code. The randomization 
code will be held in confidence until after the study database is locked and a memo documenting 
the database lock has been issued. Every effort will be made to retain the integrity of the blind. 
When issued to the sites, the study drug will be identical in appearance for all subjects, 
regardless of treatment assignment. 
The treatment each subject receives will not be disclosed to the Investigator, study site personnel, 
subjects, monitors, or the Sponsor staff except as required for the purposes of conducting this 
study. 
In the event that emergency identification of study drug is required (eg, if the Investigator 
believes that the information is necessary to properly treat a subject with an AE), the study drug 
identity can be obtained by the Investigator through the IRT system. 
Before breaking the blind for a subject, the Investigator should determine that the information is 
necessary (ie, that it will alter the subject’s immediate course of treatment and will contribute to 
the management of the AE). In many cases, particularly when the emergency is clearly not 
related to study drug, the problem may be effectively managed by assuming that the subject is 
receiving active study drug without the need for unblinding. Every effort should be made to alert 
the medical monitor before requesting that the blind be broken. If this is not possible, the medical 
monitor should be immediately notified of the breaking of the blind. The Investigator will record 
the unblinding procedures in the subject’s source documents. 
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If unblinding is necessary, the subject will be withdrawn from the study and Early Termination 
Visit (ie, Visit 5 [Week 12]) assessments will be completed. 
8.7 
Prior/Concomitant Therapy 
As necessary, subjects should use the facial cleanser Cetaphil Gentile Skin Cleanser and the 
facial moisturizer Eucerin Daily Protection Broad Spectrum SPF30 Face Lotion. Both products 
will be provided by the Sponsor. Alternative, non-medicated cleansers or moisturizers may be 
used if agreed to by the Sponsor. 
The use of or change in the dose of any and all concomitant medications, either prescription or 
over-the-counter (OTC), during the study will be recorded. The reason for use or change of dose 
of a concomitant therapy may need to be reported as an AE. Therapies (medication and non-
medication therapies) not restricted by the protocol may be used. Non-prohibited chronic 
therapies being used at Day 0/Baseline may be continued. If a female subject is using an oral 
contraceptive product, she should have been on the same product for at least 3 months and she 
should continue using the same or equivalent product for the duration of the study. 
If a subject is taking anticoagulant therapy, the subject should be advised that they may require a 
downward adjustment of their anticoagulant dosage. 
All topical or systemic medications listed in the exclusion criteria are prohibited during this 
study. Similarly, no other topical medications are permitted to be used on the face during this 
period. 
See the FMX103 Investigator’s Brochure (IB) for information about tetracyclines and possible 
drug-drug interactions. 
8.8 
Use of Contraception 
Tetracycline-class antibiotics can cause fetal harm when administered to a pregnant woman. 
Tetracycline-class antibiotics used during tooth development (last half of pregnancy, infancy, and 
childhood to the age of 8 years) may cause permanent discoloration of teeth (yellow-gray-
brown). 
Prior to study enrollment, females of childbearing potential must be advised of the importance of 
avoiding pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy. Females of childbearing potential include any female who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation/occlusion, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea 
>12 consecutive months). Females of childbearing potential must have a negative urine 
pregnancy test and, if they are sexually active or become sexually active during the study, must 
use an effective method of birth control such as those listed below during the course of the study. 
The following is not an all-inclusive list; the subject must discuss with the Investigator the most 
appropriate form of birth control: 
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• Hormonal methods 
o Oral contraceptives – (Oral antibiotics may lessen the effectiveness of oral 
contraceptives. Therefore, a second form of birth control must be utilized in 
subjects using oral contraceptives) 
o Implant 
o Injection 
o Transdermal patch 
o Intravaginal ring 
• Intrauterine device (hormonal or non-hormonal) 
• Barrier methods 
o Condom (male or female) with spermicide 
o Diaphragm with spermicide 
• Complete abstinence 
8.9 
Treatment Compliance 
Each subject is to be instructed on the importance of following the dosing schedule and returning 
all kits (empty/used/unused) at the appropriate visits. The study site personnel will question the 
subject on the history of study drug use since the last visit. A subject who deviates significantly 
from the prescribed dosage will be counseled. 
9 
EFFICACY ASSESSMENTS 
Every attempt must be made to ensure the same evaluator performs the efficacy evaluations for a 
particular subject throughout the study; when this is not possible, another approved evaluator 
may perform the evaluations. Following are the methods and scales that will be used to measure 
each of the efficacy parameters to be performed. 
9.1 
Co-Primary Efficacy Assessments 
The co-primary efficacy assessments will include the inflammatory lesion counts and the IGA of 
severity of disease. Lesion counts, IGA, and other efficacy evaluations will be performed by the 
Investigator/evaluator. 
9.1.1 
Lesion Counts 
The number of papules, pustules, and nodules will be counted and the numbers recorded. Facial 
area lesion counts will be made for the forehead, left and right cheeks, nose, and chin. The lesion 
counts will be performed at Screening and Visit 1 (Day 0/Baseline) to confirm eligibility, and 
again at Visit 3 (Week 4), Visit 4 (Week 8), and Visit 5 (Week 12/Final Visit). 
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9.1.2
Investigator Global Assessment 
The Investigator will also assess the global severity of rosacea using the IGA scale as described 
in Table 3. The IGA will be performed at Screening and Visit 1 (Day 0/Baseline) to confirm 
eligibility, and again at Visit 3 (Week 4), Visit 4 (Week 8), and Visit 5 (Week 12/Final Visit). 
Table 3 
IGA Scale for Rosacea – Study FX2016-12 
Score 
Grade 
Description 
0 
Clear 
No inflammatory papules or pustules 
1 
Almost clear 
Few inflammatory papules or pustules 
2 
Mild 
Several inflammatory papules or pustules 
3 
Moderate 
Moderate number of inflammatory papules or pustules and no nodules 
4 
Severe 
Many inflammatory papules or pustules, and up to 2 nodules 
9.2
Secondary 
 Efficacy Assessments 
9.2.1
Percent Change in Inflammatory Lesion Counts 
The percent change in inflammatory lesion counts at Visit 5 (Week 12/Final Visit) compared to 
Visit 1 (Day 0/Baseline) will be evaluated. 
9.2.2
Interim Change in Inflammatory Lesion Counts 
The absolute 
 change in inflammatory lesion counts at Visit 3 (Week 4) and Visit 4 
(Week 8) compared to Visit 1 (Day 0/Baseline) will be evaluated. 
9.2.3
Subject Global Assessment 
This score will be obtained from the subject at Visit 2 (Week 2), Visit 3 (Week 4), Visit 4 (Week 
8), and Visit 5 (Week 12/Final Visit) using the questionnaire in Appendix 1. 
9.2.4
Subject Satisfaction Questionnaire 
A subject satisfaction questionnaire (Appendix 2) will be administered at Visit 5 (Week 12/Final 
Visit). 
9.3
Photography 
Photography of the full face will be performed at Day 0/Baseline and at Weeks 4, 8, and 12 using 
recognized methods. The equipment and techniques for this photography and for archiving the 
images are described in the Study Manual. Photographs will be reviewed at the site and by the 
sponsor for quality. Photographs will not be used to assess the lesion counts or the IGA, but will 
be archived to be available for subsequent review, if required, by the sponsor, auditors, or the 
FDA. 
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10
SAFETY ASSESSMENTS 
The safety assessments in this study are standard safety measures in clinical studies, including 
physical examinations, the monitoring of vital signs, AEs (volunteered, observed, and elicited by 
general questioning in a non-suggestive manner), clinical laboratory tests, and local signs and 
symptoms assessments (including erythema, telangiectasia, burning/stinging, flushing/blushing, 
dryness/xerosis, itching, peeling/desquamation, and hyperpigmentation) scores. 
10.1
Medical/Surgical History 
A complete medical and surgical history will be obtained at Screening, which will include the 
following:  diseases of the head, ears, eyes, nose and throat; respiratory diseases; cardiovascular 
diseases; gastrointestinal diseases; hepatic diseases; genitourinary diseases; musculoskeletal 
diseases; endocrine diseases; neurological diseases; psychiatric diseases; skin diseases; allergies; 
hematological diseases; and other abnormalities. 
10.2
Medication History 
A history of medication usage (including previous use of rosacea medications and non-
medication therapies) will be recorded at Screening. The start and stop dates of previous use of 
medications in the last 3 months will be recorded. 
10.3
Concomitant Medications 
All topical or systemic medications listed in the exclusion criteria are prohibited. No other 
topical medications are permitted to be used on the face. All medication that the subject is 
currently taking or any change in medication or dosage since the last visit will be documented 
throughout the study. The use of or change in the dose of any and all concomitant medication, 
either prescription or OTC, during the study will be recorded. The reason for use or change of 
dose of a concomitant therapy may need to be reported as an AE. 
10.4
Vital Signs 
Heart rate and blood pressure (BP) will be measured at all post-Day 0/Baseline visits. All BP 
measurements will be made using a sphygmomanometer with an appropriate cuff size for the 
individual subject. Measurements will be taken while the subject is seated after at least 5 minutes 
at rest. 
10.5
Physical Examination 
A complete physical examination (excluding the genitourinary examination) will be performed. 
Weight will be recorded at the Visit 1 (Day 0/Baseline) and Visit 5 (Week 12/Final Visit). Height 
will be measured at Visit 1 (Day 0/Baseline) only. 
10.6
Clinical Laboratory Tests 
Serum chemistry, hematology and urinalysis will be evaluated at the Screening Visit and 
Visit 5 (Week 12/Final Visit). All clinical laboratory tests will be performed at a central 
laboratory. Table 4 presents the specific clinical laboratory tests to be evaluated. 
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Please refer to the manual from the central laboratory for detailed instructions on collecting, 
processing, and shipping of samples. 
Table 4 
Clinical Laboratory Tests – Study FX2016-12 
Hematology 
Urinalysis 
Serum chemistry 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) 
count with differential 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocytes esterase 
pH 
Protein 
Specific gravity 
 
 
Urine pregnancy test performed at the site 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase 
Aspartic acid transaminase (AST) 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Creatinine kinase 
Gamma glutamyl transferase (GGT) 
Globulin 
Glucose 
Phosphorus 
Potassium 
Sodium 
Total bilirubin (if elevated obtain 
direct bilirubin) 
Total protein 
Uric acid 
 
10.6.1 
Urine Pregnancy Test 
A urine pregnancy test will be performed on all females of childbearing potential at the 
Screening Visit, Visit 1 (Day 0/Baseline), Visit 3 (Week 4), Visit 4 (Week 8), and Visit 5 (Week 
12/Final Visit) or when a subject prematurely withdraws from the study. 
10.6.2 
Sample Collection, Storage, and Shipping 
Sample collection kits, requisition slips, and shipping boxes will be supplied by the central 
laboratory. Sample collection procedures and shipping instructions will be detailed in the 
laboratory manual. Study sites must be equipped to store the samples according to the laboratory 
manual procedures before shipping to the central laboratory. 
10.7 
Other Safety Measurements 
10.7.1 
Local Signs and Symptoms Assessments 
The severity of each of the following local signs and symptoms will be measured at Screening, 
Visit 1 (Day 0/Baseline), and at each study visit:  erythema, telangiectasia, burning/stinging, 
flushing/blushing, dryness/xerosis, itching, peeling/desquamation, and hyperpigmentation. The 
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score for signs will be determined by the Investigator and must represent the subject’s condition 
at the time of the evaluation; the score for symptoms (ie, burning/stinging, flushing/blushing) 
should be scored based on the subject’s symptoms reported for the previous 3 days. 
These signs/symptoms should not be included as AEs, unless a sign/symptom is believed to have 
been related to the study medication or is the reason for discontinuation from the study. 
10.7.1.1 
Erythema (Clinical Erythema Assessment Scale) 
Erythema of the face will be graded according to the following scale: 
• 0 = clear skin/no signs of erythema 
• 1 = almost clear of erythema, slight redness 
• 2 = mild erythema, definite redness 
• 3 = moderate erythema, marked redness 
• 4 = severe erythema, fiery redness 
10.7.1.2 
Telangiectasia 
The severity of facial telangiectasia will be graded according to the following scale: 
• 0 = None 
• 1 = Mild:  scattered telangiectasia 
• 2 = Moderate:  numerous telangiectasia 
• 3 = Severe:  dense telangiectasia forming sprays of vessels 
10.7.1.3 
Burning/Stinging 
The severity of facial burning/stinging will be graded according to the following scale: 
• 0 = None:  no warm or burning sensation 
• 1 = Mild:  slight warm tingling/stinging sensation; not really bothersome 
• 2 = Moderate:  constant or intermittent warm tingling/stinging sensation that is somewhat 
bothersome 
• 3 = Severe:  bothersome warm to hot tingling/stinging sensation 
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10.7.1.4 
Flushing/Blushing 
The severity of facial flushing/blushing will be graded according to the following scale: 
• 0 = None 
• 1 = Mild:  sporadic episodes lasting for a few moments to several minutes 
• 2 = Moderate:  intermittent episodes lasting for greater than 30 minutes 
• 3 = Severe:  almost constant episodes lasting for several hours 
10.7.1.5 
Dryness/Xerosis 
The severity of facial dryness/xerosis will be graded according to the following scale: 
• 0 = None 
• 1 = Mild 
• 2 = Moderate 
• 3 = Severe 
10.7.1.6 
Itching 
The severity of facial itching will be graded according to the following scale: 
• 0 = None 
• 1 = Mild:  sporadic itching lasting for a few moments to several minutes 
• 2 = Moderate:  intermittent itching lasting for greater than 30 minutes 
• 3 = Severe:  almost constant, intense itching lasting for several hours 
10.7.1.7 
Peeling/Desquamation 
The severity of facial peeling/desquamation will be graded according to the following scale: 
• 0 = No peeling 
• 1 = Mild:  small, scattered areas of scaling/flaking 
• 2 = Moderate:  larger, contiguous areas of scaling/flaking 
• 3 = Severe:  pronounced flaking/shedding scales covering entire application area 
10.7.1.8 
Hyperpigmentation 
The severity of facial skin hyperpigmentation will be graded according to the following scale: 
• 0 = None 
• 1 = Mild:  few scattered, small areas of light hyperpigmentation 
• 2 = Moderate:  larger or more intense areas of hyperpigmentation 
• 3 = Severe:  intense, extensive hyperpigmentation 
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10.8 
Adverse Events 
10.8.1 
Method of Determining Adverse Events 
Safety assessments will include recording AEs reported spontaneously by the subject or observed 
by the Investigator. AEs will be recorded at each visit on the appropriate CRF. Every attempt 
should be made to describe the AE in terms of a diagnosis. If a clear diagnosis has been made, 
individual signs and symptoms will not be recorded unless they represent atypical or extreme 
manifestations of the diagnosis, in which case they should be reported as separate events. If a 
clear diagnosis cannot be established, each sign and symptom must be recorded separately. 
Subjects should be asked whether, since the time of the last observation or visit, they had any of 
the following: 
• Experienced any changes in well-being 
• Used any new medications 
• Changed medication regimens (both prescription and OTC) 
• Were admitted to a hospital or had any accidents 
• Developed unusual headaches or changes in vision 
With exception to the above, all questions should be of a general nature and should not suggest 
symptoms. 
When an AE is suspected, all relevant evaluations will be performed and appropriate treatment 
provided. Additional follow-up will be done as necessary (Section 10.8.4) and recorded in the 
subject’s source documents, and the results will be provided to the Sponsor. 
For AE definitions and reporting requirements, refer to Section 10.8.2 and Section 10.8.3, 
respectively. 
10.8.2 
Adverse Event Definitions 
10.8.2.1 
Adverse Events 
An AE is any unfavorable or unintended sign, symptom, or disease that appears or worsens in a 
subject after the subject signs the ICF for a clinical study. 
Examples of what may be considered an AE include any of the following: 
• A new illness. 
• An exacerbation of a sign or symptom of an underlying condition or of a concomitant illness 
unrelated to participation in the clinical study or an effect of the study drug or comparator 
drug. 
No causal relationship with the study drug is implied by the use of the term “adverse event.” An 
exacerbation of a pre-existing condition/illness is defined as a more frequent occurrence or as an 
increase in the severity of the pre-existing condition/illness during the study. Planned or elective 
surgical procedures for pre-existing conditions that have not worsened are not AEs. However, 
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any complication that occurs during a planned or elective surgery is an AE (Note:  If the event 
meets the criteria for a serious adverse event [SAE], such as an extended hospitalization, it will 
be considered an SAE). Conditions leading to unplanned surgical procedures may also be AEs. 
10.8.2.2 
Serious Adverse Events 
A serious adverse event (SAE) is any AE that: 
• Results in death. 
• Is life-threatening. 
(Note:  The term “life-threatening” refers to any AE that, as it occurs, puts the subject at 
immediate risk of death. It does not refer to an AE that hypothetically might have caused 
death if it were more severe.) 
• Results in hospitalization or prolongation of current hospitalization (not including 
hospitalization for a pre-existing condition that has not increased in severity or frequency 
from the subject’s underlying medical condition prior to entry into the study). 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect in the offspring of a subject. 
• Is another serious (important medical events) event. 
(Note:  Important medical events may not be immediately life-threatening or result in 
death or hospitalization but may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the subject or require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; blood dyscrasias or convulsions that do not result in inpatient hospitalization; 
or development of drug dependency or drug abuse.) 
SAEs will be reported by the Sponsor to the regulatory authorities as required. 
10.8.2.3 
Severity of Adverse Events 
Severity of an AE refers to the extent to which an AE affects the subject’s daily activities and 
differs from “serious”, which is a regulatory classification. Severity will be categorized 
according to the following criteria: 
• Mild:  The symptom has a negligible effect or no impairing effect on the subject’s normal 
function. 
• Moderate:  The symptom impairs the subject’s normal function to some extent. 
• Severe:  The symptom has an obvious, significantly impairing effect on the subject’s normal 
function. 
10.8.2.4 
Relationship of Adverse Events to Study Treatments 
Causality refers to the relationship of the AE to study drug and will be categorized according to 
the following criteria: 
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•
Unlikely:  There is no medical evidence to suggest that the AE may be related to study drug
usage, or there is another more probable medical explanation.
•
Possible:  There is medical evidence to suggest that there is a reasonable possibility that the
AE may be related to study drug usage. However, other medical explanations cannot be
excluded as a possible cause.
•
Probable:  There is strong medical evidence to suggest that the AE is related to study drug
usage.
10.8.2.5
Adverse Events Expectedness 
Expected AEs are defined as those described in the FMX103 IB. If an event increases in intensity 
or severity from that described in the IB, it will be considered unexpected. 
10.8.3
Reporting Adverse Events 
Adverse events that occur from the time of informed consent/assent through completion of the 
last study visit should be reported. Any AE that the Investigator becomes aware of that occurs 
within 30 days of study completion or withdrawal should also be reported. 
Any SAEs occurring in a subject receiving study drug must be reported to the Sponsor or 
designee within 24 hours of the site being informed of the event, even if the event does not 
appear to be drug-related. The report must be done by faxing the completed SAE Report Form to 
the Sponsor or designee. Any pertinent follow-up information should be provided in a similar 
manner. Contact information is provided below: 
10.8.4
Adverse Event Follow-up 
Adverse events that are ongoing when a subject withdraws from or completes the study will be 
followed until resolution or stabilization (in the opinion of the Investigator), or for 30 days, 
whichever is shorter. Investigators and the Sponsor will decide if longer follow-up is appropriate 
on a case-by-case basis. Subjects who experience any clinically significant AE will remain under 
medical supervision until the Investigator or the Sponsor’s medical monitor deems the AE to be 
resolved, stabilized, or no longer serious enough to warrant follow-up. 
Laboratory values that are abnormal and not assessed as AEs may be followed at the discretion 
of the Investigator or the Sponsor’s medical monitor until resolved or stabilized. 
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10.8.4.1 
Pregnancy Reporting 
Prior to study enrollment, females of childbearing potential must be advised of the importance of 
avoiding pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy. The ICF that the subject signs must document this discussion. 
If a subject or Investigator suspects that the subject may be pregnant prior to study drug 
administration, the study drug must be withheld until the results of laboratory pregnancy testing 
are available. If pregnancy is confirmed, the subject must not receive study drug and must not be 
enrolled in the study. 
A urine pregnancy test will be performed on all females of childbearing potential as described in 
Section 10.6.1. 
During the study, all female subjects of childbearing potential should be instructed to contact the 
Investigator immediately if they suspect they might be pregnant (eg, missed or late menstrual 
period). If a subject or Investigator suspects that the subject may be pregnant at any time before 
or during the study, the study drug must be withheld until the results of laboratory pregnancy 
testing are available. The Sponsor and site monitor must be notified and relevant information 
collected on the appropriate form. If pregnancy is confirmed, the subject must be withdrawn 
from the study and the Sponsor and site monitor notified. Additional relevant information about 
the confirmed pregnancy will be recorded on the appropriate form(s); pregnancy will not be 
captured as an AE. 
The subject should be followed until the outcome of the pregnancy is known. 
10.8.5 
Clinically Significantly Abnormal Laboratory Results  
All laboratory values that are outside of the normal range for that parameter will be so flagged 
when reported to the site. The Investigator will determine which out-of-range laboratory test 
results should be characterized as clinically significant and will so annotate the laboratory report. 
If a clinically significant laboratory abnormality requires treatment or is the reason for a subject 
being discontinued from the study, the abnormal result must also be classified as an AE. 
10.9 
Appropriateness of Safety Measurement 
The safety assessments to be utilized in this study are standard safety measures in clinical trials. 
11 
STATISTICAL DESIGN AND ANALYSIS 
11.1 
Statistical Analysis Plan 
A detailed statistical analysis plan (SAP) will be finalized prior to breaking of the study blind. 
Descriptive statistics for qualitative variables (eg, race) will include the number and percentage 
of subjects with the qualitative response. Missing responses will be enumerated, but the 
calculation of percentages will exclude missing responses. For quantitative variables (eg, age), 
descriptive statistics will include the number of subjects with non-missing data, mean, standard 
deviation, median, and minimum and maximum values. All hypothesis testing will be conducted 
using two-sided tests with a 0.05 level of significance. 
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o Randomization error 
Prior to breaking the blind, additional criteria for exclusion from the PP population may 
be included to accommodate for unforeseen events that occurred during the conduct of 
the study. 
• Safety Population:  all randomized subjects who use any study product. Subjects who have 
no post-Day 0/Baseline assessments will be included in the Safety population unless all 
dispensed study drug is returned unused. 
The ITT population will be the primary population for efficacy analysis. The PP population will 
be secondary for the co-primary endpoints only. The Safety population will be used for the 
analyses of safety endpoints. 
All efficacy analyses will be conducted according to the randomized treatment assignment; all 
safety analyses will be conducted according to the treatment actually received. 
11.4 
Subject Accounting, Demographics, and Day 0/Baseline Characteristics 
Demographics, Day 0/Baseline characteristics, and prior and concomitant medications will be 
summarized by treatment. Study completion status and reasons for discontinuation will also be 
displayed by treatment. 
Medical and surgical history will only be presented in the listings. 
11.5 
Efficacy Endpoints 
The primary population for all efficacy analyses will be the ITT population. For the analyses of 
the co-primary and secondary efficacy endpoints based on the ITT population, a variety of 
methods will be used to impute missing data, including multiple imputation (MI), last-
observation-carried forward (LOCF), and Day 0/Baseline observation carried forward (BOCF). 
MI will be the primary imputation method. Sensitivity analyses using LOCF and BOCF will be 
performed only on the co-primary efficacy endpoints to assess the robustness of alternate 
imputation assumptions. For the continuous efficacy measure, a mixed effects model for repeated 
measures (MMRM) analysis will also be conducted as a sensitivity analysis. All supportive 
analyses using the PP population will use the Observed-Cases (OC) approach, that is there will 
be no imputation for missing data at any time point. No other imputations will be made unless 
otherwise specified. 
For all efficacy analyses, subjects will be analyzed according to the treatment group to which 
they were randomized. 
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and individual subject listings. No statistical tests will be performed for any of the safety 
assessments. 
Treatment-emergent AEs (TEAEs) will be defined as events that emerge having been absent 
pre-treatment, or worsen relative to the pre-treatment state. Summaries of AEs will be limited to 
TEAEs. The number and percentage of subjects reporting events under each System Organ Class 
(SOC) and preferred term (PT) will be summarized for each treatment group. At each level of 
summarization, a subject will be counted only once if he/she reported one or more events. The 
severity of TEAEs and relationship to study drug will be summarized in a similar manner. For 
summaries of relationship to study drug, a subject will be classified according to the closest 
relationship. For summaries of TEAE severity, a subject will be classified according to the 
highest severity. 
TEAEs, vital signs, and clinical laboratory measurements will be summarized by treatment group 
using descriptive statistics. For vital signs, change from Day 0/Baseline values will also be 
summarized. For all safety variables, subject data listings will be provided. 
Local signs and symptoms assessments will include active assessments of erythema, 
telangiectasia, burning/stinging, flushing/blushing, dryness/xerosis, itching, 
peeling/desquamation, and hyperpigmentation using the scales described under Section 10.7.2. 
11.6.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) terminology will be used to 
classify all AEs with respect to SOC and PT. 
Summaries of SAEs and subjects who prematurely withdraw from the study due to AEs will be 
presented. 
11.6.2 
Vital Signs and Physical Examinations 
Vital sign and physical examination parameters will be summarized using descriptive statistics at 
Day 0/Baseline and at each post-Day 0/Baseline time point. Changes from Day 0/Baseline will 
also be summarized. Day 0/Baseline is defined as the last non-missing value prior to the first 
dose of study drug. 
11.6.3 
Clinical Laboratory Results 
Shift tables for each clinical laboratory test will cross-tabulate the number of subjects with values 
below the laboratory reference range (low), values within the laboratory reference range 
(normal), or above the laboratory range (high) at Day 0/Baseline with the number of subjects 
with low, normal, or high values at the Final Visit. Day 0/Baseline is defined as the last non-
missing value prior to the first dose of study drug. 
A listing of subjects with pre-treatment and treatment-emergent clinically significant abnormal 
laboratory values will be presented for each treatment group. Clinical significance is based on 
the Investigator’s judgment. 
11.7 
Interim Analysis 
No interim analysis is planned. 
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12 
STUDY MANAGEMENT 
12.1 
Monitoring 
The Investigator will be responsible for preparing and maintaining adequate and accurate source 
documents (medical records, raw data collection forms, etc.) designed to record all observations 
and other pertinent data for each subject treated with the study drug. The Investigator will allow 
representatives of the Sponsor, contract designees, authorized regulatory authority inspectors, 
and the Institutional Review Board (IRB) to have direct access to all documents pertaining to the 
study. The Investigator is to immediately notify the Sponsor of any regulatory authority 
inspections. The Investigator will be informed about the outcome of any Sponsor audit. 
This study will be monitored regularly, by or under supervision of a monitor from the Sponsor. 
The frequency of monitoring visits will be agreed upon by the Sponsor’s representative and the 
study site. 
Monitoring visits will take place on a regular basis according to the enrollment rate and number 
of subjects enrolled at each investigational site. During these visits, the monitor will check the 
completion of the CRF entries, compliance with the study protocol and with GCP-ICH, and their 
agreement with the source data. The monitor will also verify the correct use of the study drug. At 
a final visit, the monitor will check all remaining material including the remaining quantities of 
the study drug and will organize their return to the Sponsor or designee. At each visit, the 
Investigator and staff will be expected to cooperate with the Sponsor’s representative(s) for the 
purposes of review and verification of protocol compliance, AE reporting, CRFs, source 
documents, clinical supplies and inventory records, and any additional records as may have been 
previously arranged between the Investigator and the Sponsor’s representative(s). 
The Investigator and/or other designated study personnel are expected to contact the Sponsor’s 
clinical research associate, as needed, regarding study concerns and/or questions. Contact 
information is provided in the Study Reference Manual for the site. 
12.2 
Protocol Amendments 
The Sponsor may propose to amend this protocol at any time. 
No change to the protocol will be implemented until the Sponsor and the IRB have reviewed and 
approved the amendment. 
12.3 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the IRB-approved protocol 
(intentional or unintentional). All deviations are to be documented at the site and reported to the 
IRB according to the IRB’s guidelines. 
In the event of an emergency, the Investigator shall implement any medical procedures deemed 
appropriate for subject safety. All such procedures must have written documentation and be 
promptly reported to the Sponsor and IRB. 
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12.4 
Withdrawal of Subjects 
Withdrawn subjects are those who do not complete all evaluations and procedures outlined in the 
protocol. Subjects who discontinue taking study drug for any reason must also be withdrawn 
from the study. Subjects may be withdrawn from the study because of any of the following: 
• Adverse Event:  An AE that, in the opinion of the Investigator or Sponsor, suggests that 
continued participation in the study is not in the subject’s best interest for safety reasons. All 
AEs that are present when the subject withdraws from the study will be followed as 
described in Section 10.8.4. 
• Abnormal Laboratory Result:  Any clinically significant laboratory abnormality that 
requires withdrawal of the subject from the study should be considered an AE leading to 
withdrawal. If possible, laboratory tests will be repeated for any results that were clinically 
significantly abnormal until the abnormality is resolved or stabilized to the satisfaction of the 
Investigator in consultation with the medical monitor. 
• Lost to Follow-up:  Confirmed at minimum by two phone calls and a traceable letter without 
answer. 
• Subject Request:  Subject requests, for any reason (eg, AE), to be withdrawn or withdraws 
his/her consent. 
• Protocol Deviation:  A subject may be withdrawn from the study at the discretion of the 
Investigator or Sponsor due to poor compliance with protocol requirements that may 
compromise the study results or subject safety. 
• Other:  Other reasons include but are not limited to, Investigator decision that it is in the 
subject’s best interest to be withdrawn, administrative reasons, relocation of subject, etc. If a 
subject becomes pregnant during the study, the subject will be withdrawn from the study and 
followed through conclusion of the pregnancy. 
If a subject is withdrawn from the study following the start of study drug, all Visit 5 
(Week 12/Final Visit) assessments should be completed. Subjects withdrawn from the study will 
not be replaced. 
12.5 
Termination of the Study 
The study may be terminated at any time at the request of the Sponsor or a regulatory authority, 
with proper and timely notification of all parties concerned. The IRB will be informed promptly 
and the Sponsor or the Investigator will supply reason(s) for the termination or suspension, as 
specified by the applicable regulatory requirements. Otherwise, the study is considered 
terminated upon completion of all subject treatments and evaluations. 
12.6 
Publication Policy 
The data obtained in this study are the property of the Sponsor, which will make reasonable 
efforts to assure that the results are published in a peer-reviewed journal. As some of the 
information concerning the investigational product and development activities at the Sponsor 
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may be of a strictly confidential nature, any manuscript or other presentation of data must first be 
reviewed by the Sponsor before its submission. 
13 
ETHICS 
13.1 
Conduct of the Study 
This study will be conducted in accordance with the ICH Harmonized Tripartite Guideline for 
GCP, 1997; the US Title 21 CFR parts 50, 56, and 312; and the ethical principles that have their 
origin in the Declaration of Helsinki. The study will not begin until all of the requirements of the 
appropriate regulatory authorities have been fulfilled. 
13.2 
Institutional Review Boards (IRB) 
This protocol (and any changes), all consent forms, and subject consent procedures must be 
reviewed and approved by a properly constituted IRB. The information presented to the IRB at 
the time initial approval is sought must include any plans for subject recruitment that involve 
advertising or other direct contact with potential subjects outside of the physician-subject 
relationship. A letter of approval issued by the IRB must be sent to the Sponsor prior to initiation 
of the study. Any changes made to the protocol must be approved by the IRB prior to 
implementation, except where needed to eliminate a potential imminent safety hazard to the 
subjects. In this case, immediate implementation may take place followed by IRB approval. 
Review and approval by the IRB for continuation of the study must take place at least once a 
year. 
13.3 
Written Informed Consent 
The Investigator or designee will explain the nature of the study, its purpose and associated 
procedures, the expected duration, and the potential benefits and risks of participation to each 
subject prior to his/her entry into the study (ie, before examinations and procedures associated 
with selection for the study are initiated). Each subject will have ample opportunity to ask 
questions and will be informed about the right to withdraw from the study at any time without 
any disadvantage and without having to provide reasons for this decision. 
Following this informative discussion, the subject will be asked if he/she is willing to sign a 
statement of informed consent. Only subjects who voluntarily sign the ICF may enter the study. 
The ICF must be reviewed and approved by the Sponsor and the IRB prior to their use. 
The original signed ICF will remain in the Investigator’s files. The Investigator or designee will 
indicate in each subject’s source documents that he/she has informed the subject about the study 
and its procedures, the subject has signed and dated the ICF, and the subject has been given a 
copy of the documents. The Investigator or designee will inform subjects of any new information 
that may be relevant to the subject’s willingness to continue in the study. 
13.4 
Subject Confidentiality 
The Sponsor ensures that the following have permission to review all study-related documents:  
monitor, auditor, IRB, and regulatory authorities. The subject’s identity and study-related records 
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will remain confidential throughout the duration of the study data collection and reporting 
process. 
The investigative site assigns a unique subject identification code to each potential study subject. 
The identification code protects the subject’s identity and is used in lieu of the subject’s name 
when reporting subject data. The data will always maintain the confidentiality of the subject. 
The Investigator or designee will review the subject data, which will be referenced using the 
subject identifier. At the conclusion of the study, the data obtained may be presented to regional 
regulatory authorities but the subject’s identity will not be revealed. In addition, if any clinical 
data obtained from the study is published in scientific journals or presented at scientific meetings 
the subject’s identity will not be revealed. 
13.5 
Records Retention 
The Investigator must maintain essential study documents (protocol and amendments, source 
documentation corresponding to all information contained in the CRFs, signed ICF and assent 
forms, relevant correspondence, and all other supporting documentation) until at least 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region, or at least 2 years after the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period if required by the applicable regulatory requirements or the 
hospital, institution, or private practice in which the study is being conducted. Subject 
identification codes (subject names and corresponding study numbers) will be retained for this 
same time period. Custody of the records may be transferred to another responsible party, 
acceptable to the Sponsor, who agrees to abide by the retention policies. Written notice of 
transfer must be submitted to the Sponsor. The Investigator must contact the Sponsor prior to 
disposing of any study records. 
13.6 
Financing 
Funding for this study will be agreed between the Investigator and the Sponsor and will be 
confirmed in writing before the study starts. 
Completion of Financial Disclosure Forms will be required before the study starts. Any additions 
to the primary site personnel will necessitate the completion of new Financial Disclosure Forms. 
This information will also be collected at site closure and 1 year after the completion of the 
study. 
14 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor and Investigator will take all steps possible to ensure the accuracy, consistency, 
completeness, and reliability of the data, including participating in an Investigator meeting 
and/or site initiation visit, routine site monitoring, review of CRFs against source documents, and 
quality control checks. 
In addition, a representative from the Sponsor’s Clinical Quality Assurance (CQA) Department 
may conduct periodic audits of the study processes, including, but not limited to, auditing the 
clinical site, laboratories, vendors and CROs, the clinical database, and the final study report. 
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15 
DATA HANDLING AND RECORD KEEPING 
This study will use web-based, electronic case report forms (eCRFs) developed through a 
validated, Electronic Records/Electronic Signatures-compliant platform (US Title 21 CFR 
Part 11). Foamix Clinical Data Management department or designee will create the eCRFs and 
corresponding clinical database based on the final protocol. 
All site personnel who will be using this system will receive formal training on the system, after 
which each person will be issued a unique username and password. Only the person who owns 
the username and password will enter the system using that username and password. For data 
security reasons and to be in compliance with regulatory guidelines, usernames and passwords 
are not transferable. 
The Investigator is responsible for all data entered via the remote data capture (RDC) system 
eCRFs and must confirm the accuracy of the data by electronically approving (signing) the 
eCRFs. This responsibility includes the timely completion and accuracy of the data entered into 
the eCRFs by their site personnel as well as the review and approval of some data entered 
directly into the database (eg, clinical laboratory results) by an external vendor. The Sponsor will 
review the database to identify data errors or inconsistencies, which will be posted in the RDC 
system as queries for resolution. In addition, the Sponsor may make obvious corrections to the 
data in the database (eg, obvious errors in dates) and so inform the Investigator without issuing a 
query to the site. 
16 
REFERENCE LIST 
Not applicable. 
17 
STUDY AMENDMENTS 
This section describes the amendment(s) that have been made to the protocol for Study 
FX2016-12. 
Section 17.1 describes the changes made to Protocol FX2016-12 Version 1 issued January 20, 
2017, via Amendment 1 effective March 6th, 2017. 
17.1 
Amendment 1, effective March 6th, 2017 
The following is the summary of the changes that were made to Protocol FX2016-12 Version 1 
issued January 20, 2017. 
Content changes:  
New or changed text is bolded. 
 
