Clinical trial NCT03287791
Conditions: Rosacea
Sponsor: Actavis Inc.
Start date: 2016-07-19; Completion date: 2017-06-22
Enrollment: 924 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this study were to compare the safety and efficacy profiles of a generic Azelaic Acid Foam, 15% to the reference listed Finacea® (azelaic acid) Foam, 15% and to demonstrate therapeutic equivalence and safety of the two active foams in the treatment of moderate facial rosacea, and to demonstrate superiority of the Reference and Test products over the Vehicle.

Detailed description:
Topical azelaic acid is used to treat inflammatory papules and pustules of mild to moderate rosacea. Other topical therapies and oral antibiotics are also used to treat rosacea symptoms. Finacea® (azelaic acid) Foam, 15% contains azelaic acid, a naturally occurring saturated dicarboxylic acid that has proven anti-inflammatory effects, as well as anti-keratinizing and antimicrobial actions.

Arms: arm 1: A thin layer of generic azelaic acid, 15% topical foam was to be gently massaged into the entire facial area twice daily, once in the morning and once in the evening, for 12 weeks. Contact with the mouth, eyes, and other mucous membranes was to be avoided. Hands were to be washed following application of study drug. Participants were instructed not to bathe, shower, wash, or swim for at least 4 hours after application of study drug. Participants were provided with mild cleanser, a towel, sunscreen, and moisturizing lotion to be used on treated areas while participating in the study. arm 2: A thin layer of Finacea (azelaic acid), 15% topical foam was to be gently massaged into the entire facial area twice daily, once in the morning and once in the evening, for 12 weeks. Contact with the mouth, eyes, and other mucous membranes was to be avoided. Hands were to be washed following application of study drug. Participants were instructed not to bathe, shower, wash, or swim for at least 4 hours after application of study drug. Participants were provided with mild cleanser, a towel, sunscreen, and moisturizing lotion to be used on treated areas while participating in the study. arm 3: A thin layer of the vehicle topical foam was to be gently massaged into the entire facial area twice daily, once in the morning and once in the evening, for 12 weeks. Contact with the mouth, eyes, and other mucous membranes was to be avoided. Hands were to be washed following application of study drug. Participants were instructed not to bathe, shower, wash, or swim for at least 4 hours after application of study drug. Participants were provided with mild cleanser, a towel, sunscreen, and moisturizing lotion to be used on treated areas while participating in the study.
Interventions: intervention 1: Generic Azelaic Acid Foam intervention 2: Finacea® (Azelaic Acid) Foam intervention 3: Vehicle Foam intervention 4: Cleanser intervention 5: Sunscreen intervention 6: Towel intervention 7: Moisturizing Lotion
Intervention descriptions: intervention 1: Topical foam, generic formulation of the brand product. intervention 2: Topical foam, brand product. intervention 3: Topical foam, placebo. Has no active ingredient. intervention 4: A mild cleanser provided to participants, so they can wash their face prior to applying the study drug. intervention 5: Sunscreen provided to participants, so they can apply it to their face when outdoors. intervention 6: A soft towel provided to participants, so they can pat their face dry after washing and prior to applying the study drug. intervention 7: Moisturizing lotion provided to participants, so they can apply it to their face, as needed.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol with Amendment 01 
A Multicenter, Double-blind, Randomized, Parallel-group, Vehicle-Controlled Study to 
Evaluate the Safety and Clinical Equivalence of a Generic Azelaic Acid Foam, 15% and the 
Reference Listed Finacea® (Azelaic acid) Foam, 15% in Patients with Moderate Facial 
Rosacea 
Study Number ACTA AZEL 2015 
NCT03287791 
Protocol with Amendment 01 Approval Date: 28 March 2016 


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Page 1 of 52 
1 TITLE PAGE 
Title 
A Multicenter, Double-blind, Randomized, Parallel-group, 
Vehicle-Controlled Study to Evaluate the Safety and Clinical 
Equivalence of a Generic Azelaic Acid Foam, 15% and the 
Reference Listed Finacea® (Azelaic acid) Foam, 15% in 
Patients with Moderate Facial Rosacea 
Protocol No. 
ACTA/AZEL/2015 
Sponsor 
Actavis 
Morris Corporate Center III 
400 Interpace Parkway 
Parsippany, NJ 07054 
 
Protocol Version 
Amendment 1 
Date of This FINAL 
Version of the Protocol 
Amendment 1 
03-28-2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2 AMENDMENTS 
Page 
Number 
Current Protocol 
Amended Protocol 
Reason for 
Amendment 
19 
11.3.3 Exclusion Criteria 
7d. The use within 1 month 
prior to baseline of systemic 
corticosteroids (Note: 
intranasal and inhalational 
corticosteroids do not 
require a washout and 
maybe used throughout the 
trial if the patient is on a 
stable dose).  
11.3.3 Exclusion Criteria 
7d. The use within 1 month 
prior to baseline of systemic 
corticosteroids.  
To include a washout 
period of 1 month for 
all systemic 
corticosteroids and to 
maintain consistency 
with prohibited 
medications regarding 
corticosteroids in 
section 11.3.1 
Prohibited 
medications/treatment. 
20 
11.3.4 Patient 
Discontinuation Criteria 
(No reference to missed 
visits) 
11.3.4 Patient 
Discontinuation Criteria 
7. If the subject misses more 
than 1 required visit; 
To allow for 1 missed 
visit (either visit 2 or 
visit 3) by the 
subjects. 
29 
11.7.2 Visit 2/(Day 28 ± 4 
days) 
The patient’s compliance 
with the study protocol, 
including use and 
application of 
Investigational Product, will 
be assessed.  The patient’s 
diary will be collected and 
reviewed for completion.  A 
new diary will be issued.  
11.7.2 Visit 2/(Day 28 ± 4 
days) 
The patient’s compliance 
with the study protocol, 
including use and 
application of 
Investigational Product, will 
be assessed.  The patient’s 
diary will be collected and 
reviewed for completion. 
 
The diaries consist of 
perforated, tear-off 
pages for each week. 
At each post-baseline 
visit, the completed 
pages will be teared 
off and filed with the 
subjects’ charts. The 
diary with blank pages 
for the rest of the 
weeks will be returned 
to the subject. 
29 
11.7.2 Visit 3/(Day 56 ± 4 
days) 
7. The patient’s compliance 
with the study protocol, 
including use and 
application of 
Investigational Product, will 
be assessed.  The patient’s 
diary will be collected and 
reviewed for completion.  A 
new diary will be issued.  
11.7.2 Visit 3/(Day 56 ± 4 
days) 
The patient’s compliance 
with the study protocol, 
including use and 
application of 
Investigational Product, will 
be assessed.  The patient’s 
diary will be collected and 
reviewed for completion. 
 
The diaries consist of 
perforated, tear-off 
pages for each week. 
At each post-baseline 
visit, the completed 
pages will be teared 
off and filed with the 
subjects’ charts. The 
diary with blank pages 
for the rest of the 
weeks will be returned 
to the subject. 


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3 CLINICAL STUDY PROTOCOL APPROVAL 
PROTOCOL NUMBER:  
ACTA/AZEL/2015 
STUDY TITLE:  
A Multicenter, Double-blind, Randomized, Parallel-group, 
Vehicle-Controlled Study to Evaluate the Safety and Clinical 
Equivalence of a Generic Azelaic Acid Foam, 15% and the 
Reference Listed Finacea® (azelaic acid) Foam, 15% in Patients 
with Moderate Facial Rosacea 
 
Sponsor Representative 
 
 
 
Signature: 
Date: 
Statistical Consultant  
 
Signature: 
Date: 
CRO Representative 
 
 
Signature: 
Date: 
Medical Monitor 
 
 
Signature: 
Date: 
 


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4 CONTACT LIST 
 
Sponsor: 
Actavis 
Morris Corporate Center III 
400 Interpace Parkway 
Parsippany, NJ 07054 
 
 
Contract Research Organization: 
 
 
 
 
 
Medical Monitor: 
 
 
 
 
 
Statistics and Data Management: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5 PRINCIPAL INVESTIGATOR AGREEMENT 
I have carefully read and understand the foregoing protocol and agree that it contains all the 
necessary information for conducting this study safely.  I will conduct this study in strict 
accordance with this protocol, ICH guidelines for Good Clinical Practice, the Code of Federal 
Regulations, the Health Insurance Portability and Accountability Act (HIPAA) and local 
regulatory guidelines.  I will attempt to complete the study within the time designated.  
I will ensure that the rights, safety and welfare, of patients under my care are protected.  I will 
ensure control of the drugs under investigation in this study.  
I will provide copies of the protocol and all other study-related information supplied by the 
Sponsor to all personnel responsible to me who participate in the study. I will discuss this 
information with them to assure that they are adequately informed regarding the drug and conduct 
of the study.  
I agree to keep records on all patient information (case report forms, shipment and drug return 
forms and all other information collected during the study) and drug disposition in accordance 
with FDA regulations. 
I will not enroll any patients into this protocol until FDA approval (if required by regulation), IRB 
approval and Sponsor approval are obtained. 
 
 
 
 
 
 
 
Principal Investigator 
Signature 
Date 


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6 TABLE OF CONTENTS 
1 
TITLE PAGE ..........................................................................................................................1 
2 
AMENDMENTS......................................................................................................................2 
3 
CLINICAL STUDY PROTOCOL APPROVAL .................................................................3 
4 
CONTACT LIST .....................................................................................................................4 
5 
PRINCIPAL INVESTIGATOR AGREEMENT .................................................................5 
6 
TABLE OF CONTENTS ........................................................................................................6 
7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................9 
8 
SYNOPSIS .............................................................................................................................10 
9 
INTRODUCTION AND BACKGROUND .........................................................................15 
10 STUDY OBJECTIVES .........................................................................................................15 
11 INVESTIGATIONAL AND ANALYSIS PLAN ................................................................15 
11.1 OVERALL STUDY DESIGN ..................................................................................................15 
11.2 STUDY OVERVIEW .............................................................................................................15 
11.3 STUDY POPULATION ..........................................................................................................17 
11.3.1 Number of patients ..................................................................................................17 
11.3.2 Inclusion Criteria .....................................................................................................17 
11.3.3 Exclusion Criteria ....................................................................................................18 
11.3.4 Patient Discontinuation Criteria ............................................................................20 
11.3.5 Prohibited Medications / Treatments.....................................................................21 
11.3.6 Precautions ...............................................................................................................22 
11.4 STUDY SCHEDULE ..............................................................................................................23 
11.5 ASSESSMENT OF SAFETY AND TOLERABILITY ....................................................................23 
11.5.1 Physical Examination ..............................................................................................23 
11.5.2 Urine Pregnancy Test ..............................................................................................23 
11.5.3 Medical History ........................................................................................................23 
11.5.4 Record Concomitant Medications ..........................................................................23 
11.5.5 Telangiectasia Assessment.......................................................................................24 
11.5.6 Irritation/Application Site Reactions .....................................................................24 
11.5.7 Adverse Events .........................................................................................................26 
11.6 CLINICAL ASSESSMENTS ....................................................................................................26 
11.6.1 Inflammatory Lesion Count ...................................................................................26 
11.6.2 Investigator’s Global Evaluation (IGE) .................................................................27 
11.7 STUDY PROCEDURES ..........................................................................................................27 
11.7.1 Visit 1/Baseline/Day 0 ..............................................................................................27 
11.7.2 Visit 2/ (Day 28±4 days) ...........................................................................................29 
11.7.3 Visit 3/ (Day 56±4 days) ...........................................................................................30 
11.7.4 Visit 4/ (Day 84±4 days) /End of Treatment/ Early Discontinuation ..................30 
11.7.5 Unscheduled Visit.....................................................................................................31 
11.8 INVESTIGATIONAL PRODUCT ..............................................................................................31 
11.8.1 Dosage and Formulations ........................................................................................31 


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11.8.2 Dispensing and Application ....................................................................................32 
11.8.3 Method of Treatment Assignment and Randomization .......................................32 
11.8.4 Blinding Study Medication......................................................................................33 
11.8.5 Unblinding Study Medication .................................................................................33 
11.8.6 Method of Packaging, Labeling and Storage ........................................................33 
11.8.7 Replacement Cans ....................................................................................................33 
11.8.8 Study Medication Accountability ...........................................................................33 
11.8.9 Assessment of Compliance ......................................................................................34 
11.8.10 Retention of Study Medication Samples ................................................................34 
11.8.11 Return of Clinical Supplies .....................................................................................35 
11.8.12 Additional Supplies Provided by the Sponsor .......................................................35 
11.9 ADVERSE EVENTS ........................................................................................................35 
11.9.1 Reporting of Adverse Events ..................................................................................35 
11.9.2 Assessment of Severity .............................................................................................36 
11.9.3 Relationship to Study Medication ..........................................................................36 
11.9.4 Action taken regarding the IMP .............................................................................36 
11.9.5 Assessment of Subject outcome ..............................................................................37 
11.9.6 Definition of AE outcome ........................................................................................37 
11.9.7 Treatment Required ................................................................................................37 
11.9.8 Pregnancy .................................................................................................................37 
11.9.9 Serious Adverse Events ...........................................................................................38 
12 STATISTICAL METHODS ................................................................................................40 
12.1 SAMPLE SIZE RATIONALE ..................................................................................................40 
12.2 RANDOMIZATION AND UNBLINDING PROCEDURES ............................................................40 
12.3 SIGNIFICANCE LEVEL .........................................................................................................41 
12.4 EFFICACY ASSESSMENT .....................................................................................................41 
12.4.1 Primary Endpoint ....................................................................................................41 
12.4.2 Secondary Endpoint.................................................................................................41 
12.4.3 Measures ...................................................................................................................41 
12.4.4 Datasets to be Analyzed ...........................................................................................42 
12.5 STATISTICAL ANALYSIS .....................................................................................................42 
12.5.1 Analysis of Primary Endpoint ....................................................................................42 
12.5.2 Analysis of Secondary Endpoint ................................................................................43 
12.5.3 Analysis of application site reactions .....................................................................44 
12.5.4 Safety Analyses .........................................................................................................44 
12.5.5 Concomitant Medication .........................................................................................44 
12.5.6 Demographics and Baseline/Randomization Characteristics ..............................44 
12.5.7 Summary of patients who terminate prematurely ................................................44 
13 ETHICS ..................................................................................................................................44 
13.1 INFORMED CONSENT ..........................................................................................................44 
13.2 INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE ...........................45 
13.3 PATIENT CONFIDENTIALITY ...............................................................................................45 
14 DATA HANDLING AND RECORD KEEPING ...............................................................45 
14.1 SITE REGULATORY DOCUMENTS REQUIRED FOR INITIATION .............................................45 