 
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Section(s) 
Revision 
Rationale 
Old Text 
New Text 
Sect. 7.2 Visit 1, 
Day 0/Baseline 
Visit 
New text. 
Dispense facial cleanser and 
moisturizer. 
Clarification of the 
need to dispense 
cleanser and 
moisturizer at Day 
0/Baseline. 
Sect. 7.4 
• Confirm that subject 
continues to use 
only the provided 
facial cleanser. 
• 
Confirm that subject 
continues to use only the 
provided facial cleanser 
and moisturizer. 
Reflecting the addition 
of moisturizer. 
Sect. 7.5 and 7.6 
• Confirm that subject 
continues to use 
only the provided 
facial cleanser. 
• 
Confirm that subject 
continues to use only the 
provided facial cleanser 
and moisturizer and 
dispense additional 
quantities as required. 
Clarification of cleanser 
and moisturizer re-
supply to subjects. 
Sect. 8.7 
Prior/Concomitant 
Therapy 
• Subjects should use 
the facial cleanser 
Cetaphil Gentle 
Skin Cleanser 
(which will be 
provided by the 
Sponsor). An 
alternative, non-
medicated cleanser 
may be used if 
agreed to by the 
Sponsor. 
• 
As necessary, subjects 
should use the facial 
cleanser Cetaphil Gentle 
Skin Cleanser and the 
facial moisturizer 
Eucerin Daily Protection 
Broad Spectrum SPF30 
Face Lotion. Both 
products will be 
provided by the Sponsor. 
Alternative non-
medicated cleansers or 
moisturizers may be 
used if agreed to by the 
Sponsor. 
Addition of a SPF-
containing moisturizer 
to support a positive 
skin care regimen 
during the study. 
Synopsis, 
Endpoints and 
Outcomes;   
The efficacy parameters 
will include 
inflammatory lesion 
counts, IGA at Day 
0/Baseline and at 
Weeks 4, 8, and 12 
(Final Visit), and the 
subject global 
assessment and 
satisfaction 
questionnaire at the 
Final Visit. 
The co-primary efficacy 
parameters, include 
inflammatory lesion counts 
and IGA, will be evaluated at 
Day 0/Baseline and at Weeks 
4, 8, and 12 (Final Visit). The 
Subject Global Assessment 
will be performed at Weeks 2, 
4, 8, and 12 (Final Visit). The 
subject satisfaction 
questionnaire will be assessed 
at Week 12 (Final Visit) only. 
Addition of more 
frequent subject global 
assessments to be 
conducted at each post-
Day 0/Baseline visit. 
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Section(s) 
Revision 
Rationale 
Old Text 
New Text 
Table 1 Schedule 
of Study 
Assessments and 
Procedures – Study 
FX2016-12: 
Subject Global 
Assessment 
Subject Global 
Assessment at Week 12 
(Final Visit) only 
Additional Subject Global 
Assessments added at Weeks 
2, 4, and 8. 
Addition of more 
frequent subject global 
assessments to be 
conducted at each post-
Day 0/Baseline visit. 
Sect. 7.4; 7.5 and 
7.6 
New text. 
Have the subject complete 
the Subject Global 
Assessment (Section 9.2.3) 
As above. 
Sect. 9.2.3 
This score will be 
obtained from the 
subject at Visit 7 (Week 
12/Final Visit) using 
the questionnaire in 
Appendix 1. 
This score will be obtained 
from the subject at Visit 2 
(Week 2), Visit 3 (Week 4), 
Visit 4 (Week 8), and Visit 5 
(Week 12/Final Visit) using 
the questionnaire in 
Appendix 1. 
As above. 
Sect. 6.2 Exclusion 
Criteria 23 
Screening 
electrocardiogram 
(ECG) that reveals a 
QTcF >500 msec. 
Text removed. 
A review of Solodyn® 
product labelling and 
an assessment of the 
safety and 
pharmacokinetics of 
minocycline when 
topically applied as 
FMX101 (4% 
minocycline HCl foam) 
to moderate-to-severe 
acne vulgaris subjects 
under maximum use 
conditions (4g per day 
for 21 days) warrants 
the removal of  ECG 
assessments at Day 
0/Baseline as it has 
been determined by the 
Sponsor as being an 
unnecessary procedure. 
Table 1 Schedule 
of Study 
Assessments and 
Procedures – Study 
FX2016-12 
Electrocardiogram 
Text removed. 
As above. 
Sect. 7.1 Screening 
Visit 
Perform 12-lead ECG 
(Section 10.7.1) 
Text removed. 
As above. 
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Old Text 
New Text 
Sect. 10.7.1 
Electrocardiograms 
A standard 12-lead 
ECG will be performed 
at Screening only. 
Subjects will be supine 
and at rest for at least 
10 minutes before 
measurement. Subjects 
will have their 
participation 
discontinued if an ECG 
reveals a 
QTcF>500msec (see 
Exclusion Criterion 
23). 
Text removed. 
As above. 
Global change 
Visit schedule has been 
adjusted from Visit 1 
(Day 0/Baseline); Visit 
2 (Week 1); Visit 3 
(Week 4); Visit 4 
(Week 6); Visit 5 
(Week 8); Visit 6 
(Week 10) and Visit 7 
(Week 12/Final Visit) 
New schedule is Visit 1 (Day 
0/Baseline); Early Follow-up 
(Week 1); Visit 2 (Week 2); 
Visit 3 (Week 4); Visit 4 
(Week 8) and Visit 5 (Week 
12/Final Visit). 
To remove unnecessary 
study visits. 
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Section(s) 
Revision 
Rationale 
Old Text 
New Text 
Sect. 7.3 Early 
Follow-up, Week 1 
(±3 Days) 
New text. 
7.3 Early Follow-up, Week 1 
(±3 Days) 
An early follow-up telephone 
call will be made 1 week 
after Visit 1, Day 0/Baseline. 
Record concomitant 
medications (Section 8.7). 
Record AEs (Section 10.8). 
Confirm that subject 
continues to use only the 
provided facial cleanser and 
moisturizer. 
Review application 
instructions to confirm that 
the subject continues to use 
the study drug as directed. 
Schedule/confirm the next 
study visit and remind 
subject to avoid 
overexposure to sunlight and 
to use the same make-up 
brand/type, or frequency of 
use, throughout the study as 
applicable. 
To support early 
contact with subjects to 
address outstanding 
questions and reinforce 
study instructions. 
Sect. 7.7 Visit 5, 
Week 12 (-3/+5 
days) / Final Visit 
or Early 
Termination 
Schedule/confirm a 
safety follow-up 
telephone call 4 weeks 
from Visit 7/Week 12 
(Final Visit) date (±5 
days) for subjects that 
will not participate in 
study FX2015-13 
(Open label study) 
(Section 7.9). 
Schedule/confirm a safety 
follow-up telephone call 4 
weeks from Visit 5/Week 12 
(Final Visit) date (±5 days) 
only for subjects that will not 
participate in study FX2015-
13 (Open label study) (Section 
7.9) and presented with 
either new or on-going 
adverse events at Visit 
5/Week 12 (Final Visit). 
Clarification of Safety 
Follow telephone call 
requirements. 
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Section(s) 
Revision 
Rationale 
Old Text 
New Text 
Sect. 7.8 Safety 
Follow-Up ((±5 
days) 
A safety follow-up 
telephone call will be 
made 4 weeks after 
Visit 7/Week 12 (Final 
Visit) for only those 
subjects that do not 
participate in study 
FX2015-13 (Open label 
study). Follow up on 
existing and any new 
concomitant 
medications and 
adverse events will be 
recorded. 
A safety follow-up telephone 
call will be made 4 weeks 
after Visit 5/Week 12 (Final 
Visit) for only those subjects 
that do not participate in study 
FX2015-13 (Open label study) 
and presented with either 
new or on-going adverse 
events at Visit 5/Week 12 
(Final Visit). Follow up on 
these adverse events and any 
new concomitant medications 
will be recorded. 
Clarification of AE 
reporting requirements. 
Synopsis, 
Diagnosis and 
Main Criteria for 
Inclusion 
At least 12 and not 
more than 50 
inflammatory facial 
lesions (ie, 
papules/pustules),… 
At least 15 and not more than 
75 inflammatory facial lesions 
(ie, papules/pustules),… 
Change inflammatory 
lesion count range in 
the inclusion criteria 
from 12-50 to 15-75. 
Sect. 6.1 Inclusion 
Criteria 
a. At least 12 and not 
more than 50 facial 
papules and pustules… 
a. At least 15 and not more 
than 75 facial papules and 
pustules… 
As above. 
Table 2 Study 
Drug Kits and 
Treatments – 
Study FX2016-12 
Additional kits of 
2 canisters may be 
dispensed at other visits 
if required. 
Text removed. 
Redundant text due to 
change in visit 
schedule. 
Sect. 8.1.1 Dosing 
Instructions 
Additional kits will be 
available for dispensing 
at other visits (ie, Visits 
4 and 6) to ensure 
enough product is 
available for daily 
dosing. 
Text removed. 
As above. 
Sect. 12.2 Protocol 
Amendments 
In the event of an 
emergency, the 
Investigator shall 
implement any medical 
procedures deemed 
appropriate for subject 
safety. All such 
procedures must have 
written documentation 
and be promptly 
reported to the Sponsor 
Text removed. 
Misplaced text / 
repetition. 
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Section(s) 
Revision 
Rationale 
Old Text 
New Text 
Appendix 3 
New text. 
Addition of investigator 
acknowledgement of protocol 
review and receipt. 
Investigator 
confirmation of review 
and receipt of study 
protocol. 
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APPENDIX 1:  Subject Global Assessment Questionnaire 
Question:  “Considering your rosacea just before starting treatment and considering your 
condition today, indicate the change you have experienced according to the scale below”: 
 
• 5 = Much better than prior to treatment 
• 4 = Slightly better than prior to treatment 
• 3 = Same as prior to treatment 
• 2 = Slightly worse than prior to treatment 
• 1 = Much worse than prior to treatment 
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APPENDIX 2:  Subject Satisfaction Questionnaire 
The following 8 questions will be asked of the subject at Visit 5 (Week 12 / Final Visit): 
 
1. How satisfied are you with this product in treating your rosacea? 
2. How satisfied are you with how easy this product is to use? 
3. How satisfied are you with this product compared to other products you have previously 
used for rosacea, such as gels and creams? 
4. How satisfied are you with how this product feels on your skin after treatment? 
5. How satisfied are you with the odor of this product after treatment? 
6. How satisfied are you with the color of this product after treatment? 
7. Overall, how satisfied are you with this product? 
8. Overall, how likely are you to recommend this product to a friend? 
 
Answers to Questions 1 through 7 will be selected from the following: 
• 1 = Very Satisfied 
• 2 = Satisfied 
• 3 = Somewhat Satisfied 
• 4 = Dissatisfied 
• 5 = Very Dissatisfied 
 
The answer to Question 8 will be selected from the following: 
• 1 = Very Likely 
• 2 = Likely 
• 3 = Somewhat Likely 
• 4 = Unlikely 
• 5 = Very Unlikely 
 
 
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APPENDIX 3: Acknowledgment Of Receipt And Review Of 
Protocol 
 
 
Protocol Number: FX2016-12, Version 2 
 
Protocol Title: A Randomized, Multicenter, Double-blind, Vehicle-controlled Study to Evaluate 
the Safety and Efficacy of FMX103 1.5% Topical Minocycline Foam Compared to Vehicle in 
the Treatment of Facial Papulopustular Rosacea (FX2016-12) 
 
 
I hereby acknowledge receipt and review of the following Protocol: 
 
 
1. Version 2, dated March 6th, 2017 
 
 
 
 
 
 
Principal Investigator Name (Print) 
 
 
 
 
 
Principal Investigator Signature 
Date of Signature  
 
(DD MMM YYYY) 
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CLINICAL PROTOCOL 
Title Page 
Study Title: 
A Randomized, Multicenter, Double-blind, Vehicle-
controlled Study to Evaluate the Safety and Efficacy of 
FMX103 1.5% Topical Minocycline Foam Compared to 
Vehicle in the Treatment of Facial Papulopustular Rosacea 
(FX2016-12) 
Sponsor: 
Foamix Pharmaceuticals, Inc. 
520 US Highway 22, Suite 305 
Bridgewater, NJ  08807 
Protocol Identification: 
FX2016-12 
Product: 
FMX103 1.5% minocycline foam 
Indication Studied: 
Papulopustular Rosacea 
Study Phase: 
3 
Sponsor’s Signatory: 
 
GCP Statement: 
This study will be conducted in accordance with Good 
Clinical Practice. Essential documents will be archived 
according to CPMP/ICH/135/95 
Date of Protocol: 
20 Jan 2017 
Version of Protocol: 
1 
Supercedes: 
None 
Prepared by: 
The Write Company, LLC 
 
 
Confidentiality Statement 
This document is the property of Foamix Pharmaceuticals, Inc., and is confidential and proprietary.  The information 
contained herein is believed to be accurate and complete as of the date of preparation.  The contents may not be used, 
divulged, published or otherwise disclosed without the expressed consent of Foamix Pharmaceuticals, Inc. 
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Synopsis 
Name of 
Sponsor/Company: 
Foamix Pharmaceuticals, 
Inc. 
Individual Study Table Referring to 
Part of the Dossier: 
(For National Authority 
Use Only) 
Name of Finished Product: 
FMX103 
Volume: 
Name of Active 
Ingredient: 
Minocycline hydrochloride 
Page: 
Title of Study: 
A Randomized, Multicenter, Double-blind, Vehicle-controlled Study to 
Evaluate the Safety and Efficacy of FMX103 1.5% Topical 
Minocycline Foam Compared to Vehicle in the Treatment of Facial 
Papulopustular Rosacea (Study FX2016-12) 
Protocol No: 
FX2016-12 
Study Centers: 
Multicenter (approximately 30 sites in the USA) 
Publication (reference): 
None 
Phase of Development: 
3 
Objectives: 
Primary Objectives: 
 
To determine the efficacy of FMX103 1.5% minocycline foam 
applied topically once daily for 12 weeks in the treatment of 
rosacea. 
 
To evaluate the safety of topical minocycline foam applied 
once daily for 12 weeks. 
Study Design and 
Methods: 
This is a randomized, multicenter, double-blind, vehicle-controlled, 
2-arm study to evaluate the safety and efficacy of FMX103 topical 
foam containing 1.5% minocycline compared to vehicle, in the 
treatment of subjects with moderate-to-severe facial papulopustular 
rosacea. Qualified subjects will be randomized in a 2:1 ratio 
(active:vehicle) to receive 1 of the following 2 treatments: 
 
FMX103 minocycline foam 1.5% 
 
Vehicle foam 
Subjects will be assigned to 1 of 2 treatments according to the 
randomization schedule. Subjects will apply (or have applied) the study 
drug topically once daily for 12 weeks as directed. Subjects will be 
advised to use the study drug at approximately the same time each day. 
Both the Investigator and subject will be blinded to the study drug 
identity. 
Subjects will return for visits at Weeks 1, 4, 6, 8, 10, and 12. Efficacy 
evaluations (inflammatory lesion counts and Investigator’s Global 
Assessment [IGA] score) will be performed at Weeks 4, 8, and 12 
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during the study. 
Number of Subjects 
(planned): 
The planned enrollment is approximately 450 male and female subjects. 
Subjects will be randomly assigned to the two treatment groups, 
FMX103 1.5% and vehicle, in a 2:1 ratio, respectively. 
Diagnosis and Main 
Criteria for Inclusion: 
Healthy male or non-pregnant females, aged ≥18 years with a clinical 
diagnosis of moderate to severe facial papulopustular rosacea, defined 
as the presence of: 
 
At least 12 and not more than 50 inflammatory facial lesions 
(ie, papules/pustules), and 
 
An IGA of rosacea severity of moderate or severe using the 
following scale: 
Score 
Grade 
Description 
0 
Clear 
No inflammatory papules or pustules 
1 
Almost clear 
Few inflammatory papules or pustules 
2 
Mild 
Several inflammatory papules or pustules 
3 
Moderate 
Moderate number of inflammatory papules or 
pustules and no nodules 
4 
Severe 
Many inflammatory papules or pustules, and up to 
2 nodules 
 
Current or history of erythema and/or flushing 
Subjects must be willing to minimize external factors that might trigger 
rosacea flare-ups (eg, spicy foods, thermally hot foods and drinks, hot 
environments, prolonged sun exposure, strong winds, and alcoholic 
beverages). 
Test Product, Dose and 
Mode of Administration: 
FMX103 minocycline foam 1.5%. Topical application, once daily to 
the face, for 12 weeks. 
Reference Therapy: 
Vehicle foam. Topical application, once daily to the face, for 12 weeks. 
Study Duration: 
Subject participation in the study will be up to 18 weeks:  up to 6 weeks 
for Screening and Day 0/Baseline, and 12 weeks of study treatment. A 
safety follow-up telephone call will be conducted 4 weeks after 
completion of study treatment for only those subjects that do not 
participate in study FX2015-13 (Open label study). 
Endpoints and Outcomes: 
Efficacy Evaluations 
The efficacy parameters will include inflammatory lesion counts, IGA 
at Day 0/Baseline and at Weeks 4, 8, and 12 (Final Visit), and the 
subject global assessment and satisfaction questionnaire at the Final 
Visit. 
Safety Evaluations 
The safety assessments will include adverse events (volunteered, 
observed, and elicited by general questioning in a non-suggestive 
manner), physical examinations, vital signs, clinical laboratory tests, 
and local signs and symptoms assessments (including erythema, 
telangiectasia, burning/stinging, flushing/blushing, dryness/xerosis, 
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itching, peeling/desquamation, and hyperpigmentation) scores. 
Statistical Methods: 
The primary population for efficacy analysis will be the intent-to-treat 
(ITT) population, using multiple imputations to impute missing values. 
Supportive efficacy analyses will be conducted on the per-protocol (PP) 
population, with no imputation for missing values. 
The co-primary efficacy endpoints will be the dichotomized IGA score 
where treatment success is defined as a 2-step improvement resulting in 
a 0 (clear) or 1 (almost clear) score at Week 12 compared to Day 
0/Baseline and the absolute change in inflammatory lesion count at 
Week 12 compared to Day 0/Baseline. 
The key secondary endpoints will be analyzed hierarchically: 
 
Dichotomized IGA score where treatment success is defined as 
a 2-step improvement in score at Week 12 compared to Day 
0/Baseline. 
 
Percent change in inflammatory lesion count at Week 12 
compared to Day 0/Baseline. 
Continuous efficacy endpoints will be analyzed using analysis of 
covariance (ANCOVA). Dichotomized efficacy endpoints will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) test. 
The tolerability and safety of topical minocycline foam applied daily 
for 12 weeks will be evaluated using summary statistics and individual 
subject data listings. 
The active treatment group will be tested against vehicle at the 0.05 
two-sided level of significance. No statistical tests will be performed 
for any of the safety assessments. 
 
 
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Table of Contents 
Page 
TITLE PAGE ........................................................................................................................................................ 1 
SIGNATURE PAGE ............................................................................................................................................ 2 
SYNOPSIS............................................................................................................................................................. 3 
TABLE OF CONTENTS ..................................................................................................................................... 6 
LIST OF TABLES ................................................................................................................................................ 8 
1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................... 9 
2 
STUDY ADMINISTRATIVE STRUCTURE ........................................................................................10 
3 
INTRODUCTION ....................................................................................................................................11 
4 
STUDY OBJECTIVES ............................................................................................................................12 
5 
INVESTIGATIONAL PLAN ..................................................................................................................12 
5.1 
OVERALL STUDY DESIGN ................................................................................................................12 
5.2 
RATIONALE FOR STUDY DESIGN AND DOSE SELECTION ..................................................................12 
6 
STUDY POPULATION ...........................................................................................................................13 
6.1 
INCLUSION CRITERIA .......................................................................................................................13 
6.2 
EXCLUSION CRITERIA ......................................................................................................................13 
7 
STUDY PROCEDURES ..........................................................................................................................15 
7.1 
SCREENING VISIT .............................................................................................................................17 
7.2 
VISIT 1, DAY 0/BASELINE VISIT.......................................................................................................17 
7.3 
VISIT 2, WEEK 1 (±3 DAYS) .............................................................................................................18 
7.4 
VISIT 3, WEEK 4 (±3 DAYS) .............................................................................................................18 
7.5 
VISIT 4, WEEK 6 (±3 DAYS) .............................................................................................................19 
7.6 
VISIT 5, WEEK 8 (±3 DAYS) .............................................................................................................19 
7.7 
VISIT 6, WEEK 10 (±3 DAYS) ...........................................................................................................20 
7.8 
VISIT 7, WEEK 12 (-3/+5 DAYS)/ FINAL OR EARLY TERMINATION ...................................................20 
7.9 
SAFETY FOLLOW-UP (±5 DAYS) .......................................................................................................21 
8 
STUDY TREATMENTS ..........................................................................................................................21 
8.1 
TREATMENTS ADMINISTERED ..........................................................................................................21 
8.1.1 
Dosing Instructions ........................................................................................................21 
8.1.2 
Manufacturer ..................................................................................................................22 
8.1.3 
Labeling of Study Drug ..................................................................................................22 
8.1.4 
Storage of Study Drug ....................................................................................................22 
8.2 
STUDY DRUG ACCOUNTABILITY ......................................................................................................23 
8.3 
HANDLING AND DISPOSAL OF STUDY DRUG ....................................................................................23 
8.4 
METHOD OF ASSIGNMENT OF STUDY DRUG ....................................................................................23 
8.5 
SELECTION AND TIMING OF DOSES IN THE STUDY ...........................................................................23 
8.6 
BLINDING  ........................................................................................................................................23 
8.7 
PRIOR/CONCOMITANT THERAPY ......................................................................................................24 
8.8 
USE OF CONTRACEPTION .................................................................................................................24 
8.9 
TREATMENT COMPLIANCE ...............................................................................................................25 
9 
EFFICACY ASSESSMENTS ..................................................................................................................25 
9.1 
CO-PRIMARY EFFICACY ASSESSMENTS ...........................................................................................26 
9.1.1 
Lesion Counts.................................................................................................................26 
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9.1.2 
Investigator Global Assessment .....................................................................................26 
9.2 
SECONDARY AND TERTIARY EFFICACY ASSESSMENTS ....................................................................26 
9.2.1 
Percent Change in Inflammatory Lesion Counts ............................................................26 
9.2.2 
Interim Change in Inflammatory Lesion Counts ............................................................26 
9.2.3 
Subject Global Assessment ............................................................................................26 
9.2.4 
Subject Satisfaction Questionnaire .................................................................................26 
9.3 
PHOTOGRAPHY ................................................................................................................................27 
10 
SAFETY ASSESSMENTS .......................................................................................................................27 
10.1 
MEDICAL/SURGICAL HISTORY .........................................................................................................27 
10.2 
MEDICATION HISTORY.....................................................................................................................27 
10.3 
CONCOMITANT MEDICATIONS .........................................................................................................27 
10.4 
VITAL SIGNS ....................................................................................................................................27 
10.5 
PHYSICAL EXAMINATION .................................................................................................................28 
10.6 
CLINICAL LABORATORY TESTS........................................................................................................28 
10.6.1 
Urine Pregnancy Test .....................................................................................................28 
10.6.2 
Sample Collection, Storage, and Shipping .....................................................................29 
10.7 
OTHER SAFETY MEASUREMENTS .....................................................................................................29 
10.7.1 
Electrocardiograms ........................................................................................................29 
10.7.2 
Local Signs and Symptoms Assessments .......................................................................29 
10.7.2.1 Erythema (Clinical Erythema Assessment Scale) .........................................29 
10.7.2.2 Telangiectasia ................................................................................................29 
10.7.2.3 Burning/Stinging ...........................................................................................30 
10.7.2.4 Flushing/Blushing .........................................................................................30 
10.7.2.5 Dryness/Xerosis ............................................................................................30 
10.7.2.6 Itching ...........................................................................................................30 
10.7.2.7 Peeling/Desquamation ...................................................................................30 
10.7.2.8 Hyperpigmentation ........................................................................................31 
10.8 
ADVERSE EVENTS ............................................................................................................................31 
10.8.1 
Method of Determining Adverse Events ........................................................................31 
10.8.2 
Adverse Event Definitions .............................................................................................31 
10.8.2.1 Adverse Events ..............................................................................................31 
10.8.2.2 Serious Adverse Events .................................................................................32 
10.8.2.3 Severity of Adverse Events ...........................................................................32 
10.8.2.4 Relationship of Adverse Events to Study Treatments ...................................33 
10.8.2.5 Adverse Events Expectedness .......................................................................33 
10.8.3 
Reporting Adverse Events ..............................................................................................33 
10.8.4 
Adverse Event Follow-up ...............................................................................................33 
10.8.4.1 Pregnancy Reporting .....................................................................................34 
10.8.5 
Clinically Significantly Abnormal Laboratory Results ..................................................34 
10.9 
APPROPRIATENESS OF SAFETY MEASUREMENT ...............................................................................34 
11 
STATISTICAL DESIGN AND ANALYSIS ..........................................................................................34 
11.1 
STATISTICAL ANALYSIS PLAN .........................................................................................................34 
11.2 
DETERMINATION OF SAMPLE SIZE ...................................................................................................35 
11.3 
ANALYSIS POPULATIONS .................................................................................................................35 
11.4 
SUBJECT ACCOUNTING, DEMOGRAPHICS, AND DAY 0/BASELINE CHARACTERISTICS ......................36 
11.5 
EFFICACY ENDPOINTS ......................................................................................................................36 
11.5.1 
Primary Efficacy Endpoints ...........................................................................................37 
11.5.2 
Secondary Efficacy Endpoints .......................................................................................37 
11.5.3 
Tertiary Efficacy Endpoints ...........................................................................................37 
11.6 
SAFETY ENDPOINTS .........................................................................................................................37 
11.6.1 
Adverse Events ...............................................................................................................38 
11.6.2 
Vital Signs and Physical Examinations ..........................................................................38 
11.6.3 
Clinical Laboratory Results ............................................................................................38 
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11.7 
INTERIM ANALYSIS ..........................................................................................................................38 
12 
STUDY MANAGEMENT .......................................................................................................................39 
12.1 
MONITORING ...................................................................................................................................39 
12.2 
PROTOCOL AMENDMENTS................................................................................................................39 
12.3 
PROTOCOL DEVIATIONS ...................................................................................................................39 
12.4 
WITHDRAWAL OF SUBJECTS ............................................................................................................40 
12.5 
TERMINATION OF THE STUDY ..........................................................................................................40 
12.6 
PUBLICATION POLICY ......................................................................................................................41 
13 
ETHICS .....................................................................................................................................................41 
13.1 
CONDUCT OF THE STUDY .................................................................................................................41 
13.2 
INSTITUTIONAL REVIEW BOARDS (IRB) ..........................................................................................41 
13.3 
WRITTEN INFORMED CONSENT ........................................................................................................41 
13.4 
SUBJECT CONFIDENTIALITY .............................................................................................................42 
13.5 
RECORDS RETENTION ......................................................................................................................42 
13.6 
FINANCING .......................................................................................................................................42 
14 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................................................42 
15 
DATA HANDLING AND RECORD KEEPING ...................................................................................43 
16 
REFERENCE LIST .................................................................................................................................43 
APPENDIX 1:  SUBJECT GLOBAL ASSESSMENT QUESTIONNAIRE ..................................................44 
APPENDIX 2:  SUBJECT SATISFACTION QUESTIONNAIRE .................................................................45 
 