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14.2 MAINTENANCE AND RETENTION OF RECORDS ...................................................................46 
14.3 DATA COLLECTION AND REPORTING .................................................................................46 
14.4 PRIMARY SOURCE DOCUMENTS .........................................................................................47 
14.5 STUDY MONITORING ..........................................................................................................47 
14.6 AUDITS AND INSPECTIONS .................................................................................................48 
14.7 MODIFICATIONS TO THE PROTOCOL ...................................................................................48 
14.8 TERMINATION OF THE STUDY ............................................................................................48 
14.9 COMPLETION OF THE STUDY ..............................................................................................48 
14.10 PUBLICATIONS ...................................................................................................................49 
15 REFERENCES ......................................................................................................................50 
APPENDIX I: STUDY FLOW CHART ....................................................................................51 
APPENDIX II: FINACEA ® PACKAGE INSERT ...................................................................52 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Term 
Definition 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
hCG 
Human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IGE 
Investigator’s Global Evaluation 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IU 
International Units 
IUD 
Intrauterine Device 
kg 
Kilogram 
LOCF 
Last-Observation-Carried-Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-To-Treat 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OTC 
Over-the-counter 
PP 
Per-Protocol 
RLD 
Reference Listed Drug 
SAE 
Serious Adverse Event 
SPF 
Sun Protection Factor 


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8 SYNOPSIS 
Protocol number:   
Title of Study:  
A Multicenter, Double-blind, Randomized, Parallel-group, Vehicle-
Controlled Study to Evaluate the Safety and Clinical Equivalence of a Generic 
Azelaic Acid Foam, 15% and the Reference Listed Finacea® (azelaic acid) 
Foam, 15% in Patients with Moderate Facial Rosacea 
Sponsor: 
Actavis Laboratories UT  
Test Product:                Azelaic Acid, 15% topical foam (Actavis Laboratories UT) 
Reference Product:      Finacea® (Azelaic acid) Foam, 15% (Bayer HealthCare) 
Vehicle:                         Foam Vehicle of the test product (Actavis Laboratories UT) 
Objectives: 
To compare the safety and efficacy profiles of a generic Azelaic Acid Foam, 
15% to the reference listed Finacea® (azelaic acid) Foam, 15% and to 
demonstrate therapeutic equivalence and safety of the two active foams in the 
treatment of moderate facial rosacea, and to demonstrate superiority of the 
reference and test products over the vehicle. 
Study Design: 
This is a randomized, vehicle-controlled, parallel-group, multicenter, double-
blind study of Azelaic Acid Foam, 15% and the reference listed Finacea® 
(azelaic acid) Foam, 15% in patients with moderate facial rosacea. 
Number of Study 
Centers:   
Approximately 26 centers 
Duration of Patient 
Participation:   
Each patient will participate in the study for approximately 12 weeks from 
the time the patient signs the Informed Consent Form (ICF) through date of 
the final contact with the subject.  The study treatment period will last for 
84 days (12 weeks).   
Key Inclusion 
Criteria:  
Healthy male and non-pregnant female patients aged ≥ 18 years with a 
diagnosis of moderate facial rosacea will be selected to participate in the 
study.  Moderate facial rosacea is defined as the presence of at least eight 
and not more than fifty inflammatory facial lesions (i.e. papules/ pustules) 
and the presence of persistent erythema and telangiectasia.   
Dosage and 
Administration:  
Randomized patients will apply the foam to the entire facial area (cheeks, 
chin, forehead, and nose) twice daily for 12 weeks. 
Number of Patients:  Up to 1010 patients will be enrolled in the study to randomize 924 patients 
to obtain at least 840 mITT  patients in a 1:1:1 ratio (280:280:280 patients, 
respectively) to each treatment group and 672 (224:224:224) evaluable 
subjects in PP population: 
• Azelaic Acid, 15% topical foam (Actavis Laboratories UT) 
• Finacea® (azelaic acid) Foam, 15% (Bayer HealthCare) 
• Foam Vehicle of the test product (Actavis Laboratories UT) 


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Clinical 
Evaluations will 
be performed at: 
  
Visit 1: Baseline Visit (Day 0);  
Visit 2:  (Day 28 ± 4 Days); 
Visit 3: (Day 56 ± 4 Days);  
Visit 4: End of Treatment (Day 84 ± 4 Days). 
Early Discontinuation Visit:  Same Evaluations as End of Treatment Visit 
Criteria for 
Evaluation:   
  
Primary Endpoint:  
Percent change from baseline to Week 12 in the inflammatory (papules and  
pustules) lesion counts. 
Secondary Endpoint: 
The Investigator’s Global Evaluation outcome at Week 12, expressed as 
“success” or “failure”  A patient is considered to have success if the IGE 
score is either 0 (clear) or 1 (almost clear), and is considered to have a 
failure, otherwise. 
Measures:  
 
1. 
Lesion Counts will be performed using the following definitions:  
Lesion 
Name 
Lesion Definition 
Papule 
Inflammatory lesion; small (≤ 5mm in diameter), 
solid palpable lesion, usually with inflamed 
elevation of the skin that does not contain pus.  
Pustule 
Inflammatory lesion; small (≤ 5mm in diameter), 
inflamed skin swelling that is filled with pus.  
Nodule 
Large, hard bumps under the skin's surface. 
All facial papules, pustules and nodules, located above the jaw line to 
the hairline, will be counted, including those present on the nose. 
Counts of nodules will be reported separately and not included in the 
inflammatory lesion counts.  
2. 
The IGE will be performed and documented using the definitions in 
table below:   
Score 
Grade  
Definition  
0 
Clear  
No inflammatory lesions present; at most, 
mild erythema.  
1 
Almost 
Clear  
Very mild erythema present.  Very few small 
papules/pustules.  


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2 
Mild  
Mild erythema.  Several small 
papules/pustules.  
3 
Moderate  
Moderate erythema.  Several small or large 
papules/pustules, and up to 2 nodules. 
4 
Severe  
Severe erythema.  Numerous small and/or 
large papules/pustules, up to several nodules.  
3. 
Application site reactions such as erythema, dryness, scaling, pruritus, 
stinging/burning, and edema, will be recorded at each visit to allow a 
comparison between treatment groups. 
Data Sets to be 
Analyzed:   
Three patient populations are defined as follows: 
1. The Safety Population includes any patient who was randomized in the 
study and had at least one dose of Investigational product.  
2. The Modified Intent-to-Treat (mITT) Population includes all 
randomized patients who met all inclusion/exclusion criteria, received 
study treatment, and returned for at least one post-baseline visit with 
lesion count. 
3. The Per-Protocol (PP) Population includes all randomized patients who 
met all inclusion/exclusion criteria, were compliant with the assigned 
study treatment (who applied 75% to 125% of the scheduled 
applications), returned to the study site for the primary endpoint visit (12 
week evaluation) within +/- 4 days OR discontinued from the study as a 
treatment failure and did not have any protocol violations.   
4. Patients who are discontinued early from the study due to lack of 
treatment effect after completing at least eight weeks of treatment will 
be included in the mITT and PP population as treatment failures (i.e., 
non-responders) and the change in inflammatory lesion count from the 
baseline visit to the last completed visit prior to discontinuation due to 
lack of efficacy will be carried forward in the primary endpoint analysis.  
In addition, patients whose condition worsens after completing at least 
eight weeks of treatment and require alternate or supplemental therapy 
for the treatment of facial rosacea during the study will be discontinued, 
included in the PP population analysis, and provided with effective 
treatment.  A last observation carried forward (LOCF) approach will be 
used for imputing missing efficacy results in these PP patients and they 
will be considered as failures in the IGE evaluations.  
Patients discontinued prematurely for other reasons will be excluded from 
the PP population, but included in the mITT population, for which missing 
efficacy data will be imputed using LOCF.  
For the purpose of determining the per-protocol status of the patient, a 
“protocol violation” is any patient or investigator activity that could have 


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possibly interfered with the therapeutic administration of the treatment or 
the precise evaluation of treatment efficacy. 
Efficacy analyses will be performed on the mITT and per-protocol 
populations.  All efficacy data will be listed by treatment and patient in data 
listings. 
Statistical 
Methods: 
 
Analysis of Primary Endpoint 
The percent change from baseline to Week 12 in the inflammatory (papules 
and pustules) lesion counts is the primary endpoint for the study. A LOCF 
approach will be used for imputation of missing efficacy results, where 
appropriate. 
Demonstration of Bioequivalence 
A two-way ANOVA on the test and reference results for the primary 
endpoint will be conducted using a statistical model containing terms for 
treatment and site.  Bioequivalence for the primary endpoint will be 
established if the 90% confidence interval for the test/reference ratio of the 
mean percent change from baseline to Week 12 in the inflammatory 
(papules and pustules) lesion counts is contained within [0.80, 1.25], using 
the PP population.  Non-parametric methods will be used if the skewness 
factor for the residuals from the ANOVA model are outside the range -2 to 
+2.  
Demonstration of Superiority 
To ensure that the study is sensitive enough, the test product and reference 
listed drug (RLD) will each be compared to the vehicle group to 
demonstrate their statistical superiority at p<0.05 (two sided) for the 
primary endpoint, using the mITT study population.  This evaluation will 
be performed using separate two-way ANOVA of Test vs. Vehicle and 
Reference vs. Vehicle, with the statistical model containing terms for 
treatment and site.  Non-parametric methods will be used if the skewness 
factor for the residuals from the ANOVA model are outside the range -2 to 
+2. 
Analysis of Secondary Endpoint 
The dichotomized Investigator’s Global Evaluation (IGE) will be treated as 
a secondary endpoint for supportive evidence.  This secondary endpoint 
will be evaluated as the proportion of patients with a clinical response of 
“success” at Week 12.  Success is defined as an either IGE score 0 (clear) 
or 1 (almost clear) at the final visit.  Any patient who is not considered a 
success will be considered to be a failure.  A LOCF approach will be used 
for imputation of missing efficacy results, where appropriate. 
 
Demonstration of Bioequivalence 
 
Bioequivalence for the secondary endpoint will be established if the 90% 
continuity-corrected confidence interval for the difference in clinical 


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success proportions between the test and reference product is contained 
within the interval [-0.20, +0.20] for the PP population.  
 
Demonstration of Superiority 
Superiority of the efficacy of the test treatment over that of the vehicle will 
be demonstrated if the test success proportion is greater than, and 
statistically different from (p<0.05) that of the vehicle by two-sided 
Fisher’s exact test.  The superiority of the efficacy of the reference 
treatment over that of the vehicle will be demonstrated in an identical 
manner.  
Analysis of application site reactions 
A descriptive analysis comparing the application site reactions for each 
treatment group will be conducted to ensure that the test product is not 
worse than the reference product with regard to the expected and 
unexpected application site reactions.  
Safety Analyses 
Safety analyses will be conducted on the safety population.  Incidence of 
all adverse events reported during the study will be coded using the 
MedDRA dictionary and summarized by treatment group, body system, 
severity, preferred term, and relationship to study drug.  In addition, an 
evaluation will be conducted of the comparability of the test and reference 
treatments in regard to any treatment emergent adverse events that occur in 
5%, or more, of the patients in either test or reference treatment group. 
The report of AEs will include date of onset, description of the AE, and date 
of resolution. 
Concomitant medication 
The start and stop date of concomitant medication use during the study will 
be provided in the data listings in addition to the reason for the medication 
use.  
Demographics and Baseline/Randomization Characteristics 
Demographic and baseline/randomization characteristics will be compared 
for the mITT, PP, and Safety populations.  Continuous variables will be 
analyzed with an analysis of variance with factors of treatment and 
investigational site.  Categorical variables such as gender, ethnicity, and 
race will be analyzed with a Cochran-Mantel-Haenszel test, stratified by 
investigational site.  
Summary of patients who terminate prematurely 
Reasons for premature termination will be summarized by treatment group. 


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9 INTRODUCTION AND BACKGROUND 
Rosacea is a chronic disorder characterized by vascular dilation (persistent erythema) of the 
nose, cheeks and forehead which most commonly occurs in patients between the ages of 30 
and 60 years-of-age.  The vascular dilation cause is unknown but has been linked with hair 
follicle mites, Demodex folliculorum and D. brevis, as well as Helicobacter pylori infection.  
However, after successful treatment (wherein rosacea symptoms were improved) with 
tetracycline or metronidazole, respectively, actual numbers of the organisms were not found 
to be reduced.  The earliest stage of rosacea is characterized by facial erythema, often primarily 
on the nose and cheeks, recurrent episodes of flushing, and telangiectasia.  The erythema is 
usually worsened by exposure to sun or heat, or ingestion of trigger foods or beverages.  
Inflammatory lesions develop in the areas of erythema and appear similar to the inflammatory 
lesions of acne vulgaris, but present without comedones.  The diagnosis of rosacea is based on 
the presence of one or more of the following:  flushing, nontransient erythema, 
papules/pustules, or telangiectasia. 
Topical azelaic acid is used to treat inflammatory papules and pustules of mild to moderate 
rosacea.  Other topical therapies and oral antibiotics are also used to treat rosacea symptoms.  
FINACEA® (azelaic acid) FOAM, 15% contains azelaic acid, a naturally occurring saturated 
dicarboxylic acid that has proven anti-inflammatory effects, as well as anti-keratinizing and 
antimicrobial action, although its mechanism of action in rosacea is not well understood.  This 
study will be conducted in compliance with the protocol, Good Clinical Practices (GCP) and 
the applicable regulatory requirement(s).  Marketed by Bayer HealthCare, Finacea® (azelaic 
acid) Foam, 15% is a safe and effective topical therapy used for the treatment of moderate 
facial rosacea.  Actavis Laboratories UT has developed a generic formulation of azelaic acid 
15% foam and the current study is designed to evaluate the safety and efficacy of this 
formulation.  
10 STUDY OBJECTIVES 
The objectives of this study are to evaluate the therapeutic equivalence and safety of a generic 
Azelaic Acid Foam, 15% and Finacea® (Azelaic acid) Foam, 15% in the treatment of moderate 
facial rosacea, and to demonstrate superiority of the efficacy of the two active foams over the 
vehicle control. 
11 INVESTIGATIONAL AND ANALYSIS PLAN 
11.1 
Overall Study Design 
This is a randomized, vehicle-controlled, parallel-group, multicenter, double-blind study of a 
generic Azelaic Acid Foam, 15% and the reference listed Finacea® (Azelaic acid) Foam, 15% 
in patients with moderate facial rosacea. 
11.2 
Study Overview 
Up to 1010 patients will be enrolled in the study to randomize 924 patients to obtain at least 
840 mITT  patients in a 1:1:1 ratio (280:280:280 patients, respectively) to each treatment group 
and 672 (224:224:224) evaluable subjects in PP population.  Patients will be assigned in a 1:1:1 
ratio to treatment with the test product, Azelaic Acid Foam, 15% (Actavis Laboratories UT), 


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the reference product, Finacea® (Azelaic acid) Foam, 15% (Bayer HealthCare) or the vehicle 
control (Actavis Laboratories UT) in this multicenter, double-blind, randomized, vehicle-
controlled, parallel-group study.   
The assigned Investigational Product will be self-applied topically to the entire facial area 
(cheeks, chin, forehead, and nose) twice daily for 84 consecutive days.  The Investigational 
Product should be gently massaged into the affected areas on the face twice daily, in the 
morning and evening after the patient’s face has been washed with a mild cleanser and patted 
dry with a soft towel.  Patients will be required to use diaries to document study treatments, 
any missed treatments and the occurrence of all adverse events. 
The duration of each patient’s participation in the study will be 84 days.  Scheduled study visits 
will include: Visit 1 (Baseline Visit, Day 0), Visit 2 (Day 28±4 days), Visit 3 (Day 56±4 days) 
and Visit 4 (End of Treatment, Day 84±4 days).  A window ± 4 days will be considered 
acceptable for each scheduled visit following the baseline visit. 
If the Principal Investigator determines that the patient’s condition has worsened to the degree 
that it is unsafe for the patient to continue in the study, the patient may be discontinued from 
the study as a treatment failure and the patient may be treated using the standard care.  
An Unscheduled Visit is allowed at any time, for any reason, if in the Principal Investigator’s 
opinion it is warranted.  If a patient is discontinued from the study during an Unscheduled 
Visit, the Unscheduled Visit will be referred to as an Early Discontinuation Visit and all 
procedures scheduled for Visit 4 will be performed.  If the Unscheduled Visit is not an Early 
Discontinuation Visit (i.e., the patient will continue to take part in the study), then the activities 
performed will depend on the reason for the unscheduled visit and will be left to the discretion 
of the Investigator.  The Investigator should perform any activities necessary to appropriately 
evaluate the patient at this Unscheduled Visit.  If the Unscheduled Visit is due to an AE, the 
Investigator will determine whether additional visits are needed. 
At Visit 1, an informed consent will be obtained from the potential study patient before any 
study procedures take place.  After the patient has been consented, the patient’s medical history 
will then be documented, including the patient’s concomitant medications.  A urine pregnancy 
test will be performed for all female patients of child-bearing potential.  A baseline facial 
rosacea grade will be assigned to the patient using the Investigator’s Global Evaluation (IGE) 
and a baseline lesion count will be performed.  The patient will undergo a physical 
examination, including the recording of vital signs.  The patient will be evaluated for signs 
and/or symptoms of erythema and telangiectasia.  The patient will be reviewed against the 
inclusion/exclusion criteria.  Blinded Investigational Product will be dispensed to patients who 
meet all of the inclusion and exclusion criteria.  Patients will be instructed on the application 
of Investigational Product and completion of patient diaries. 
Patients will return to the study site for Visit 2, Visit 3 and Visit 4.  The patient’s concomitant 
medications will be reviewed and documented.  A urine pregnancy test will be performed for 
female patients of child-bearing potential.  The patient’s facial rosacea will be assessed using 
the IGE, the patient’s lesions will be counted and all results will be documented.  The signs 
and/or symptoms of local irritation will be evaluated for the patient and any other adverse 
events will be documented.  The patient will bring their used Investigational Product and their 
study diaries to each study visit after the baseline visit.  Compliance with drug applications 
will be assessed at each visit after the baseline visit.  New can(s) of Investigational Product 


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will be dispensed during Visit 2 and Visit 3.  In addition, all Investigational Product and diaries 
will be collected from the patient during each scheduled visit or the Early Discontinuation 
Visit. 
11.3 
Study Population 
11.3.1 Number of patients 
This multicenter study will be comprised of patients presenting with a clinical diagnosis of 
moderate facial rosacea and who meet all of the inclusion, and none of the exclusion, criteria.  
Up to 1010 patients will be enrolled in the study to randomize 924 patients to obtain at least 
840 mITT patients in a 1:1:1 ratio (280:280:280 patients, respectively) to each treatment group 
and 672 (224:224:224) evaluable subjects in PP population.   
11.3.2 Inclusion Criteria 
Each patient must meet all of the following criteria: 
1. Patient must be willing and able to provide written informed consent for the study. 
2. Healthy male or non-pregnant female ≥18 years-of-age with a clinical diagnosis of 
moderate facial rosacea.  
3. Patient must have at least eight and not more than fifty inflammatory facial lesions (i.e., 
papules/pustules) and ≤2 nodules on the face.  For the purposes of study treatment and 
evaluation, these lesions should be limited to the facial treatment area including those 
present on the nose.  Lesions involving the eyes, and scalp should be excluded from the 
count. 
4. Patients must have persistent erythema on the face with moderate (3) score as per the table 
below: 
Score 
Grade 
Definition  
0 
None 
No redness present. 
1 
Very Mild 
Slight pinkness. 
2 
Mild 
Pink to light red. 
3 
Moderate 
Definite redness, easily recognized. 
4 
Severe 
Marked erythema; fiery red. 
 
5. Patients must have a mild (1) to moderate (2) score for telangiectasia on the face as per the 
table below: 
Score 
Grade 
Definition  
0 
Clear 
No telangiectasia. 
1 
Mild 
Only few fine vessels discernible, involves 10% or less of 
the facial area. 
2 
Moderate 
Multiple fine vessels and/or few large vessels discernible, 
involves > 10% - 30% of the facial area. 
3 
Severe 
Many fine vessels and/or large vessels discernable, involves 
> 30% of the facial area. 
 


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6. Patients must have a definite clinical diagnosis of moderate facial rosacea (severity score 
3) as per the IGE as per table below: 
Score 
Grade 
Definition  
0 
Clear 
No inflammatory lesions present; at most, mild erythema.  
1 
Almost Clear 
Very mild erythema present.  Very few small 
papules/pustules.  
2 
Mild 
Mild erythema. Several small papules/pustules.  
3 
Moderate 
Moderate erythema.  Several small or large 
papules/pustules, and up to 2 nodules.  
4 
Severe 
Severe erythema.  Numerous small and/or large 
papules/pustules, up to several nodules.  
 
7. Patient must be willing to minimize external factors that might trigger rosacea flare-ups 
(e.g., spicy foods, thermally hot foods and drinks, hot environments, prolonged sun 
exposure, strong winds and alcoholic beverages) during the course of the study.  
8. Patient must be in general good health and free from any clinically significant disease other 
than rosacea on the face, that might interfere with the study evaluations.  
9. Patient must be willing and able to understand and comply with the requirements of the 
study, apply the medication as instructed, return for the required treatment period visits, 
comply with therapy prohibitions, and be able to complete the study.  
10. Male patients and female patients of childbearing potential must use accepted methods of 
birth control or must agree to practice abstinence, from study start to 30 days after the last 
administration of study drug. All female patients are considered to be of childbearing 
potential unless they have been surgically sterilized (hysterectomy, bilateral 
oophorectomy, or tubal ligation) or have been postmenopausal for at least a year. Any of 
the following methods of birth control are acceptable: oral contraceptives, contraceptive 
patches/implants (e.g., Norplant®), vaginal ring (NuvaRing®), Depo-Provera® (Medroxy 
progesterone acetate), double barrier methods (e.g., condom and spermicide), Essure or 
IUD. 
11. Female patients of child bearing potential must have a negative urine pregnancy test at 
baseline. 
12. Patients 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.  
11.3.3 Exclusion Criteria 
Patients may not be enrolled if any of the following criteria exist: 
1. Pregnant or 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.  
3. Excessive facial hair (e.g. beards, sideburns, moustaches, etc.) that would interfere with 
diagnosis or assessment of rosacea.  


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4. History of hypersensitivity or allergy to Azelaic acid, propylene glycol or any other 
component of the formulation.  
5. The use within 6 months prior to baseline of oral retinoids (e.g. Accutane®) or therapeutic 
vitamin A supplements of greater than 10,000 units/day (multivitamins are allowed).  
6. The use of estrogens or oral contraceptives for less than 3 months prior to baseline. 
7. The use within 1 month prior to baseline of: 
a) topical retinoids to the face; 
b) systemic antibiotics known to have an impact on the severity of facial rosacea (e.g., 
containing tetracycline and its derivatives, erythromycin and its derivatives, 
sulfamethoxazole, or trimethoprim);  
c) systemic corticosteroids  
8. Use within 2 weeks prior to baseline of: 
a. topical corticosteroids; 
b. topical antibiotics; 
c. topical medications for rosacea (e.g., metronidazole, azelaic acid).  
9. Antipruritics, including antihistamines, within 24 hours of any study visit. 
 
10. Patients with moderate or severe rhinophyma, dense telangiectasia (score 3, severe), or 
plaque-like facial edema.  
 
11. Patients with a severe irritation grade for erythema, dryness, scaling, pruritus, 
stinging/burning, and edema. 
12. Ocular rosacea (e.g., conjunctivitis, blepharitis, or keratitis) of sufficient severity to require 
topical or systemic antibiotics.  
13. A patient who has used a sauna during the 2 weeks prior to study entry and during the 
study.  
14. Patients who have performed wax epilation of the face within 14 days prior to baseline  
15. A patient who has a history of being unresponsive to topical Azelaic acid therapy. 
16. A patient with bacterial folliculitis. 
17. A patient who consumes excessive alcohol, abuses licit or illicit drugs, or has a condition 
that could compromise the patient’s ability to comply with study requirements. 
18. Patients who engage in activities that involve excessive or prolonged exposure to sunlight 
or weather extremes, such as wind or cold. 
19. A patient who has 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. 
20. A patient who has used any topical Azelaic acid therapy within 30 days of baseline visit. 
21. Patients who have participated in an investigational drug study (i.e., patients have been 
treated with an Investigational Drug) within 30 days prior to baseline will be excluded from 
study participation.  Patients who are participating in non-treatment studies such as 


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observational studies or registry studies can be considered for inclusion. 
22. Patients who have been previously randomized in this study. 
23. Patients who have had laser therapy (for telangiectasia or other conditions), 
electrodessication and phototherapy (e.g., ClearLight®) to the facial area within 180 days 
prior to study entry. 
24. Patients who have had cosmetic procedures (e.g., facials) which may affect the efficacy 
and safety profile of the Investigational Product within 14 days prior to study entry. 
25. Employees or staff of the research site are excluded from participation in the study.  
26. No more than one (1) person from the same household can participate in the study. 
11.3.4 Patient Discontinuation Criteria 
Investigators are urged to enroll only those eligible patients who are likely to complete the 
entire study and who are willing to comply with the protocol-specified procedures.  It is the 
right and duty of the investigator to interrupt the treatment of any patient whose safety and 
well-being are determined to be at risk, or who may be experiencing unmanageable factors 
that may interfere with the study procedures and/or the interpretation of study results.  Such 
patients should be withdrawn from the study rather than continued under a modified regimen. 
Discontinuation is permanent; once a patient is discontinued, he/she shall not be allowed to 
enroll again. 
A patient may be discontinued from the study for any of the following reasons: 
1. Patient decision/withdrawal of consent; 
2. Adverse event, including intercurrent illness, which required study discontinuation; 
3. If the patient’s condition has worsened to the degree that the Principal Investigator feels 
it is unsafe for the patient to continue in the study; 
4. If the patient’s drug code is unblinded; 
5. Insufficient therapeutic response (after at least 8 weeks of compliant treatment); 
6. If a patient misses more than 6 consecutive doses;  
7. If the subject misses more than 1 required visit; 
8. Significant protocol violation; 
9. If the patient is lost to follow-up; 
10. If the patient becomes pregnant; 
11. If the patient becomes a prisoner or becomes involuntarily incarcerated; 
12. Any other reason that may affect the outcome of the study or the safety of patients; or 
13. Termination of the study by the Sponsor. 
A patient that discontinues from the study will not be replaced. 
A significant protocol violation is defined as any patient or Investigator activity that could 
have possibly interfered with the therapeutic administration of the treatment or the precise 
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The reasons for a patient discontinuation will be documented.  If a patient is discontinued 
from the study for any reason, the procedures scheduled for Visit 4 will be completed and any 
outstanding data and study drug should be collected, if possible.  Information, in addition to 
the reason for discontinuation and the date of removal, will be documented on the Electronic 
Case Report Form (eCRF). 
Before a patient is considered to be lost to follow-up, the Principal Investigator will attempt 
to reach the patient twice by telephone and will send a certified follow-up letter and document 
all these activities. In the event that a patient discontinues from the study at any time due to 
an adverse event, the reason for discontinuation, the nature of the event and its clinical course 
must be fully documented.  For such a patient, the Principal Investigator must strive to follow 
the patient until the adverse event has resolved, becomes clinically insignificant, is stabilized 
or the patient is lost to follow-up.  Should a serious adverse event be noted, procedures stated 
in Section 10.9.5 must be followed. 
11.3.5 Prohibited Medications / Treatments 
The following are prohibited during this study.  If any of the following prohibited activities 
occur during the course of the study, the Investigator must consult with the Sponsor and 
determine if the patient should be disqualified from further study participation. 
1. Any other topical products applied to the target site (e.g., metronidazole, topical antibiotics, 
topical steroids); Patients are allowed to use other topical treatments on other areas of the 
body. 
2. Oral retinoids; 
3. Systemic (e.g., oral or injectable) antibiotics known to have an impact on the severity of 
facial rosacea (e.g., containing tetracycline, erythromycin, sulfamethoxazole, or 
trimethoprim or their derivatives);  
4. Systemic 
corticosteroid 
(including 
intranasal 
or 
inhaled 
corticosteroids) 
or 
immunosuppressive drugs; 
5. Antipruritics, including antihistamines, within 24 hours of study visits;  
6. The use of any treatment for rosacea, other than the assigned study treatment; 
7. The application of new cosmetics or new cleansers to the face is prohibited during this 
study, other than the cleanser, moisturizer, and sunscreen provided by the Sponsor. Patients 
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 not change make-up brand/type or 
frequency of use throughout the study; 
8. The application of alcohol based toners, astringents, medicated topical preparations 
(prescription and OTC products) or medicated make-up to the face; 
9. The use of abrasive cleansers or washes (e.g., exfoliating facial scrubs) on the face; 
10. The use of adhesive cleansing strips (e.g., Bioré® Pore Strips) on the face; 
11. The use of anti-inflammatory medications (e.g., NSAIDs) and vitamins in quantities above 
the recommended daily dose (e.g., Vitamin A above about 10,000 IU; NSAID use allowed 