 
List of Tables 
Table 1 
Schedule of Study Assessments and Procedures – Study FX2016-12 ........................... 16 
Table 2 
Study Drug Kits and Treatments – Study FX2016-12 ................................................... 21 
Table 3 
IGA Scale for Rosacea – Study FX2016-12 ................................................................... 26 
Table 4 
Clinical Laboratory Tests – Study FX2016-12 .............................................................. 28 
Table 5 
Sample Size Calculations Based on IGA Scores after 12 Weeks of Treatment in Phase 2 
Study FX2015-10 ........................................................................................................... 35 
 
 
 
 
 
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1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation/Term 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartic acid transaminase 
BOCF 
Baseline observation carried forward 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CRO 
Contract Research Organization 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IGA 
Investigator’s Global Assessment 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology System 
ITT 
Intent-to-treat (population) 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed effects model for repeated measures 
OC 
Observed cases 
OTC 
Over-the-counter 
PP 
Per-protocol (population) 
PT 
Preferred term 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RBC 
Red blood cell 
RDC 
Remote data capture 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
US 
United States 
WBC 
White blood cell 
 
 
 
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2 
STUDY ADMINISTRATIVE STRUCTURE 
 
 
Internal 
 
Name 
Affiliation / Address / 
Telephone Number 
Responsibility 
Foamix Pharmaceuticals, Inc. 
520 US Highway 22 
Bridgewater, NJ 08807 
Sponsor 
 
 
External – Contract Research Organization (CRO) 
 
Name 
Affiliation / Address / 
Telephone Number 
Responsibility 
 
 
 
 
 
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PPD
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3 
INTRODUCTION 
Papulopustular rosacea is a chronic disorder affecting both the skin and the eye. It is a syndrome 
of undetermined etiology characterized by both vascular and papulopustular components 
involving the face and occasionally the neck and upper trunk. Clinical findings are usually 
limited to the sun exposed areas of the face and chest and include mid-facial erythema, 
telangiectasia, papules and pustules, and sebaceous gland hypertrophy. Rosacea is characterized 
by episodic flushing of affected areas, which may be associated with consumption of alcohol, hot 
drinks, or spicy foods. During inflammatory episodes, affected areas of the skin, primarily the 
convexities of the face, develop swelling, papules, and pustules. 
Rosacea occurs most commonly in adult life, between the ages of 30 and 60 years. It is very 
common in the United States (US) and Europe. Ocular involvement occurs in more than 50% of 
patients. 
Mainstays of treatment for papulopustular rosacea are the oral tetracyclines:  doxycycline and 
minocycline. Systemic doxycycline (Oracea®, doxycycline 40 mg capsules) is approved. Topical 
treatments for rosacea include metronidazole, azelaic acid, and brimonidine tartrate. 
Foamix has developed a topical minocycline foam product that is being evaluated for safety and 
efficacy in the treatment of rosacea. Minocycline hydrochloride is an established broad spectrum 
antibiotic that is used orally in the treatment of rosacea. The study medication FMX103 
(minocycline HCl 1.5% foam), facilitates easy application and even distribution of the agent, 
thereby improving treatment convenience. 
The efficacy and safety of FMX103 has been evaluated in a Phase 2 study at two minocycline 
concentrations, 1.5% and 3%. The study included 232 subjects (males/females, aged ≥18 years) 
with moderate-to-severe papulopustular rosacea defined by the Investigator’s Global Assessment 
(IGA) score and with ≥12 inflammatory facial lesions (papules/pustules) at Day 0/Baseline. 
Subjects were treated with FMX103 1.5%, FMX103 3%, or vehicle foam, once daily for 12 
weeks. Efficacy and safety were evaluated at Weeks 2, 4, 8, and 12, with an additional safety 
follow-up visit at Week 16. The primary efficacy end point was the absolute change in 
inflammatory lesion count at Week 12. Other assessments included IGA improvement of ≥2 
grades and reaching an IGA score of “clear” or “almost clear” (IGA 0/1), clinical assessment of 
erythema, and safety and tolerability. 
At Week 12, both the 1.5% and 3% doses of FMX103 significantly reduced the number of 
papules and pustules vs. vehicle (both p<0.001, intent-to-treat [ITT] population). The mean 
reduction in lesion count from Day 0/Baseline was 21.1 for the FMX103 1.5% dose, 19.9 for the 
FMX103 3% dose, and 7.8 for the vehicle. The corresponding percent reductions were 61.4% 
and 55.5% for the 1.5% and 3% doses, respectively, and 29.7% for the vehicle. 
Both the 1.5% and 3% doses of FMX103 were statistically significantly better than vehicle in 
improving IGA scores by ≥2 grades at week 12 (p=0.002 and p=0.032, respectively). Both doses 
were also statistically significantly better than vehicle in achieving an IGA of “clear or almost 
clear” (score 0/1) at Week 12 (p=0.001 and p=0.041, respectively). Both FMX103 1.5% and 3% 
doses appeared to be generally safe and well-tolerated. Treatment-related dermal reactions were 
reported in 1 subject from the FMX103 1.5% dose group (considered mild) and in a few subjects 
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from the FMX103 3% dose group (mild, n=1; moderate, n=2; severe, n=1). No treatment-related 
systemic adverse events (AEs) were reported and discontinuation due to AEs (eczema, n=1; 
rosacea, n=1; burning sensation, n=1) was reported in 3 subjects in the FMX103 3% dose group. 
As a consequence of the above, the FMX103 1.5% dose concentration has been selected for 
further development. This Phase 3 study will further assess the safety and efficacy of topical 
minocycline HCl foam, 1.5%, applied once daily compared with vehicle foam for the treatment 
of moderate-to-severe papulopustular rosacea. 
4 
STUDY OBJECTIVES 
The primary objectives of the study are: 
 To determine the efficacy of FMX103 1.5% minocycline foam applied topically once 
daily for 12 weeks in the treatment of rosacea. 
 To evaluate the tolerability and safety of topical minocycline foam applied once daily for 
12 weeks. 
5 
INVESTIGATIONAL PLAN 
5.1 
Overall Study Design 
This is a randomized, multicenter, double-blind, vehicle-controlled, 2-arm study to evaluate the 
safety and efficacy of FMX103 topical foam containing 1.5% minocycline compared to vehicle, 
in the treatment of subjects with moderate-to-severe facial papulopustular acne rosacea. 
Qualified subjects will be randomized in a 2:1 ratio (active:vehicle) to use once daily one of the 
following two treatments: 
 FMX103 minocycline foam 1.5% 
 Vehicle foam 
Subjects will be assigned to 1 of 2 treatments according to the randomization schedule. Subjects 
will apply (or have applied) the study drug topically once daily for 12 weeks as directed. 
Subjects will be advised to use the study drug at approximately the same time each day, 
preferably in the evening about 1 hour before bedtime. Both the Investigator and subject will be 
blinded to the study drug identity. 
Subjects will return for visits at Weeks 1, 4, 6, 8, 10, and 12. Efficacy evaluations (inflammatory 
lesion counts [Section 9.1.1] and IGA score [Section 9.1.2]) will be performed at Weeks 4, 8, and 
12 during the study. Other assessments will be performed as described in Section 9 and 
Section 10. 
5.2 
Rationale for Study Design and Dose Selection 
A randomized, multicenter, double-blind, vehicle-controlled study design has been selected in 
order to assess the efficacy of the study drug. The subjects will be selected according to 
predefined entry criteria. The study treatment duration of 12 weeks is expected to be sufficient to 
show a treatment effect. 
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The concentration of minocycline in the composition was selected according to formulation 
integrity and stability considerations and based on the results of Phase 2 Study FX2015-10 
(described above in Section 3). 
Because of the mode of action of tetracycline drugs, the primary efficacy endpoints will be the 
effect on inflammatory lesion counts and IGA scores (Section 9). 
6 
STUDY POPULATION 
The study will randomize approximately 450 subjects to active or vehicle treatment (in a 2:1 
ratio) at approximately 30 sites in the US. 
6.1 
Inclusion Criteria 
Subjects were included in the study if they met all of the following inclusion criteria at the time 
of enrollment: 
1. Male or female ≥18 years-of-age.
2. Moderate-to-severe rosacea (as per the IGA score; Table 3) on the proposed facial 
treatment area consisting of:
a.
At least 12 and not more than 50 facial papules and pustules, excluding lesions 
involving the eyes and scalp;
b.
No more than 2 nodules on the face.
3. Presence of or history of erythema and/or flushing on the face.
4. If a female of child-bearing potential, have a negative urine pregnancy test and agree to 
use an effective method of contraception (Section 8.8). A sterile sexual partner is NOT 
considered an adequate form of birth control.
5. Willing to minimize external factors that might trigger rosacea flare-ups (eg, spicy foods, 
thermally hot foods and drinks, hot environments, prolonged sun exposure, strong winds, 
and alcoholic beverages).
6. Subjects who use make-up must have used the same brands/types of make-up for a 
minimum period of 14 days prior to study entry and must agree to use the same make-up, 
brand/type, or frequency of use, throughout the study.
7. Completed and signed an appropriately administered Informed Consent Form (ICF) prior 
to any study-related procedures. 
6.2 
Exclusion Criteria 
Subjects were excluded from enrollment in the study for any of the following reasons: 
1. Woman who is pregnant, lactating, or planning to become pregnant during the study
period.
2. Presence of any skin condition on the face that would interfere with the diagnosis or
assessment of rosacea.
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3. Moderate or severe rhinophyma, dense telangiectasia (score 3, severe; Section 10.7.2.2), 
or plaque-like facial edema. 
4. An active nodule on the face >5 mm in diameter. 
5. Excessive facial hair (eg, beards, sideburns, moustaches, etc.) that would interfere with 
diagnosis or assessment of rosacea. 
6. History of hypersensitivity or allergy to minocycline, any other tetracycline, or of any 
other component of the formulation. 
7. Severe erythema, dryness, scaling, pruritus, stinging/burning, or edema. 
8. Active ocular rosacea (eg, conjunctivitis, blepharitis, or keratitis) of sufficient severity to 
require topical or systemic antibiotics. 
9. Use within 6 months prior to Day 0/Baseline of oral retinoids (eg, Accutane®) or 
therapeutic vitamin A supplements of greater than 10,000 units/day (multivitamins are 
allowed). 
10. Initiation of use of estrogens or oral contraceptives less than 3 months prior to Day 
0/Baseline. 
11. Use within 1 month prior to Day 0/Baseline of: 
a. Topical retinoids to the face. 
b. Systemic antibiotics known to have an impact on the severity of facial rosacea 
(eg, containing tetracycline and its derivatives, erythromycin and its derivatives, 
sulfamethoxazole, or trimethoprim). Subjects requiring systemic antibiotics not 
known to affect rosacea will be considered on a case-by-case basis. 
c. Systemic corticosteroids (Note: intranasal and inhalational corticosteroids do not 
require a washout and maybe used throughout the trial if the subject is on a stable 
dose). 
12. Use within 2 weeks prior to Day 0/Baseline of: 
a. Topical corticosteroids. 
b. Topical antibiotics. 
c. Topical medications for rosacea (eg, metronidazole). 
13. Use of a sauna during the 2 weeks prior to Day 0/Baseline and during the study. 
14. Had wax epilation of the face within 2 weeks prior to Day 0/Baseline. 
15. Active bacterial folliculitis. 
16. Consumption of excessive alcohol, abuse of licit or illicit drugs, or a condition that, in the 
opinion of the Investigator, could compromise the subject’s ability to comply with study 
requirements. 
17. Participation in activities that involve excessive or prolonged exposure to sunlight or 
weather extremes, such as wind or cold. 
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18. Presence of any clinically significant condition or situation, other than the condition being
studied, that in the opinion of the Investigator would interfere with the study evaluations
or optimal participation in the study.
19. Participation in an investigational drug study (ie, subject has been treated with an
investigational drug) within 30 days prior to Day 0/Baseline. Subjects who are
participating in non-treatment studies such as observational studies or registry studies can
be considered for inclusion.
20. Previously enrolled in this study.
21. Prior laser therapy (for telangiectasia or other conditions), electrodessication, or
phototherapy (eg, ClearLight®) to the facial area within 180 days prior to Day 0/Baseline.
22. Prior cosmetic procedures (eg, facials) that may affect the efficacy and safety profile of
the investigational product within 14 days prior to Day 0/Baseline.
23. Screening electrocardiogram (ECG) that reveals a QTcF >500 msec.
7 
STUDY PROCEDURES 
Potential subjects will be assessed for eligibility at Screening. During this visit, the purpose, 
timing, procedures, and risks of the study will be explained to the subject, including 
requirements for enrollment and participation in the study, medication restrictions during the 
study, and requirements for washout of certain medications that the subject may already be 
taking. 
The eligible subject who is willing to participate in the study will then sign an appropriately 
administered ICF prior to any study-related procedures being performed. 
Procedures at the Screening Visit will include obtaining blood and urine samples for clinical 
laboratory tests. The results of these tests must be no more than 45 days old at the time of the 
Day 0/Baseline Visit and randomization. 
If a subject who has agreed to participate in the study and signed the ICF is currently undergoing 
rosacea therapy identified in Exclusion Criteria 11 and 12, they must first enter a washout period 
(ie,1 month or 2 weeks, as specified in Exclusion Criteria 11 and 12, respectively) before 
beginning the screening procedures. 
The schedule of study assessments and procedures and the time point at which they will be 
performed during the study is presented in Table 1. If a subject prematurely withdraws from the 
study, the subject should return to the study site for an early termination visit during which all 
evaluations described under Final Visit 7/Week 12 must be performed. 
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Table 1 
Schedule of Study Assessments and Procedures – Study FX2016-12 
Assessment or Procedure 
Screening 
Day 0 / 
Baselinea 
Visits 
Final 
Visitb 
Safety 
Follow-upg 
Visit 
 
1 
2 
3 
4 
5 
6 
7 
 
Week 
 
 
1 
4 
6 
8 
10 
12 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
Assign subject identification 
X 
 
 
 
 
 
 
 
 
Medical/surgical/medication history 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Physical examination, height, weightc  
 
X 
 
 
 
 
 
X 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
Blood pressure/heart rated  
 
X 
X 
X 
X 
X 
X 
X 
 
Blood and urine samples for clinical 
laboratory tests  
X 
 
 
 
 
 
 
X 
 
Urine pregnancy test (females of 
childbearing potential only) 
X 
X 
 
X 
 
X 
 
X 
 
Lesion counts 
X 
X 
 
X 
 
X 
 
X 
 
Investigator’s Global Assessment 
X 
X 
 
X 
 
X 
 
X 
 
Subject Global Assessment 
 
 
 
 
 
 
 
X 
 
Subject Satisfaction Questionnaire 
 
 
 
 
 
 
 
X 
 
Local signs and symptoms 
assessmentse 
X 
X 
X 
X 
X 
X 
X 
X 
 
Photography 
 
X 
 
X 
 
X 
 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
Perform drug accountability 
 
 
 
X 
 
X 
 
X 
 
Collect used drug canister(s) 
 
 
 
X 
X 
X 
X 
X 
 
Dispense study drug 
 
X 
X 
X 
Xf 
X 
Xf 
 
 
Schedule/confirm next visit 
X 
X 
X 
X 
X 
X 
X 
 
 
a. 
Day 0/Baseline must occur within 45 days of Screening. Blood test results must not show clinically significant 
abnormalities. 
b. 
If a subject prematurely withdraws from the study, all evaluations described under Visit 7/Week 12 (Final Visit) must be 
performed at an Early Termination Visit. 
c. 
Height to be measured only at Day 0/Baseline. 
d. 
Measure blood pressure and heart rate after the subject has been sitting for at least 5 minutes at rest. 
e. 
The severity of each of the following local rosacea signs/symptoms will be measured:  erythema, telangiectasia, 
burning/stinging, flushing/blushing, dryness/xerosis, itching, peeling/desquamation, and hyperpigmentation. 
f. 
Dispense one kit (2 canisters) of study drug only if necessary at Visits 4 and 6. 
g. 
A safety follow-up telephone call will be made 4 weeks after Visit 7/Week 12 (Final Visit) for only those subjects that do 
not participate in study FX2015-13 (Open label study). 
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7.1 
Screening Visit 
 Obtain a signed and dated, written ICF prior to any study-related procedures. 
 Obtain demographic data. 
 Using the Interactive Response Technology System (IRT), assign the subject an 
identification number. 
 Obtain medical/surgical history (Section 10.1). 
 Obtain history of prior medication usage (including previous use of rosacea medications); 
record start and stop dates of any medications used in the last 3 months (Section 10.2). 
 Assess eligibility according to the inclusion (Section 6.1) and exclusion criteria 
(Section 6.2). 
 Collect a urine sample from female subjects of childbearing potential for a urine 
pregnancy test (Section 10.6.1). 
 Collect blood and urine samples for clinical laboratory tests and send to the central 
laboratory (Section 10.6.2). 
 Perform 12-lead ECG (Section 10.7.1). 
 Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
 Perform IGA (Section 9.1.2). 
 Perform local signs and symptoms assessments (Section 10.7.2). 
 Schedule/confirm the next study visit. 
7.2 
Visit 1, Day 0/Baseline Visit 
 Confirm eligibility according to the inclusion (Section 6.1) and exclusion criteria 
(Section 6.2). 
 Perform physical examination including height and weight (Section 10.5). 
 Measure blood pressure and heart rate (Section 10.4). 
 Collect a urine sample from female subjects of childbearing potential for a urine 
pregnancy test (Section 10.6.1). 
 Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
 Perform IGA (Section 9.1.2). 
 Perform photography (Section 9.3). 
 Perform local signs and symptoms assessments (Section 10.7.2). 
 Randomize the subject using the IRT when all criteria have been met. 
 Record concomitant medications  (Section 8.7). 
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 Record AEs (Section 10.8). 
 Dispense one kit (2 canisters) of study drug. 
 Schedule/confirm the next study visit and remind subject to avoid overexposure to 
sunlight and to use the same make-up brand/type, or frequency of use, throughout the 
study as applicable. 
7.3 
Visit 2, Week 1 (±3 Days) 
 Measure blood pressure and heart rate (Section 10.4). 
 Perform local signs and symptoms assessments (Section 10.7.2). 
 Record concomitant medications  (Section 8.7). 
 Record AEs (Section 10.8). 
 Confirm that subject continues to use only the provided facial cleanser. 
 Collect used study canister (if applicable). 
 Dispense one kit (2 canisters) of study drug. 
 Schedule/confirm the next study visit and remind subject to avoid overexposure to 
sunlight and to use the same make-up brand/type, or frequency of use, throughout the 
study as applicable. 
7.4 
Visit 3, Week 4 (±3 Days) 
 Measure blood pressure and heart rate (Section 10.4). 
 Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
 Perform IGA (Section 9.1.2). 
 Perform photography (Section 9.3). 
 Perform local signs and symptoms assessments (Section 10.7.2). 
 Collect a urine sample from female subjects of childbearing potential for a urine 
pregnancy test (Section 10.6.1). 
 Record concomitant medications  (Section 8.7). 
 Record AEs (Section 10.8). 
 Perform drug accountability to assess compliance (Section 8.2). 
 Collect used study drug canister (if applicable). 
 Dispense one kit (2 canisters) of study drug. 
 Confirm that subject continues to use only the provided facial cleanser. 
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 Schedule/confirm the next study visit and remind subject to avoid overexposure to 
sunlight and to use the same make-up brand/type, or frequency of use, throughout the 
study as applicable. 
7.5 
Visit 4, Week 6 (±3 Days) 
 Measure blood pressure and heart rate (Section 10.4). 
 Perform local signs and symptoms assessments (Section 10.7.2). 
 Record concomitant medications (Section 8.7). 
 Record AEs (Section 10.8). 
 Collect used study drug canister (if applicable). 
 Dispense one kit (2 canisters) of study drug (if necessary). 
 Confirm that subject continues to use only the provided facial cleanser. 
 Schedule/confirm the next study visit and remind subject to avoid overexposure to 
sunlight and to use the same make-up brand/type, or frequency of use, throughout the 
study as applicable. 
7.6 
Visit 5, Week 8 (±3 Days) 
 Measure blood pressure and heart rate (Section 10.4). 
 Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
 Perform IGA (Section 9.1.2). 
 Perform photography (Section 9.3). 
 Perform local signs and symptoms assessments (Section 10.7.2). 
 Collect a urine sample from female subjects of childbearing potential for a urine 
pregnancy test (Section 10.6.1). 
 Record concomitant medications (Section 8.7). 
 Record AEs (Section 10.8). 
 Perform drug accountability to assess compliance (Section 8.2). 
 Collect used study canister (if applicable). 
 Dispense one kit (2 canisters) of study drug. 
 Confirm that subject continues to use only the provided facial cleanser. 
 Schedule/confirm the next study visit and remind subject to avoid overexposure to 
sunlight and to use the same make-up brand/type, or frequency of use, throughout the 
study as applicable. 
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7.7 
Visit 6, Week 10 (±3 Days) 
 Measure blood pressure and heart rate (Section 10.4). 
 Perform local signs and symptoms assessments (Section 10.7.2). 
 Record concomitant medications (Section 8.7). 
 Record AEs (Section 10.8). 
 Collect used study drug canister (if applicable). 
 Dispense one kit (2 canisters) of study drug (if necessary). 
 Confirm that subject continues to use only the provided facial cleanser. 
 Schedule/confirm the next study visit and remind subject to avoid overexposure to 
sunlight and to use the same make-up brand/type, or frequency of use, throughout the 
study as applicable. 
7.8 
Visit 7, Week 12 (-3/+5 days)/ Final or Early Termination 
 Perform physical examination including weight (Section 10.5). 
 Measure blood pressure and heart rate (Section 10.4). 
 Collect blood and urine samples for clinical laboratory tests and send to the central 
laboratory (Section 10.6.2). 
 Collect a urine sample from female subjects of childbearing potential for a urine 
pregnancy test (Section 10.6.1). 
 Perform facial lesion count of inflammatory lesions (Section 9.1.1). 
 Perform IGA (Section 9.1.2). 
 Perform photography (Section 9.3). 
 Perform local signs and symptoms assessments (Section 10.7.2). 
 Have the subject complete the Subject Global Assessment (Section 9.2.3). 
 Have the subject complete the Subject Satisfaction Questionnaire (Section 9.2.4). 
 Record concomitant medications (Section 8.7). 
 Record AEs (Section 10.8). 
 Collect all used and full study drug canisters. 
 Perform drug accountability to assess compliance and record the date of the last dose 
(Section 8.2). 
 Schedule/confirm a safety follow-up telephone call 4 weeks from Visit 7/Week 12 (Final 
Visit) date (±5 days) for subjects that will not participate in study FX2015-13 (Open label 
study) (Section 7.9). 
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7.9 
Safety Follow-Up (±5 days) 
A safety follow-up telephone call will be made 4 weeks after Visit 7/Week 12 (Final Visit) for 
only those subjects that do not participate in study FX2015-13 (Open label study). Follow up on 
existing and any new concomitant medications and adverse events will be recorded.  
8 
STUDY TREATMENTS 
This study will include FMX103 minocycline foam 1.5% and vehicle foam. 
8.1 
Treatments Administered 
The description of study drug kits and treatments is shown below in Table 2. 
Table 2 
Study Drug Kits and Treatments – Study FX2016-12 
Dosage form description: 
Foam containing minocycline HCl 1.5% or vehicle foam 
Package description: 
Canisters, each containing 25 g of the clinical trial supply foam 
Daily dose: 
Once daily application of a sufficient amount of foam to cover the involved 
area. Estimated maximum is 0.5 g of drug product containing 7.5 mg (1.5% 
active) or 0.0 mg (vehicle) of minocycline. 
Cumulative maximal dose for 
dosing (12 weeks): 
630 mg (1.5%) minocycline 
Dispensing: 
Kits consisting of 2 canisters, each canister containing 25 g of FMX103 
minocycline formulation, 1.5%, or vehicle dispensed at Visit 1 (Day 
0/Baseline), Visit 2 (Week 1), Visit 3 (Week 4), and Visit 5 (Week 8). 
Additional kits of 2 canisters may be dispensed at other visits if required. 
8.1.1 
Dosing Instructions 
The dosing regimen will be the same for both treatment groups. 
Study drug kits containing 2 canisters of investigational drug will be dispensed at Visit 1 (Day 
0/Baseline), Visit 2 (Week 1), Visit 3 (Week 4), and Visit 5 (Week 8). Additional kits will be 
available for dispensing at other visits (ie, Visits 4 and 6) to ensure enough product is available 
for daily dosing. 
After shaking the canister well, a small amount of study drug (about ½ gram or a cherry-sized 
amount) should be expressed from the canister onto the finger tips and then applied as a thin 
layer over all involved areas of the face. Additional drug may be used as needed to assure the 
entire involved area is treated.  
Study drug should be applied at approximately the same time each day, preferably in the evening 
about 1 hour before bedtime. 
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8.1.2 
Manufacturer 
The manufacturer of the investigational product is ASM Aerosol-Service AG, Moehlin, 
Switzerland. 
8.1.3 
Labeling of Study Drug 
The Sponsor or designee will label study drug supplies according to the requirements of the 
Code of Federal Regulations (21CFR§ 210, Subpart G-Packaging & Labeling Control). 
The labels of the investigational (test) product will contain appropriate information as required 
by regional regulatory authorities and include, as needed, the following information: 
 Name and address of the Sponsor 
 Protocol number 
 Product name/dosage form/mode of administration 
 Kit Number/Canister Number 
 Site number/Subject number 
 Name and address of manufacturer 
 Date of manufacture 
 Lot/batch number 
 Canister contents 
 Storage conditions 
 Caution statements, as follow: 
o “New Drug – Limited by Federal Law to Investigational Use” 
o “Flammable” 
o “Shake well before use” 
o “Keep out of the reach of children” 
The composition, pharmaceutical quality, batch number, and expiration date of the 
investigational (test) product will be traceable via the kit number. 
8.1.4 
Storage of Study Drug 
FMX103 1.5% and vehicle canisters must be stored at 2°C – 8°C until being dispensed to the 
subject. Subsequently, they must be stored at 20°C – 25°C (refer to USP Controlled Room 
Temperature). The Investigator will be responsible for the suitable storage of the investigational 
product in compliance with the storage instructions and must restrict access to the study 
personnel only. 
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8.2 
Study Drug Accountability 
The Investigator will have overall responsibility for the use of the study drug. The Investigator or 
designee will verify the contents of the drug shipment and confirm receipt of the study drug in 
the IRT system. In addition, an accurate study drug dispensing record that specifies the date and 
amount dispensed to each subject must be kept. This inventory record must be available for 
inspection by representatives of the Sponsor and is subject to regional regulatory authority 
inspection at any time. At the conclusion of the study, the Investigator must provide a copy of 
this record to the Sponsor and each canister that has been retrieved from a subject will be 
returned to the vendor to be weighed. 
Under no circumstances will the Investigator allow the investigational drugs to be used other 
than as directed by this protocol. Qualified study personnel must use the IRT to assign and 
dispense kits to the subjects. Reasons for digression from the expected dispensing regimen must 
also be recorded. 
8.3 
Handling and Disposal of Study Drug 
The study drug must be protected from unauthorized access (eg, in a locked storage facility). 
Any unused, partially used, or empty bottles of study drug will be returned to the Sponsor or 
designee by the time of the site’s close-out visit. Receipt, distribution, and return of the study 
drug must be properly documented on forms provided by the Sponsor or designee. 
8.4 
Method of Assignment of Study Drug 
After pretreatment clinical evaluations and all other Screening procedures have been completed, 
authorized site personnel will acknowledge that the applicable subject met all the specified 
inclusion criteria (Section 6.1) and none of the exclusion criteria (Section 6.2). Assignment to a 
treatment group will then follow a predetermined list of randomization numbers, with each 
successive number receiving 1 of the 2 treatments in random order. Authorized site personnel 
will use the IRT system to assign a kit number that corresponds to the randomization schedule. 
The kit box with the assigned kit number will be dispensed to the subject. 
The randomization code will be provided by Premier Research, Research Triangle Park, NC. 
8.5 
Selection and Timing of Doses in the Study 
The 1.5% concentration of minocycline has been shown to be effective compared to vehicle in a 
Phase 2 study in subjects with rosacea. The once-daily dosing regimen is appropriate given the 
pharmacokinetic characteristics of minocycline. 
8.6 
Blinding 
This is a double-blind study, with limited access to the randomization code. The randomization 
code will be held in confidence until after the study database is locked and a memo documenting 
the database lock has been issued. Every effort will be made to retain the integrity of the blind. 
When issued to the sites, the study drug will be identical in appearance for all subjects, 
regardless of treatment assignment. 
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The treatment each subject receives will not be disclosed to the Investigator, study site personnel, 
subjects, monitors, or the Sponsor staff except as required for the purposes of conducting this 
study. 
In the event that emergency identification of study drug is required (eg, if the Investigator 
believes that the information is necessary to properly treat a subject with an AE), the study drug 
identity can be obtained by the Investigator through the IRT system. 
Before breaking the blind for a subject, the Investigator should determine that the information is 
necessary (ie, that it will alter the subject’s immediate course of treatment and will contribute to 
the management of the AE). In many cases, particularly when the emergency is clearly not 
related to study drug, the problem may be effectively managed by assuming that the subject is 
receiving active study drug without the need for unblinding. Every effort should be made to alert 
the medical monitor before requesting that the blind be broken. If this is not possible, the medical 
monitor should be immediately notified of the breaking of the blind. The Investigator will record 
the unblinding procedures in the subject’s source documents. 
If unblinding is necessary, the subject will be withdrawn from the study and Early Termination 
Visit (ie, Visit 7 [Week 12]) assessments will be completed. 
8.7 
Prior/Concomitant Therapy 
Subjects should use the facial cleanser Cetaphil Gentle Skin Cleanser (which will be provided by 
the Sponsor). An alternative, non-medicated cleanser may be used if agreed to by the Sponsor. 
The use of or change in the dose of any and all concomitant medications, either prescription or 
over-the-counter (OTC), during the study will be recorded. The reason for use or change of dose 
of a concomitant therapy may need to be reported as an AE. Therapies (medication and non-
medication therapies) not restricted by the protocol may be used. Non-prohibited chronic 
therapies being used at Day 0/Baseline may be continued. If a female subject is using an oral 
contraceptive product, she should have been on the same product for at least 3 months and she 
should continue using the same or equivalent product for the duration of the study. 
If a subject is taking anticoagulant therapy, the subject should be advised that they may require a 
downward adjustment of their anticoagulant dosage. 
All topical or systemic medications listed in the exclusion criteria are prohibited during this 
study. Similarly, no other topical medications are permitted to be used on the face during this 
period. 
See the FMX103 Investigator’s Brochure (IB) for information about tetracyclines and possible 
drug-drug interactions. 
8.8 
Use of Contraception 
Tetracycline-class antibiotics can cause fetal harm when administered to a pregnant woman. 
Tetracycline-class antibiotics used during tooth development (last half of pregnancy, infancy, and 
childhood to the age of 8 years) may cause permanent discoloration of teeth (yellow-gray-
brown). 
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Prior to study enrollment, females of childbearing potential must be advised of the importance of 
avoiding pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy. Females of childbearing potential include any female who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation/occlusion, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea 
>12 consecutive months). Females of childbearing potential must have a negative urine 
pregnancy test and, if they are sexually active or become sexually active during the study, must 
use an effective method of birth control such as those listed below during the course of the study. 
The following is not an all-inclusive list; the subject must discuss with the Investigator the most 
appropriate form of birth control: 
 Hormonal methods 
o Oral contraceptives – (Oral antibiotics may lessen the effectiveness of oral 
contraceptives. Therefore, a second form of birth control must be utilized in 
subjects using oral contraceptives) 
o Implant 
o Injection 
o Transdermal patch 
o Intravaginal ring 
 Intrauterine device (hormonal or non-hormonal) 
 Barrier methods 
o Condom (male or female) with spermicide 
o Diaphragm with spermicide 
 Complete abstinence 
8.9 
Treatment Compliance 
Each subject is to be instructed on the importance of following the dosing schedule and returning 
all kits (empty/used/unused) at the appropriate visits. The study site personnel will question the 
subject on the history of study drug use since the last visit. A subject who deviates significantly 
from the prescribed dosage will be counseled. 
9 
EFFICACY ASSESSMENTS 
Every attempt must be made to ensure the same evaluator performs the efficacy evaluations for a 
particular subject throughout the study; when this is not possible, another approved evaluator 
may perform the evaluations. Following are the methods and scales that will be used to measure 
each of the efficacy parameters to be performed. 
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9.1 
Co-Primary Efficacy Assessments 
The co-primary efficacy assessments will include the inflammatory lesion counts and the IGA of 
severity of disease. Lesion counts, IGA, and other efficacy evaluations will be performed by the 
Investigator/evaluator. 
9.1.1 
Lesion Counts 
The number of papules, pustules, and nodules will be counted and the numbers recorded. Facial 
area lesion counts will be made for the forehead, left and right cheeks, nose, and chin. The lesion 
counts will be performed at Screening and Visit 1 (Day 0/Baseline) to confirm eligibility, and 
again at Visit 3 (Week 4), Visit 5 (Week 8), and Visit 7 (Week 12/Final Visit). 
9.1.2 
Investigator Global Assessment 
The Investigator will also assess the global severity of rosacea using the IGA scale as 
described in Table 3. The IGA will be performed at Screening and Visit 1 (Day 0/Baseline) to 
confirm eligibility, and again at Visit 3 (Week 4), Visit 5 (Week 8), and Visit 7 (Week 12/Final 
Visit). 
Table 3 
IGA Scale for Rosacea – Study FX2016-12 
Score 
Grade 
Description 
0 
Clear 
No inflammatory papules or pustules 
1 
Almost clear 
Few inflammatory papules or pustules 
2 
Mild 
Several inflammatory papules or pustules 
3 
Moderate 
Moderate number of inflammatory papules or pustules and no nodules 
4 
Severe 
Many inflammatory papules or pustules, and up to 2 nodules 
9.2 
Secondary 
 Efficacy Assessments 
9.2.1 
Percent Change in Inflammatory Lesion Counts 
The percent change in inflammatory lesion counts at Visit 7 (Week 12/Final Visit) compared to 
Visit 1 (Day 0/Baseline) will be evaluated. 
9.2.2 
Interim Change in Inflammatory Lesion Counts 
The absolute 
 change in inflammatory lesion counts at Visit 3 (Week 4) and Visit 5 
(Week 8) compared to Visit 1 (Day 0/Baseline) will be evaluated. 
9.2.3 
Subject Global Assessment 
This score will be obtained from the subject at Visit 7 (Week 12/Final Visit) using the 
questionnaire in Appendix 1. 
9.2.4 
Subject Satisfaction Questionnaire 
A subject satisfaction questionnaire (Appendix 2) will be administered at Visit 7 (Week 12/Final 
Visit). 
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9.3 
Photography 
Photography of the full face will be performed at Day 0/Baseline and at Weeks 4, 8, and 12 using 
recognized methods. The equipment and techniques for this photography and for archiving the 
images are described in the Study Manual. Photographs will be reviewed at the site and by the 
sponsor for quality. Photographs will not be used to assess the lesion counts or the IGA, but will 
be archived to be available for subsequent review, if required, by the sponsor, auditors, or the 
FDA. 
10 
SAFETY ASSESSMENTS 
The safety assessments in this study are standard safety measures in clinical studies, including 
physical examinations, the monitoring of vital signs, AEs (volunteered, observed, and elicited by 
general questioning in a non-suggestive manner), clinical laboratory tests, and local signs and 
symptoms assessments (including erythema, telangiectasia, burning/stinging, flushing/blushing, 
dryness/xerosis, itching, peeling/desquamation, and hyperpigmentation) scores. 
10.1 
Medical/Surgical History 
A complete medical and surgical history will be obtained at Screening, which will include the 
following:  diseases of the head, ears, eyes, nose and throat; respiratory diseases; cardiovascular 
diseases; gastrointestinal diseases; hepatic diseases; genitourinary diseases; musculoskeletal 
diseases; endocrine diseases; neurological diseases; psychiatric diseases; skin diseases; allergies; 
hematological diseases; and other abnormalities. 
10.2 
Medication History 
A history of medication usage (including previous use of rosacea medications and non-
medication therapies) will be recorded at Screening. The start and stop dates of previous use of 
medications in the last 3 months will be recorded. 
10.3 
Concomitant Medications 
All topical or systemic medications listed in the exclusion criteria are prohibited. No other 
topical medications are permitted to be used on the face. All medication that the subject is 
currently taking or any change in medication or dosage since the last visit will be documented 
throughout the study. The use of or change in the dose of any and all concomitant medication, 
either prescription or OTC, during the study will be recorded. The reason for use or change of 
dose of a concomitant therapy may need to be reported as an AE. 
10.4 
Vital Signs 
Heart rate and blood pressure (BP) will be measured at all post-Day 0/Baseline visits. All BP 
measurements will be made using a sphygmomanometer with an appropriate cuff size for the 
individual subject. Measurements will be taken while the subject is seated after at least 5 minutes 
at rest. 
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10.5 
Physical Examination 
A complete physical examination (excluding the genitourinary examination) will be performed. 
Weight will be recorded at the Visit 1 (Day 0/Baseline) and Visit 7 (Week 12/Final Visit). Height 
will be measured at Visit 1 (Day 0/Baseline) only. 
10.6 
Clinical Laboratory Tests 
Serum chemistry, hematology and urinalysis will be evaluated at the Screening Visit and 
Visit 7 (Week 12/Final Visit). All clinical laboratory tests will be performed at a central 
laboratory. Table 4 presents the specific clinical laboratory tests to be evaluated. 
Please refer to the manual from the central laboratory for detailed instructions on collecting, 
processing, and shipping of samples. 
Table 4 
Clinical Laboratory Tests – Study FX2016-12 
Hematology 
Urinalysis 
Serum chemistry 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) 
count with differential 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocytes esterase 
pH 
Protein 
Specific gravity 
Urine pregnancy test performed at the site 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase 
Aspartic acid transaminase (AST) 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Creatinine kinase 
Gamma glutamyl transferase (GGT) 
Globulin 
Glucose 
Phosphorus 
Potassium 
Sodium 
Total bilirubin (if elevated obtain 
direct bilirubin) 
Total protein 
Uric acid 
10.6.1 
Urine Pregnancy Test 
A urine pregnancy test will be performed on all females of childbearing potential at the 
Screening Visit, Visit 1 (Day 0/Baseline), Visit 3 (Week 4), Visit 5 (Week 8), and Visit 7 (Week 
12/Final Visit) or when a subject prematurely withdraws from the study. 
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10.6.2 
Sample Collection, Storage, and Shipping 
Sample collection kits, requisition slips, and shipping boxes will be supplied by the central 
laboratory. Sample collection procedures and shipping instructions will be detailed in the 
laboratory manual. Study sites must be equipped to store the samples according to the laboratory 
manual procedures before shipping to the central laboratory. 
10.7 
Other Safety Measurements 
10.7.1 
Electrocardiograms 
A standard 12-lead ECG will be performed at Screening only. Subjects will be supine and at rest 
for at least 10 minutes before measurement. Subjects will have their participation discontinued 
if an ECG reveals a QTcF >500 msec (see Exclusion Criterion 23). 
10.7.2 
Local Signs and Symptoms Assessments 
The severity of each of the following local signs and symptoms will be measured at Screening, 
Visit 1 (Day 0/Baseline), and at each study visit:  erythema, telangiectasia, burning/stinging, 
flushing/blushing, dryness/xerosis, itching, peeling/desquamation, and hyperpigmentation. The 
score for signs will be determined by the Investigator and must represent the subject’s condition 
at the time of the evaluation; the score for symptoms (ie, burning/stinging, flushing/blushing) 
should be scored based on the subject’s symptoms reported for the previous 3 days. 
These signs/symptoms should not be included as AEs, unless a sign/symptom is believed to have 
been related to the study medication or is the reason for discontinuation from the study. 
10.7.2.1 
Erythema (Clinical Erythema Assessment Scale) 
Erythema of the face will be graded according to the following scale: 