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on as needed basis for conditions such as headache, menstrual cramps, and minor injuries; 
Low dose aspirin is also allowed);  
12. Patients may use acetaminophen for pain relief, as needed, while taking part in this study;  
13. Cosmetic procedures (e.g., facials) which can affect the efficacy and safety profile; 
14. Patients are prohibited from use of saunas or PUVA therapy while participating in the 
study; 
15. Use of tanning booths, sunbathing, or excessive exposure to the sun; 
16. Wax epilation should not be performed on skin treated with the Investigational Product. 
11.3.6 Precautions 
The following precautions are to be taken during this study: 
1. 
Patients should avoid any foods or beverages that provoke erythema, flushing/blushing 
(e.g., spicy foods, alcoholic beverages, and thermally hot drinks, including hot coffee and 
tea); 
2. 
Patients should avoid contact of the study medication with the mouth, eyes, and other 
mucous membranes; The hands should be washed following application; 
3. 
Patients should limit all sun exposure to the extent possible; Patients should use sunscreen 
when outdoors and avoid tanning beds; 
4. 
To minimize exposure to sunlight, a wide-brimmed hat or other protective clothing should 
be worn;  
5. 
The non-comedogenic sunscreen with a SPF 15 rating or higher provided by the Sponsor 
may be used;  
6. 
Patients should avoid exposure to weather extremes including strong wind or cold; 
7. 
Patients should not apply any moisturizers (other than the provided moisturizer), new 
brands of make-up, creams, lotions, powders or any topical product other than the study 
medication to the treatment area; 
8. 
Cosmetics should be applied only after the application of IP has dried; 
9. 
Occlusive dressings or wrappings should be avoided in treatment areas;  
10. Patients must not wear make-up to any study visits to avoid interference with the 
evaluations; 
11. The Investigational Product should not be applied to cuts, abrasions or eczematous skin; 
12. Patients should report abnormal changes in skin color to the Principal Investigator. 
If a reaction suggesting sensitivity or chemical irritation occurs, the Principal Investigator 
should assess the patient’s condition as soon as possible (i.e., during an Unscheduled Visit) 
and determine whether treatment should be discontinued.  If the patient is discontinued from 
the study during an Unscheduled Visit, procedures from Visit 4 should be followed and the 
visit will be referred to as an Early Discontinuation Visit. 


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There have been isolated reports of hypopigmentation after use of Azelaic acid.  Since Azelaic 
acid has not been well studied in patients with dark complexion, these patients should be 
monitored for early signs of hypopigmentation.  
11.4 
Study Schedule 
This study will require 4 “scheduled” patient visits: 
Visit 1: Baseline Visit (Day 0);  
Visit 2: Day 28 ± 4 Days;  
Visit 3: Day 56 ± 4 Days;  
Visit 4: End of Treatment (Day 84 ± 4 Days). 
11.5 
Assessment of Safety and Tolerability 
11.5.1 Physical Examination 
A physical examination including heart, lung and abdomen evaluation as well as height, 
weight, and vital signs will be performed. 
Vital signs are to include sitting blood pressure, oral temperature, heart rate and respiratory 
rate.  Vital signs will be measured after the patient has rested in a seated position for at least 
5 minutes. 
11.5.2 Urine Pregnancy Test 
All female patients of child-bearing potential will undergo a urine pregnancy test during 
Visit 1 and at each subsequent study visit.   
All female patients of childbearing potential must use accepted methods of birth control or 
must agree to practice abstinence, from study start to 30 days after the last administration of 
study drug. All female patients are considered to be of childbearing potential unless they have 
been surgically sterilized (hysterectomy, bilateral oophorectomy, or tubal ligation) or have 
been postmenopausal for at least a year. Any of the following methods of birth control are 
acceptable: oral contraceptives, contraceptive patches/implants (e.g., Norplant®), vaginal 
ring (NuvaRing®), Depo-Provera® (Medroxy progesterone acetate), double barrier methods 
(e.g., condom and spermicide), Essure or IUD. 
11.5.3 Medical History 
A complete medical history will be obtained for the patient’s current and past medical 
conditions.  Significant medical history should include, but not be limited to, evidence of 
hypertension, lipid disorders, obesity, heart attack, stroke, congestive heart failure, kidney 
disease, auto immune disease and gestational diabetes.  Significant surgical history should 
include, but not be limited to, removal of blockage from an artery and gallbladder removal. 
11.5.4 Record Concomitant Medications 
Concomitant medications, including the use of sunscreen and the moisturizer, in addition to 
the reason for the medication use, will be assessed at baseline and at each subsequent study 
visit.  The start and stop date of concomitant medication use during the study should be 
provided in the data set in addition to the reason for the medication use. 
A record of concomitant medications taken by the patient is to be obtained using generic 
name, if known, with the corresponding indication.  The medications to be recorded will 


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include prescription and over-the-counter (OTC) medications and dietary supplements.  All 
medications taken on a regular basis, including aspirin and acetaminophen, should be 
recorded. 
11.5.5 Telangiectasia Assessment 
The severity of telangiectasia is to be rated at baseline as follows.  Patients must have a mild 
(1) to moderate (2) score for telangiectasia on the face at the baseline visit to be enrolled in 
the study.  Patients with severe (3) score for telangiectasia will not be enrolled in the study.  
Talangiectasia: 
 
11.5.6 Irritation/Application Site Reactions 
The severity of Irritation/Application site reactions such as erythema, dryness, scaling, 
pruritus, stinging/burning, and edema will be rated at each visit to allow a comparison between 
treatment groups.  These are some of the expected application site reactions. 
Patients with a severe irritation grade at baseline will not be enrolled in the study.  
After baseline, increase in irritation will be reported as an adverse event. 
Erythema:  
Score 
Grade 
Definition  
0 
None 
No redness present. 
1 
Very Mild 
Slight pinkness. 
2 
Mild 
Pink to light red. 
3 
Moderate 
Definite redness, easily recognized. 
4 
Severe 
Marked erythema; fiery red. 
Dryness:   
Score 
Grade 
Definition  
0 
None 
No dryness. 
1 
Mild 
Slight but definite dryness. 
2 
Moderate 
Moderate dryness. 
3 
Severe 
Marked dryness. 
Score 
Grade 
Description 
0 
None 
No telangiectasia 
1 
Mild 
Only few fine vessels discernible, involves 10% or less of the facial 
area. 
2 
Moderate Multiple fine vessels and/or few large vessels discernible, involves 
> 10% - 30% of the facial area. 
3 
Severe 
Many fine vessels and/or large vessels discernable, involves > 30% 
of the facial area. 


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Scaling:  
Score 
Grade 
Definition  
0 
None 
No scaling. 
1 
Mild 
Barely perceptible shedding, noticeable only on light scratching 
or rubbing. 
2 
Moderate 
Obvious but not profuse scaling. 
3 
Severe 
Heavy scale production. 
Pruritus:  
Score 
Grade 
Definition  
0 
None 
No itching. 
1 
Mild 
Slight itching but not bothersome. 
2 
Moderate 
Definite itching, somewhat bothersome without loss of sleep. 
3 
Severe 
Intense itching that has caused pronounced discomfort; 
interrupted sleep and excoriation of the skin may be present. 
Stinging/Burning:  
Score 
Grade 
Definition  
0 
None 
No stinging/burning. 
1 
Mild 
Slight warm stinging/burning sensation but not bothersome. 
2 
Moderate 
Definite warm stinging/burning sensation somewhat 
bothersome. 
3 
Severe 
Hot stinging/burning sensation that has caused definite 
discomfort. 
Edema:  
Score 
Grade 
Definition  
0 
None 
No swelling. 
1 
Mild 
Slightly or barely perceptible swelling. 
2 
Moderate 
Distinct presence of swelling. 
3 
Severe 
Marked or intense swelling. 
 
Local irritation reactions in the treatment area are common and the Investigator may instruct 
patients to stop the application of treatment (“rest period”) to reduce patient discomfort and 
to allow local skin reactions to subside based upon the Investigator’s clinical assessment.  
Treatment should resume as soon as the reaction subsides sufficiently to allow reapplication.  
If significant discomfort continues, or if the patient cannot return to daily applications after 
missing more than six consecutive doses the patient should be discontinued from the study.  
Multiple rest periods during the study are allowed, but they should only be used when 
absolutely necessary based upon the patient’s tolerability needs as determined by the 
Investigator.  The patient should not modify or resume the treatment regimen without 
consultation with the Investigator.  The Investigator may make this decision based upon a 


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documented phone consultation or at an unscheduled visit.  All dose modifications will be 
captured in the source documents. 
The treatment period should not be extended beyond 12 weeks due to missed doses or rest 
periods.  Patients whose condition worsens or lesions that do not respond to treatment should 
be re-evaluated by the Investigator and treatment management reconsidered.  
11.5.7  Adverse Events  
An adverse event is defined as any untoward medical occurrence (sign, symptom or laboratory 
finding) regardless of severity and whether or not attributed to the Investigational Product.  All 
adverse events, whether observed by an Investigator or Study Coordinator or reported by the 
patient, whether related to study drug or not related to study drug, shall be documented in the 
eCRF and patient records.  Details such as date of onset, the duration and intensity of each 
episode, the action taken, the relationship to the Investigational Product, and the degree of 
severity, the seriousness, and the outcome should be recorded. 
11.6 
Clinical Assessments 
An examination of the patient’s face 
 will be performed at baseline and at each subsequent visit.  During the dermatologic 
examination, evaluations to determine efficacy of treatment will be conducted, including lesion 
counts and grading of the patient’s facial rosacea using the criteria outlined in the IGE.  
Whenever possible, a single Investigator (i.e., Principal Investigator or Sub-Investigator) will 
perform evaluations of efficacy (i.e., lesion counts and IGE) for each patient at each visit from 
the beginning to the end of the patient’s participation to maintain consistency.  However, up to 
two Investigators may perform evaluations of efficacy for a single patient if necessary.  All 
Investigators who will perform evaluations of efficacy must attend study-specific training for 
the conduct of these evaluations (i.e., lesion counts and IGE). 
11.6.1 Inflammatory Lesion Count 
All facial papules, pustules and nodules, located above the jaw line and extending to the 
hairline, are to be counted at Visit 1/Baseline and at each subsequent visit.  When counting 
facial lesions, it is important that all lesions be counted, including those present on the nose.  
The total count for each lesion type is to be recorded and the total number of inflammatory 
lesions (papules and pustules) will be calculated.  A papule with a pustule on its apex will be 
counted as a pustule. 
A patient must have at least eight and not more than fifty inflammatory facial lesions (i.e., 
papules/pustules) and ≤2 nodules on the face to be eligible for the study.  Counts of nodules 
and cysts will be reported separately and not included in the inflammatory counts. 


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Inflammatory lesion types: 
Lesion Name 
Lesion Definition 
Papule 
Inflammatory lesion; small (≤ 5mm in diameter), solid palpable 
lesion, usually with inflamed elevation of the skin that does not 
contain pus.  
Pustule 
Inflammatory lesion; small (≤ 5mm in diameter), inflamed skin 
swelling that is filled with pus.  
Nodule 
Large (>5 mm in diameter), hard bumps under the skin's surface. 
 
For optimal visualization, the Investigator, or other qualified lesion counter, should use the 
same light source, either fluorescent or natural light, in approximately the same position during 
each count.  To avoid counting sub-clinical lesions, the skin should not be stretched and 
magnification should not be used during this assessment. 
11.6.2 Investigator’s Global Evaluation (IGE) 
For each patient at each visit, the Investigator will make an independent clinical evaluation of 
the patient’s rosacea severity.  For study enrollment, the patient must have an IGE rosacea 
severity score of 3 at Visit 1/Baseline. 
IGE: 
Score 
Grade 
Definition  
0 
Clear 
No inflammatory lesions present; at most, mild erythema.  
1 
Almost Clear 
Very mild erythema present.  Very few small 
papules/pustules.  
2 
Mild 
Mild erythema. Several small papules/pustules.  
3 
Moderate 
Moderate erythema.  Several small or large 
papules/pustules, and up to 2 nodules.  
4 
Severe 
Severe erythema.  Numerous small and/or large 
papules/pustules, up to several nodules.  
 
11.7 
Study Procedures 
A study flow chart can be found in Appendix I, outlining visit procedures. 
11.7.1 Visit 1/Baseline/Day 0 
The prospective patients will visit the study center and be examined by the study physician.  If the 
patient is screened and not randomized to study drug on the same day (e.g. due to the required 
washout of a prohibited medication), the Visit 1/Day 0 procedures should be re-confirmed on the 
day the patient returns prior to being randomized to study medication.  The following procedures 
will be performed at the Baseline Visit: 
1. The study personnel will review the ICF with each patient and give the patient an 
opportunity to have all questions answered before proceeding.  A copy of the signed 
consent will be given to every patient and the original will be maintained with the patient’s 
records. 