0 = clear skin/no signs of erythema

1 = almost clear of erythema, slight redness

2 = mild erythema, definite redness

3 = moderate erythema, marked redness

4 = severe erythema, fiery redness
10.7.2.2 
Telangiectasia 
The severity of facial telangiectasia will be graded according to the following scale: 

0 = None

1 = Mild:  scattered telangiectasia

2 = Moderate:  numerous telangiectasia

3 = Severe:  dense telangiectasia forming sprays of vessels
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10.7.2.3 
Burning/Stinging 
The severity of facial burning/stinging will be graded according to the following scale: 
 0 = None:  no warm or burning sensation 
 1 = Mild:  slight warm tingling/stinging sensation; not really bothersome 
 2 = Moderate:  constant or intermittent warm tingling/stinging sensation that is somewhat 
bothersome 
 3 = Severe:  bothersome warm to hot tingling/stinging sensation 
10.7.2.4 
Flushing/Blushing 
The severity of facial flushing/blushing will be graded according to the following scale: 
 0 = None 
 1 = Mild:  sporadic episodes lasting for a few moments to several minutes 
 2 = Moderate:  intermittent episodes lasting for greater than 30 minutes 
 3 = Severe:  almost constant episodes lasting for several hours 
10.7.2.5 
Dryness/Xerosis 
The severity of facial dryness/xerosis will be graded according to the following scale: 
 0 = None 
 1 = Mild 
 2 = Moderate 
 3 = Severe 
10.7.2.6 
Itching 
The severity of facial itching will be graded according to the following scale: 
 0 = None 
 1 = Mild:  sporadic itching lasting for a few moments to several minutes 
 2 = Moderate:  intermittent itching lasting for greater than 30 minutes 
 3 = Severe:  almost constant, intense itching lasting for several hours 
10.7.2.7 
Peeling/Desquamation 
The severity of facial peeling/desquamation will be graded according to the following scale: 
 0 = No peeling 
 1 = Mild:  small, scattered areas of scaling/flaking 
 2 = Moderate:  larger, contiguous areas of scaling/flaking 
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 3 = Severe:  pronounced flaking/shedding scales covering entire application area 
10.7.2.8 
Hyperpigmentation 
The severity of facial skin hyperpigmentation will be graded according to the following scale: 
 0 = None 
 1 = Mild:  few scattered, small areas of light hyperpigmentation 
 2 = Moderate:  larger or more intense areas of hyperpigmentation 
 3 = Severe:  intense, extensive hyperpigmentation 
10.8 
Adverse Events 
10.8.1 
Method of Determining Adverse Events 
Safety assessments will include recording AEs reported spontaneously by the subject or observed 
by the Investigator. AEs will be recorded at each visit on the appropriate CRF. Every attempt 
should be made to describe the AE in terms of a diagnosis. If a clear diagnosis has been made, 
individual signs and symptoms will not be recorded unless they represent atypical or extreme 
manifestations of the diagnosis, in which case they should be reported as separate events. If a 
clear diagnosis cannot be established, each sign and symptom must be recorded separately. 
Subjects should be asked whether, since the time of the last observation or visit, they had any of 
the following: 
 Experienced any changes in well-being 
 Used any new medications 
 Changed medication regimens (both prescription and OTC) 
 Were admitted to a hospital or had any accidents 
 Developed unusual headaches or changes in vision 
With exception to the above, all questions should be of a general nature and should not suggest 
symptoms. 
When an AE is suspected, all relevant evaluations will be performed and appropriate treatment 
provided. Additional follow-up will be done as necessary (Section 10.8.4) and recorded in the 
subject’s source documents, and the results will be provided to the Sponsor. 
For AE definitions and reporting requirements, refer to Section 10.8.2 and Section 10.8.3, 
respectively. 
10.8.2 
Adverse Event Definitions 
10.8.2.1 
Adverse Events 
An AE is any unfavorable or unintended sign, symptom, or disease that appears or worsens in a 
subject after the subject signs the ICF for a clinical study. 
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Examples of what may be considered an AE include any of the following: 
 A new illness. 
 An exacerbation of a sign or symptom of an underlying condition or of a concomitant 
illness unrelated to participation in the clinical study or an effect of the study drug or 
comparator drug. 
No causal relationship with the study drug is implied by the use of the term “adverse event.” An 
exacerbation of a pre-existing condition/illness is defined as a more frequent occurrence or as an 
increase in the severity of the pre-existing condition/illness during the study. Planned or elective 
surgical procedures for pre-existing conditions that have not worsened are not AEs. However, 
any complication that occurs during a planned or elective surgery is an AE (Note:  If the event 
meets the criteria for a serious adverse event [SAE], such as an extended hospitalization, it will 
be considered an SAE). Conditions leading to unplanned surgical procedures may also be AEs. 
10.8.2.2 
Serious Adverse Events 
A serious adverse event (SAE) is any AE that: 
 Results in death. 
 Is life-threatening. 
(Note:  The term “life-threatening” refers to any AE that, as it occurs, puts the subject at 
immediate risk of death. It does not refer to an AE that hypothetically might have caused 
death if it were more severe.) 
 Results in hospitalization or prolongation of current hospitalization (not including 
hospitalization for a pre-existing condition that has not increased in severity or frequency 
from the subject’s underlying medical condition prior to entry into the study). 
 Results in persistent or significant disability/incapacity. 
 Is a congenital anomaly/birth defect in the offspring of a subject. 
 Is another serious (important medical events) event. 
(Note:  Important medical events may not be immediately life-threatening or result in 
death or hospitalization but may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the subject or require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; blood dyscrasias or convulsions that do not result in inpatient hospitalization; 
or development of drug dependency or drug abuse.) 
SAEs will be reported by the Sponsor to the regulatory authorities as required. 
10.8.2.3 
Severity of Adverse Events 
Severity of an AE refers to the extent to which an AE affects the subject’s daily activities and 
differs from “serious”, which is a regulatory classification. Severity will be categorized 
according to the following criteria: 
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
Mild:  The symptom has a negligible effect or no impairing effect on the subject’s normal
function.

Moderate:  The symptom impairs the subject’s normal function to some extent.

Severe:  The symptom has an obvious, significantly impairing effect on the subject’s
normal function.
10.8.2.4 
Relationship of Adverse Events to Study Treatments 
Causality refers to the relationship of the AE to study drug and will be categorized according to 
the following criteria: 

Unlikely:  There is no medical evidence to suggest that the AE may be related to study
drug usage, or there is another more probable medical explanation.

Possible:  There is medical evidence to suggest that there is a reasonable possibility that
the AE may be related to study drug usage. However, other medical explanations cannot
be excluded as a possible cause.

Probable:  There is strong medical evidence to suggest that the AE is related to study
drug usage.
10.8.2.5 
Adverse Events Expectedness 
Expected AEs are defined as those described in the FMX103 IB. If an event increases in intensity 
or severity from that described in the IB, it will be considered unexpected. 
10.8.3 
Reporting Adverse Events 
Adverse events that occur from the time of informed consent/assent through completion of the 
last study visit should be reported. Any AE that the Investigator becomes aware of that occurs 
within 30 days of study completion or withdrawal should also be reported. 
Any SAEs occurring in a subject receiving study drug must be reported to the Sponsor or 
designee within 24 hours of the site being informed of the event, even if the event does not 
appear to be drug-related. The report must be done by faxing the completed SAE Report Form to 
the Sponsor or designee. Any pertinent follow-up information should be provided in a similar 
manner. Contact information is provided below: 
10.8.4 
Adverse Event Follow-up 
Adverse events that are ongoing when a subject withdraws from or completes the study will be 
followed until resolution or stabilization (in the opinion of the Investigator), or for 30 days, 
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whichever is shorter. Investigators and the Sponsor will decide if longer follow-up is appropriate 
on a case-by-case basis. Subjects who experience any clinically significant AE will remain under 
medical supervision until the Investigator or the Sponsor’s medical monitor deems the AE to be 
resolved, stabilized, or no longer serious enough to warrant follow-up. 
Laboratory values that are abnormal and not assessed as AEs may be followed at the discretion 
of the Investigator or the Sponsor’s medical monitor until resolved or stabilized. 
10.8.4.1 
Pregnancy Reporting 
Prior to study enrollment, females of childbearing potential must be advised of the importance of 
avoiding pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy. The ICF that the subject signs must document this discussion. 
If a subject or Investigator suspects that the subject may be pregnant prior to study drug 
administration, the study drug must be withheld until the results of laboratory pregnancy testing 
are available. If pregnancy is confirmed, the subject must not receive study drug and must not be 
enrolled in the study. 
A urine pregnancy test will be performed on all females of childbearing potential as described in 
Section 10.6.1. 
During the study, all female subjects of childbearing potential should be instructed to contact the 
Investigator immediately if they suspect they might be pregnant (eg, missed or late menstrual 
period). If a subject or Investigator suspects that the subject may be pregnant at any time before 
or during the study, the study drug must be withheld until the results of laboratory pregnancy 
testing are available. The Sponsor and site monitor must be notified and relevant information 
collected on the appropriate form. If pregnancy is confirmed, the subject must be withdrawn 
from the study and the Sponsor and site monitor notified. Additional relevant information about 
the confirmed pregnancy will be recorded on the appropriate form(s); pregnancy will not be 
captured as an AE. 
The subject should be followed until the outcome of the pregnancy is known. 
10.8.5 
Clinically Significantly Abnormal Laboratory Results  
All laboratory values that are outside of the normal range for that parameter will be so flagged 
when reported to the site. The Investigator will determine which out-of-range laboratory test 
results should be characterized as clinically significant and will so annotate the laboratory report. 
If a clinically significant laboratory abnormality requires treatment or is the reason for a subject 
being discontinued from the study, the abnormal result must also be classified as an AE. 
10.9 
Appropriateness of Safety Measurement 
The safety assessments to be utilized in this study are standard safety measures in clinical trials. 
11 
STATISTICAL DESIGN AND ANALYSIS 
11.1 
Statistical Analysis Plan 
A detailed statistical analysis plan (SAP) will be finalized prior to breaking of the study blind. 
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Descriptive statistics for qualitative variables (eg, race) will include the number and percentage 
of subjects with the qualitative response. Missing responses will be enumerated, but the 
calculation of percentages will exclude missing responses. For quantitative variables (eg, age), 
descriptive statistics will include the number of subjects with non-missing data, mean, standard 
deviation, median, and minimum and maximum values. All hypothesis testing will be conducted 
using two-sided tests with a 0.05 level of significance. 
11.2 
Determination of Sample Size 
In the Phase 2 Study FX2015-10, the proportion of subjects with an IGA score of 0 or 1 after 
 of treatment was 
 in the FMX103 1.5% dose group compared to 
 for the 
vehicle dose group. Table 5 provides alternate assumptions on this primary response criterion 
with corresponding implications on sample size. Power was set to 90% and a type-1 error was set 
to a two-sided test with a 0.05 level of significance. Sample size was calculated based on 
Fisher’s Exact test. 
Table 5 
Sample Size Calculations Based on IGA Scores after 
 of 
Treatment in Phase 2 Study FX2015-10 
Vehicle IGA (Score 0,1) 
FMX103 1.5% IGA (Score 0,1) 
Sample Size (Vehicle, Active) 
 
 
 
 
 
 
 
 
 
 
 
 
Assuming a 
 dropout rate, 300 subjects receiving FMX103 and 150 subjects receiving 
vehicle will provide at least 90% power for a statistically significant difference on an IGA score 
of 0 or 1. 
For the co-primary endpoint of change from Day 0/Baseline to 
 in inflammatory lesion 
count, in the Phase 2 study the FMX103 1.5% dose group had a mean reduction of 
 lesions 
whereas the vehicle had a mean reduction of 
 lesions. The standard deviation was 
. For a 
90% power, 
 and 
 subjects in the FMX103 1.5% and vehicle groups, respectively, will be 
needed. Therefore, the sample size needed to provide 90% power for both co-primary endpoints 
is 
 and 
 subjects in the FMX103 1.5% and vehicle groups, respectively. 
11.3 
Analysis Populations 
The following populations will be defined for analysis: 

Intent-to-Treat (ITT) population:  all randomized subjects.

Per-Protocol (PP) population:  defined as the subset of the ITT population without any
protocol deviations that may have an impact on the efficacy assessments. Subjects to be
included in the PP population will be determined by the Sponsor/CRO prior to the
unblinding of the study.
Subjects may be excluded from the PP population if any of the following are met:
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o Failure to meet inclusion/exclusion criteria 
o Have administered any interfering concomitant medications 
o Have not, in the opinion of the Investigator, been compliant with the treatment 
regimen (eg, reported frequent missed doses) 
o Randomization error 
Prior to breaking the blind, additional criteria for exclusion from the PP population may 
be included to accommodate for unforeseen events that occurred during the conduct of 
the study. 
 Safety Population:  all randomized subjects who use any study product. Subjects who 
have no post-Day 0/Baseline assessments will be included in the Safety population unless 
all dispensed study drug is returned unused. 
The ITT population will be the primary population for efficacy analysis. The PP population will 
be secondary for the co-primary endpoints only. The Safety population will be used for the 
analyses of safety endpoints. 
All efficacy analyses will be conducted according to the randomized treatment assignment; all 
safety analyses will be conducted according to the treatment actually received. 
11.4 
Subject Accounting, Demographics, and Day 0/Baseline Characteristics 
Demographics, Day 0/Baseline characteristics, and prior and concomitant medications will be 
summarized by treatment. Study completion status and reasons for discontinuation will also be 
displayed by treatment. 
Medical and surgical history will only be presented in the listings. 
11.5 
Efficacy Endpoints 
The primary population for all efficacy analyses will be the ITT population. For the analyses of 
the co-primary and secondary efficacy endpoints based on the ITT population, a variety of 
methods will be used to impute missing data, including multiple imputation (MI), last-
observation-carried forward (LOCF), and Day 0/Baseline observation carried forward (BOCF). 
MI will be the primary imputation method. Sensitivity analyses using LOCF and BOCF will be 
performed only on the co-primary efficacy endpoints to assess the robustness of alternate 
imputation assumptions. For the continuous efficacy measure, a mixed effects model for repeated 
measures (MMRM) analysis will also be conducted as a sensitivity analysis. All supportive 
analyses using the PP population will use the Observed-Cases (OC) approach, that is there will 
be no imputation for missing data at any time point. No other imputations will be made unless 
otherwise specified. 
For all efficacy analyses, subjects will be analyzed according to the treatment group to which 
they were randomized. 
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11.5.1 
Primary Efficacy Endpoints 
The co-primary efficacy endpoints are: 
 The absolute change in the inflammatory lesion count at Week 12 compared to Day 
0/Baseline. 
 The dichotomized IGA score where treatment success is defined as a 2-step improvement 
resulting in a 0 (clear) or 1 (almost clear) score at Week 12 compared to Day 0/Baseline. 
The null hypothesis of the equality of the FMX103 1.5% and vehicle means for absolute change 
from Day 0/Baseline to Week 12 in the inflammatory lesion count and the equality of IGA 
success rates at Week 12 will each be tested at a two-sided 0.05 level of significance. Change 
from Day 0/Baseline in inflammatory lesion count will be analyzed using an analysis of 
covariance (ANCOVA), with treatment as a main effect, Day 0/Baseline inflammatory lesion 
count as a covariate, and investigational site as a blocking factor. Investigational site-by-
treatment interaction will be tested at a two-sided 0.1 level, and if significant, will be further 
explored. The dichotomized IGA will be analyzed using the Cochran-Mantel-Haenszel (CMH) 
test, stratified by investigational site. 
11.5.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
 The dichotomized IGA score where success is defined as a 2-step improvement in score at 
Week 12 compared to Day 0/Baseline. 
 The percent change in inflammatory lesion count at Week 12 compared to Day 0/Baseline. 
 The absolute change from Day 0/Baseline in the inflammatory lesion count and IGA 
treatment success at the interim visit at Week 8. 
 The absolute change from Day 0/Baseline in the inflammatory lesion count and IGA 
treatment success at the interim visit at Week 4. 
Secondary efficacy endpoints will be treated sequentially in the order listed above, at a 0.05 level 
of significance, only if the co-primary efficacy endpoints are significant. 
11.5.3 
 
 
 
 
 
 
 
 
11.6 
Safety Endpoints 
Safety endpoints will be reported on the Safety population. Subjects will be reported according 
to the treatment they actually received. Safety assessment will be based on descriptive statistics 
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and individual subject listings. No statistical tests will be performed for any of the safety 
assessments. 
Treatment-emergent AEs (TEAEs) will be defined as events that emerge having been absent 
pre-treatment, or worsen relative to the pre-treatment state. Summaries of AEs will be limited to 
TEAEs. The number and percentage of subjects reporting events under each System Organ Class 
(SOC) and preferred term (PT) will be summarized for each treatment group. At each level of 
summarization, a subject will be counted only once if he/she reported one or more events. The 
severity of TEAEs and relationship to study drug will be summarized in a similar manner. For 
summaries of relationship to study drug, a subject will be classified according to the closest 
relationship. For summaries of TEAE severity, a subject will be classified according to the 
highest severity. 
TEAEs, vital signs, and clinical laboratory measurements will be summarized by treatment group 
using descriptive statistics. For vital signs, change from Day 0/Baseline values will also be 
summarized. For all safety variables, subject data listings will be provided. 
Local signs and symptoms assessments will include active assessments of erythema, 
telangiectasia, burning/stinging, flushing/blushing, dryness/xerosis, itching, 
peeling/desquamation, and hyperpigmentation using the scales described under Section 10.7.2. 
11.6.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) terminology will be used to 
classify all AEs with respect to SOC and PT. 
Summaries of SAEs and subjects who prematurely withdraw from the study due to AEs will be 
presented. 
11.6.2 
Vital Signs and Physical Examinations 
Vital sign and physical examination parameters will be summarized using descriptive statistics at 
Day 0/Baseline and at each post-Day 0/Baseline time point. Changes from Day 0/Baseline will 
also be summarized. Day 0/Baseline is defined as the last non-missing value prior to the first 
dose of study drug. 
11.6.3 
Clinical Laboratory Results 
Shift tables for each clinical laboratory test will cross-tabulate the number of subjects with values 
below the laboratory reference range (low), values within the laboratory reference range 
(normal), or above the laboratory range (high) at Day 0/Baseline with the number of subjects 
with low, normal, or high values at the Final Visit. Day 0/Baseline is defined as the last non-
missing value prior to the first dose of study drug. 
A listing of subjects with pre-treatment and treatment-emergent clinically significant abnormal 
laboratory values will be presented for each treatment group. Clinical significance is based on 
the Investigator’s judgment. 
11.7 
Interim Analysis 
No interim analysis is planned. 
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12 
STUDY MANAGEMENT 
12.1 
Monitoring 
The Investigator will be responsible for preparing and maintaining adequate and accurate source 
documents (medical records, raw data collection forms, etc.) designed to record all observations 
and other pertinent data for each subject treated with the study drug. The Investigator will allow 
representatives of the Sponsor, contract designees, authorized regulatory authority inspectors, 
and the Institutional Review Board (IRB) to have direct access to all documents pertaining to the 
study. The Investigator is to immediately notify the Sponsor of any regulatory authority 
inspections. The Investigator will be informed about the outcome of any Sponsor audit. 
This study will be monitored regularly, by or under supervision of a monitor from the Sponsor. 
The frequency of monitoring visits will be agreed upon by the Sponsor’s representative and the 
study site. 
Monitoring visits will take place on a regular basis according to the enrollment rate and number 
of subjects enrolled at each investigational site. During these visits, the monitor will check the 
completion of the CRF entries, compliance with the study protocol and with GCP-ICH, and their 
agreement with the source data. The monitor will also verify the correct use of the study drug. At 
a final visit, the monitor will check all remaining material including the remaining quantities of 
the study drug and will organize their return to the Sponsor or designee. At each visit, the 
Investigator and staff will be expected to cooperate with the Sponsor’s representative(s) for the 
purposes of review and verification of protocol compliance, AE reporting, CRFs, source 
documents, clinical supplies and inventory records, and any additional records as may have been 
previously arranged between the Investigator and the Sponsor’s representative(s). 
The Investigator and/or other designated study personnel are expected to contact the Sponsor’s 
clinical research associate, as needed, regarding study concerns and/or questions. Contact 
information is provided in the Study Reference Manual for the site. 
12.2 
Protocol Amendments 
The Sponsor may propose to amend this protocol at any time. 
No change to the protocol will be implemented until the Sponsor and the IRB have reviewed and 
approved the amendment. 
In the event of an emergency, the Investigator shall implement any medical procedures deemed 
appropriate for subject safety. All such procedures must have written documentation and be 
promptly reported to the Sponsor. 
12.3 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the IRB-approved protocol 
(intentional or unintentional). All deviations are to be documented at the site and reported to the 
IRB according to the IRB’s guidelines. 
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In the event of an emergency, the Investigator shall implement any medical procedures deemed 
appropriate for subject safety. All such procedures must have written documentation and be 
promptly reported to the Sponsor and IRB. 
12.4 
Withdrawal of Subjects 
Withdrawn subjects are those who do not complete all evaluations and procedures outlined in the 
protocol. Subjects who discontinue taking study drug for any reason must also be withdrawn 
from the study. Subjects may be withdrawn from the study because of any of the following: 
 Adverse Event:  An AE that, in the opinion of the Investigator or Sponsor, suggests that 
continued participation in the study is not in the subject’s best interest for safety reasons. 
All AEs that are present when the subject withdraws from the study will be followed as 
described in Section 10.8.4. 
 Abnormal Laboratory Result:  Any clinically significant laboratory abnormality that 
requires withdrawal of the subject from the study should be considered an AE leading to 
withdrawal. If possible, laboratory tests will be repeated for any results that were 
clinically significantly abnormal until the abnormality is resolved or stabilized to the 
satisfaction of the Investigator in consultation with the medical monitor. 
 Lost to Follow-up:  Confirmed at minimum by two phone calls and a traceable letter 
without answer. 
 Subject Request:  Subject requests, for any reason (eg, AE), to be withdrawn or 
withdraws his/her consent. 
 Protocol Deviation:  A subject may be withdrawn from the study at the discretion of the 
Investigator or Sponsor due to poor compliance with protocol requirements that may 
compromise the study results or subject safety. 
 Other:  Other reasons include but are not limited to, Investigator decision that it is in the 
subject’s best interest to be withdrawn, administrative reasons, relocation of subject, etc. If 
a subject becomes pregnant during the study, the subject will be withdrawn from the study 
and followed through conclusion of the pregnancy. 
If a subject is withdrawn from the study following the start of study drug, all Visit 7 
(Week 12/Final Visit) assessments should be completed. Subjects withdrawn from the study will 
not be replaced. 
12.5 
Termination of the Study 
The study may be terminated at any time at the request of the Sponsor or a regulatory authority, 
with proper and timely notification of all parties concerned. The IRB will be informed promptly 
and the Sponsor or the Investigator will supply reason(s) for the termination or suspension, as 
specified by the applicable regulatory requirements. Otherwise, the study is considered 
terminated upon completion of all subject treatments and evaluations. 
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12.6 
Publication Policy 
The data obtained in this study are the property of the Sponsor, which will make reasonable 
efforts to assure that the results are published in a peer-reviewed journal. As some of the 
information concerning the investigational product and development activities at the Sponsor 
may be of a strictly confidential nature, any manuscript or other presentation of data must first be 
reviewed by the Sponsor before its submission. 
13 
ETHICS 
13.1 
Conduct of the Study 
This study will be conducted in accordance with the ICH Harmonized Tripartite Guideline for 
GCP, 1997; the US Title 21 CFR parts 50, 56, and 312; and the ethical principles that have their 
origin in the Declaration of Helsinki. The study will not begin until all of the requirements of the 
appropriate regulatory authorities have been fulfilled. 
13.2 
Institutional Review Boards (IRB) 
This protocol (and any changes), all consent forms, and subject consent procedures must be 
reviewed and approved by a properly constituted IRB. The information presented to the IRB at 
the time initial approval is sought must include any plans for subject recruitment that involve 
advertising or other direct contact with potential subjects outside of the physician-subject 
relationship. A letter of approval issued by the IRB must be sent to the Sponsor prior to initiation 
of the study. Any changes made to the protocol must be approved by the IRB prior to 
implementation, except where needed to eliminate a potential imminent safety hazard to the 
subjects. In this case, immediate implementation may take place followed by IRB approval. 
Review and approval by the IRB for continuation of the study must take place at least once a 
year. 
13.3 
Written Informed Consent 
The Investigator or designee will explain the nature of the study, its purpose and associated 
procedures, the expected duration, and the potential benefits and risks of participation to each 
subject prior to his/her entry into the study (ie, before examinations and procedures associated 
with selection for the study are initiated). Each subject will have ample opportunity to ask 
questions and will be informed about the right to withdraw from the study at any time without 
any disadvantage and without having to provide reasons for this decision. 
Following this informative discussion, the subject will be asked if he/she is willing to sign a 
statement of informed consent. Only subjects who voluntarily sign the ICF may enter the study. 
The ICF must be reviewed and approved by the Sponsor and the IRB prior to their use. 
The original signed ICF will remain in the Investigator’s files. The Investigator or designee will 
indicate in each subject’s source documents that he/she has informed the subject about the study 
and its procedures, the subject has signed and dated the ICF, and the subject has been given a 
copy of the documents. The Investigator or designee will inform subjects of any new information 
that may be relevant to the subject’s willingness to continue in the study. 
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13.4 
Subject Confidentiality 
The Sponsor ensures that the following have permission to review all study-related documents:  
monitor, auditor, IRB, and regulatory authorities. The subject’s identity and study-related records 
will remain confidential throughout the duration of the study data collection and reporting 
process. 
The investigative site assigns a unique subject identification code to each potential study subject. 
The identification code protects the subject’s identity and is used in lieu of the subject’s name 
when reporting subject data. The data will always maintain the confidentiality of the subject. 
The Investigator or designee will review the subject data, which will be referenced using the 
subject identifier. At the conclusion of the study, the data obtained may be presented to regional 
regulatory authorities but the subject’s identity will not be revealed. In addition, if any clinical 
data obtained from the study is published in scientific journals or presented at scientific meetings 
the subject’s identity will not be revealed. 
13.5 
Records Retention 
The Investigator must maintain essential study documents (protocol and amendments, source 
documentation corresponding to all information contained in the CRFs, signed ICF and assent 
forms, relevant correspondence, and all other supporting documentation) until at least 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region, or at least 2 years after the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period if required by the applicable regulatory requirements or the 
hospital, institution, or private practice in which the study is being conducted. Subject 
identification codes (subject names and corresponding study numbers) will be retained for this 
same time period. Custody of the records may be transferred to another responsible party, 
acceptable to the Sponsor, who agrees to abide by the retention policies. Written notice of 
transfer must be submitted to the Sponsor. The Investigator must contact the Sponsor prior to 
disposing of any study records. 
13.6 
Financing 
Funding for this study will be agreed between the Investigator and the Sponsor and will be 
confirmed in writing before the study starts. 
Completion of Financial Disclosure Forms will be required before the study starts. Any additions 
to the primary site personnel will necessitate the completion of new Financial Disclosure Forms. 
This information will also be collected at site closure and 1 year after the completion of the 
study. 
14 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor and Investigator will take all steps possible to ensure the accuracy, consistency, 
completeness, and reliability of the data, including participating in an Investigator meeting 
and/or site initiation visit, routine site monitoring, review of CRFs against source documents, and 
quality control checks. 
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In addition, a representative from the Sponsor’s Clinical Quality Assurance (CQA) Department 
may conduct periodic audits of the study processes, including, but not limited to, auditing the 
clinical site, laboratories, vendors and CROs, the clinical database, and the final study report. 
15 
DATA HANDLING AND RECORD KEEPING 
This study will use web-based, electronic case report forms (eCRFs) developed through a 
validated, Electronic Records/Electronic Signatures-compliant platform (US Title 21 CFR 
Part 11). Foamix Clinical Data Management department or designee will create the eCRFs and 
corresponding clinical database based on the final protocol. 
All site personnel who will be using this system will receive formal training on the system, after 
which each person will be issued a unique username and password. Only the person who owns 
the username and password will enter the system using that username and password. For data 
security reasons and to be in compliance with regulatory guidelines, usernames and passwords 
are not transferable. 
The Investigator is responsible for all data entered via the remote data capture (RDC) system 
eCRFs and must confirm the accuracy of the data by electronically approving (signing) the 
eCRFs. This responsibility includes the timely completion and accuracy of the data entered into 
the eCRFs by their site personnel as well as the review and approval of some data entered 
directly into the database (eg, clinical laboratory results) by an external vendor. The Sponsor will 
review the database to identify data errors or inconsistencies, which will be posted in the RDC 
system as queries for resolution. In addition, the Sponsor may make obvious corrections to the 
data in the database (eg, obvious errors in dates) and so inform the Investigator without issuing a 
query to the site. 
16 
REFERENCE LIST 
Not applicable. 
 
 
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Privileged and Confidential 
 
Clinical Protocol:  Version 1 
44 of 45 
Final 
Protocol:  FX2016-12 
 
Date:  20 Jan 2017 
APPENDIX 1:  Subject Global Assessment Questionnaire 
Question:  “Considering your rosacea just before starting treatment and considering your 
condition today, indicate the change you have experienced according to the scale below”: 
 5 = Much better than prior to treatment 
 4 = Slightly better than prior to treatment 
 3 = Same as prior to treatment 
 2 = Slightly worse than prior to treatment 
 1 = Much worse than prior to treatment 
 
 
 
Page 155 of 156


 
Privileged and Confidential 
 
Clinical Protocol:  Version 1 
45 of 45 
Final 
Protocol:  FX2016-12 
 
Date:  20 Jan 2017 
APPENDIX 2:  Subject Satisfaction Questionnaire 
The following 8 questions will be asked of the subject at Visit 7 (Week 12 / Final Visit): 
 
1. How satisfied are you with this product in treating your rosacea? 
2. How satisfied are you with how easy this product is to use? 
3. How satisfied are you with this product compared to other products you have previously 
used for rosacea, such as gels and creams? 
4. How satisfied are you with how this product feels on your skin after treatment? 
5. How satisfied are you with the odor of this product after treatment? 
6. How satisfied are you with the color of this product after treatment? 
7. Overall, how satisfied are you with this product? 
8. Overall, how likely are you to recommend this product to a friend? 
 
Answers to Questions 1 through 7 will be selected from the following: 
 1 = Very Satisfied 
 2 = Satisfied 
 3 = Somewhat Satisfied 
 4 = Dissatisfied 
 5 = Very Dissatisfied 
 
The answer to Question 8 will be selected from the following: 
 1 = Very Likely 
 2 = Likely 
 3 = Somewhat Likely 
 4 = Unlikely 
 5 = Very Unlikely 
 
 
 
Page 156 of 156

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
A Randomized, Multicenter, Double-blind, Vehicle-controlled Study to 
Evaluate the Safety and Efficacy of FMX103 1.5% Topical Minocycline Foam 
Compared to Vehicle in the Treatment of Facial Papulopustular Rosacea 
(FX2016-12) 
 
 
 
ClinicalTrials.gov Identifier: NCT04608500  
 
 
 
Date of Statistical Analysis Plan: 09 July 2018 




Statistical Analysis Plan,  
Sponsor Foamix Pharmaceuticals  
Protocol Number FX2016-12  
PCN Number FOAM166107
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 2 of 38 
Table of Contents 
Approvals ........................................................................................................................................ 1 
Table of Contents ............................................................................................................................ 2 
List of Tables .................................................................................................................................. 4 
1.
Overview ............................................................................................................................. 5 
2.
Study Objectives and Endpoints ......................................................................................... 5 
2.1. 
Study Objectives ........................................................................................................... 5 
2.2. 
Study Endpoints ............................................................................................................ 6 
2.2.1. Safety Endpoints ........................................................................................................... 6 
2.2.2. Efficacy Endpoints ........................................................................................................ 6 
3.
Overall Study Design and Plan ........................................................................................... 7 
3.1. 
Overall Design .............................................................................................................. 7 
3.2. 
Sample Size and Power ................................................................................................. 7 
3.3. 
Study Population ........................................................................................................... 8 
3.4. 
Treatments Administered .............................................................................................. 8 
3.5. 
Method of Assigning Subjects to Treatment Groups .................................................... 8 
3.6. 
Blinding and Unblinding............................................................................................... 8 
3.7. 
Schedule of Events ........................................................................................................ 9 
4.
Statistical Analysis and Reporting .................................................................................... 11 
4.1. 
Introduction ................................................................................................................. 11 
4.2. 
Interim Analysis and Data Monitoring ....................................................................... 11 
5.
Analysis Populations ......................................................................................................... 11 
6.
General Issues for Statistical Analysis .............................................................................. 12 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 12 
6.1.1. Baseline ....................................................................................................................... 12 
6.1.2. Study Day.................................................................................................................... 12 
6.1.3. Adjustments for Covariates......................................................................................... 13 
6.1.4. Multiple Comparisons ................................................................................................. 13 
6.1.5. Handling of Dropouts or Missing Data ....................................................................... 13 
6.1.6. Analysis Visit Windows ............................................................................................. 15 
6.1.7. Pooling of Sites ........................................................................................................... 15 
6.1.8. Derived Variables ....................................................................................................... 16 
6.1.9. Data Adjustments/Handling/Conventions .................................................................. 18 
Page 3 of 101


 
Statistical Analysis Plan,  
 
Sponsor Foamix Pharmaceuticals  
 
Protocol Number FX2016-12  
 
PCN Number FOAM166107 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 3 of 38 
 
7. 
Study Subjects and Demographics.................................................................................... 19 
7.1. 
Disposition of Subjects and Withdrawals ................................................................... 19 
7.2. 
Protocol Deviations ..................................................................................................... 20 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 20 
7.4. 
Study Drug Exposure and Compliance ....................................................................... 20 
8. 
Efficacy Analysis .............................................................................................................. 21 
8.1. 
Primary Efficacy Analysis .......................................................................................... 21 
8.2. 
Secondary and Tertiary Efficacy Analysis ................................................................. 22 
8.3. 
Subject Satisfaction Questionnaire ............................................................................. 22 
8.4. 
Subject Global Assessment ......................................................................................... 22 
9. 
Safety and Tolerability Analysis ....................................................................................... 22 
9.1. 
Adverse Events ........................................................................................................... 23 
9.1.1. Adverse Events Leading to Withdrawal ..................................................................... 24 
9.1.2. Deaths and Serious Adverse Events ........................................................................... 24 
9.2. 
Clinical Laboratory Evaluations ................................................................................. 24 
9.3. 
Vital Signs ................................................................................................................... 25 
9.4. 
Physical Examinations ................................................................................................ 25 
9.5. 
Local Signs and Symptoms Assessments ................................................................... 25 
9.6. 
Prior and Concomitant Medication ............................................................................. 25 
10. 
Changes from Planned Analysis ....................................................................................... 26 
11. 
Other Planned Analysis..................................................................................................... 26 
11.1. Pharmacokinetic Analysis ........................................................................................... 26 
12. 
References ......................................................................................................................... 27 
13. 
Tables, Listings, and Figures ............................................................................................ 27 
14. 
Planned Table Descriptions .............................................................................................. 27 
14.1. Planned Listing Descriptions ...................................................................................... 32 
14.2. Planned Figure Descriptions ....................................................................................... 35 
15. 
Tables, Listings, and Listing Shells .................................................................................. 36 
15.1. Standard Layout for all Tables, Listings, and Figures ................................................ 36 
 
Appendix 1: Premier Research Library of Abbreviations ............................................................ 37 
 
 
Page 4 of 101


Statistical Analysis Plan,  
Sponsor Foamix Pharmaceuticals  
Protocol Number FX2016-12  
PCN Number FOAM166107
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 4 of 38 
List of Tables 
Table 1:  Schedule of Events ........................................................................................................ 10 
Table 2:  Analysis Visit Windows ................................................................................................ 15 
Table 3:  Disposition, Demographic, Prior Medications, and Study Drug Exposure Data 
Summary Tables ................................................................................................................... 28 
Table 4:  Efficacy Data ................................................................................................................. 29 
Table 5:  Safety Data..................................................................................................................... 30 
Table 6:  Planned Listings............................................................................................................. 32 
Page 5 of 101


 
Statistical Analysis Plan,  
 
Sponsor Foamix Pharmaceuticals  
 
Protocol Number FX2016-12  
 
PCN Number FOAM166107 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 5 of 38 
 
1. 
Overview 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Foamix 
Pharmaceuticals protocol number FX2016-12 (A Randomized, Multicenter, Double-blind, 
Vehicle-controlled Study to Evaluate the Safety and Efficacy of FMX103 1.5% Topical 
Minocycline Foam Compared to Vehicle in the Treatment of Facial Papulopustular Rosacea), 
Version 3 dated 12 May 2017. Reference materials for this statistical plan include the protocol 
and the accompanying sample data collection documents. Operational aspects related to the 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration, European Medicines Agency, and International 
Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals 
for Human Use: Guidance on Statistical Principles in Clinical Trials1. All work planned and 
reported for this SAP will follow internationally accepted guidelines, published by the American 
Statistical Association2 and the Royal Statistical Society3, for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be submitted to file prior to any 
unblinded inferential or descriptive analysis of data pertaining to study FX2016-12. 
Subjects who complete the Week 12 study visit may be invited to continue in an open-label 
extension study of FMX103 1.5% minocycline foam (protocol FX2016-13) for an additional 
40-week treatment period. Analyses for FX2016-13 are reported separately. 
2. 
Study Objectives and Endpoints 
2.1. 
Study Objectives 
The objectives of this study are: 
• To determine the efficacy of FMX103 1.5% minocycline foam applied topically once 
daily for 12 weeks in the treatment of rosacea. 
• To evaluate the tolerability and safety of topical minocycline foam applied once daily for 
12 weeks. 
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Statistical Analysis Plan,  
 
Sponsor Foamix Pharmaceuticals  
 
Protocol Number FX2016-12  
 
PCN Number FOAM166107 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 6 of 38 
 
2.2. 
Study Endpoints 
2.2.1. Safety Endpoints 
The safety endpoints of this study include the following: 
• Incidence, severity, and causality of any adverse events (AEs), treatment-emergent AEs 
(TEAEs), serious TEAE (SAE), treatment-related TEAEs, and TEAEs leading to study 
discontinuation 
• Changes from baseline in vital signs, laboratory parameters, and physical examinations 
• Assessment of local signs and symptoms assessments including erythema, telangiectasia, 
burning/stinging, flushing/blushing, dryness/xerosis, itching, pealing/desquamation, and 
hyperpigmentation 
2.2.2. Efficacy Endpoints 
2.2.2.1. 
Primary Efficacy Endpoint 
The co-primary efficacy endpoints of this study are:  
• The absolute change from Day 0/Baseline in the inflammatory lesion count at Week 12  
• Investigator Global Assessment (IGA) Treatment Success (dichotomized as yes/no) at 
Week 12, where success is defined as an IGA score of 0 (clear) or 1 (almost clear), and at 
least a 2-step improvement (decrease) from Day 0/Baseline 
2.2.2.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study include the following: 
• The dichotomized IGA score, where success is defined as a 2-step improvement in 
score at Week 12 compared to Day 0/Baseline 
• The percent change from Day 0/Baseline in the inflammatory lesion count at Week 12 
• The absolute change from Day 0/Baseline in the inflammatory lesion count and IGA 
Treatment Success at the interim visits at Weeks 4 and 8 
2.2.2.3. 
 
: 
• 
 
 
Page 7 of 101
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Statistical Analysis Plan,  
 
Sponsor Foamix Pharmaceuticals  
 
Protocol Number FX2016-12  
 
PCN Number FOAM166107 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 7 of 38 
 
3. 
Overall Study Design and Plan 
3.1. 
Overall Design 
This is a randomized, multicenter, double-blind, vehicle-controlled, 2-arm study to evaluate the 
safety and efficacy of FMX103 topical foam containing 1.5% minocycline compared to vehicle 
in the treatment of subjects with moderate-to-severe facial papulopustular rosacea over 
12 weeks. Subjects with qualifying inflammatory lesion counts and IGA of rosacea severity 
scores will be enrolled and randomly assigned in a 2:1 ratio (active:vehicle) to receive 1 of the 
following 2 treatments: 
• FMX103 1.5% minocycline foam 
• Vehicle foam 
Subjects will apply (or have applied) the assigned study drug topically once daily for 12 weeks 
as directed. Subjects will be advised to apply the study drug at approximately the same time each 
day, preferably about 1 hour before bedtime. Both the Investigator and the subject will be 
blinded to the study drug identity. 
Subjects will return for in-person visits at Weeks 2, 4, 8, and 12. At the discretion of the clinic 
staff and for the convenience of subjects or clinic staff, visits can be scheduled to occur 3 days 
before or after the nominal scheduled date for the Weeks 2, 4, and 8 visits and 3 days before or 
5 days after for the Week 12 visit. Efficacy evaluations (inflammatory lesion counts and IGA) 
will be performed at Screening/Baseline and at Weeks 4, 8, and 12 during the study. An early 
follow-up telephone call will be made 1 week after the baseline clinic visit to review study 
procedures and record concomitant medications and AEs. For subjects who presented with new 
or on-going AEs and do not participate in study FX2016-13 (open-label extension study), a 
safety telephone call will be made 4 weeks after the Week 12 clinic visit to follow-up on these 
AEs and record any new concomitant medications.  
3.2. 
Sample Size and Power 
In Phase 2 Study FX2015-10, the proportion of subjects with an IGA score of 0 or 1 after 
 of treatment was 
 in the FMX103 1.5% dose group compared to 
 for the 
vehicle dose group. Table 5 in the protocol provides alternate assumptions on this primary 
response criterion with corresponding implications on sample size. Power was set to 90% and a 
type-1 error was set to a 2-sided test with a 0.05 level of significance. The sample size was 
calculated based on Fisher’s exact test.   
Assuming a 
 dropout rate and a 2:1 randomization, 500 subjects receiving FMX103 1.5% 
and 250 subjects receiving vehicle will provide at least 90% power to demonstrate a statistically 
significant difference in IGA success (ie, score of 0 or 1) between treatment groups. 
For the co-primary endpoint of change from Day 0/Baseline to Week 12 in inflammatory lesion 
count, in the Phase 2 study, the FMX103 1.5% dose group had a mean reduction of 
 lesions 
whereas the vehicle had a mean reduction of 
 lesions. The standard deviation (SD) was 
. 
Page 8 of 101
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Statistical Analysis Plan,  
 
Sponsor Foamix Pharmaceuticals  
 
Protocol Number FX2016-12  
 
PCN Number FOAM166107 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 8 of 38 
 
For 90% power, 
 and 
 subjects in the FMX103 1.5% and vehicle groups, respectively, will 
be needed. Therefore, the sample size needed to provide at least 90% power for both co-primary 
endpoints is 
 and 
 subjects in the FMX103 1.5% and vehicle groups, respectively. 
3.3. 
Study Population 
The study population comprises healthy male and non-pregnant females aged ≥18 years with a 
clinical diagnosis of moderate-to-severe facial papulopustular rosacea. 
3.4. 
Treatments Administered 
This is a double-blind study with 2:1 randomization between FMX103 1.5% and vehicle foam. 
FMX103 1.5% and vehicle will be supplied in identical canisters. Treatments will be 
administered daily for 12 weeks. The description of study drug kits and treatments is shown in 
Table 2 of the protocol. The dosing regimen is the same for both treatment groups.  
3.5. 
Method of Assigning Subjects to Treatment Groups 
During the baseline visit, subjects are randomly assigned to treatment using the interactive 
response technology (IRT) system. Authorized site personnel will use the IRT system to assign a 
kit number that corresponds to the randomization schedule. The kit box with the assigned kit 
number will be dispensed to the subject. Kits are dispensed at the Day 0/Baseline, Week 4, and 
Week 8 clinic visits. 
3.6. 
Blinding and Unblinding 
This is a double-blind study with limited access to the randomization code. The randomization 
code will be held in confidence until after the study database is locked and a memo documenting 
the database lock has been issued. Every effort will be made to retain the integrity of the blind. 
When issued to the sites, the study drug will be identical in appearance for all subjects, 
regardless of treatment assignment. 
The treatment that each subject receives will not be disclosed to the Investigator, study site 
personnel, subjects, monitors, or Sponsor staff, except as required for the purposes of conducting 
this study. 
In the event that emergency identification of study drug is required (eg, if the Investigator 
believes that the information is necessary to properly treat a subject with an AE), the study drug 
identity can be obtained by the Investigator through the IRT system. 
Before breaking the blind for a subject, the Investigator should determine that the information is 
necessary (ie, that it will alter the subject’s immediate course of treatment and contribute to the 
management of the AE). In many cases, particularly when the emergency is clearly not related to 
study drug, the problem may be managed effectively by assuming that the subject is receiving 
active study drug without the need for unblinding. Every effort should be made to alert the 
medical monitor before requesting that the blind be broken. If this is not possible, the medical 
Page 9 of 101
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Statistical Analysis Plan,  
 
Sponsor Foamix Pharmaceuticals  
 
Protocol Number FX2016-12  
 
PCN Number FOAM166107 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 9 of 38 
 
monitor should be notified immediately of the breaking of the blind. The Investigator will record 
the unblinding procedures in the subject’s source documents. 
If unblinding is necessary, the subject will be withdrawn from the study and Early Termination 
(ET) Visit (ie, Visit 5 [Week 12]) assessments will be completed. 
3.7. 
Schedule of Events 
A detailed schedule of events for the study is provided in Table 1. 
 
 
Page 10 of 101


 
Statistical Analysis Plan,  
 
Sponsor Foamix Pharmaceuticals  
 
Protocol Number FX2016-12  
 
PCN Number FOAM166107 
 
 
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Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 10 of 38 
 
Table 1:  Schedule of Events 
Assessment or Procedure 
Screening 
Day 0 / 
Baselinea 
Visits/Early Follow-
up 
Final 
Visitb 
Safety 
Follow-upf 
Visit 
 
1 
EF 
2 
3 
4 
5 
 
Week 
 
 
1 
2 
4 
8 
12 
 
Informed consent 
X 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Assign subject identification 
X 
 
 
 
 
 
 
 
Medical/surgical/medication history 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Physical examination, height, weightc  
 
X 
 
 
 
 
X 
 
Blood pressure/heart rated  
 
X 
 
X 
X 
X 
X 
 
Blood and urine samples for clinical 
laboratory tests  
X 
 
 
 
 
 
X 
 
Urine pregnancy test (females of 
childbearing potential only) 
X 
X 
 
 
X 
X 
X 
 
Lesion counts 
X 
X 
 
 
X 
X 
X 
 
Investigator’s Global Assessment 
X 
X 
 
 
X 
X 
X 
 
Subject Global Assessment 
 
 
 
X 
X 
X 
X 
 
Subject Satisfaction Questionnaire 
 
 
 
 
 
 
X 
 
Local signs and symptoms assessmentse  
X 
X 
 
X 
X 
X 
X 
 
Photography† 
 
X 
 
 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
Perform drug accountability 
 
 
 
X 
X 
X 
X 
 
Collect used drug canister(s) 
 
 
 
X 
X 
X 
X 
 
Dispense study drug 
 
X 
 
 
X 
X 
 
 
Schedule/confirm next visit 
X 
X 
X 
X 
X 
X 
 
 
EF – Early Follow-up telephone call, no visit 
† only for study centers participating in subject photography 
a. 
Day 0/Baseline must occur within 45 days of Screening. Blood test results must not show clinically significant abnormalities. 
b. 
If a subject withdraws from the study prematurely, all evaluations described under Visit 5/Week 12 (Final Visit) must be 
performed at an Early Termination Visit. 
c. 
Height to be measured only at Day 0/Baseline. 
d. 
Measure blood pressure and heart rate after the subject has been sitting for at least 5 minutes at rest. 
e. 
The severity of each of the following local rosacea signs/symptoms will be measured:  erythema, telangiectasia, 
burning/stinging, flushing/blushing, dryness/xerosis, itching, peeling/desquamation, and hyperpigmentation. 
f. 
A safety follow-up telephone call will be made 4 weeks after Visit 5/Week 12 (Final Visit) only for those subjects who do not 
participate in study FX2016-13 (open-label study) and presented with either new or ongoing adverse events at 
Visit 5/Week 12 (Final Visit). 
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Statistical Analysis Plan,  
 
Sponsor Foamix Pharmaceuticals  
 
Protocol Number FX2016-12  
 
PCN Number FOAM166107 
 
 
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Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017  
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4. 
Statistical Analysis and Reporting 
Statistical analysis will be performed following Premier Research’s standard operating procedures. 
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS® software (release 9.4 or 
higher). If the use of other software is warranted, the final statistical methodology report will 
detail what software was used and for what purposes.   
Continuous (quantitative) variable summaries will include the number of subjects with 
non-missing values, mean, SD, median, minimum, and maximum.  
Categorical (qualitative) variable summaries will include the frequency and percentage of 
subjects who are in the particular category or each possible value. Missing responses will be 
enumerated, unless otherwise specified. 
The minimum and maximum will be reported with the same degree of precision (ie, the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will 
be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
Unless otherwise indicated, all statistical tests will be conducted at the 0.05 significance level 
using 2-tailed tests, and p values will be reported. Corresponding 95% confidence intervals (CIs) 
will be presented for statistical tests. 
4.2. 
Interim Analysis and Data Monitoring 
No interim analyses are planned. 
5. 
Analysis Populations 
The following analysis populations are planned for this study:  
• Safety Population (SAF): The SAF Population includes all randomized subjects who 
use at least 1 dose of study drug, including subjects who have no post-baseline 
assessments. Analyses using the Safety Population will be based on treatment received. 
• Intent-To-Treat Population (ITT): The ITT Population includes all randomized 
subjects. Analyses using the ITT Population will be based on randomized treatment. 
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Statistical Analysis Plan,  
 
Sponsor Foamix Pharmaceuticals  
 
Protocol Number FX2016-12  
 
PCN Number FOAM166107 
 
 
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Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017  
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• Per-Protocol (PP): The PP Population is defined as the subset of the ITT population 
without any protocol deviations that may impact on the efficacy assessments. Analyses 
using the PP Population will be based on randomized treatment.  
Subjects to be included in the PP Population will be determined by the Sponsor/contract 
research organization prior to the unblinding of the study. A subject with a protocol 
deviation whose severity is classified as ‘Not Evaluable’ per the Protocol Deviation 
Guidance Plan for protocol FX2016-12 will be excluded from the PP Population. 
Subjects may be excluded from the PP Population if any of the following are met: 
o Failure to meet inclusion/exclusion criteria; 
o Have been administered any interfering concomitant medications  
o Have not been compliant with the treatment regimen (eg, less than 80% 
compliant) 
o Did not complete Week 12 efficacy assessments  
o Randomization error 
Prior to breaking the blind, additional criteria for exclusion from the PP Population 
may be included to accommodate for unforeseen events that occurred during the 
conduct of the study. 
The ITT Population will be the primary population for the efficacy analysis. The PP Population 
will be secondary for the co-primary endpoints. The Safety Population will be used for the 
analyses of all safety endpoints.  
All efficacy analyses will be conducted according to the randomized treatment assignment; all 
safety analyses will be conducted according to the treatment actually received.  
6. 
General Issues for Statistical Analysis 
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
The last non-missing value prior to the first application of study drug will be used as the baseline 
observation for all calculations of change from baseline.  
6.1.2. Study Day 
Day 1 is defined as the date of first study drug administration. Study day is calculated relative to 
the date of Day 1.  
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Protocol Number FX2016-12  
 
PCN Number FOAM166107 
 
 
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6.1.3. Adjustments for Covariates 
Analysis centers (see Section 6.1.7, Pooling of Sites) will be taken into account either by 
including it as a blocking factor in the analysis of covariance (ANCOVA) model or by 
conducting the categorical analysis stratified by analysis center in the Cochran-Mantel-Haenszel 
(CMH) test.  
In addition to analysis centers, baseline inflammatory lesion count will be included as a covariate 
in the ANCOVA for the change in inflammatory lesion count.  
No other covariates will be included in the analyses of the co-primary endpoints.  
6.1.4. Multiple Comparisons 
No adjustments will be made for multiple comparisons of endpoints. 
6.1.5. Handling of Dropouts or Missing Data 
The primary population for all efficacy analyses will be the ITT Population. For the analyses of 
the co-primary and secondary efficacy endpoints based on the ITT Population, a variety of 
methods will be used to deal with missing data for inflammatory lesion counts and IGA, 
including: 
• multiple imputation (MI) 
• last observation carried forward (LOCF) 
• baseline observation carried forward (BOCF) 
The MI method will be the imputation used for the primary analysis. Sensitivity analyses using 
LOCF and BOCF will be performed to assess the robustness of alternate imputation assumptions.  
No variables that have missing values other than inflammatory lesion counts and IGA will be 
imputed. 
All analyses using the PP Population will use the observed-cases (OC) approach; there will be no 
imputation for missing data at any time point. No other imputations will be made unless 
otherwise specified.  
The imputation procedures for post-baseline missing inflammatory lesion counts and missing 
IGA scores are as follows: 
• LOCF: The last observed value will be carried forward for any subsequent missing 
values. Baseline values will not be carried forward. 
• BOCF: The baseline value will be used for any missing post-baseline values. 
• MI: Multiple imputations is a simulation-based approach where missing values are 
replaced by multiple Bayesian draws from the conditional distribution of missing data 
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Statistical Analysis Plan,  
 
Sponsor Foamix Pharmaceuticals  
 
Protocol Number FX2016-12  
 
PCN Number FOAM166107 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017  
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given the observed data and covariates, creating multiple completed data sets. These 
completed datasets can then be analyzed using standard analysis methods. 
6.1.5.1. 
MI Procedures for Inflammatory Lesion Counts 
Intermittent missing value of inflammatory lesion counts will be imputed separately for each 
treatment group using the Markov Chain Monte Carlo (MCMC) method. Ten copies of the 
dataset with a monotonic missing pattern will be generated using the monotone data 
augmentation method4,5 to impute the amount of missing data that is required to make the 
missing data pattern monotone before applying the multiple imputation algorithm. This method 
uses a non-informative Jeffreys prior to derive the posterior mode from the expectation-
maximization algorithm as the starting values for the MCMC method. For each of the 
10 monotonic missing pattern datasets, an additional 10 datasets will be imputed to replace 
missing values at scheduled visits (Weeks 4, 8, and 12) for a total of 100 datasets.  These 
datasets will be generated using a regression-based multiple imputation model.6  For subjects 
with complete data up to a particular visit, a multiple regression model will be fit that includes 
the outcome at that visit as the dependent variable and outcomes at previous visits and treatment 
group as independent variables. Using these regression models, a missing value for a subject at a 
particular visit will be imputed as a draw from the predictive distribution given the outcomes at 
previous visits (some possibly imputed) and treatment group.6  
The SAS MI procedure (ie PROC MI) using the monotone regression method will be used. The 
ROUND option will be used to round the imputed values to the same precision as the observed 
values and the minimum value for imputed lesion counts will be specified as zero to avoid 
negative values. When an intended imputed value is less than the minimum, PROC MI will 
redraw another value for imputation. The ANCOVA analyses will be performed separately for 
each of the 100 complete analysis data sets, and the results will be combined into one multiple 
imputation inference (estimated treatment effect and associated confidence interval and 
p-value).6, 7  
6.1.5.2. 
MI Procedures for IGA Treatment Success 
The imputation of post-baseline IGA scores will be performed following a similar approach as 
described above for inflammatory lesion counts. Intermittent missing IGA scores will be imputed 
separately for each treatment group where 10 copies of the dataset with monotonic missing 
pattern will be generated. For each of the 10 datasets, missing values at scheduled visits 
(Weeks 4, 8, and 12) will be imputed 10 more times using scores at the previous scheduled visits, 
creating a total of 100 copies of a full dataset. The logistic regression method for monotone data 
will be used for imputation. The CMH analyses will be performed separately for each of the 
100 complete analysis sets and the risk ratios resulting from each imputed dataset will be log 
transformed to normalize prior to combining. The estimated log(𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅) and corresponding 
95% CI will be back-transformed from the combined results.8 
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Statistical Analysis Plan,  
 