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2. A medical history and demographic information will be obtained by the Investigator or 
qualified designee prior to starting study medication.  The medical history will include a 
complete review of all past and current diseases and their respective durations and 
treatments. It will also include the date of original onset of rosacea 
3. A record of prior medications taken by the patient within at least the last 6 months of 
signing the Informed Consent is to be obtained using generic name, if known, with the 
corresponding indication.  The medications to be recorded will include prescription and 
over-the-counter (OTC) medications and dietary supplements.  All medications taken on a 
regular basis, including aspirin and acetaminophen, should be recorded. 
4. A physical examination including heart, lung and abdomen evaluation as well as height, 
weight, and vital signs will be performed.  Vital signs are to include sitting blood pressure, 
oral temperature, heart rate and respiratory rate. 
5. A urine pregnancy test will be conducted for all females of child-bearing potential.  
6. All facial papules, pustules and nodules, located above the jaw line and extending to the 
hairline, will be counted (see Section 10.6.1). 
7. The overall status of the patient’s facial rosacea will be assessed using the IGE (see Section 
10.6.2). 
8. Telangiectasia assessment will be performed (see Section 10.5.5). 
9. Patients will be evaluated for any signs and/or symptoms of facial irritation (see Section 
10.5.6). 
10. When the patient has completed all screening procedures, compliance with the inclusion 
and exclusion criteria will be reviewed.  After the inclusion and exclusion criteria have 
been confirmed, the patient will be randomized to a treatment group.  The patient will be 
assigned a randomization number (see Section 10.8.3). 
11. The following will be dispensed during Visit 1:  
• One can of the Investigational Product 
• A diary card to record product use from Visit 1 to Visit 2 
• One bottle of cleanser 
• One bottle of sunscreen 
• One bottle of moisturizing lotion 
• One pack of towels 
Depending upon the severity of facial irritation and to prevent the side effects, the 
Investigator may instruct the patient to use a non-medicated moisturizer.  
12. Randomized patients will be instructed on the correct method for the application of the 
Investigational Product.  Investigational Product will not be applied during the patient’s 
clinic visit and must be applied at home.  The Investigational Product can be applied the 
night of Visit 1 or the day following Visit 1.  The Investigational product must not be 
opened at the clinic. The day the patient begins dosing will be captured as Day 1. 
13. The study restrictions will be reviewed with the patient.  


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14. Randomized patients will be provided with a diary and instructed on how and when to 
complete the diary.  They will be told that they are to document all treatments administered, 
and all treatments missed.  In addition, patients will be instructed to document all AEs.  
Patients will also be instructed to call the study site if they experience any severe 
intolerability (i.e., local skin reactions) to Investigational Product. 
15. Visit 2 (Day 28 ± 4 days) will be scheduled and the patient will be instructed to bring all 
Investigational Product (used, unused and partially used) and the patient diary with him or 
her to this visit. 
11.7.2 Visit 2/ (Day 28±4 days) 
The following procedures will be performed at Visit 2: 
1. A urine pregnancy test will be conducted for all females of child-bearing potential.  
2. All facial papules, pustules and nodules, located above the jaw line and extending to the 
hairline will be counted (see Section 10.6.1). 
3. The overall status of the patient’s facial rosacea will be assessed using the IGE (see Section 
10.6.2). 
4. Patients will be evaluated for any signs and/or symptoms of facial irritation (see Section 
10.5.6). 
5. The occurrence of all AEs will be assessed and documented following procedures in 
Section 10.9. 
6. The use of concomitant medications since the previous study visit will be documented for 
each patient.  The use of moisturizer, including the type and how often it has been used, 
will also be documented. (see Section 10.5.4). 
7. The patient’s compliance with the study protocol, including use and application of 
Investigational Product, will be assessed.  The patient’s diary will be collected and 
reviewed for completion.    
8. Study drug compliance will be performed and the patient’s used Investigational Product 
will be returned to the site. 
9. The following will be dispensed during Visit 2:  
• One can of the Investigational Product 
• Diary will be returned to patient  
Depending upon the severity of the side effects, the Investigator may instruct the patient to use 
a non-medicated moisturizer.  Additional supplies will be dispensed if required. 
10. Study instructions will be reviewed with the patient, including the procedure for application 
of the Investigational Product.  
11. Visit 3 (Day 56 ± 4 days) will be scheduled and the patient will be instructed to bring all 
Investigational Product (used, unused and partially used) and the patient diary with him or 
her to this visit. 


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11.7.3 Visit 3/ (Day 56±4 days) 
The following procedures will be performed at Visit 3: 
1. A urine pregnancy test will be conducted for all females of child-bearing potential. 
2. All facial papules, pustules and nodules, located above the jaw line and extending to the 
hairline will be counted (see Section 10.6.1). 
3. The overall status of the patient’s facial rosacea will be assessed using the IGE (see Section 
10.6.2). 
4. Patients will be evaluated for any signs and/or symptoms of facial irritation (see Section 
10.5.6) 
5. The occurrence of all AEs will be assessed and documented following procedures in 
Section 10.9. 
6. The use of concomitant medications since the previous study visit will be documented for 
each patient.  The use of moisturizer, including the type and how often it was used, will 
also be documented. (See Section 10.5.4). 
7. The patient’s compliance with the study protocol, including use and application of 
Investigational Product, will be assessed.  The patient’s diary will be collected and 
reviewed for completion.    
8. Study drug compliance will be performed and the patient’s used Investigational Product 
will be returned to the site. 
9. The following will be dispensed during Visit 3:  
• One can of the Investigational Product 
• Diary will be returned to patient 
Depending upon the severity of the side effects, the Investigator may instruct the patient to 
use a non-medicated moisturizer.  Additional supplies will be dispensed, if required. 
10. Study instructions will be reviewed with the patient, including the procedure for application 
of the Investigational Product.  
11. Visit 4 (Day 84 ± 4) will be scheduled and the patient will be instructed to bring all 
Investigational Product (used, unused and partially used) and the patient diary with him or 
her to this visit. 
11.7.4 Visit 4/ (Day 84±4 days) /End of Treatment/ Early Discontinuation 
The following procedures will be performed at Visit 4: 
1. A urine pregnancy test will be conducted for all females of child-bearing potential.  
2. All facial papules, pustules and nodules, located above the jaw line and extending to the 
hairline, will be counted (see Section 10.6.1). 
3. The overall status of the patient’s facial rosacea will be assessed using the IGE (see Section 
10.6.2). 


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4. Patients will be evaluated for any signs and/or symptoms of facial irritation (see Section 
10.5.6). 
5. The occurrence of all AEs will be assessed and documented following procedures in 
Section 10.9. 
6. The use of concomitant medications since the previous study visit will be documented for 
each patient.  The use of moisturizer, including the type and how often it was used, will 
also be documented. (see Section 10.5.4). 
7. The patient’s compliance with the study protocol, including use and application of 
Investigational Product, will be assessed.  The patient’s diary will be collected and 
reviewed for completion.  
8. Study drug compliance will be performed and the patient’s used Investigational Product 
will be returned to the site. 
11.7.5 Unscheduled Visit 
An Unscheduled Visit is allowed at any time, for any reason, if, in the Principal Investigator’s 
opinion, it is warranted.  
If a patient is discontinued from the study during an Unscheduled Visit, the Unscheduled Visit 
will be referred to as an Early Discontinuation Visit and all procedures scheduled for Visit 4 
will be performed.  If the Unscheduled Visit is not an Early Discontinuation Visit (i.e., the 
patient will continue to take part in the study), then the activities performed will depend on the 
reason for the unscheduled visit and will be left to the discretion of the Investigator. 
The Investigator should perform any activities necessary to appropriately evaluate the patient.  
If the Unscheduled Visit is due to an AE, the Principal Investigator will determine whether 
additional visits are needed. 
If the patient’s condition has worsened to the degree that it is unsafe for the patient to continue 
in the study, the patient may be discontinued from the study as treatment failure and a standard 
of care treatment may be advised at the Principal Investigator’s discretion. 
11.8 
Investigational Product 
The Investigator will take responsibility for, and will take all steps, to maintain appropriate 
records and ensure appropriate supply, handling, storage, distribution, and usage of study 
materials in accordance with the protocol and any applicable laws and regulations. IMP will 
be handled by an independent dispenser at the site who will be unblinded with regard to 
treatment the subject is receiving.  
11.8.1 Dosage and Formulations 
Test Product:  
Azelaic Acid, 15% topical foam (Actavis Laboratories UT) 
Reference Product: 
Finacea® (azelaic acid) Foam, 15% (Bayer HealthCare) 
Vehicle: 
Foam Vehicle of the test product (Actavis Laboratories UT) 


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11.8.2 Dispensing and Application 
All study medication will be stored at controlled room temperature 68° - 77°F (20° - 25°C) 
with excursions permitted between 59° - 86°F (15° - 30°C), in a climate-controlled, limited 
access area. 
The Investigator agrees to store and dispense the study medication only at the site(s) listed on 
the Form FDA 1572 (or Investigator Agreement/Statement).  The Investigator agrees that the 
study medication will be dispensed by the Investigator or Sub-Investigator(s) named on the 
Form FDA 1572 (or Investigator Agreement/Statement), or their qualified designees.  The 
Investigator, Sub-Investigator(s), or qualified designees also agree that the study medication 
will be dispensed only to patients who have provided written informed consent, and have met 
all entry criteria.  Clinical supplies may not be used for any purpose other than as stated in the 
protocol. 
At baseline, and as needed during the study, Investigational Product will be dispensed to 
randomized patients along with a diary, which includes study instructions.  Dispensing will be 
done by an independent dispenser who is unblinded to the treatment the subject is receiving. 
The containers should not be opened by the patient at the study center.  Each patient will 
receive training, which details the proper application method of the Investigational Product 
and general study instructions. 
Areas to be treated should be washed with a mild cleanser before application and patted dry 
with the provided towel.  A thin layer of study treatment should be gently massaged into the  
entire facial area (cheeks, chin, forehead, and nose) twice daily, once in the morning after 
waking up and once in the evening before going to bed, for 12 weeks.  Contact with the mouth, 
eyes and other mucous membranes should be avoided.  The hands must be washed following 
application of study treatment. 
Patients will be instructed not to bathe, shower, wash or swim for at least 4 hours after the 
application of the Investigational Product.  
At each visit during the study, the Investigator or designee should review proper application 
of the Investigational Product. 
The Investigational Product is to be applied at home.  The Investigational product should not 
be opened at the clinic.   
11.8.3 Method of Treatment Assignment and Randomization 
After satisfying all of the inclusion/exclusion criteria, patient will be eligible to enter the study 
and be randomly allocated in a 1:1:1 ratio to Test, Reference or Vehicle treatment groups 
respectively.  Randomization will be performed according to a computer-generated, block 
randomization code, with 3 sequential patient numbers assigned to each block.  The 
randomization code will be generated by an independent third party.  A sealed copy of the 
randomization scheme will be provided to each study site and will be retained at the study site 
and should be available to FDA investigators at the time of site inspection to allow for 
verification of the treatment identity of each patient. 
Only one patient number will be assigned to each patient.  The patient will maintain the same 
patient number and treatment assignment throughout the study.   


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11.8.4 Blinding Study Medication 
A double-blind technique will be used.  The test, the reference product, and the vehicle will be 
identical in appearance and will be packaged identically so that treatment blind is maintained.  
Neither the patient nor the investigational staff (Sponsor, Investigator, and evaluators) will 
know which treatment the patient is receiving. 
The Investigator must not break the blind unless absolutely necessary, in order to provide 
medical treatment to a patient in an emergency, and only with prior authorization from the 
Sponsor or designee.  If the blind is broken for a patient, the patient will be discontinued from 
the study and the reason recorded. 
11.8.5 Unblinding Study Medication 
In the event of an emergency, the patient-specific treatment may be identified, however, every 
effort should be made to maintain the blind.  Each patient kit will be labeled with a 2-part label.  
In the blinded part of the label, included information will contain the compound name, strength 
and lot number.  To unblind, scratch-off the black portion of the label to reveal the treatment 
received. 
11.8.6 Method of Packaging, Labeling and Storage  
Study medications will be supplied in cans by the Sponsor.  Cans will be labeled and packaged 
so that neither the patient nor the Investigator can identify the treatment.   
The medication will be supplied to the sites in blocks. Each block will contain 3 patient kits 
(in a 1:1:1 randomization). Each patient kit includes a can; each patient kit will also have a 2-
part label on the outside. Each 2-part label will clearly disclose the protocol number, patient 
number, content statement, storage statement, caution statement, and sponsor's name and 
address.  The label will also contain the compound name, strength and lot number in the blinded 
panel.  The tear-off kit label will be attached to the source document.  
The Sponsor’s independent packaging and labeling facility will be responsible for labeling 
and assembly of investigational product, as well as, for shipment of clinical supplies to 
investigational sites.   
All study medication will be stored at controlled room temperature 68° - 77°F (20° - 25°C) 
with excursions permitted between 59° - 86°F (15° - 30°C), in a climate-controlled, limited 
access area. 
11.8.7 Replacement Cans 
In the event of loss/spillage, extra cans of medication may need to be dispensed. See IMP 
manual for details. 
Before dispensing the replacement can, the information will be recorded on the Study 
Medication Accountability Log.  
11.8.8 Study Medication Accountability 
Patients will be instructed to return all used, partially used and unused test articles at all 
protocol-specified visits for study medication inventory and assessment of patient compliance. 