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PCN Number FOAM166107 
 
 
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A pre-specified seed number of 
 will be used in all imputation procedures as 
described previously. 
6.1.6. Analysis Visit Windows 
All visit-based variables for this study will be analyzed according to their windowed visits 
defined by actual study day (see Table 2 below). Scheduled visits will be selected over 
unscheduled visits.  
For those subjects who discontinue early from the study, Table 2 will be used to assign the 
appropriate analysis visit.  
The study day (relative to first dose of study drug) will be calculated for each scheduled or ET 
visit and compared to the lower and upper bounds presented in Table 2 to define the visit 
window used for analyses. The analysis visit windows only apply to those visits that are 
applicable to the specific assessment. For example, if the scheduled or ET visit falls at Week 2 
but a specific assessment was not scheduled at that visit (see Table 1, Schedule of Events) then 
that assessment will not be used. 
The following analysis visit windows will apply: 
Table 2:  Analysis Visit Windows 
Analysis 
Visit 
Analysis 
Visit 
Name 
Target Day 
of Planned 
Visit 
Assessment Window (Days) 
2 
Week 2 
14 
Post-dose ─ 20 
3 
Week 4 
28 
21 ─ 41 
4 
Week 8 
56 
42 ─ 69 
5 
 Week 12 
84 
70 ─ 97 
If more than 1 visit occurs within a single visit window, then the analysis will use the visit 
closest to the target day. If 2 visits within the same visit window are equidistant from the target 
day, then the analysis will use the later visit. 
6.1.7. Pooling of Sites 
Analysis by investigative site will not be conducted, except for subject disposition.  
However, investigative sites will be taken into account either by including it as a blocking factor 
in the ANCOVA model or by conducting the categorical analysis stratified by investigational site 
in the CMH test. If a site has randomized at least 30 subjects and has at least 16 subjects assigned 
to the FMX103 1.5% group and at least 8 subjects assigned to the vehicle group, then this site 
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satisfies the criteria of an ‘analysis center.’ Otherwise, the site is considered as a small site. To 
make up analysis centers from the small sites, the following approach will be followed: 
(1) Small sites are ordered by site number,  
(2) From the first site into the next site, the number of subjects randomized to each 
treatment group and total are added together until the pooled sites meet the criteria of an 
‘analysis center.’ 
(3) If there is (are) small site(s) left, the left over small sites(s) is (are) added to the last 
‘analysis center.’ 
An unspecified number of small sites can be combined to meet the criteria of an ‘analysis center’ 
until the pre-specified criteria are met. These analysis centers will be used for statistical analyses.  
6.1.8. Derived Variables 
• Total number of inflammatory lesion count = number of papules + number of pustules + 
number of nodules in all facial areas (forehead, left and right cheeks, nose, and chin) 
• Change from baseline in inflammatory lesion count  = (value at baseline) – (post-baseline 
value) 
Thus, a positive change will reflect a reduction in inflammatory lesion count. 
Change from baseline will be calculated at the following time points:  4, 8, and 
12 weeks. 
• Percentage change from baseline inflammatory lesion count =  
100 × 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏−𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏
 
Thus, a positive percentage change will reflect a reduction in inflammatory lesion 
count. The percentage change from baseline will be calculated at the following 
time points: 4, 8, and 12 weeks. 
• TEAE = any adverse event with an onset date on or after the first application of study 
drug and before the last application of study drug plus 3 days having been absent 
pre-treatment or worsening relative to the pre-treatment state (for subjects not 
participating in the FX2016-13 open-label extension study), or events reported through 
the Week 12 clinic visit (for subjects participating in the extension study).  
• Body mass index (kg/m2) = 
𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 𝑖𝑖𝑖𝑖 𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑔𝑔𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟
(ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡 𝑖𝑖𝑖𝑖 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚)2  
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• Age groups 
Age group=1 if 18≤ age (full years) ≤ 40 
Age group=2 if 41≤ age (full years) ≤ 64 
Age group=3 if 65≤ age (full years) 
• Treatment duration (days) =  
Date of last dose of study drug – Date of first dose of study drug + 1 day 
For subjects who are missing the date of last study drug application, the last known contact 
date will be used in the calculation of treatment duration and study drug exposure. 
• Study drug exposure (days) =  
Treatment duration (days) – Number of days that a subject reported 
missing a dose (between the date of first and last dose) 
• Compliance (%) = 100 x Study drug exposure (days) / Treatment duration (days) 
Study drug compliance will not be calculated for subjects whose date of last study drug 
application is unknown. 
• Days on incorrect study drug = Date of correct drug re-dispense – Date of incorrect study 
drug dispensation 
Percent duration on incorrect drug (%) = 100 x Days on incorrect study drug (days) / 
Treatment duration (days) 
Derivations only apply to subjects that were dispensed incorrect kits with inconsistent 
treatment regimen, if this occurs over the course of this study. Date of study drug 
application is assumed to be the date of dispensation. Percent duration on incorrect drug 
is used, if applicable, in determining the “actual” treatment group to which a subject will 
be assigned for purposes of analyzing safety data (see Sections 6.1.9 and 9).  
• IGA treatment success = yes if the following conditions are both satisfied: 
o IGA score of 0 or 1 
o at least a 2-grade improvement (decrease) from baseline 
Otherwise the IGA treatment success = no 
• IGA treatment success-secondary = yes if the subject has at least a 2-grade improvement 
(decrease) from baseline, otherwise the IGA treatment success = no 
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6.1.9. Data Adjustments/Handling/Conventions 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but rather will be included in the data listings. 
All p-values will be displayed in 4 decimals and rounded using standard scientific notation 
(eg, 0.xxxx). If a p-value less than 0.0001 occurs it will be shown in tables as <0.0001. 
If during the course of this study it is determined that subjects were inadvertently dispensed 
incorrect kits, the following criteria will be used to determine treatment group for safety 
analyses: Subjects who were exposed to the study drug that they had not been randomized for 
≥ 20% of their treatment duration will be included in the FMX103 1.5% group for all safety 
assessments. Subjects who were exposed to the study drug for which they had not been 
randomized for < 20% of their treatment duration will be assessed according to the treatment 
they actually received for the majority of the study. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 20.0. In general, a TEAE is defined as an AE with an onset date on or after 
the first application of study drug and before the last application of study drug plus 3 days (for 
subjects not participating in the FX2016-13 open-label extension study), or events reported 
through the Week 12 clinic visit (for subjects participating in the extension study). For subjects 
missing the date of last study drug application due to being lost to follow-up (LTFU), or for any 
other reason, any AE with an onset date after the first study drug application with be considered 
a TEAE.  
Any AE that started before the first dose of study drug and worsens in severity or changes from 
nonserious to serious on or after the first dose date will also be designated as a TEAE. If an event 
worsens in severity during the study, the outcome of the lower grade event would be 
RECOVERED/RESOLVED or RECOVERED/RESOLVED WITH SEQUELAE with an end 
date (of that grade). A new event is recorded on the AE case report form (CRF) with a start date 
that matches the end date, and the term recorded includes “Worsened” (eg, “Worsened 
Headaches”). If an event becomes serious, the date that the event became serious is recorded on 
the AE CRF as the End Date of that AE and the Start Date of the corresponding SAE. 
For subjects participating in the extension study, AEs and concomitant medications that are 
ongoing as of the Week 12 visit will be closed out with a stop date of “ongoing”. Adverse events 
and concomitant medications that are continuing from this study will be copied into the 
extension study database with start dates entered as the original start date from this study.  
A treatment-related AE is any AE with a relationship to the study drug of possible or probable. 
Adverse events or medications with missing complete start dates will be classified as treatment 
emergent or concomitant, as appropriate. 
For analysis purposes, an AE that does not have a recorded relationship to the study drug value 
will be considered as “Probably Related” to the study drug, unless the start date of the AE is 
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before the date of first study drug administration, in which case the event would be considered as 
“Unlikely Related.” If the severity of an AE is missing, the severity will be considered as 
“Missing.”  
If partial AE or concomitant medication onset dates occur, the convention for replacing missing 
dates for the purpose of statistical analysis is as follows: if just day is missing then the day 
assigned is the first day of the month or the date of first dose (if in the same month), whichever is 
later; if just month is missing then the month assigned is the month of the first dose, unless that 
results in a date prior to the first dose in which case the month after the first dose is used; and if 
both month and day are missing then the month assigned is the month of the first dose and the 
day assigned is either the first day of the month or the first dose date, whichever is later. 
These conventions will be applied only to onset dates with the following precaution related to 
AE onset dates: if the missing date reflects the date of onset of an AE, the modified date will be 
constructed to match the first documented date post drug administration while preserving the 
order in which the AE was reported in the case report form (CRF). 
For partial end dates, the convention for replacing missing dates for the purpose of statistical 
analysis is as follows: if only the day is missing, then the day is assigned the last day of the 
month; if both day and month are missing, they are assigned the last day of the year (31 Dec). 
For subjects who are missing the date of last study drug application, for any reason, the last 
known contact date will be used in the calculation of treatment duration and study drug exposure. 
Study drug compliance will not be calculated for those subjects whose date of last study drug 
application is unknown. 
For analysis purposes, repeat laboratory test results will not be used unless the original 
laboratory value is missing or indicated as invalid, in which case the first non-missing repeat 
laboratory value will be used for data analysis. 
7. 
Study Subjects and Demographics 
7.1. 
Disposition of Subjects and Withdrawals 
The number and percentage of subjects who are included in each analysis population, who 
complete the study, who participate in study FX2016-13 (open-label extension study), withdraw 
from the study (overall and by reason for withdrawal), and who are excluded from the PP 
Population (overall and by reason for exclusion) will be summarized overall and by treatment 
group. The overall number of subjects who were screened will also be presented.  
A by-subject enrollment and disposition listing will be presented for all randomized subjects. 
Subjects who are screen failures will be presented in a separate listing. 
Percentages and counts will be calculated using randomized subjects, where applicable.  
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7.2. 
Protocol Deviations 
Protocol deviations will be listed for all randomized subjects.  
7.3. 
Demographics and Other Baseline Characteristics 
Summary statistics of demographics and baseline characteristics will be summarized overall and 
by treatment group. The following demographic and baseline variables will be included: 
• 
Age (years) 
• 
Age group in full years (18 to 40 years, 41 to 64 years, ≥ 65 years) 
• 
Sex 
• 
Race  
• 
Ethnicity  
• 
Baseline body weight (kg), height (cm), and body mass index (BMI) (kg/m2) 
• 
Baseline inflammatory lesion count  
• 
Baseline IGA score (moderate=3, severe=4) 
For continuous variables, the number of non-missing values and the mean, SD, minimum, 
median, and maximum will be tabulated.  
For categorical variables, the counts and proportions of each value will be tabulated. Subjects 
reporting more than 1 race will be included in a “More than one race” category for purposes of 
tabulating summary statistics.  
These analyses will be conducted for the ITT, PP, and Safety Populations. 
Past medical histories for all randomized subjects will be provided in a by-subject listing. 
7.4. 
Study Drug Exposure and Compliance 
The following parameters of study drug exposure and compliance will be summarized by 
randomized treatment group for the ITT and PP populations: 
• Treatment duration (days) 
• Study drug exposure (days) 
• Study drug compliance (%) 
For a given day, a subject is considered compliant with treatment if any amount of study drug is 
applied to the facial area. For subjects who are missing the date of last study drug application, for 
any reason, the last known contact date will be used in the calculation of treatment duration and 
study drug exposure. Study drug compliance will not be calculated for those subjects whose date 
of last study drug application is unknown.  
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8. 
Efficacy Analysis 
8.1. 
Primary Efficacy Analysis 
To attain the primary efficacy goal of FMX103 1.5% being considered superior to vehicle, both 
co-primary efficacy endpoints must be significant (ie, attaining significance at the 2-sided 
0.05 level without adjustment for multiplicity).  
The null hypotheses of the equality of FMX103 1.5% and vehicle are as follows: 
• H01: the absolute changes from baseline in inflammatory lesion count at Week 12 in the 
2 treatment groups are equal 
• H02: the IGA success rates at Week 12 in the 2 treatment groups are equal 
The primary efficacy analyses will be based on the ITT Population using MI and are as follows: 
• Absolute change from baseline in inflammatory lesion count: 
For each of the multiple imputed datasets, change from baseline in inflammatory lesion 
count will be analyzed using an ANCOVA model, with treatment as a main effect, 
baseline inflammatory lesion count as a covariate, and analysis center as a blocking 
factor. These results will be combined with the SAS MIANALYZE procedure (ie, PROC 
MIANALYZE) using Rubin’s formula and the resulting p-value will be used for 
inference at the 0.05 level of significance8. The combined estimated mean difference in 
change from baseline (FMX103 1.5% minus vehicle) and the associated 95% CI will be 
reported. 
• Dichotomized IGA Success Rate: 
For each of the multiple imputed datasets, the dichotomized IGA (yes/no) will be 
analyzed using a CMH test, stratified by analysis center. These results will be combined 
in Proc MIANALYZE and the resulting p-value will be used for inference at the 
0.05 level. The combined estimated log (𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅) of FMX103 1.5% vs. vehicle foam, 
and associated 95% confidence limits will be back-transformed. The combined Mantel-
Haenszel risk ratio, along with its estimated standard error (SE), 95% CI, and the 
associated p-value will be reported.  
If the overall IGA Treatment Success rate is less than 10%, the simple proportion of 
responders in each treatment group, the proportion difference, along with the estimated 
SE will be reported and combined in Proc MIANALYZE. The resulting p-value, 
proportions, proportion difference, and their 95% CIs will be presented. 
Sensitivity analyses of the co-primary efficacy endpoints will be performed using the same 
analysis methods described previously. Sensitivity analyses will include: 
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• ITT Population (OC, LOCF, and BOCF)  
• PP Population (OC) 
Homogeneity among analysis centers will be assessed by including an analysis center by 
treatment interaction in the ANCOVA model of the ITT OC analysis of the absolute change from 
baseline in inflammatory lesion counts. Analysis center by treatment interaction will be tested at 
the 0.1 level, and if significant, will further be explored.  
To account for the possibility of extreme outliers in the analysis of lesion counts, a sensitivity 
analysis will be conducted on the primary endpoint of absolute change from baseline in 
inflammatory lesion counts at Week 12 using multiple imputation in which the data will be rank-
transformed prior to analysis.  
8.2. 
Secondary 
 Efficacy Analysis 
Descriptive summaries will be used to summarize all endpoints, including secondary 
 
endpoints, for each visit: 
• absolute 
 change from baseline in inflammatory lesion count  
• dichotomized IGA score, where success is defined as a 2-step improvement in score at 
Week 12 compared to baseline. 
Secondary 
 efficacy endpoints will be analyzed similarly to the appropriate 
co-primary efficacy parameter.  
Secondary 
 efficacy endpoints will be tested at the 0.05 level of significance, only if 
both co-primary efficacy endpoints are significant in the primary analyses. 
8.3. 
Subject Satisfaction Questionnaire 
Answers to the Subject Satisfaction Questionnaire will be summarized for Week 12 (or the ET 
visit) using frequency counts and percentages by randomized treatment group for the ITT 
Population. 
8.4. 
Subject Global Assessment  
Responses from the Subject Global Assessment (SGA) questionnaire will be summarized for 
Weeks 2, 4, 8, and 12 using frequency counts and percentages by randomized treatment group 
for the ITT Population. 
9. 
Safety and Tolerability Analysis 
Safety will be evaluated from reported TEAEs, changes in clinical laboratory values, changes in 
vital signs, physical examination results, and local signs and symptoms assessments. 
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All safety analyses will be performed on the Safety Population. Subjects will be reported 
according to the treatment they actually received. If during the course of this study it is 
determined that subjects were inadvertently dispensed incorrect kits, the following criteria will 
be used to determine treatment group for the safety analyses: Subjects who were exposed to the 
study drug that they had not been randomized for ≥ 20% of their treatment duration will be 
included in the FMX103 1.5% group for all safety assessments. Subjects who were exposed to 
the study drug for which they had not been randomized for < 20% of their treatment duration 
will be assessed according to the treatment they actually received for the majority of the study. 
Safety assessments will be summarized using descriptive statistics by treatment group and in 
individual subject listings.  
No statistical tests will be performed for any of the safety assessments. 
9.1. 
Adverse Events 
All AE terms will be coded using MedDRA, Version 20.0. 
All AEs that occur after informed consent but before administration of the study drug will be 
recorded as medical history. If relationship to treatment is missing, the event will be summarized 
conservatively as probably related to study drug unless the start date of the AE is before the date 
of first study drug administration, in which case the event would be considered as not related. If 
severity is missing, the event will be summarized conservatively as severe. Through the data 
cleaning process, all attempts will be made to avoid missing values for relationship and severity. 
All TEAEs summarized by system organ class (SOC) and preferred term (PT) will be sorted in 
order of descending frequency of the SOC and then by descending frequency order (total across 
treatment groups) of the PT within each SOC.  
An overall summary of AEs will be presented by treatment group. This summary will include the 
total number of events, frequency counts, and percentages for: 
• Any AEs 
• Any TEAEs 
• Any SAEs 
• Any treatment-related TEAEs  
• Any TEAE leading to study discontinuation 
• TEAEs resulting in death 
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Summaries of the incidence of TEAEs and SAEs will be displayed by treatment group and by: 
• SOC and PT 
• SOC, PT, and maximum severity (mild, moderate, severe) 
• SOC, PT, and maximum causality (not related, related) to the study drug 
If there are multiple occurrences of the same TEAE within the same subject, each subject will 
only be counted once for each PT. In the summaries showing severity and relationship to the 
study drug, the event with the maximum severity or strongest relationship will be reported.  
All AEs will be presented in a by-treatment and by-subject listing, detailing the verbatim term 
given by the Investigator, the PT, SOC, onset date and time, end date and time, severity, 
outcome, relationship to study drug, action taken with study drug, other action taken, 
seriousness, and criteria for seriousness. All SAEs will be presented in a separate listing.  
9.1.1. Adverse Events Leading to Withdrawal 
The incidence (frequencies and percentages) of TEAEs leading to withdrawal of study drug, by 
treatment group, SOC, and PT will be summarized for the Safety Population. Summaries will 
also be presented by maximum severity and by maximum causality.  
A data listing of AEs leading to withdrawal of the study drug will also be provided, displaying 
details of the event(s) captured on the CRF. 
9.1.2. Deaths and Serious Adverse Events 
Any deaths that occur during the study will be listed. 
Serious adverse events will be listed and tabulated by SOC and PT and presented by treatment 
group. All SAEs will also be presented by maximum severity and by maximum causality.  
9.2. 
Clinical Laboratory Evaluations 
Absolute values and changes from baseline will be summarized by treatment group for clinical 
laboratory (chemistry and hematology) results using descriptive statistics. The number of 
subjects with clinical laboratory values below, within, or above the normal range will be 
tabulated for each clinical laboratory test by time point. Shift tables for each clinical laboratory 
test will cross-tabulate the number of subjects with values below the laboratory reference range 
(low), values within the laboratory reference range (normal), or above the laboratory range 
(high) at baseline with the number of subjects with low, normal or high values at each post-
baseline time point. Normal ranges and values outside the normal ranges will be identified by the 
central laboratory. A separate listing of out of normal range laboratory results will be provided. 
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PCN Number FOAM166107 
 
 
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A listing of all randomized subjects with pre-treatment and treatment-emergent clinically 
significant abnormal laboratory values will be presented for each treatment group. Clinical 
significance will be based on the Investigator’s judgment. 
Urinalysis and urine pregnancy test results will be presented in by-subject listings. 
9.3. 
Vital Signs 
Descriptive summaries of actual values and changes from baseline by treatment group will be 
presented for systolic and diastolic blood pressure, heart rate, and body weight. Height and BMI 
will be summarized at baseline only.   
9.4. 
Physical Examinations 
Physical examinations will be summarized using descriptive statistics for baseline and each 
post-baseline time point by treatment group. Shifts from baseline will also be summarized.  
Abnormal physical examination findings will be displayed in a by-subject listing. 
9.5. 
Local Signs and Symptoms Assessments 
Erythema, telangiectasia, burning/stinging, flushing/blushing, dryness/xerosis, itching, 
peeling/desquamation, and hyperpigmentation at the sites of study drug application will be 
assessed at each study visit. All signs/symptoms with the exception of erythema will be graded 
on a 0 to 3 scale (0=none; 1=mild; 2=moderate; 3=severe). Erythema will be graded on a 
0 to 4 scale (0=clear skin/no signs of erythema; 1=almost clear of erythema, slight redness; 
2=mild erythema, definite redness; 3=moderate erythema, marked redness; 4=severe erythema, 
fiery redness). Itching will be assessed on the same 0 to 3 scaled based on the subjects’ 
subjective assessment. 
The severity of erythema, telangiectasia, burning/stinging, flushing/blushing, dryness/xerosis, 
itching, peeling/desquamation, and hyperpigmentation will be summarized using frequency 
counts and percentages at each visit by treatment group.  
9.6. 
Prior and Concomitant Medication 
A concomitant medication is any non-protocol specified drug or substance administered during 
participation in the study, including medications that are ongoing at the time of informed 
consent. For subjects not continuing into the FX2016-13 open-label extension study, this period 
of participation is from the first day of screening through the last contact at 4 weeks after the 
Week 12 clinic visit. For subjects continuing into the extension study, this period is from the first 
day of screening through the Week 12 clinic visit. 
Page 26 of 101


 
Statistical Analysis Plan,  
 
Sponsor Foamix Pharmaceuticals  
 
Protocol Number FX2016-12  
 
PCN Number FOAM166107 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 26 of 38 
 
Prior and concomitant medications will be summarized descriptively by treatment group and 
overall using counts and percentages in each Anatomical Therapeutic Chemical (ATC) level 2 
group and PT (ie, generic name) for the ITT, PP, and Safety Populations. 
Prior medications will be presented separately from concomitant medications. Medications that 
started prior to Day 1 will be considered prior medications whether or not they were stopped 
prior to Day 1. Any medications continuing or starting after Day 1 will be considered to be 
concomitant. If a medication starts prior to Day 1 and continues after Day 1 it will be considered 
both prior and concomitant.  
• Medications will be coded using the World Health Organization Drug Dictionary Version 
March 2017. 
10. 
Changes from Planned Analysis 
The protocol specifies that ‘analysis centers’ will be defined as sites, or groups of sites, that have 
at least 8 randomized subjects. Based on the proposed analysis strategy for IGA treatment 
success, this definition has been revised such that an analysis center is a site, or group of smaller 
sites, that has at least 30 subjects and has at least 16 subjects assigned to the FMX103 1.5% 
group and at least 8 subjects to the vehicle group. This will minimize the likelihood of zero-cell 
counts in the CMH test.  
11. 
Other Planned Analysis 
11.1. Pharmacokinetic Analysis 
No pharmacokinetic analysis is planned for this study. 
 
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Statistical Analysis Plan,  
Sponsor Foamix Pharmaceuticals  
Protocol Number FX2016-12  
PCN Number FOAM166107
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 27 of 38 
12.
References
1. US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food and 
Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, 
pages 49583-49598. September 16, 1998.
2. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm
3. RSS. (2014) The Royal Statistical Society: Code of Conduct,
2014. http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf
4. Li KH (1988) Imputation using Markov chains.  J Statist Comp Simul; 30:57-79.
5. Liu C (1993) Bartlett’s decomposition of the posterior distribution of the covariance for 
normal monotone ignorable missing data.  J Mult Anal; 46:198-206.
6. Little R, Yau L (1996) Intent-to-treat analysis for longitudinal studies with drop-outs. 
Biometrics; 52:1324-1333.
7. Schafer, JL (1997) Analysis of Incomplete Multivariate Data, New York: Chapman and Hall.
8. Rubin, D.B (1987). Multiple Imputation for Nonresponse in Surveys. New York. John Wiley 
& Sons. 
13.
Tables, Listings, and Figures
All listings, tables, and graphs will have a header showing the Sponsor company name and 
protocol and a footer showing the version of SAS, the file name and path, and the source of the 
data (ie, listing number where applicable). 
14.
Planned Table Descriptions
The following are planned summary tables for protocol FX2016-12. The table numbers and page 
numbers are place holders only and will be determined when the tables are produced. 
Page 28 of 101
















 
Statistical Analysis Plan,  
 
Sponsor Foamix Pharmaceuticals  
 
Protocol Number FX2016-12  
 
PCN Number FOAM166107 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 35 of 38 
 
14.2. Planned Figure Descriptions 
There are no planned figures. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 36 of 101


 
Statistical Analysis Plan,  
 
Sponsor Foamix Pharmaceuticals  
 
Protocol Number FX2016-12  
 
PCN Number FOAM166107 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 1.0    |    Date: 09-Jul-2018      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 36 of 38 
 
15. 
Tables, Listings, and Listing Shells 
15.1. Standard Layout for all Tables, Listings, and Figures 
Table and listing shells are provided in a separate document. 
Note that programming notes may be added after each TLF shell if appropriate.  
 
 
 
Page 37 of 101






Table and Listing Shells 
Sponsor: Foamix Pharmaceuticals 
Final 1.0 
Protocol Number FX2016-12 
09-Jul-2018 
CONFIDENTIAL  
Page 1 of 62
Statistical Analysis 
Table and Listing Shells 
Sponsor 
Foamix Pharmaceuticals 
Protocol Title: 
A Randomized, Multicenter, Double-blind, Vehicle-
controlled Study to Evaluate the Safety and Efficacy of 
FMX103 1.5% Topical Minocycline Foam Compared to 
Vehicle in the Treatment of Facial Papulopustular Rosacea 
(Study FX2016-12) 
Protocol Number: 
FX2016-12 
Premier Research PCN: 
FOAM166107 
Document Version: 
Final Version 1.0 
Document Date: 
09-Jul-2018
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Protocol: FX2016-12 
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Table and Listing Shells Final 1.0 
 
CONFIDENTIAL 
09-Jul-2018 
 
 
Table and Listing Shells for Foamix FX2016-12 
14.1 
Demographic Data Summary Tables .................................................................................................................................................................. 6 
Table 14.1.1 Summary of Subject Enrollment and Disposition ............................................................................................................................. 6 
Table 14.1.2.x Summary of Demographics and Baseline Characteristics .............................................................................................................. 7 
Table 14.1.3.x Summary of Prior Medications by ATC Level 2 and Preferred Term .............................................................................................. 9 
Table 14.1.4.x Summary of Study Drug Exposure ................................................................................................................................................ 10 
Table 14.1.5.x Summary of Subject Enrollment by Analysis Center .................................................................................................................... 11 
Table 14.1.6.x Study Drug Compliance ................................................................................................................................................................ 12 
14.2 
Efficacy Data ..................................................................................................................................................................................................... 13 
Table 14.2.1.1.x Descriptive Summary of Inflammatory Lesion Count................................................................................................................ 13 
Table 14.2.1.2.x Descriptive Summary of IGA Treatment Success ...................................................................................................................... 14 
Table 14.2.2.1 Analysis of Change from Baseline in Inflammatory Lesion Count - Multiple Imputation ............................................................ 15 
Table 14.2.2.2 Analysis of IGA Treatment Success - Multiple Imputation ........................................................................................................... 16 
Table 14.2.3.1 Analysis of Change from Baseline in Inflammatory Lesion Count - LOCF .................................................................................... 17 
Table 14.2.3.2 Analysis of Change from Baseline in Inflammatory Lesion Count - BOCF .................................................................................... 17 
Table 14.2.3.3.x Analysis of Change from Baseline in Inflammatory Lesion Count - Observed Cases ................................................................ 18 
Table 14.2.3.4.x Analysis of Percent Change from Baseline in Inflammatory Lesion Count - Observed Cases ................................................... 19 
Table 14.2.3.5 Analysis of Ranked Change from Baseline in Inflammatory Lesion Count - Multiple Imputation ............................................... 20 
Table 14.2.3.6 Analysis of Change from Baseline in Inflammatory Lesion Count - Analysis Center Interaction - Observed Cases (Week 12) ... 21 
Table 14.2.4.1 Analysis of IGA Treatment Success - LOCF ................................................................................................................................... 22 
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09-Jul-2018 
 
Table 14.2.4.2 Analysis of IGA Treatment Success - BOCF ................................................................................................................................... 22 
Table 14.2.4.3.x Analysis of IGA Treatment Success - Observed Cases ............................................................................................................... 23 
Table 14.2.5 Descriptive Summary of Subject Global Assessment ...................................................................................................................... 24 
Table 14.2.6 Descriptive Summary of Subject Satisfaction Questionnaire .......................................................................................................... 25 
14.3 
Safety Data ....................................................................................................................................................................................................... 26 
14.3.1 
Displays of Adverse Events .......................................................................................................................................................................... 27 
Table 14.3.1.1 Summary of All Adverse Events ................................................................................................................................................... 27 
Table 14.3.1.2 Treatment-Emergent Adverse Events by System Organ Class and Preferred Term .................................................................... 28 
Table 14.3.1.3 Treatment-Emergent Adverse Events by Severity, System Organ Class, and Preferred Term .................................................... 29 
Table 14.3.1.4 Treatment-Emergent Adverse Events by Relationship to Study Drug, System Organ Class, and Preferred Term ...................... 30 
14.3.2 
Other Serious and Significant Adverse Events ......................................................................................................................................... 31 
Table 14.3.2.1 Serious Adverse Events by System Organ Class and Preferred Term .......................................................................................... 31 
Table 14.3.2.2 Serious Adverse Events by Severity, System Organ Class, and Preferred Term .......................................................................... 31 
Table 14.3.2.3 Serious Adverse Events by Relationship to Study Drug, System Organ Class, and Preferred Term ............................................ 32 
Table 14.3.2.4 Adverse Events Leading to Withdrawal from the Study by System Organ Class and Preferred Term ........................................ 32 
Table 14.3.2.5 Adverse Events Leading to Withdrawal from the Study by Severity, System Organ Class, and Preferred Term ........................ 33 
Table 14.3.2.6 Adverse Events Leading to Withdrawal from the Study by Relationship to Study Drug, System Organ Class, and Preferred 
Term ..................................................................................................................................................................................................................... 33 
14.3.5 
Laboratory Data Summary Tables ............................................................................................................................................................ 34 
Table 14.3.5.1 Clinical Chemistry Results ............................................................................................................................................................ 34 
Table 14.3.5.2 Shift Table of Clinical Chemistry Results ...................................................................................................................................... 35 
Table 14.3.5.3 Hematology Results...................................................................................................................................................................... 36 
Table 14.3.5.4 Shift Table of Hematology Results ............................................................................................................................................... 36 
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09-Jul-2018 
 
14.3.6 
Other Safety and Tolerability Summary Tables ....................................................................................................................................... 37 
Table 14.3.6.1 Shift Table of Physical Examination Results ................................................................................................................................. 37 
Table 14.3.6.2 Vital Sign Results .......................................................................................................................................................................... 38 
Table 14.3.6.3 Concomitant Medications by ATC Level 2 and Preferred Term ................................................................................................... 39 
Table 14.3.6.4 Summary of Local Signs and Symptoms Assessments ................................................................................................................. 40 
16.2 
Subject Data Listings ........................................................................................................................................................................................ 41 
16.2.1 
Subject Discontinuations/Completions .................................................................................................................................................... 42 
Listing 16.2.1.1 Assignment to Analysis Populations and Treatment Group ....................................................................................................... 42 
Listing 16.2.1.2 Study Completion Status ............................................................................................................................................................ 43 
Listing 16.2.1.3 List of Reasons for Screening Failure .......................................................................................................................................... 43 
16.2.2 
Protocol Deviations .................................................................................................................................................................................. 44 
Listing 16.2.2.3 Protocol Deviations ..................................................................................................................................................................... 44 
16.2.3 
Subjects Excluded from the Efficacy Analyses ......................................................................................................................................... 45 
Listing 16.2.3.1 List of Subjects Excluded from Analysis Populations .................................................................................................................. 45 
16.2.4 
Demographic Data and Other Baseline Characteristics ........................................................................................................................... 46 
Listing 16.2.4.1 Demographic Data ...................................................................................................................................................................... 46 
Listing 16.2.4.2 Medical History ........................................................................................................................................................................... 46 
Listing 16.2.4.3 Prior Medications ....................................................................................................................................................................... 47 
16.2.5 
Compliance Data ...................................................................................................................................................................................... 48 
Listing 16.2.5.1 Study Drug Accountability .......................................................................................................................................................... 48 
Listing 16.2.5.2 Study Drug Compliance .............................................................................................................................................................. 49 
16.2.6 
Individual Efficacy Response Data ........................................................................................................................................................... 50 
Listing 16.2.6.1 IGA Score .................................................................................................................................................................................... 50 
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Listing 16.2.6.2 Inflammatory Lesion Count by Facial Area ................................................................................................................................. 51 
Listing 16.2.6.3 Subject Satisfaction Questionnaire (SSQ) ................................................................................................................................... 52 
Listing 16.2.6.4 Subject Global Assessment (SGA) ............................................................................................................................................... 53 
16.2.7 
Adverse Event Listings.............................................................................................................................................................................. 54 
Listing 16.2.7.1 Adverse Events ........................................................................................................................................................................... 54 
Listing 16.2.7.2 Serious Adverse Events ............................................................................................................................................................... 55 
Listing 16.2.7.3 Adverse Events Leading to Withdrawal ...................................................................................................................................... 55 
Listing 16.2.7.4 Deaths ......................................................................................................................................................................................... 55 
16.2.8 
Laboratory Values .................................................................................................................................................................................... 56 
Listing 16.2.8.1 Clinical Chemistry Results ........................................................................................................................................................... 56 
Listing 16.2.8.2 Hematology Results .................................................................................................................................................................... 56 
Listing 16.2.8.3 Urinalysis Results ........................................................................................................................................................................ 57 
Listing 16.2.8.4 Clinically Significant Laboratory Tests for Hematology, Chemistry, and Urinalysis ................................................................... 57 
Listing 16.2.8.5 Out of Range (Abnormal) Laboratory Tests for Hematology, Chemistry, and Urinalysis ........................................................... 58 
Listing 16.2.8.6 Pregnancy Test Results ............................................................................................................................................................... 58 
16.2.9 
Other Clinical Observations and Measurements ..................................................................................................................................... 59 
Listing 16.2.9.1 Vital Signs .................................................................................................................................................................................... 59 
Listing 16.2.9.2 Abnormal Physical Examination Results ..................................................................................................................................... 59 
Listing 16.2.9.3 Concomitant Medications .......................................................................................................................................................... 60 
Listing 16.2.9.4 Local Signs and Symptoms Assessments .................................................................................................................................... 61 
Listing 16.2.9.5 Photography of the Face ............................................................................................................................................................ 62 
  
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09-Jul-2018 
 
14.1 Demographic Data Summary Tables 
 
Table 14.1.1 
Summary of Subject Enrollment and Disposition 
All Subjects  
 
Number of Subjects 
FMX103 1.5% 
Vehicle Foam 
Overall 
 
 
 
 
Number of subjects screened 
 
 
xxx 
 
 
 
 
Number of subjects in ITT population 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Number of subjects in PP population 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Number of subjects in SAF population 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
Number of subjects completing the study 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Number of subjects participating in study FX2016-13 
 (open-label extension study) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
Number of subjects discontinued 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Reason for discontinuation 
 
 
 
    Adverse event 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Abnormal laboratory result 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Lost to follow-up 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Subject request 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Protocol deviation 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Other 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
Number of subjects excluded from PP population 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Reason for exclusion 
 
 
 
    Failure to meet inclusion/exclusion criteria 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Have administered any interfering concomitant medications 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Not compliant with the treatment regimen 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Randomization error 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Other 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
Note: Percentages are based on the number of subjects randomized. 
The Safety (SAF) population includes all randomized subjects who use at least 1 dose of study drug.  Subjects who have no post-
baseline assessments will be included unless all dispensed study drug is returned unused. 
The Intent-to-treat (ITT) population includes all randomized subjects. 
The Per-Protocol (PP) population is defined as the subset of the ITT population without any protocol deviations that may impact 
on the efficacy assessments. 
Source: Listing 16.2.1.1, 16.2.1.2, 16.2.1.3, 16.2.3.1 
 
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09-Jul-2018 
 
 
 
Table 14.1.2.x 
Summary of Demographics and Baseline Characteristics  
 ITT Population 
 
 
Sample 
FMX103 1.5% 
Vehicle Foam 
Overall 
Variable 
Characteristics/Category 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
 
 
 
 
Age [years] 
n (# missing) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
 
Min to Max 
xx to xx 
xx to xx 
xx to xx 
 
 
 
 
 
Body Weight [kg] 
n (# missing) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
 
Min to Max 
xx to xx 
xx to xx 
xx to xx 
 
 
 
 
 
Body Height [cm] 
n (# missing) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
 
Min to Max 
xx to xx 
xx to xx 
xx to xx 
 
 
 
 
 
Body Mass Index (BMI) [kg/m2] 
n (# missing) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
 
Min to Max 
xx to xx 
xx to xx 
xx to xx 
 
Age groups [full years] 
18 to 40 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
41 to 64 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
≥ 65 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Missing 
xx 
xx 
xx 
 
 
 
 
 
Sex 
Male 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Female 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Missing 
xx 
xx 
xx 
 
 
 
 
 
 
 
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09-Jul-2018 
 
Table 14.1.2.x (cont’d) 
 
Sample 
FMX103 1.5% 
Vehicle Foam 
Overall 
Variable 
Characteristics/Category 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
 
 
 
 
Ethnicity 
Hispanic or latino 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Non Hispanic or latino 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Missing 
xx  
xx  
xx  
 
 
 
 
 
Race 
American Indian or Alaska native 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Asian 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Black or African American 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Native Hawaiian or other Pacific Islander 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
White 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
More than one race 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Missing 
xx 
xx 
xx 
 
 
 
 
 
IGA Score 
3 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
4 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Missing 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Inflammatory Lesion Count 
n (# missing) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
 
Min to Max 
xx to xx 
xx to xx 
xx to xx 
 
 
 
 
 
Note: Percentages exclude missing data. 
Source: Listing 16.2.4.1, 16.2.6.1, 16.2.6.2 
 
Programming Note: Table 14.1.2.1 for ITT Population; Table 14.1.2.2 for PP Population; Table 14.1.2.3 for Safety Population. For all 
tables that use the ITT or PP populations, include ‘Randomized treatment groups are presented’ in the note. For tables using the 
safety population, include ‘Treatment groups presented are treatment received.’ 
 
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Table 14.1.3.x 
Summary of Prior Medications by ATC Level 2 and Preferred Term 
ITT Population 
 
ATC Level 2 
FMX103 1.5% 
Vehicle Foam 
Overall 
   Preferred Term [1] 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
 
 
 
Any prior medication 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
ATC level 2 entry 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     PT 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     PT 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     PT 3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     ... 
 
 
 
ATC level 2 entry 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     PT 4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     PT 5 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     PT 6 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
ATC level 2 entry 3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
... 
... 
... 
... 
.. 
.. 
.. 
.. 
. 
. 
. 
. 
Note: Percentages are 100*n/N. Subjects were counted only once for each Anatomical Therapeutic Chemical 
(ATC) or preferred term. Medications that started prior to Day 1 are considered prior whether or not 
they were stopped prior to Day 1.  
[1] Medications were coded using WHO-DD (Enhanced version March 2017) ATC level 2. Preferred Term is 
ATC level 5. 
Source: Listing 16.2.4.3 
 
 
Programming Note: Table 14.1.3.1 for ITT Population; Table 14.1.3.2 for PP Population; Table 14.1.3.3 for Safety Population; For all 
tables that use the ITT or PP populations, include ‘Randomized treatment groups are presented’ in the note. For tables using the 
safety population, include ‘Treatment groups presented are treatment received.’ 
 
 
 
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09-Jul-2018 
 
 
 
Table 14.1.4.x 
Summary of Study Drug Exposure  
ITT Population 
 
 
 
FMX103 1.5% 
Vehicle Foam 
Overall 
Variable 
Sample Characteristics 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
 
 
 
 
Treatment Duration (days) [1] 
n (# missing) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
 
Min to Max 
xx to xx 
xx to xx 
xx to xx 
 
 
 
 
 
 Total Days of Exposure [2] 
n (# missing) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
 
Min to Max 
xx to xx 
xx to xx 
xx to xx 
 
 
 
 
 
 
 
 
 
 
Note: For subjects who are missing the date of last dose, the last known contact date will be used in the calculation of 
treatment duration and exposure. 
[1] Treatment duration (days) is defined as the date of last dose of study drug minus the date of first dose of study drug 
plus 1 day. 
[2] Total days of exposure is defined as the difference in treatment duration (days) and the number of days that a subject 
reported missing a dose (between the date of first and last dose).  
 
Source: Listing 16.2.5.1 
 
Programming Note: Table 14.1.4.1 for ITT Population; Table 14.1.4.2 for PP Population; For all tables that use the ITT or PP 
populations, include ‘Randomized treatment groups are presented’ in the note. For tables using the safety population, include 
‘Treatment groups presented are treatment received.’ 
 
 
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09-Jul-2018 
 
 
 
 
 
 
 
 
Table 14.1.5.x 
Summary of Subject Enrollment by Analysis Center 
ITT Population 
 
 
 
 
 
           Number of Subjects Randomized 
Analysis 
Center[1] 
 
Sites 
 FMX103 1.5% 
(N=xxx) 
Vehicle Foam 
(N=xxx) 
Overall 
(N=xxx) 
 
 
 
 
 
xxx 
xxx/xxx 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
xxx 
xxx/xxx/xxx 
xxx (xx.x%) 
xxx (xx.x%) 
 xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N. 
[1] Analysis centers are sites, or groups of sites that have randomized at least 30 subjects and 
have at least 16 subjects assigned to the FMX103 1.5% group and at least 8 subjects in the 
vehicle group.  
Source: Listing 16.2.1.1 
 
Programming Note: Table 14.1.5.1 for ITT Population; Table 14.1.5.2 for PP Population; For all tables that use the ITT or PP 
populations, include ‘Randomized treatment groups are presented’ in the note. For tables using the safety population, include 
‘Treatment groups presented are treatment received.’ 
 
 
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Table 14.1.6.x 
Study Drug Compliance 
ITT Population 
 
 
FMX103 1.5% 
Vehicle Foam 
 
Overall 
Statistic 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
 
 
 
n (# missing) 
xx (xx) 
xx (xx) 
xx (xx) 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
Min to Max 
xx.x to xx.x 
xx.x to xx.x 
xx.x to xx.x 
 
 
 
 
Note: Compliance (%) = 100 x Study drug exposure (days) / Treatment 
duration (days). 
Subjects who are missing last dose dates are not included.  
Source: Listing 16.2.5.2 
 
Programming Note: Table 14.1.6.1 for ITT Population; Table 14.1.6.2 for PP Population; For all tables that use the ITT or PP 
populations, include ‘Randomized treatment groups are presented’ in the note. For tables using the safety population, include 
‘Treatment groups presented are treatment received.’  
 
 
 
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14.2 Efficacy Data  
 
Table 14.2.1.1.x 
Descriptive Summary of Inflammatory Lesion Count 
ITT Population 
 
 
 
 
FMX103 1.5% 
Vehicle Foam 
Visit 
Variable 
Sample Characteristics 
(N=xxx) 
(N=xxx) 
 
 
 
 
 
Baseline 
Observed value 
n (# missing) 
xxx (xx) 
xxx (xx) 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Min to Max 
xx to xx 
xx to xx 
 
 
 
 
 
Week 4 
Observed value 
n (# missing) 
xxx (xx) 
xxx (xx) 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Min to Max 
xx to xx 
xx to xx 
 
 
 
 
 
 
Change from baseline [1] 
n (# missing) 
xxx (xx) 
xxx (xx) 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Min to Max 
xx to xx 
xx to xx 
 
 
 
 
 
 
Percent change from baseline [1] 
n (# missing) 
xxx (xx) 
xxx (xx) 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Min to Max 
xx to xx 
xx to xx 
 
 
 
 
 
 
 
 
 
 
Programming Note:  Continue for Weeks 8 and 12 
 
[1] Change from baseline is calculated as the value at baseline minus the post-baseline value. Thus, a positive 
change will reflect a reduction in lesion count. The same definition is used in the numerator for percent 
change. Source: Listing 16.2.6.2 
 
Programming Note: Table 14.2.1.1.1 for ITT Population; Table 14.2.1.1.2 for PP Population; For all tables that use the ITT or PP 
populations, include ‘Randomized treatment groups are presented’ in the note. For tables using the safety population, include 
‘Treatment groups presented are treatment received.’ 
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Table 14.2.1.2.x 
Descriptive Summary of IGA Treatment Success 
ITT Population 
 
 
 
 
 
IGA Treatment Success[1] 
IGA Treatment Success-
Secondary[2] 
 
Score/ 
FMX103 1.5% 
Vehicle Foam 
FMX103 1.5% 
Vehicle Foam 
Visit 
Category 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
 
 
 
 
 
Baseline [3] 
n (# missing) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
 
3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Week 4 
n (# missing) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
 
Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Week 8 
n (# missing) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
 
Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Week 12 
n (# missing) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
xxx (xx) 
 
Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Note: Percentages are based on the number of subjects with non-missing value (yes or no) at each visit. 
[1] IGA Treatment Success is defined as an IGA of 0 or 1 and a 2-grade improvement in IGA from baseline. 
[2] IGA Treatment Success-Secondary is defined as a 2-grade improvement (decrease) in IGA from baseline. 
[3] Values presented are Baseline IGA score.  
Source: Listing 16.2.6.1 
 
Programming Note: Table 14.2.1.3.1 for ITT Population; Table 14.2.1.3.2 for PP Population; For all tables that use the ITT or PP 
populations, include ‘Randomized treatment groups are presented’ in the note. For tables using the safety population, include 
‘Treatment groups presented are treatment received.’ 
 
 
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Table 14.2.2.1 
Analysis of Change from Baseline in Inflammatory Lesion Count - Multiple Imputation 
ITT Population 
 
 
 
 
 
Visit 
Comparison 
FMX103 1.5% 
Vehicle Foam 
 
 
 
 
Week 12 
Number of subjects 
xxx 
xxx 
 
Imputed Mean 
xx.xx 
xx.xx 
 
 
 
 
 
LSM (SE) 
xx.xx (xx.xx)  
xx.xx (xx.xx)  
 
LSM 95% CI 
xx.xx to xx.xx 
xx.xx to xx.xx 
 
 
 
 
 
LSM Difference (FMX103 1.5% - Vehicle Foam) (SE) 
xx.xx (xx.xx) 
 
 
LSM Difference 95% CI 
xx.xx to xx.xx 
 
LSM Difference p-value 
0.xxxx 
... 
 
 
 
 
 
Programming Note: Repeat for Week 8 and Week 4 
 
 
 
 
Note: ANCOVA model includes treatment, baseline inflammatory lesion count, and analysis center. ANCOVA = analysis of covariance; 
CI = confidence interval; LSM = least squares mean; SE = standard error 
Source: Listing 16.2.6.2 
 
 
 
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Table 14.2.2.2 
Analysis of IGA Treatment Success - Multiple Imputation 
ITT Population 
 
 
Visit 
Comparison 
FMX103 1.5% 
Vehicle Foam 
 
 
 
 
Week 12 
Number of subjects 
xxx 
xxx 
 
 
IGA Success - Number (%) of subjects 
 
xxxx (xx.x%) 
xxxx (xx.x%) 
 
Risk Ratio 
  Risk Ratio Estimate 
x.xxx  
 
 
  95% Confidence Interval 
x.xxx to x.xxx 
 
 
  p-value 
0.xxxx 
 
... 
 
 
 
 
Programming Note: Repeat for Week 8 and Week 4 
 
 
 
 
Note: Cochran-Mantel-Haenszel test stratified by analysis center. P-value is for the null hypothesis that the 
combined Risk Ratio equals 1. 
Source: Listing 16.2.6.1 
  
 
 
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Table 14.2.3.1 
Analysis of Change from Baseline in Inflammatory Lesion Count - LOCF 
ITT Population 
 
 
See Table 14.2.2.1 
 
Note: ANCOVA model includes treatment, baseline inflammatory lesion count, and analysis center. SE = standard error; LSM = least 
squares mean; CI = confidence interval 
Source: Listing 16.2.6.2 
 
 
 
Table 14.2.3.2 
Analysis of Change from Baseline in Inflammatory Lesion Count - BOCF 
ITT Population 
 
 
See Table 14.2.2.1 
 
Note: ANCOVA model includes treatment, baseline inflammatory lesion count, and analysis center. SE = standard error; LSM = least 
squares mean; CI = confidence interval 
Source: Listing 16.2.6.2 
 
 
 
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Table 14.2.3.3.x 
Analysis of Change from Baseline in Inflammatory Lesion Count - Observed Cases 
ITT Population 
 
 
See Table 14.2.2.1  (include Weeks 4, 8, and 12) 
 
Note: ANCOVA model includes treatment, baseline inflammatory lesion count, and analysis center. SE = standard error; LSM = least 
squares mean; CI = confidence interval 
Source: Listing 16.2.6.2 
 
Programming Note: Table 14.2.3.3.1 for ITT Population; Table 14.2.3.3.2 for PP Population; Remove line for imputed mean in this 
observed cases table. For all tables that use the ITT or PP populations, include ‘Randomized treatment groups are presented’ in the 
note. For tables using the safety population, include ‘Treatment groups presented are treatment received.’ 
 
 
 
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Table 14.2.3.4.x 
Analysis of Percent Change from Baseline in Inflammatory Lesion Count - Observed Cases 
ITT Population 
 
 
See Table 14.2.2.1 (include Weeks 4, 8, and 12) 
 
Note: ANCOVA model includes treatment, baseline inflammatory lesion count, and analysis center. SE = standard error; LSM = least 
squares mean; CI = confidence interval 
Source: Listing 16.2.6.2 
  
Programming Note: Table 14.2.3.4.1 for ITT Population; Table 14.2.3.4.2 for PP Population; Remove line for imputed mean in this 
observed cases table. For all tables that use the ITT or PP populations, include ‘Randomized treatment groups are presented’ in the 
note. For tables using the safety population, include ‘Treatment groups presented are treatment received.’ 
 
 
 
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Table 14.2.3.5 
Analysis of Ranked Change from Baseline in Inflammatory Lesion Count - Multiple Imputation 
ITT Population 
 
 
 
 
 
Visit 
Comparison 
FMX103 1.5% 
Vehicle Foam 
 
 
 
 
Week 12 
Number of subjects 
xxx 
xxx 
 
Median 
xx.xx 
xx.xx 
 
Q1, Q3 
xx.xx, xx.xx 
xx.xx, xx.xx 
 
 
 
 
 
 
 
 
 
LSM Difference p-value (ranks) 
0.xxxx 
 
 
 
 
Note: Q1 = first quartile or 25th percentile, Q3 = third quartile or 75th percentile. 
Source: Listing 16.2.6.2 
 
 
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Table 14.2.3.6 
Analysis of Change from Baseline in Inflammatory Lesion Count - Analysis Center Interaction - Observed Cases (Week 12) 
ITT Population  
 
 
Model Effect 
Overall 
p-value [1] 
 
Treatment  
x.xxxx 
Analysis Center 
x.xxxx 
Treatment x Analysis Center 
x.xxxx 
Baseline Inflammatory Lesion Count  
x.xxxx 
 
[1] P-value for testing the statistical significance of each effect in the 
model. Analysis center by treatment interaction tested using a 0.10 
significance level. 
Source: 16.2.6.2 
 
 
 
 
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Table 14.2.4.1 
Analysis of IGA Treatment Success - LOCF 
ITT Population 
 
 
 
See Table 14.2.2.2  
 
Note: Cochran-Mantel-Haenszel test stratified by analysis center. P-value is for the null hypothesis that the Risk Ratio 
equals 1. 
Source: Listing 16.2.6.1 
 
 
 
 
Table 14.2.4.2 
Analysis of IGA Treatment Success - BOCF 
ITT Population 
 
 
See Table 14.2.2.2 
 
Note: Cochran-Mantel-Haenszel test stratified by analysis center. P-value is for the null hypothesis that the Risk Ratio 
equals 1. 
Source: Listing 16.2.6.1 
 
 
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Table 14.2.4.3.x 
Analysis of IGA Treatment Success - Observed Cases 
ITT Population 
 
 
See Table 14.2.2.2  (include Weeks 3, 6, 9, and 12) 
 
Note: Cochran-Mantel-Haenszel test stratified by analysis center. P-value is for the null hypothesis that the Risk Ratio 
equals 1. 
Source: Listing 16.2.6.1 
 
Programming Note: Table 14.2.4.3.1 for ITT Population; Table 14.2.4.3.2 for PP Population; For all tables that use the ITT or PP 
populations, include ‘Randomized treatment groups are presented’ in the note. For tables using the safety population, include 
‘Treatment groups presented are treatment received.’ 
 
 
 
Table 14.2.4.4 
Analysis of IGA Treatment Success-Secondary - Observed Cases 
ITT Population 
 
 
See Table 14.2.2.2  (Week 12 data only) 
 
Note: IGA Treatment Success-Secondary is defined as a 2-step improvement in score compared to baseline.  
Cochran-Mantel-Haenszel test stratified by analysis center. P-value is for the null hypothesis that the Risk Ratio 
equals 1. 
Source: Listing 16.2.6.1 
 
 
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Table 14.2.5 
Descriptive Summary of Subject Global Assessment  
ITT Population 
 
 
 
FMX103 1.5% 
Vehicle Foam 
Visit 
Category 
(N=xxx) 
(N=xxx) 
 
 
 
 
Week 12 
Non-missing response 
xx 
xx 
 
5-Much better than prior to treatment 
xx (xx.x%) 
xx (xx.x%) 
 
4-Slightly better than prior to treatment 
xx (xx.x%) 
xx (xx.x%) 
 
3-Same as prior to treatment 
xx (xx.x%) 
xx (xx.x%) 
 
2-Slightly worse than prior to treatment 
xx (xx.x%) 
xx (xx.x%) 
 
1-Much worse than prior to treatment 
xx (xx.x%) 
xx (xx.x%) 
 
Missing response 
xx 
xx 
 
 
 
 
 
 
 
 
Programming Note:  Continue for Week 8, Week 4, and Week 2 
 
 
 
 
 
 
 
 
Note: Percentages exclude missing responses. 
Source: Listing 16.2.6.4 
 
 
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Table 14.2.6 
Descriptive Summary of Subject Satisfaction Questionnaire  
ITT Population 
 
 
 
FMX103 1.5% 
Vehicle Foam 
Variable 
Category 
(N=xxx) 
(N=xxx) 
 
 
 
 
Rosacea Treatment 
Non-missing response 
xx 
xx 
 
1-Very satisfied 
xx (xx.x%) 
xx (xx.x%) 
 
2-Satisfied 
xx (xx.x%) 
xx (xx.x%) 
 
3-Somewhat satisfied 
xx (xx.x%) 
xx (xx.x%) 
 
4-Dissatisfied 
xx (xx.x%) 
xx (xx.x%) 
 
5-Very dissatisfied 
xx (xx.x%) 
xx (xx.x%) 
 
Missing response 
xx 
xx 
 
 
 
 
Easy to Use 
Non-missing response 
xx 
xx 
 
1-Very satisfied 
xx (xx.x%) 
xx (xx.x%) 
 
2-Satisfied 
xx (xx.x%) 
xx (xx.x%) 
 
3-Somewhat satisfied 
xx (xx.x%) 
xx (xx.x%) 
 
4-Dissatisfied 
xx (xx.x%) 
xx (xx.x%) 
 
5-Very dissatisfied 
xx (xx.x%) 
xx (xx.x%) 
 
Missing response 
xx 
xx 
 
 
 
 
 
 
 
 
Programming Note:  Continue for ‘Compared to Other Products’, ‘Feels on Skin’, ‘Odor’, ‘Color’, 
‘Overall Satisfaction’ 
 
 
 
 
 
 
 
 
Recommend to Friend 
Non-missing response 
xx 
xx 
 
1-Very likely 
xx (xx.x%) 
xx (xx.x%) 
 
2-Likely 
xx (xx.x%) 
xx (xx.x%) 
 
3-Somewhat likely 
xx (xx.x%) 
xx (xx.x%) 
 
4-Unlikely 
xx (xx.x%) 
xx (xx.x%) 
 
5-Very unlikely 
xx (xx.x%) 
xx (xx.x%) 
 
Missing response 
xx 
xx 
 
 
 
 
Note: Percentages exclude missing responses. Subject Satisfaction Questionnaire is completed at the 
Week 12 visit or at the final visit for those subjects that prematurely withdraw from the study. 
Source: Listing 16.2.6.4 
 
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14.3 Safety Data 
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14.3.1 
Displays of Adverse Events 
 
Table 14.3.1.1 
Summary of All Adverse Events  
Safety Population 
 
 
FMX103 1.5% 
Vehicle Foam 
 
(N=xxx) 
(N=xxx) 
 
 
 
All Adverse Events (AEs) 
xx (xx.x%)  
xx (xx.x%)  
 
 
 
Treatment-emergent adverse events (TEAEs) [1] 
xx (xx.x%)  
xx (xx.x%)  
 
 
 
Serious TEAEs (SAEs) 
xx (xx.x%)  
xx (xx.x%)  
 
 
 
Treatment-related TEAEs [2] 
xx (xx.x%)  
xx (xx.x%)  
 
 
 
Adverse events leading to study discontinuation 
xx (xx.x%)  
xx (xx.x%)  
 
 
 
TEAEs resulting in death 
xx (xx.x%)  
xx (xx.x%)  
 
 
 
 
 
 
Note: Percentages are 100*n/N. Number (%) of subjects with at least 1 AE in the category are presented. 
Adverse events were coded using MedDRA, Version 20.0. Treatment groups are based on treatment received.  
[1] For subjects who are missing the date of last dose, any AE occurring after the first dose is considered 
treatment emergent. 
[2] Any TEAE reported as possibly related or probably related, or is missing, is considered as related to 
study drug. 
Source: Listing 16.2.7.1 
 
 
 
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Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term  
Safety Population 
 
System Organ Class 
 
FMX103 1.5% 
Vehicle Foam 
   Preferred Term 
 
(N=xxx) 
(N=xxx) 
 
 
 
 
Number of Any event 
 
xx (xx.x%)  
xx (xx.x%)  
 
 
 
 
SOC 1 
 
xx (xx.x%)  
xx (xx.x%)  
   PT 1 
 
xx (xx.x%)  
xx (xx.x%)  
   PT 2 
 
xx (xx.x%)  
xx (xx.x%)  
 
 
 
 
SOC 2 
 
xx (xx.x%)  
xx (xx.x%)  
   PT 1 
 
xx (xx.x%)  
xx (xx.x%)  
   PT 2 
 
xx (xx.x%)  
xx (xx.x%)  
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
Programming Note: Order SOCs by descending number of subjects (total within both treatment 
groups) and preferred terms within SOC also by descending number of subjects (and for all 
other tables where AEs are arranged by SOC and PT) 
 
 
 
 
Note: Percentages are 100*n/N. Subjects were counted only once for each System Organ Class and 
Preferred Term. Adverse events were coded using MedDRA, Version 20.0. Treatment groups are based on 
treatment received. For subjects who are missing the date of last dose, any AE occuring after the 
first dose is considered treatment emergent. AEs are sorted in descending frequency of SOC and PT.  
Source: Listing 16.2.7.1 
 
 
 
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Table 14.3.1.3 
Treatment-Emergent Adverse Events by Severity, System Organ Class, and Preferred Term 
Safety Population 
 
System Organ Class 
 
 
 
 
   Preferred Term 
 
 
FMX103 1.5% 
Vehicle Foam 
      Severity [1] 
 
 
(N=xxx) 
(N=xxx) 
 
 
 
 
 
Any System Organ Class 
 
 
 
 
  Any Event (Total) 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Severe 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Moderate 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Mild 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Missing 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
SOC 1 
 
 
 
 
  Any Event (Total) 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Severe 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Moderate 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Mild 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
  PT 1 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Severe 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Moderate 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Mild 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
  PT 2 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Severe 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Moderate 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Mild 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
SOC 2 
 
 
 
 
  Any Event (Total) 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Severe 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Moderate 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Mild 
 
 
xx (xx.x%) 
xx (xx.x%) 
... 
Programming Note: Only include Missing category when SOC or PT has missing values, otherwise 
just include Severe, Moderate, and Mild 
 
 
 
 
 
Note: Percentages are 100*n/N. Subjects were counted only once for each System Organ Class and 
Preferred Term. Adverse events were coded using MedDRA version 20.0. For subjects who are missing 
the date of last dose, any AE occurring after the first dose is considered treatment emergent. 
Treatment groups are based on treatment received. 
Source: Listing 16.2.7.1  
 
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Table 14.3.1.4 
Treatment-Emergent Adverse Events by Relationship to Study Drug, System Organ Class, and Preferred Term 
Safety Population  
 
System Organ Class 
 
 
 
 
   Preferred Term 
 
 
FMX103 1.5% 
Vehicle Foam 
      Relationship to Study Drug [1] 
 
 
(N=xxx) 
(N=xxx) 
 
 
 
 
 
Any System Organ Class 
 
 
 
 
  Any Event (Total) 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Related 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Not Related 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
SOC 1 
 
 
 
 
  Any Event (Total) 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Related 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Not Related 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
  PT 1 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Related 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Not Related 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
  PT 2 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Related 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Not Related 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
SOC 2 
 
 
 
 
  Any Event (Total) 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Related 
 
 
xx (xx.x%) 
xx (xx.x%) 
    Not Related 
 
 
xx (xx.x%) 
xx (xx.x%) 
... 
 
 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N. Subjects were counted only once for each System Organ Class and Preferred Term. 
Adverse events were coded using MedDRA version 20.0. For subjects who are missing the date of last dose, any 
AE occurring after the first dose is considered treatment emergent. Treatment groups are based on treatment 
received. 
[1] Any TEAE reported as possibly related or probably related, or is missing, is considered as related to 
study drug unless the start date is prior to the first date of study drug administration.  
Source: Listing 16.2.7.1  
 
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14.3.2 
Other Serious and Significant Adverse Events 
 
Table 14.3.2.1 
Serious Adverse Events by System Organ Class and Preferred Term 
Safety Population 
 
 
See Table 14.3.1.2 
______________________________________________________________________________________________________________________________________ 
Note: Percentages are 100*n/N. Subjects were counted only once for each System Organ Class and Preferred Term. Adverse events were 
coded using MedDRA, Version 20.0. Treatment groups are based on treatment received. 
Source: Listing 16.2.7.2  
 
 
 
 
 
Table 14.3.2.2 
Serious Adverse Events by Severity, System Organ Class, and Preferred Term 
Safety Population 
 
 
See Table 14.3.1.3 
______________________________________________________________________________________________________________________________________ 
Note: Percentages are 100*n/N. Subjects were counted only once for each System Organ Class and Preferred Term. Adverse events were 
coded using MedDRA version 20.0. Treatment groups are based on treatment received. 
Source: Listing 16.2.7.2 
 
 
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Table 14.3.2.3 
Serious Adverse Events by Relationship to Study Drug, System Organ Class, and Preferred Term 
Safety Population 
 
 
See Table 14.3.1.4 
____________________________________________________________________________________________________________________________ 
Note: Percentages are 100*n/N. Subjects were counted only once for each System Organ Class and Preferred Term. Adverse events were 
coded using MedDRA, Version 20.0. Treatment groups are based on treatment received. 
Source: Listing 16.2.7.2 
 
 
 
 
 
 
Table 14.3.2.4 
Adverse Events Leading to Withdrawal from the Study by System Organ Class and Preferred Term  
Safety Population 
 
 
See Table 14.3.1.2 
____________________________________________________________________________________________________________________________ 
Note: Percentages are 100*n/N. Subjects were counted only once for each System Organ Class and Preferred Term. Adverse events were 
coded using MedDRA, Version 20.0. Treatment groups are based on treatment received. 
Source: Listing 16.2.7.3 
 
 
 
 
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09-Jul-2018 
 
 
 
Table 14.3.2.5 
Adverse Events Leading to Withdrawal from the Study by Severity, System Organ Class, and Preferred Term 
Safety Population 
 
 
See Table 14.3.1.3 
____________________________________________________________________________________________________________________________ 
Note: Percentages are 100*n/N. Subjects were counted only once for each System Organ Class and Preferred Term. Adverse events were 
coded using MedDRA, Version 20.0. Treatment groups are based on treatment received. 
Source: Listing 16.2.7.3 
 
 
 
 
 
Table 14.3.2.6 
Adverse Events Leading to Withdrawal from the Study by Relationship to Study Drug, System Organ Class, and Preferred Term 
Safety Population 
 
 
See Table 14.3.1.4 
____________________________________________________________________________________________________________________________ 
Note: Percentages are 100*n/N. Subjects were counted only once for each System Organ Class and Preferred Term. Adverse events were 
coded using MedDRA, Version 20.0. Treatment groups are based on treatment received. 
Source: Listing 16.2.7.3 
 
 
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09-Jul-2018 
 
14.3.5 
Laboratory Data Summary Tables 
 
Table 14.3.5.1 
Clinical Chemistry Results 
Safety Population 
 
 
 
 
FMX103 1.5% 
Vehicle Foam 
Analyte 
Visit 
Statistic 
(N=xxx) 
(N=xxx) 
 
 
 
 
 
Analyte 1 (unit) - Absolute value  
Baseline 
n (# missing) 
xx (xx) 
xx (xx) 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Min to Max 
xx.x to xx.x 
xx.x to xx.x 
 
 
 
 
 
 
Week x 
n (# missing) 
xx (xx) 
xx (xx) 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Min to Max 
xx.x to xx.x 
xx.x to xx.x 
... 
 