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The dispensing and return of all study medication will be recorded on the Study Medication 
Accountability Log.  The patient number/initials, and the initials and date of the person 
dispensing and receiving the returned medication will be documented on this form.  
Each can will be weighed before dispensing to a subject and after collecting from the subject 
at each visit and the weights recorded in the source documents. 
Inventory records must be readily available for inspection by the study monitor and/or auditor, 
and open to government inspection at any time. 
11.8.9 Assessment of Compliance 
At all protocol-specified visits, the Investigator or qualified designee is to record whether 
treatment was applied according to protocol instructions in the preceding interval.   
Patients will apply the medication twice daily for 12 weeks.  Compliance will be determined 
from the diary cards, in which the patient will be instructed to record all applications.  The 
number of applications will be totaled by the study personnel and recorded on the eCRF.  
Patients who miss more than six (6) consecutive doses of medication during the treatment 
period will be considered non-compliant and will be excluded from PP population and 
discontinued from the study.  The used cans of study medication will be collected by the study 
site at appropriate visits or early termination.  Patients will be considered compliant if they 
apply at least 75% and not more than 125% of doses for the entire duration of the study.  
11.8.10Retention of Study Medication Samples 
Samples of study drug will be randomly selected for retention at the investigational site prior 
to dispensing to patients, in accordance with 21 CFR 320.38, 320.63 and the Guidance for 
Industry, “Handling and Retention of BA and BE Testing Samples”, regarding retention of 
study drug samples and 21 CFR 320.36 for requirements for maintenance of records of 
bioequivalence testing.  In addition, the Investigators should follow the procedures of 21 CFR 
58 and ICH E6, “Good Clinical Practice: Consolidated Guideline”, for retention of study 
records and data in order to conduct their studies in compliance with Good Laboratory 
Practices (GLP) and Good Clinical Practices (GCP).  Retention samples should not be returned 
to sponsor at any time. 
The retention samples will be shipped to a third party storage facility as instructed in the 
Investigational Product Manual. 
The samples can be retrieved from the storage facility at any time upon FDA notification of 
the visit or during a preapproval inspection conducted by authorized FDA personnel. The 
samples can be returned to the investigational site or submitted to the place identified in the 
agency's request.  
 
The request has to be sent directly to the BioRepository Resources by email or fax. The 
Sponsor (Actavis) and CRO (
) must be notified and copies of documentation should be 
sent to the individuals listed below:  
 
 
 


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Retention Samples Storage 
Facility: 
Sponsor:  
CRO: 
  
 
  
 
 
    
or faxing a copy at  
 
 
 
 
Actavis 
Morris Corporate Center III 
400 Interpace Parkway 
Parsippany, NJ 07054 
 
 
 
 
 
 
 
 
 
 
11.8.11Return of Clinical Supplies  
With the exception of the retention samples, at the completion of the study all used and unused 
cans of Investigational Product will be returned to Actavis’s Drug Labeling, Packaging and 
Shipping Facility. Instructions for returning IP will be provided in the IP Manual. 
11.8.12Additional Supplies Provided by the Sponsor 
Patients will be provided with a non-medicated cleanser to cleanse the face, paper towels to 
pat the face dry before applying the study medication, and sun screen for use after product 
application.  A non-medicated moisturizer will also be provided.  Depending upon the severity 
of the side effects, the Investigator may instruct the patient to use the non-medicated 
moisturizer; instructions for use will be provided.  
For the purpose of this study, the following will be provided by the Sponsor: 
• Cleanser 
• Sunscreen 
• Towels 
• Moisturizing Lotion 
 
11.9 
ADVERSE EVENTS  
11.9.1 Reporting of Adverse Events  
An adverse event is any untoward medical occurrence in a patient or clinical-trial patient 
administered a medicinal product and which does not necessarily have to have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign, symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Any adverse event associated with the use of a drug in humans, whether or not considered 
product-related, includes the following: An adverse event occurring in the course of the use of 
a drug product in professional practice; an adverse event occurring from drug overdose whether 
accidental or intentional; an adverse event occurring from drug abuse; an adverse event 
occurring from drug withdrawal; and any failure of expected pharmacological action.  


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Reporting an adverse event does not necessarily reflect a conclusion that the product caused or 
contributed to the adverse event. 
All adverse events, whether observed by an Investigator, Study Coordinator or reported by the 
patient, whether related to study drug or not related to study drug, shall be documented in the 
eCRF and patient records, together with details of the duration and intensity of each episode, 
the action taken, the relationship to the Investigational Product and the degree of severity, the 
seriousness and the outcome. 
The potential adverse reactions of Actavis Laboratories UT azelaic acid, 15% topical foam are 
anticipated to be similar to those observed with the use of Bayer HealthCare’s Finacea® 
(azelaic acid) Foam, 15%.  The following adverse experiences have been reported with the use 
of Finacea® (azelaic acid) Foam, 15%: erythema, dryness, pain and pruritus. 
The Principal Investigator must strive to follow the patient until the adverse event has resolved, 
becomes clinically insignificant, is stabilized or the patient is lost to follow-up.  The Principal 
Investigator must immediately report all patients who discontinue use of study drug due to 
adverse events to the Contract Research Organization by telephone and follow-up in writing.  
11.9.2 Assessment of Severity  
The intensity or severity of an adverse event (AE) is characterized as:  
• 
Mild: an AE that is easily tolerated  
• 
Moderate: an AE sufficiently discomforting to interfere with daily activity  
• 
Severe: an AE that prevents normal daily activities  
11.9.3 Relationship to Study Medication  
The relationship is characterized as:  
• 
Not Related: This applies to any AE that is clearly not related to use of the study 
drug.  
• 
Possible: This means the association of the AE with the study drug is unknown; 
however, a relationship between drug and event cannot be ruled out.  
• 
Probable: There is a reasonable temporal relationship between the use of the study 
drug and the AE.  Based upon the Principal Investigator’s clinical experience, the 
association of the event with the study drug seems likely.  
• 
Definite: The AE occurs following the application of the study drug and it cannot 
be reasonably explained by any known characteristics of the patient’s clinical state, 
environmental or toxic factors or other modes of therapy administered to the 
patient.  It disappears or decreases upon discontinuation of the study drug and 
reappears on a re-challenge of the Investigational Product.  
11.9.4 Action taken regarding the IMP 
• 
None: There was no action taken. The subject receives IMP in accordance 
with the protocol. 
• 
Dose reduced: The dosage of IMP was reduced. 
• 
Interrupted: Discontinued temporarily. The treatment is expected to be re- 


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introduced. 
• 
Discontinued: Discontinued permanently. Subject is taken off the trial therapy. 
• 
Not applicable: The adverse event occurred during the Screening Period 
11.9.5 Assessment of Subject outcome 
• 
Subject remains in the trial 
• 
Withdrawn from the trial 
• 
Lost to follow-up 
• 
Death 
11.9.6 Definition of AE outcome 
• 
Recovered without sequelae: Subject has recovered fully from the AE without 
any remaining effects or impairment. 
• 
Recovered with sequelae: Subject has recovered but with remaining effects or 
impairment present at the time of the report. 
• 
Not yet recovered: The outcome is not yet known or the AE is still ongoing 
• 
Died 
• 
Unknown 
11.9.7 Treatment Required 
• 
Yes (if yes specify on concomitant therapy page of the CRF) 
• 
No 
11.9.8 Pregnancy 
All female patients of childbearing potential must use accepted methods of birth control or 
must agree to practice abstinence, from study start to 30 days after the last administration of 
study drug. All female patients are considered to be of childbearing potential unless they have 
been surgically sterilized (hysterectomy, bilateral oophorectomy, or tubal ligation) or have 
been postmenopausal for at least a year. Any of the following methods of birth control are 
acceptable: oral contraceptives, contraceptive patches/implants (e.g., Norplant®), vaginal 
ring (NuvaRing®), Depo-Provera® (Medroxy progesterone acetate), double barrier methods 
(e.g., condom and spermicide), Essure or IUD.  
A negative result of a urine pregnancy test having a minimum sensitivity of at least 50mIU/ml 
for hCG should be obtained, prior to study participation, at Visit 1.  Pregnancy testing will 
also be performed at every study visit and the results of all pregnancy tests (positive or 
negative) will be documented. 
If following initiation of study treatment, it is subsequently discovered that a study patient is 
pregnant or may have been pregnant at the time of Investigational Product exposure, the 
subject will be permanently discontinued.  The Principal Investigator must immediately notify 
the Medical Monitor of this event. 
Protocol-required procedures for study discontinuation and follow-up must be performed on 
the patient.  Other appropriate pregnancy follow-up procedures should be considered if 


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indicated.  In addition, the Principal Investigator must report to the sponsor follow-up 
information regarding the course of the pregnancy, including prenatal and neonatal outcome. 
Infants should be followed for a minimum of eight weeks after birth. 
Pregnancy occurring during a patient’s participation in a clinical trial must be notified to the 
sponsor within 24 hours after Study Coordinator becomes aware of its occurrence.  Outcome 
of a pregnancy should be followed up carefully and any abnormal outcome of the mother or 
the child should be reported.  This also applies to pregnancies following the administration of 
the investigational product to the father prior to sexual intercourse. 
Timeline for follow up: 
• 
Site should follow the patient until termination of the pregnancy or until at least 30 
days after the birth. 
• 
Infant(s) should be followed for a minimum of eight weeks after birth. 
 
Timeline for reports: 
• 
Pregnancy notification: within 24 hours after Study Coordinator becomes aware of 
its occurrence; 
• 
Pregnancy initial report: expected within 1to 3 days of notification; 
• 
Pregnancy follow up report: at least every 3 months; 
• 
Pregnancy final report: upon termination of the pregnancy or until at least 30 days 
after the birth; 
• 
Infant follow up report: 30 days after the birth; 
• 
Infant final report: eight weeks after birth. 
 
Cases of pregnancy must be reported on a Pregnancy Report and sent to the Sponsor Study 
Manager. 
An SAE needs to be reported for pregnancy with abnormal outcome before or after the end of 
study. 
11.9.9 Serious Adverse Events  
An Adverse Event or Suspected Adverse Reaction is considered ‘‘serious’’ if, in the view 
of either the investigator or sponsor, it results in any of the following outcomes: 
• 
Death;  
• 
A life threatening adverse event; (Note: the term “life-threatening” as used here 
refers to an event in which the patient was at risk of death at the time of the event; 
it does not refer to an event which hypothetically might have caused death if it were 
more severe);  
• 
In-patient hospitalization or prolongation of existing hospitalization;  
• 
A persistent or significant disability/incapacity (substantial disruption of the ability 
to conduct normal life functions); 
• 
A congenital anomaly/birth defect; 
• 
Any “other” important medical event. 
Important medical events that may not result in death, be life-threatening or require 
hospitalization may be considered Serious Adverse Events when, based on appropriate 


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medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  
Regardless of the above, any additional adverse events which the Principal Investigator 
considers significant should be immediately reported to the Contract Research Organization 
(
. 
Any Serious Adverse Event, whether deemed drug-related or not, must be reported by the 
Investigator to the Contract Research Organization (
) Project Manager by telephone 
within 24 hours after the Principal Investigator or Study Coordinator becomes aware of its 
occurrence.  The Principal Investigator or the Principal Investigator’s Designee must complete 
a Serious Adverse Event (SAE) Form and fax it to the Contract Research Organization 
(
, along with the patient’s Adverse Events Log and Concomitant Medications Log 
within 24 hours of notification of the event.  The CRO 
 must notify the Medical 
Monitor, Actavis Study Manager and Actavis’s Drug Safety Department within 24 hours of 
the initial notification of the event.  When appropriate, the Actavis’s Drug Safety Department 
will notify the U.S. Food and Drug Administration (FDA) of drug related Serious Adverse 
Events. 
Documentation should be sent to the CRO Study Manager and Actavis’s Drug Safety 
Department listed below:  
CRO Study Manager 
 
         
 
 
 
 
Medical Monitor 
 
 
 
 
 
Sponsor Study Manager 
 
 
Actavis. 
Morris Corporate Center 
III 
400 Interpace Parkway 
Parsippany, NJ 07054 
 
 
Drug Safety Department 
Actavis   
Pharmacovigilance 
  
 
 
 
The Principal Investigator or the Principal Investigator’s Designee must be prepared to supply 
the Medical Monitor with the following information: 
a.  
Principal Investigator name and Site Number 
b.  
Patient I.D. Number 
c.  
Patient initials and date of birth 
d.  
Patient demographics 
e.  
Clinical event 
1) Description 
2) Date of onset 
3) Severity 
4) Treatment (including hospitalization) 
5) Relationship to study drug 
6) Action taken regarding study drug  
f. 
If the AE was fatal or life-threatening  
1) Cause of death (whether or not the death was related to study drug) 


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2) Autopsy findings (if available) 
3) Death Certificate 
The Sponsor must notify FDA as soon as possible, but no later than 7 calendar days for a fatal 
or life threatening adverse event.  The Sponsor must notify FDA and all participating 
investigators within 15 calendar days for any drug-related serious adverse events observed 
during the conduct of the study.  
The Principal Investigator must provide a follow-up written report within 5 calendar days of 
reporting the event to the CRO.  The written report must contain a full description of the event 
and any sequelae. Patients who have had an SAE must be followed clinically until all 
parameters (including laboratory) have either returned to normal or are stabilized.  The 
Investigator must also report follow-up information if it becomes known to the Investigator.  
Actavis Study Manager and Actavis Drug Safety Department must receive any follow-up 
within 24 hours of receipt by Medical Monitor.   
Reports of all SAEs must be communicated as soon as possible to the appropriate Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) and/or reported in accordance 
with local laws and regulations. 
12 STATISTICAL METHODS 
12.1 
Sample Size Rationale  
The sample size for this protocol is based on published data (Finacea® Summary Basis of 
Approval); Finacea® produced a percent reduction for inflammatory lesions of approximately 
55% and the vehicle had a percent reduction of 40% after 12 weeks of treatment.   
The anticipated standard deviation for inflammatory lesions is < 47%.  A sample size of  
n1 = 280, n2 = 280 and n3 = 280 evaluable mITT patients  (1:1:1 ratio) to provide at least  
224 PP patients in each of the Test and Reference treatment groups  should provide at least 
an
 probability of showing that, the 90% confidence interval on the Test/Reference ratio 
of percent reduction from baseline is contained within the interval 0.800 to 1.250 in the PP 
population and at the same time demonstrating that the Test and Reference products are 
superior to the vehicle in the mITT population.  
In this study, enrolled patients will be randomized in the ratio of 1:1:1 to test, reference and 
vehicle treatments.  It is anticipated that 75% of the mITT patients will qualify for the PP 
population.  Accordingly, approximately 924 patients will be randomized in the study to 
obtain at least 840 mITT patients in a 1:1:1 ratio (280:280:280 patients, respectively) to each 
treatment group. 
12.2 
Randomization and Unblinding Procedures  
Patients will be randomly assigned in a 1:1:1 ratio to receive the test product, the reference 
product, or the vehicle control, respectively. The randomization assignment will be a block 
randomization, with 3 sequential patient numbers in each block. 
An independent third party will generate the randomization code using SAS and hold it 
throughout the conduct of the study in order to minimize bias.  A sealed copy of the 
randomization scheme will be retained at each study site.  


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The treatment assignments will remain blinded until the final database is locked.  The contents 
of the cans of IP may not be viewed by the PI, any Sub-investigator, evaluator or any other 
(blinded) member of the site staff. 
In the event of an emergency, the patient-specific treatment may be identified; however, every 
effort should be made to maintain the blind.   
In the event of unblinding, the patient should be excluded from the PP population.  The 
Sponsor or designee must be notified in the event the blind is broken. 
12.3 
Significance Level  
All statistical tests will be carried out at a significance level of α = 0.05 (two sided), unless 
otherwise indicated.  No adjustment will be made for multiplicity. 
12.4 
Efficacy Assessment 
12.4.1 Primary Endpoint  
The primary endpoint is the percent change from baseline to Week 12 in the inflammatory 
(papules and pustules) lesion counts. 
12.4.2 Secondary Endpoint 
The secondary endpoint is the clinical response of “success” or “failure” at Week 12 on the 
IGE.  Success is defined as an IGE score of 0 (clear) or 1 (almost clear).  Any patient who is 
not considered to be a success will be considered to be a failure. 
12.4.3 Measures  
 
Lesion Counts will be performed using the following definitions:  
Lesion Name 
Lesion Definition 
Papule 
Inflammatory lesion; small (≤ 5mm in diameter), solid palpable 
lesion, usually with inflamed elevation of the skin that does not 
contain pus.  
Pustule 
Inflammatory lesion; small (≤ 5mm in diameter), inflamed skin 
swelling that is filled with pus.  
Nodule 
Large (> 5 mm in diameter), hard bumps under the skin's surface. 
 
When counting facial lesions, all lesions will be counted, including those present on the nose.  
Counts of nodules will be reported separately and not included in the inflammatory lesion 
counts.  
The IGE will be performed and documented using the definitions in table below: 
IGE: 
Score 
Grade  
Definition  
0 
Clear 
No inflammatory lesions present; at most, mild erythema.  
1 
Almost Clear 
Very mild erythema present. Very few small 
papules/pustules.  
2 
Mild 
Mild erythema. Several small papules/pustules.  


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3 
Moderate 
Moderate erythema. Several small or large 
papules/pustules, and up to 2 nodules.  
4 
Severe 
Severe erythema. Numerous small and/or large 
papules/pustules, up to several nodules.  
Application site reactions such as erythema, dryness, scaling, pruritus, stinging/burning, and 
edema, will be recorded at each visit to allow a comparison between treatment groups.  A 
detailed scale is presented in Section 10.5.6. 
12.4.4 Datasets to be Analyzed  
Three analysis populations will be used in the analysis of the clinical data and they are defined 
as follows: 
1. The Safety population includes any individual who was randomized into the study and used 
at least one dose of Investigational Product. 
2. The mITT population includes all randomized patients who met all inclusion/exclusion 
criteria, received study treatment, and returned for at least one post-baseline visit with 
lesion count. 
3. The PP population includes all randomized patients who met all inclusion/exclusion 
criteria, were compliant with the assigned study treatment (who applied 75% to 125% of 
the scheduled applications), returned to the study site for the primary endpoint visit (12 
week evaluation) within +/- 4 days OR discontinued from the study as a treatment failure 
(after completing at least 8 weeks of compliant study medication use), and did not have 
any protocol violations.  The compliance will be verified by the use of patient diaries. 
Patients who are discontinued early from the study due to lack of treatment effect, or who 
require alternate or supplemental therapy to treat their rosacea, after completing at least 
eight weeks of treatment will be included in the mITT and PP population as treatment 
failures on the IGE and their change in inflammatory lesion count from baseline to the last 
completed visit prior to discontinuation will be carried forward (LOCF).   
Patients discontinued prematurely for other reasons will be excluded from the PP population, 
but included in the mITT population, with missing efficacy data imputed using LOCF.  
For the purpose of determining the per-protocol status of the patient, a “protocol violation” is 
any patient or investigator activity that could have possibly interfered with the therapeutic 
administration of the treatment or the precise evaluation of treatment efficacy. 
Efficacy analyses will be performed on the mITT and Per-protocol populations.   
 
12.5 
Statistical Analysis 
12.5.1 
Analysis of Primary Endpoint  
Demonstration of Bioequivalence 
The 90% confidence interval on the test-to-reference ratio for the mean change from baseline 
in inflammatory lesions will be constructed using Fieller’s method. The analysis will use the 
common error term from the Analysis of Variance (ANOVA) of the test and reference results 
with a statistical model containing terms for treatment and site.  


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Bioequivalence will be established if the 90% confidence interval on the test-to-reference 
ratio is contained within the interval [0.80, 1.25] in the PP population. 
An identical analysis will be performed on the results from the mITT population to test for 
robustness of the findings in the PP population.  A LOCF approach will be used for missing 
efficacy results in the mITT analysis. 
Demonstration of Superiority 
To ensure that the study has adequate sensitivity to a difference between products, should 
such a difference exist, the primary efficacy results for the test and reference treatments will 
each be compared to those of the vehicle treatment. 
The evaluation of the superiority of the test treatment over the vehicle treatment will be 
conducted using ANOVA with a statistical model containing terms for treatment and center.  
If the mean percent change from baseline for inflammatory lesions for the test treatment is 
greater than, and statistically different from (p<0.05) that of the vehicle in the mITT 
population, then the test product will be considered superior to the vehicle.  The results for 
the reference treatment will be compared to those for the vehicle in an identical manner.  The 
same analyses will be conducted for the results from the PP population to test for robustness 
of the findings in the mITT population.  A LOCF approach will be used for missing efficacy 
results in the mITT analysis. 
For both the Bioequivalence and Superiority evaluations, a non-parametric rank based 
ANOVA will be considered when the data is highly skewed. The evaluation of skewness, 
(SAS® PROC UNIVARIATE) will be performed using the residuals from each ANOVA and 
if the skewness statistic is less than -2 or greater than +2, the analysis will be performed on 
the ranks of the percent change in inflammatory lesion count values. 
12.5.2 
Analysis of Secondary Endpoint 
Demonstration of Bioequivalence 
Bioequivalence for the secondary endpoint, will be established if the 90% confidence interval, 
Wald’s method with Yate’s continuity correction, for the test-to-reference difference in IGE 
success proportions is contained within the interval [-0.20, +0.20] in the PP population.  An 
identical analysis will be conducted on the mITT population to test for the robustness of the 
findings for the PP population. A LOCF approach will be used for missing efficacy results in 
the mITT analysis. 
Demonstration of Superiority 
The evaluation of the superiority of the test treatment over the vehicle treatment for the 
proportion of patients with success on the IGE at Week 12 will be conducted using Fisher’s 
exact test. If the success proportion for the test treatment is greater than, and statistically 
different from (p<0.05) that of the vehicle in the mITT population, then the test product will 
be considered superior to the vehicle.  The results for the reference treatment will be compared 
to those for the vehicle in an identical manner.  The same analyses will be conducted for the 
results from the PP population to test for robustness of the findings in the mITT population.  
A LOCF approach will be used for missing efficacy results in the mITT analysis. 


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12.5.3 Analysis of application site reactions 
A descriptive analysis comparing the application site reactions for each treatment group will 
be conducted to ensure that the test product is not worse than the reference product with regard 
to the expected and unexpected application site reactions.  
12.5.4 Safety Analyses 
Safety analyses will be conducted on the safety population.  Incidence of all adverse events 
reported during the study will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary and summarized by treatment group, body system, severity, preferred 
term, and relationship to study drug.  In addition, an evaluation will be conducted of the 
comparability of the test and reference treatments in regard to any treatment emergent AEs that 
occur in 5%, or more of the patients in either test or reference treatment group. 
The report of AEs will include date of onset, description of the AE, and date of resolution. 
12.5.5 Concomitant Medication 
The start and stop dates of concomitant medication used during the study will be provided in 
the data listings in addition to the reason for the medication use.  
12.5.6 Demographics and Baseline/Randomization Characteristics   
Demographic and baseline/randomization characteristics will be compared for the mITT, PP, 
and Safety populations.  Continuous variables will be analyzed with an analysis of variance 
with factors of treatment and investigational site.  Categorical variables including gender, 
ethnicity, race, and some baseline/randomization characteristics will be analyzed with a 
Cochran-Mantel-Haenszel test, stratified by investigational site.  
12.5.7 Summary of patients who terminate prematurely 
Reasons for premature termination will be summarized by treatment group. 
13 ETHICS 
13.1 
Informed Consent 
The principles of Informed Consent, according to FDA Regulations and ICH guidelines on 
GCPs, will be followed.  A copy of the proposed consent form must be submitted to the IRB, 
together with the protocol, for approval. 
Patients must provide written informed consent prior to any study procedures being completed.  
The Investigator is responsible for obtaining informed consent, signed by each patient prior to 
entry into the study.  Each patient’s signed informed consent must be kept on file by the 
Investigator for Regulatory Authorities’ inspection at any time.  A copy of the signed consent 
form will be given to the patient.  A notation will be made in the patient’s medical record 
indicating the date and time informed consent was obtained. 
A volunteer who signs the ICF but is not eligible at Visit 1 will be listed on the Screening Log 
as a screen failure and may rescreen at a later date.  The signed consent document will be in 
effect for 28 days from the date of signature.   


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13.2 
Institutional Review Board or Independent Ethics Committee 
The study and the patient informed consent form must be approved in writing by an appropriate 
IRB or Independent Ethics Committee (IEC) as defined by FDA regulations prior to enrollment 
of any study patients. 
Any changes to the protocol as well as a change of Investigator, which is approved by the 
Sponsor, must also be approved by the site’s IRB/IEC and documentation of this approval 
provided to the Sponsor or designee.  Records of the IRB/IEC review and approval of all 
documents pertaining to this study must be kept on file by the Investigator and are patient to 
inspection by FDA or other Regulatory Authorities during or after completion of the study.  
SAEs must also be reported to the IRB/IEC. 
Periodic status reports must be submitted to the IRB/IEC at least annually, as well as 
notification of completion of the study and a final report within approximately 1 month of 
study completion or termination.  A copy of all reports submitted to the IRB/IEC must be sent 
to the Sponsor or designee. 
The Investigator will ensure that an IRB/IEC that complies with the requirements set forth in 
Part 56 (Title 21 Code of Federal Regulations) will be responsible for the initial and continuing 
review and approval of the proposed clinical study. 
13.3 
Patient Confidentiality 
All patient data will be identified only by a patient identification number and patient initials.  
However, in compliance with federal guidelines regarding the monitoring of clinical studies 
and in fulfillment of his/her obligations to the Sponsor, it is required that the Investigator permit 
the study monitor, Sponsor representative or auditor, and/or FDA representative to review that 
portion of the patient’s medical record that is directly related to the study.  This shall include 
all study relevant documentation including patient medical histories to verify eligibility, 
admission/ discharge summaries for hospital stays occurring while the patient is enrolled in 
the study and autopsy reports for deaths occurring during the study. 
As part of the required content of informed consent, the patients must be informed that his/her 
medical chart may be reviewed by the Sponsor, the Sponsor’s authorized representatives, or 
FDA.  Should access to the medical record require a separate waiver or authorization, it is the 
Investigator’s responsibility to obtain such permission from the patient in writing before the 
patient is enrolled into the study. 
14 DATA HANDLING AND RECORD KEEPING 
14.1 
Site Regulatory Documents Required for Initiation 
The Sponsor, or designee, will receive the following documents prior to the initiation of the 
study: 
1. Completed, signed Form FDA 1572. 
2. Current curricula vitae, signed and dated, for the Principal Investigator and sub-
investigators named on the Form FDA 1572. 
3. Current license(s) of the Principal Investigator and sub-Investigators named on Form FDA 
1572. 
4. Documentation of IRB approval of this study protocol, Investigator, and informed consent. 