 
 
 
 
Analyte 1 (unit) - Change from 
baseline 
Week x 
n (# missing) 
xx (xx) 
xx (xx) 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Min to Max 
xx.x to xx.x 
xx.x to xx.x 
... 
 
 
 
 
 
Programming Note: Repeat for all applicable visits and all clinical chemistry analytes. 
 
 
 
Note: Change from baseline is calculated as the value at the specified visit minus the value recorded at baseline; negative 
values represent a decrease in laboratory values since baseline. 
Source: Listing 16.2.8.1 
 
 
 
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09-Jul-2018 
 
 
Table 14.3.5.2 
Shift Table of Clinical Chemistry Results 
Safety Population 
 
 
 
 
 
 
 
 
 
 
Assessment at Baseline 
 
Analyte 
Visit 
Treatment 
Assessment 
at Post-
Baseline 
Missing 
N (%) 
Low  
N (%) 
Normal 
N (%) 
High 
N (%) 
Total 
N (%) 
 
 
 
 
 
 
 
 
 
Analyte 1 
[unit] 
Week x 
FMX103 1.5% 
Missing 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
 
 
 
Low 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
 
 
 
Normal 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
 
 
 
High 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
 
 
 
Total 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
 
 
 
 
 
 
 
 
 
 
 
Vehicle Foam 
Missing 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
 
 
 
Low 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
 
 
 
Normal 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
 
 
 
High 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
 
 
 
Total 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
xx (xxx.x%) 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Note: Repeat for all applicable visits and analytes 
 
 
 
 
 
Source: Listing 16.2.8.1 
 
 
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09-Jul-2018 
 
 
 
Table 14.3.5.3 
Hematology Results 
Safety Population 
 
 
     See Table 14.3.5.1 
     ____________________________________________________________________________________________________________________________ 
Note: Change from baseline is calculated as the value at the specified visit minus the value recorded at baseline; negative 
values represent a decrease in laboratory values since baseline. 
Source: Listing 16.2.8.2 
 
 
 
 
 
 
Table 14.3.5.4 
Shift Table of Hematology Results 
Safety Population 
 
 
 See Table 14.3.5.2 
 ____________________________________________________________________________________________________________________________________ 
Source: Listing 16.2.8.2 
 
 
 
 
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09-Jul-2018 
 
14.3.6 
Other Safety and Tolerability Summary Tables 
 
Table 14.3.6.1 
Shift Table of Physical Examination Results 
Safety Population 
 
 
 
 
 
Assessment at Baseline 
 
 
 
Assessment at 
Normal 
Abnormal, 
NCS 
Abnormal, CS 
Not Done 
Total 
Assessment 
Visit 
Treatment 
Post-Baseline 
Visit 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 
 
 
 
General 
appearence 
Week x 
FMX103 
1.5% 
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Abnormal, NCS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Abnormal, CS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Not done 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Total 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
Vehicle 
Foam 
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Abnormal, NCS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Abnormal, CS 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Not done 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Total 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
Programming Note: Repeat for all applicable visits and variables 
 
 
 
 
 
 
 
 
 
Note: Percentages exclude missing data. NCS = not clinically significant; CS = clinically significant 
Source: Listing 16.2.9.2 
 
 
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09-Jul-2018 
 
 
 
Table 14.3.6.2 
Vital Sign Results 
Safety Population 
 
 
 
 
FMX103 1.5% 
Vehicle Foam 
Variable 
Visit 
Sample Characteristics 
(N=xxx) 
(N=xxx) 
 
 
 
 
 
Variable1- Absolute value 
Baseline 
n (# missing) 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Min to Max 
xx.x to xx.x 
xx.x to xx.x 
 
 
 
 
 
 
Week x 
n (# missing) 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Min to Max 
xx.x to xx.x 
xx.x to xx.x 
... 
 
 
 
 
 
Variable1- Change from baseline 
Week x 
n (# missing) 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Min to Max 
xx.x to xx.x 
xx.x to xx.x 
 
 
 
 
 
 
 
 
 
 
Programming Note: Repeat for all vital signs variables and all scheduled visits 
 
 
 
 
 
 
Note: Change from baseline is calculated as the value at the specified visit minus the value recorded at baseline; 
negative values represent a decrease from baseline. 
Source: Listing 16.2.9.1 
 
 
 
 
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09-Jul-2018 
 
 
 
Table 14.3.6.3 
Concomitant Medications by ATC Level 2 and Preferred Term 
Safety Population 
 
 
See Table 14.1.3.x  
______________________________________________________________________________________________________________________________________ 
Note: Percentages are 100*n/N. Subjects were counted only once for each Anatomical Therapeutic Chemical (ATC) or preferred term. Any 
medications continuing or starting after Day 1 were considered to be concomitant.  
[1] Medications were coded using WHO-DD (Enhanced version March 2017) ATC level 2. Preferred term is ATC level 5. 
Source: Listing 16.2.9.3 
 
 
 
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09-Jul-2018 
 
 
 
Table 14.3.6.4 
 
Summary of Local Signs and Symptoms Assessments 
 
Safety Population  
 
 
 
 
 
FMX103 1.5% 
Vehicle Foam 
Visit 
Sign/Symptom 
Category 
(N=xxx) 
(N=xxx) 
 
 
 
 
 
Baseline 
 
 
 
 
 Erythema 
Non-missing response 
xx 
xx 
 
 
0-clear skin/no signs of erythema 
xx (xx.x%) 
xx (xx.x%) 
 
 
1-almost clear of erythema, slight redness 
xx (xx.x%) 
xx (xx.x%) 
 
 
2-mild erythema, definite redness 
xx (xx.x%) 
xx (xx.x%) 
 
 
3-moderate erythema, marked redness 
xx (xx.x%) 
xx (xx.x%) 
 
 
4-severe erythema, fiery redness 
xx (xx.x%) 
xx (xx.x%) 
 
 
Missing response 
xx 
xx 
 
 
 
 
 
 Telangiectasia 
Non-missing response 
xx 
xx 
  
0-None 
xx (xx.x%) 
xx (xx.x%) 
 
 
1-Mild: scattered telangiectasia 
xx (xx.x%) 
xx (xx.x%) 
 
 
2-Moderate: numerous telangiectasia 
xx (xx.x%) 
xx (xx.x%) 
 
 
3-Severe: dense telangiectasia forming sprays of vessels 
xx (xx.x%) 
xx (xx.x%) 
 
 
Missing response 
xx 
xx 
 
 
 
 
 
Programming Note:  Continue for ‘Burning/Stinging’, ‘Flushing/Blushing’, ‘Dryness/Xerosis’, ‘Itching’, 
‘Peeling/Desquamation’, ‘Hyperpigmentation’ 
 
 
 
 
 
 
 
 
 
 
 Hyperpigmentation 
Non-missing response 
xx 
xx 
 
 
0-None 
xx (xx.x%) 
xx (xx.x%) 
 
 
1-Mild: few scattered, small areas of light 
hyperpigmentation 
xx (xx.x%) 
xx (xx.x%) 
 
 
2-Moderate: larger or more intense areas of 
hyperpigmentation 
xx (xx.x%) 
xx (xx.x%) 
 
 
3-Severe: intense, extensive hyperpigmentation 
xx (xx.x%) 
xx (xx.x%) 
 
 
Missing response 
xx 
xx 
 
 
 
 
 
Programming Note: continue for Week 2, Week 4, Week 8, and Week 12. See protocol Section 10.7.1.1 for categories.  
    Note: Percentages exclude missing responses.  
    Source: Listing 16.2.9.4 
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09-Jul-2018 
 
16.2 Subject Data Listings 
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09-Jul-2018 
 
16.2.1 
Subject Discontinuations/Completions 
 
 
Listing 16.2.1.1 
Assignment to Analysis Populations and Treatment Group 
All Randomized Subjects 
Planned Treatment: xxxxx 
 
 
 
Date 
Consent 
Randomization 
 
 
Treatment 
 
Analysis 
Population 
Subject 
ID 
Date of 
ICF 
Assent Not 
Applicable 
Assent 
Signed 
for 
Photo 
Date 
Number 
 
Treatment 
Received 
Start      
Date 
Treatment 
End Date 
SAF 
ITT 
PP 
xxxxxx 
ddmmmyyyy xxxx 
ddmmmyyyy 
xxxx 
ddmmmyyyy xxxxx 
 
xxxx 
ddmmmyyyy 
ddmmmyyyy 
xxx 
xxx 
xxx 
xxxxxx 
ddmmmyyyy xxxx 
ddmmmyyyy 
xxxx 
ddmmmyyyy xxxxx 
 
xxxx 
ddmmmyyyy 
ddmmmyyyy 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICF = Informed Consent Form; SAF = Safety; ITT = Intent to Treat; PP = Per Protocol 
 
 
 
 
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09-Jul-2018 
 
 
Listing 16.2.1.2 
Study Completion Status 
All Randomized Subjects 
 
Planned Treatment: xxxxx 
 
Subject 
ID 
Completed 
Study? 
 
Discontinued 
From Study? 
Date of 
Completion or 
Discontinuation 
Reason for 
Discontinuation 
Dose Before 
Completing/ 
Discontinuing? 
AEs at 
Final 
Visit? 
Date of 
Last 
Contact 
Participate 
in FX2016-13 
Study? 
xxxxxx 
xxxxx 
xxxxx 
ddmmmyyyy 
xxxxx 
xxxxx 
xxxxx 
ddmmmyyyy 
no 
xxxxxx 
xxxxx 
xxxxx 
ddmmmyyyy 
xxxxx 
xxxxx 
xxxxx 
ddmmmyyyy 
yes 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.1.3 
List of Reasons for Screening Failure 
Screen Failures 
 
 
 
 
 
 
 
 
 
 
 
Subject 
ID 
Date of 
ICF 
Date of 
Screening 
 
Date of 
Screen 
Failure 
Date of 
Birth 
Age 
(full 
years) Sex 
Race 
Ethnicity 
Primary Reason 
for  
Screen Failure 
Failed 
Inclusion/ 
Exclusion 
Criteria 
xxxxxx 
ddmmmyyyy ddmmmyyyy 
ddmmmyyyy ddmmmyyyy xx 
x 
xxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxxx 
ddmmmyyyy ddmmmyyyy 
ddmmmyyyy ddmmmyyyy xx 
x 
xxxxx 
xxxxx 
xxxxx 
xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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09-Jul-2018 
 
16.2.2 
Protocol Deviations 
 
 
Listing 16.2.2.3 
Protocol Deviations 
All Randomized Subjects 
 
Planned Treatment: xxxxx 
Subject 
ID 
Date of 
Deviation 
Severity 
Classification Type 
Description 
Action Taken 
Submitted to 
IRB? 
xxxxxx 
ddmmmyyyy xxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxxx 
ddmmmyyyy xxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxx 
 
 
 
 
 
 
 
 
 
 
Page 83 of 101


Protocol: FX2016-12 
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09-Jul-2018 
 
16.2.3 
Subjects Excluded from the Efficacy Analyses 
 
 
Listing 16.2.3.1 
List of Subjects Excluded from Analysis Populations 
All Randomized Subjects 
 
Planned Treatment: xxxxx 
Subject 
ID 
ITT 
Population 
PP 
Population 
Safety 
Population 
Reason for Exclusion from PP Population 
xxxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxxx 
xxxxx 
xxxxx 
xxxxx 
xxxxx 
 
 
 
 
 
 
Programming Note: Reason for Exclusion from PP Population will be populated from the Protocol Deviation data 
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09-Jul-2018 
 
16.2.4 
Demographic Data and Other Baseline Characteristics 
 
Listing 16.2.4.1 
Demographic Data 
All Randomized Subjects 
 
Planned Treatment: xxxxx 
 
 
 
 
 
Subject ID 
Date of Birth 
Age  
(full years) 
Sex 
Child-Bearing 
Potential? 
Ethnicity 
Race 
xxxxxx 
ddmmmyyyy 
xx 
xxxxx 
xxx 
xxxxx 
xxxxx 
xxxxxx 
ddmmmyyyy 
xx 
xxxxx 
xxx 
xxxxx 
xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.4.2 
Medical History 
All Randomized Subjects 
 
Planned Treatment: xxxxx 
 
 
Subject 
ID 
Any 
Medical 
History? 
System Organ Class/ 
  Preferred Term/ 
    Verbatim Term 
Start Date 
End Date 
 
xxxxxx 
 
xxxxx 
 
xxxxxxxxxxx/ 
  xxxxxxxx/ 
    xxxxxxxxx 
 
ddmmmyyyy 
 
ddmmmyyyy 
 
xxxxxx 
 
xxxxx 
 
xxxxxxxxxxx/ 
  xxxxxxxx/ 
    xxxxxxxxx 
 
ddmmmyyyy 
 
Ongoing 
 
 
 
 
 
 
Programming Note:  If Medical Condition is Ongoing, then End Date will be “Ongoing”. 
 
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09-Jul-2018 
 
 
 
 
Listing 16.2.4.3 
Prior Medications 
All Randomized Subjects 
 
Planned Treatment: xxxxx 
Subject 
ID 
Any 
Medication? 
Anatomic Therapeutic Class Level 2/ 
  Preferred Term/ 
    Verbatim Term 
Start Date 
End Date 
Indication 
Dose (unit) 
  Route/ 
    Frequency 
 
 
 
 
 
 
 
xxxxxx 
xxxxx 
xxxxxxxxxxx/ 
  xxxxxxxx/ 
    xxxxxxxxx 
ddmmmyyyy 
ddmmmyyyy 
xxxxx 
xxx/ 
  xxxxx/ 
    xxxxxxx 
 
 
 
 
 
 
 
xxxxxx 
xxxxx 
xxxxxxxxx/ 
  xxxxxxxx/ 
    xxxxxxxxxxxx 
ddmmmyyyy 
Ongoing 
xxxxx 
xxx/ 
  xxxxxxxxx/ 
    xxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Medications were coded using WHO-DD (Enhanced version March 2017) ATC level 2. Preferred Term is ATC level 5. 
 
 
Programming Note:  If Medication is Ongoing, then End Date will be “Ongoing”. 
 
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09-Jul-2018 
 
16.2.5 
Compliance Data 
 
Listing 16.2.5.1 
Study Drug Accountability 
All Randomized Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Planned Treatment: xxxxx 
 
 
 
 
Dispensed 
 
 
 
Returned 
 
Subject 
ID 
Visit 
Study Drug 
Dispensed? 
Reason 
Not 
Dispensed 
 
Date 
Kit 
ID  
Canister 
ID  
Study 
Drug 
Returned? 
Reason 
Not 
Returned 
Date 
Kit 
ID  
Canister 
ID  
Any Doses 
Missed?/Number 
xxxxxx 
xxxxx 
xxx 
xxxx 
ddmmmyyyy 
xxx 
xxxx 
xxx 
xxxx 
ddmmmyyyy 
xxx 
xxxx 
Yes/xx 
xxxxxx 
xxxxx 
xxx 
xxxx 
ddmmmyyyy 
xxx 
xxxx 
xxx 
xxxx 
ddmmmyyyy 
xxx 
xxxx 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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09-Jul-2018 
 
Listing 16.2.5.2 
Study Drug Compliance 
All Randomized Subjects 
 
 
 
Planned Treatment: xxxxx 
Subject ID 
First Dose Date 
Last Dose Date 
Treatment Duration 
(Days) [1] 
Number of 
Missed Doses 
Compliance (%) [2] 
xxxxxx 
ddmmmyyyy 
ddmmmyyyy 
xxx 
xx 
xxxx 
xxxxxx 
ddmmmyyyy 
ddmmmyyyy 
xxx 
xx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Treatment duration (days) = Date of last dose of study drug - Date of first dose of study drug + 1 day.  
[2] Compliance (%) = 100 x Study drug exposure (days) / Treatment duration (days).  
Subjects who are missing last dose dates are not included.  
 
 
 
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09-Jul-2018 
 
16.2.6 
Individual Efficacy Response Data 
 
Listing 16.2.6.1 
IGA Score  
ITT Population 
 
 
Planned Treatment: xxxxx 
 
Analysis 
Center 
Subject 
ID 
Visit 
Was 
Assessment 
Performed? 
Reason 
Not 
Performed 
Assessor 
Initials 
Date  
Study Day 
IGA Score 
IGA 
Treatment 
Success [1] 
IGA 
Treatment 
Success - 
secondary 
[2] 
 
 
 
 
 
 
 
 
 
 
 
xxx 
xxxxxx 
Screening 
xxx 
xxxx 
xx 
ddmmmyyyy 
xx 
x 
- 
- 
 
 
Baseline 
xxx 
xxxx 
xx 
ddmmmyyyy 
xx 
x 
- 
- 
 
 
Week 4 
xxx 
xxxx 
xx 
ddmmmyyyy 
xx 
x 
xxx 
xxx 
 
 
Week 8 
xxx 
xxxx 
xx 
ddmmmyyyy 
xx 
x 
xxx 
xxx 
 
 
Week 12 
xxx 
xxxx 
xx 
ddmmmyyyy 
xx 
x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
xxx 
xxxxxx 
Screening 
xxx 
xxxx 
xx 
ddmmmyyyy 
xx 
x 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
[1] IGA treatment success is Yes if the IGA score is either 0 or 1 and there is at least a 2-grade improvement (decrease) from 
baseline.  Otherwise IGA treatment success is No. 
[2] IGA treatment success - secondary is Yes if there is at least a 2-grade improvement (decrease) from baseline.  Otherwise IGA 
treatment success - secondary is No. 
 
 
 
 
 
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09-Jul-2018 
 
 
 
Listing 16.2.6.2 
Inflammatory Lesion Count by Facial Area 
ITT Population 
 
Planned Treatment: xxxxx 
 
Analysis 
Center 
Subject 
ID 
Visit 
Assessor 
Initials Date 
Study 
Day 
Facial 
Area 
Facial 
Area Not 
Assessed? 
Reason 
Not 
Assessed 
Papules Pustules 
Nodules 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxx 
xxxxxx 
Screening 
xx 
ddmmmyyyy 
xx 
Forehead 
xxx 
xxxxx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Right 
cheek 
xxx 
xxxxx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Left 
cheek 
xxx 
xxxxx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Nose 
xxx 
xxxxx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Chin 
xxx 
xxxxx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Total 
 
 
 
xx 
xx 
xx 
xx 
 
 
Baseline 
xx 
ddmmmyyyy 
xx 
Forehead 
xxx 
xxxxx 
xx 
xx 
xx 
xx 
 
 
Week 4 
xx 
ddmmmyyyy 
xx 
Forehead 
xxx 
xxxxx 
xx 
xx 
xx 
xx 
 
 
Week 8 
xx 
ddmmmyyyy 
xx 
Forehead 
xxx 
xxxxx 
xx 
xx 
xx 
xx 
 
 
Week 12 
xx 
ddmmmyyyy 
xx 
Forehead 
xxx 
xxxxx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxx 
xxxxxx 
Screening 
xx 
ddmmmyyyy 
xx 
Left 
cheek 
xxx 
xxxxx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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09-Jul-2018 
 
 
Listing 16.2.6.3 
Subject Satisfaction Questionnaire (SSQ) 
ITT Population 
 
 
Planned Treatment: xxxxx 
Subject 
ID 
Date 
Study 
Day 
Question 
Response 
 
 
 
 
 
xxxxxx 
ddmmmyyyy xx 
How satisfied are you with this product in treating your rosacea? 
xxxxx 
 
 
 
How satisfied are you with how easy this product is to use? 
xxxxx 
 
 
 
How satisfied are you with this product compared to other products you  
have previously used for rosacea, such as gels and creams? 
xxxxx 
 
 
 
How satisfied are you with how this product feels on you skin after treatment? 
xxxxx 
 
 
 
How satisfied are you with the odor of this product after treatment? 
xxxxx 
 
 
 
How satisfied are you with the color of this product after treatment? 
xxxxx 
 
 
 
Overall, how satisfied are you with this product? 
xxxxx 
 
 
 
Overall, how likely are you to recommend this product to a friend? 
xxxxx 
 
 
 
 
 
xxxxxx 
ddmmmyyyy xx 
How satisfied are you with this product in treating your rosacea? 
xxxxx 
 
 
 
 
 
 
 
 
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09-Jul-2018 
 
Listing 16.2.6.4 
Subject Global Assessment (SGA) 
ITT Population 
Planned Treatment: xxxxx 
Subject 
ID 
Date 
Study 
Day 
Visit 
Response 
 
 
 
 
 
xxxxxx 
ddmmmyyyy xx 
Week 2 
xxxxx 
 
 
 
Week 4 
xxxxx 
 
 
 
Week 8 
xxxxx 
 
 
 
Week 12 
xxxxx 
xxxxxx 
ddmmmyyyy xx 
xxxxx 
xxxxx 
 
 
 
 
 
 
 
 
 
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09-Jul-2018 
 
16.2.7 
Adverse Event Listings  
 
Listing 16.2.7.1 
Adverse Events 
Safety Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ 
Class/ 
 
 
Severity/  
Rel to 
Outcome/  
Study Drug 
 
Serious?/ 
 
 
 
 
Subj 
Any 
 
  Preferred Term/ 
Start 
End 
  Study 
  Action 
 Life- 
 
 
Birth 
Med 
ID 
AEs? TEAE? 
    Verbatim Term 
Date 
Date 
  Drug 
  Taken 
 Threat? 
Hosp 
Disab 
Defect? Sig? 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx xxx 
xx 
xxxxx/ 
  xxxxxxx/ 
    xxxxxxxxx 
ddmmmyyyy 
ddmmmyyyy 
xxxx/ 
  xxxxxx 
xxxx/ 
  xxxxxxxx 
xx/ 
  xx 
 
xx 
xxx 
xxx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx xxx 
xxx 
xxxxx/ 
  xxxxxxx/ 
    xxxxxxxxx 
ddmmmyyyy 
Ongoing 
xxxx/ 
  xxxxxx 
xxxx/ 
  xxxxxxx 
xx/ 
  xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Adverse events were coded using MedDRA, Version 20.0. Rel = Relationship; Threat = Threatening; Hosp = Requires Inpatient/Prolonged 
Hospitalization; Disab = Results in Persistent or Significant Disability or Incapacity; Birth Defect = Congenital Anomaly or Birth 
Defect; Med Sig = Medically Significant; Trtmnt Req = Treatment Required 
 
Programming Note:  If AE is Ongoing then report ‘Ongoing’ for ‘End Date’ 
 
 
Page 93 of 101


Protocol: FX2016-12 
Page 55 of 62 
Table and Listing Shells Final 1.0 
 
CONFIDENTIAL 
09-Jul-2018 
 
 
 
Listing 16.2.7.2 
Serious Adverse Events 
Safety Population 
 
Treatment Received: xxxxx 
 
 
 
 
 
 
 
 
 
 
See Listing 16.2.7.1; Remove ‘Any AEs?’ column 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.7.3 
Adverse Events Leading to Withdrawal 
Safety Population 
 
Treatment Received: xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Listing 16.2.7.1; Remove ‘Any AEs?’ column 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.7.4 
Deaths 
Safety Population 
 
Treatment Received: xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Listing 16.2.7.1; Remove ‘Any AEs?’ column 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 94 of 101


Protocol: FX2016-12 
Page 56 of 62 
Table and Listing Shells Final 1.0 
 
CONFIDENTIAL 
09-Jul-2018 
 
16.2.8 
Laboratory Values  
 
Listing 16.2.8.1 
Clinical Chemistry Results 
Safety Population 
 
Treatment Received: xxxxx 
 
Subject 
ID 
Lab 
Test 
(unit) 
Visit 
Samples 
Collected? 
Reason 
Not 
Collected 
Collection 
Date 
Result 
Reference 
Range Low 
Reference 
Range 
High 
Abnormal? 
Clinically 
Significant? 
xxxxxx 
xxxxx 
xxxxx xxxx 
xxxx 
ddmmmyyyy 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
xxxxx xxxx 
xxxx 
ddmmmyyyy 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.8.2 
Hematology Results 
Safety Population 
 
Treatment Received: xxxxx 
 
Subject 
ID 
Lab 
Test 
(unit) 
Visit 
Samples 
Collected? 
Reason 
Not 
Collected 
Collection 
Date 
Result 
Reference 
Range Low 
Reference 
Range High 
Abnormal?  
Clinically 
Significant? 
xxxxxx 
xxxxx 
xxxxx xxxx 
xxxx 
ddmmmyyyy 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
xxxxx xxxx 
xxxx 
ddmmmyyyy 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 95 of 101


Protocol: FX2016-12 
Page 57 of 62 
Table and Listing Shells Final 1.0 
 
CONFIDENTIAL 
09-Jul-2018 
 
 
 
Listing 16.2.8.3 
Urinalysis Results 
Safety Population 
 
Treatment Received: xxxxx 
 
Subject 
ID 
Lab 
Test 
(unit) 
Visit 
Samples 
collected? 
Reason 
Not 
Collected 
Collection 
Date 
Result 
Reference 
Range Low 
Reference 
Range 
High 
Abnormal? 
Clinically 
Significant? 
xxxxxx 
xxxxx 
xxxxx xxxx 
xxxx 
ddmmmyyyy 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
xxxxx xxxx 
xxxx 
ddmmmyyyy 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.8.4 
Clinically Significant Laboratory Tests for Hematology, Chemistry, and Urinalysis 
All Randomized Subjects 
 
Treatment Received: xxxxx 
Subject 
ID 
Visit Category 
Lab Test 
(unit) 
Collection 
Date 
Result 
Reference 
Range Low 
Reference 
Range High 
Abnormal? 
xxxxxx 
xxxxx xxxx 
xxxxx 
ddmmmyyyy 
xxxx 
xxxx 
xxxx 
xxxx 
 
xxxxx xxxx 
xxxxx 
ddmmmyyyy 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Note:  Include pre-treatment portion for ‘Not Treated’ group, variable Abnormal should be high or low 
 
 
 
Page 96 of 101


Protocol: FX2016-12 
Page 58 of 62 
Table and Listing Shells Final 1.0 
 
CONFIDENTIAL 
09-Jul-2018 
 
Listing 16.2.8.5 
Out of Range (Abnormal) Laboratory Tests for Hematology, Chemistry, and Urinalysis 
All Randomized Subjects 
 
Treatment Received: xxxxx 
Subject 
ID 
Visit Category 
Lab Test 
(unit) 
Collection 
Date 
Result 
Reference 
Range Low 
Reference 
Range High 
Abnormal? 
Clinically 
Significant? 
xxxxxx 
xxxxx xxxx 
xxxxx 
ddmmmyyyy 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 
xxxxx xxxx 
xxxxx 
ddmmmyyyy 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Note:  Include pre-treatment portion for ‘Not Treated’ group 
 
 
 
Listing 16.2.8.6 
Pregnancy Test Results 
Safety Population 
 
Treatment Received: xxxxx 
Subject 
ID 
Visit 
Pregnancy Test 
Performed? 
Reason Not 
Performed 
Collection  
Date 
Result 
xxxxxx 
xxxxx 
xxxx 
xxxx 
ddmmmyyyy 
xxxxx 
 
xxxxx 
xxxx 
xxxx 
ddmmmyyyy 
xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 97 of 101


Protocol: FX2016-12 
Page 59 of 62 
Table and Listing Shells Final 1.0 
 
CONFIDENTIAL 
09-Jul-2018 
 
16.2.9 
Other Clinical Observations and Measurements 
 
 
Listing 16.2.9.1 
Vital Signs 
Safety Population 
 
Treatment Received: xxxxx 
Subject 
ID 
Visit 
Vital 
Signs 
Collected? 
Collection 
Date 
Height 
(cm) 
Weight 
(kg) 
Body Mass 
Index 
(kg/m2) 
Heart Rate 
(beats/min) 
Systolic BP 
(mmHg) 
Diastolic 
BP (mmHg) 
xxxxxx 
xxxxx 
xxx 
ddmmmyyyy 
xxxx 
xxxx 
xxxx 
xxx 
xxx 
xxx 
 
xxxxx 
xxx 
ddmmmyyyy 
xxxx 
xxxx 
xxxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.9.2 
Abnormal Physical Examination Results 
Safety Population 
 
Treatment Received: xxxxx 
 
 
 
 
Subject 
ID 
Visit 
Examination 
Date 
Body System 
Result 
 
Abnormal Finding 
xxxxxx 
xxxxx 
ddmmmyyyy 
xxxx 
xxxx 
xxxx 
 
 
 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 98 of 101


Protocol: FX2016-12 
Page 60 of 62 
Table and Listing Shells Final 1.0 
 
CONFIDENTIAL 
09-Jul-2018 
 
 
 
Listing 16.2.9.3 
Concomitant Medications 
Safety Population 
 
Treatment Received: xxxxx 
 
 
 
 
 
 
 
 
See Listing 16.2.4.3 
 
 
 
 
 
 
 
 
 
 
Programming Note:  If Medication is Ongoing, then End Date will be “Ongoing”. 
 
 
 
Page 99 of 101


Protocol: FX2016-12 
Page 61 of 62 
Table and Listing Shells Final 1.0 
 
CONFIDENTIAL 
09-Jul-2018 
 
 
Listing 16.2.9.4 
Local Signs and Symptoms Assessments 
Safety Population 
 
Treatment Received: xxxxx 
Subject 
ID 
Date 
Assessment 
Performed? 
Study 
Day 
Assessor 
Initials 
Sign/Symptom 
Severity 
[1] 
xxxxxx 
ddmmmyyyy 
xxxxx 
xxxxx 
xxxxx 
Erythema 
xxxx 
 
 
 
 
 
Telangiectasia 
xxxx 
 
 
 
 
 
Burning/Stinging 
xxxx 
 
 
 
 
 
Flushing/Blushing 
xxxx 
 
 
 
 
 
Dryness/Xerosis 
xxxx 
 
 
 
 
 
Itching 
xxxx 
 
 
 
 
 
Peeling/Desquamation 
xxxx 
 
 
 
 
 
Hyperpigmentation 
xxxx 
xxxxxx 
ddmmmyyyy 
xxxxx 
xxxxx 
xxxxx 
Erythema 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] All signs/symptoms, except erythema, are based on a 4-point scale with 0=none, 1=mild, 2=moderate, 
and 3=severe. Erythema is based on a 5-point scale with 0=clear, 1=almost clear, 2=mild erythema, 
3=moderate erythema, and 4=severe erythema.  
 
 
Page 100 of 101


Protocol: FX2016-12 
Page 62 of 62 
Table and Listing Shells Final 1.0 
 
CONFIDENTIAL 
09-Jul-2018 
 
 
 
Listing 16.2.9.5 
Photography of the Face 
Safety Population 
 
Treatment Received: xxxxx 
Subject  
ID 
Visit 
Photography 
Performed? 
Photography  
Date 
Photography  
Study Day 
xxxxxx 
Baseline 
xxxxx 
ddmmmyyyy 
xxx 
 
Week 4 
xxxxx 
ddmmmyyyy 
xxx 
 
Week 8 
xxxxx 
ddmmmyyyy 
xxx 
 
Week 12 
xxxxx 
ddmmmyyyy 
xxx 
xxxxxx 
xxxxx 
xxxxx 
ddmmmyyyy 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
Page 101 of 101