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5. Current IRB membership list. 
6. A copy of the protocol agreement page signed by the Principal Investigator. 
7. Financial Disclosure Statement for all individuals captured on the Form FDA 1572. 
8. Debarment Certification for the Principal Investigator and sub-investigators named in 
Form FDA 1572. 
14.2 
Maintenance and Retention of Records 
The study will be conducted according to Good Clinical Practices as outlined in ICH step 5 
guidelines by the Food and Drug Administration.  It is the responsibility of the Investigator to 
maintain a comprehensive and centralized filing system of all relevant documentation. 
Investigators will be instructed to retain all study records required by the Sponsor, as well as 
the regulations, in a secure and safe facility with limited access.  Regulations require retention 
for a period of at least two (2) years after marketing approval and notification from the Sponsor.  
These regulatory documents should be retained for a longer period if required by local 
regulatory authorities. 
Archiving of data - Copies of all pertinent records will be retained by the Investigator for at 
least two (2) years following final approval of the drug and notification from the Sponsor.  
These records include documents pertaining to the receipt and return of drug supplies, IRB, 
Informed Consent, source documents, as well as final signed case report forms.  No documents 
shall be transferred from the site or destroyed without first notifying the Sponsor. 
A sealed copy of the randomization scheme should be retained at the study site and should be 
available to FDA investigators at the time of site inspection to allow for verification of the 
treatment identity of each patient. 
14.3 
Data Collection and Reporting 
Data for individual patients will be collected on source documents designed by the Contract 
Research Organization and then entered into a data management system, which for this study 
will be Electronic Data Capture (EDC).  The Investigator and his/her study site personnel 
will be responsible for completing the eCRFs.  The Investigator is required to verify that all 
of the requested information is accurately recorded in the eCRFs.  All information requested 
in the eCRFs needs to be supplied, including patient identification, date(s), assessment 
values, etc., and any omission or discrepancy will require explanation.  All information on 
eCRFs must be traceable to source documents.  
Source documents such as the clinic chart are to be maintained in order to allow data 
verification.  Because of the potential for errors, inaccuracies and illegibility in transcribing 
data into eCRFs, originals of laboratory and other test results must be kept on file.  Source 
documents and copies of test results must be available at all times for inspection by the study 
monitor.  The following should also be available for review:   
1. Patient Screening Log – reflecting the reason any patient screened for the study was 
found to be ineligible 
2. Delegation of Authority/Study Personnel Signature Log – all site personnel will be listed 
along with their responsibilities and signatures; to be maintained at the site throughout 
the study 
3. Monitoring Log – the date and purpose of all monitoring visits by the Sponsor/Designee 


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will be documented 
4. Enrollment Log – documenting patient initials and start and end dates for all patients 
enrolled 
5. Drug Accountability Log – reflecting the total amount of Investigational Product 
dispensed to and returned by each patient 
6. Informed Consent Form – which must be available for each patient and be verified for 
proper documentation 
The study monitor will be responsible for reviewing and verifying the data recorded in the 
eCRFs, utilizing the original source documentation and will query discrepant findings.  The 
Investigator and study site personnel will be responsible for answering all queries.  All 
queries issued by the CRO’s data management personnel will be answered by site personnel 
and verified by the monitor. 
14.4 
Primary Source Documents 
The investigator must maintain primary source documents supporting significant data for each 
patient’s medical notes.  These documents, which are considered “source data”, should include 
documentation of: 
• Demographic information 
• Evidence supporting the diagnosis/condition for which the patient is being studied 
• General information supporting the patient’s participation in the study 
• General history and physical findings 
• Hospitalization or Emergency Room records (if applicable) 
• Each study visit by date, including any relevant findings/notes by the Investigator(s), 
occurrence (or lack) of adverse events, and changes in medication usage, including the date 
the study drug commenced and completed 
• Any additional visits during the study 
• Any relevant telephone conversations with the patient regarding the study or possible 
adverse events 
• An original, signed informed consent form for study participation 
• Patient Diary 
The Investigator must also retain all patient-specific printouts/reports of tests and procedures 
performed as a requirement of the study.  During monitoring visits the monitor will need to 
verify data on the eCRFs against these sources of data. 
14.5 
Study Monitoring 
The study will be monitored by a representative of the CRO to assess compliance with ICH-
GCP and applicable regulations.  The Principal Investigator will be visited by a study monitor 
prior to the study and at regular intervals during the course of the study.  These visits are for 
the purposes of verifying adherence to the protocol.  The study monitor will review the 
informed consent forms and verify CRF entries by comparing them with the source documents 
(hospital/clinic/office records) that will be made available for this purpose.  The study monitor 
will review the maintenance of regulatory documentation and drug accountability (to the can 
level).  The study monitor will review on a regular basis the progress of the study with the 
Investigator and other site personnel.  Electronic case report forms may be monitored during 
these visits.  At the end of the study, a closeout monitoring visit will be performed.  Monitoring 


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visits will be arranged in advance at a mutually acceptable time with site personnel.  Sufficient 
time must be allowed by the site personnel for the monitoring of eCRFs and relevant source 
documents.  The study coordinator and/or Investigator should be available to answer questions 
or resolve data clarifications.  Adequate time and space for these visits should be made 
available by the Investigator and study staff. 
14.6 
Audits and Inspections 
During the course of the study and/or after it has been completed, one or more site visits may 
be audited by authorized representatives of the Sponsor.  The purpose of the audit is to 
determine whether or not the study is being conducted and monitored in compliance with 
recognized GCP/ICH guidelines and laws. 
Additionally, the study may be inspected by regulatory agencies.  These inspections may take 
place at any time during the course of the study and/or after it has been completed.  
THE INVESTIGATOR MUST NOTIFY THE CONTRACT RESEARCH ORGANIZATION 
 and SPONSOR PROMPTLY OF ANY INSPECTIONS SCHEDULED BY 
REGULATORY 
AUTHORITIES, 
AND 
PROMPTLY 
FORWARD 
COPIES 
OF 
INSPECTION REPORTS TO THE SPONSOR.   
A sealed copy of the randomization scheme should be retained at the study site and should be 
available to FDA investigators at the time of site inspection to allow for verification of the 
treatment identity of each patient. 
14.7 
Modifications to the Protocol 
The procedures defined in the protocol and in the eCRF will be carefully reviewed to ensure 
that all parties involved with the study fully understand the protocol.  In order to ensure the 
validity of the data, no deviations from the protocol, with minimal exceptions, may be made 
unless the issue is broad enough to warrant revision of the protocol.  Such revisions must be 
submitted to and have documented approval from the Sponsor and the IRB prior to 
implementation.  All amendments to the protocol, which involve substantial changes in study 
design, procedure or analyses, will be submitted to the IRB for prior approval.  The only 
circumstance in which an amendment may be initiated without prior IRB approval is to 
eliminate apparent immediate hazards to a patient or patients.  However, the Investigator must 
notify the Sponsor immediately and the IRB within 5 working days after implementation. 
14.8 
Termination of the Study 
The Sponsor reserves the right to terminate the clinical study at any time upon written notice. 
The termination of the study for any reason will be communicated to the IRB. 
14.9 
Completion of the Study 
The Investigator is required to submit all close-out documents and any other  required  records 
to the Contract Research organization
   
The Investigator must submit a final report to the IRB and the Sponsor within one (1) month 
of study completion or discontinuation of study. 


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14.10 
Publications 
Direct publications arising from this study may only be published with the consent of the 
sponsor while maintaining the patient’s confidentiality. 
 
 


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15 REFERENCES 
• Package insert - FINACEA® (azelaic acid) Foam, 15% 
• U.S. 
Food 
and 
Drug 
Administration: 
Individual 
Product 
Bioequivalence 
Recommendations for Azelaic Acid (http://www.fda.gov). 
• 
http://www.finacea-us.com/ 
 
 


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APPENDIX I: STUDY FLOW CHART 
Visit Title 
Baseline 
Interim 
Interim 
End of Treatment/ 
Early Discontinuation 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Scheduled Day 
Day 0 
 Day 28±4 
Day 56±4 
Day 84±4 
 
 
 
 
 
Informed Consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical History 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
Physical Exam including vital signs 
X 
 
 
 
Pregnancy Test* 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
Inflammatory Lesion Count 
X 
X 
X 
X 
Investigator’s Global Evaluation (IGE) 
X 
X 
X 
X 
Telangiectasia Assessment 
X 
 
 
 
Irritation Assessment 
X 
X 
X 
X 
Patient Instruction/Compliance Review 
X 
X 
X 
X 
Dispense Study Medication and Diary** 
X 
X 
X 
 
Collect Study Medication and Diary 
(Accountability) 
 
X 
X 
X 
* Urine pregnancy test for all females of child-bearing potential enrolled in study. 
**Day 1 will occur the date patient begins dosing. This may be the evening of Visit 1 or the following day. 


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APPENDIX II: FINACEA ® PACKAGE INSERT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
A Multicenter, Double-blind, Randomized, Parallel-group, Vehicle-Controlled Study to 
Evaluate the Safety and Clinical Equivalence of a Generic Azelaic Acid Foam, 15% and the 
Reference Listed Finacea® (Azelaic acid) Foam, 15% in Patients with Moderate Facial 
Rosacea 
Study Number ACTA/AZEL/2015 
NCT03287791 
Statistical Analysis Plan Approval Date: 06 April 2017 


Statistical Analysis Plan 
Study code 
ACTA/AZEL/2015 
Version 
Final 
Date 
06/Apr/2017 
A MULTICENTER, DOUBLE-BLIND, RANDOMIZED, PARALLEL-
GROUP, VEHICLE-CONTROLLED STUDY TO EVALUATE THE 
SAFETY AND CLINICAL EQUIVALENCE OF A GENERIC 
AZELAIC ACID FOAM, 15% AND THE REFERENCE LISTED 
FINACEA® (AZELAIC ACID) FOAM, 15% IN PATIENTS WITH 
MODERATE FACIAL ROSACEA. 
Study Statistician 
<<Name>> 
Date 
Sponsor Representative 
<<Name>> 
Date 
 
 


Statistical Analysis Plan  
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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ............................................................................................................................ 1 
TABLE OF CONTENTS ......................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................. 4 
1. 
INTRODUCTION ................................................................................................... 5 
2. 
OBJECTIVES .......................................................................................................... 5 
3. 
STUDY OVERVIEW .............................................................................................. 5 
3.1 
Study Design ............................................................................................................ 5 
3.2 
Sample Size .............................................................................................................. 7 
3.3 
Randomization and Unblinding Procedures ............................................................ 8 
4. 
STUDY ENDPOINTS/OUTCOMES ...................................................................... 8 
5. 
HYPOTHESES TESTING ...................................................................................... 9 
6. 
ANALYSIS SUBSETS .......................................................................................... 10 
6.1 
Safety Population ................................................................................................... 10 
6.2 
Modified Intent to Treat Population (mITT Population) ....................................... 10 
6.3 
Per Protocol Population (PP Population) ............................................................... 10 
7. 
STATISTICAL METHODS OF ANALYSIS ....................................................... 11 
7.1 
General Principles .................................................................................................. 11 
7.2 
Patient Disposition ................................................................................................. 12 
7.3 
Demographic and Baseline Characteristics ........................................................... 13 
7.4 
Protocol Deviations ................................................................................................ 14 
7.5 
Efficacy Analyses .................................................................................................. 15 
7.5.1 
Center pooling ........................................................................................................ 15 
7.5.2 
Analyses of Primary Endpoint ............................................................................... 16 
7.5.3 
Analyses of Secondary Endpoint Outcome ........................................................... 18 
7.5.4 
Analyses of IGE ..................................................................................................... 19 
7.6 
Safety Analyses ...................................................................................................... 19 
7.6.1 
Adverse Events ...................................................................................................... 19 
7.6.2 
Signs/Symptoms of Local Irritation ....................................................................... 21 
7.6.3 
Exposure to Product ............................................................................................... 21 
7.6.4 
Exposure to Concomitant Medication.................................................................... 22 
8. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ............................... 22 


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9. 
LIST OF PLANNED TABLES, FIGURES, AND LISTINGS ............................. 23 
10. 
LITERATURE CITATIONS / REFERENCES ..................................................... 23 
11. 
APPENDICES ....................................................................................................... 24 
11.1 
Study visit Schedule ............................................................................................... 24 
11.2 
IGE Scale ............................................................................................................... 24 
11.3 
Application Site Reactions Scores ......................................................................... 25 
11.4 
Code Fragments ..................................................................................................... 26 
 


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LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CFR 
Code of Federal Regulations 
DOB 
Date of Birth 
eCRF 
Electronic Case Report Form 
ICF 
Informed Consent Form 
IGE 
Investigator’s Global Evaluation 
IP 
Investigational Product 
LOCF  
Last Observation Carried Forward 
LS 
Least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat 
mm 
Millimeter 
PI 
Principal Investigator 
PP 
Per Protocol 
PT 
Preferred Term 
TEAE 
Treatment Emergent Adverse Event 
SAE 
Serious Adverse Event 
SOC 
System Organ Class 
UV 
Unscheduled Visit 
 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol "A Multicenter, Double-blind, 
Randomized, Parallel-group, Vehicle-Controlled Study to Evaluate the Safety and Clinical 
Equivalence of a Generic Azelaic Acid Foam, 15% and the Reference Listed Finacea® 
(azelaic acid) Foam, 15% in Patients with Moderate Facial Rosacea" dated January 27, 2016. 
Marketed by Bayer HealthCare, Finacea® (azelaic acid) Foam, 15% is a safe and effective 
topical therapy used for the treatment of moderate facial rosacea. Actavis Laboratories UT has 
developed a generic formulation of azelaic acid 15% foam and the current study is designed to 
evaluate the safety and efficacy of this formulation.  This randomized, vehicle-controlled, 
parallel-group, multicenter, double-blind study was designed to evaluate the therapeutic 
equivalence and safety of a generic Azelaic Acid Foam, 15% and Finacea® (Azelaic acid) 
Foam 15%, in the treatment of moderate facial rosacea, and to demonstrate the superiority of 
the efficacy of the two active foams over the vehicle control. 
This document will give a description of the planned methods of the analysis. 
2. 
OBJECTIVES 
The objectives of this study are: 
- 
to evaluate the therapeutic equivalence and safety of a generic Azelaic Acid Foam, 
15% and Finacea® (azelaic acid) Foam, 15% in the treatment of moderate facial 
rosacea; 
- 
to demonstrate superiority of the efficacy of the two active foams over the vehicle 
control.  
3. 
STUDY OVERVIEW 
3.1 
Study Design 
Up to 1010 patients will be enrolled in the study to randomize 924 patients to obtain at least 
840 modified Intent-to-Treat (mITT) patients in a 1:1:1 ratio (280:280:280 patients, 
respectively) to each treatment group and 672 (224:224:224) evaluable subjects in the Per 
protocol (PP) population. Patients will be assigned in a 1:1:1 ratio to treatment with the Test 
product, Azelaic Acid Foam, 15% (Actavis Laboratories UT), the Reference product, 


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Finacea® (Azelaic acid) Foam, 15% (Bayer HealthCare) or the Vehicle control (Actavis 
Laboratories UT) in this multicenter, double-blind, randomized, vehicle-controlled, parallel-
group study.     
The assigned Investigational Product (IP) will be self-applied topically to the entire facial area 
(cheeks, chin, forehead, and nose) twice daily for 84 consecutive days.  The IP should be 
gently massaged into the affected areas on the face twice daily, in the morning and evening 
after the patient’s face has been washed with a mild cleanser and patted dry with a soft towel.  
Patients will be required to use diaries to document study treatments, any missed treatments 
and the occurrence of all adverse events.    
The duration of each patient’s participation in the study will be 84 days.  Scheduled study 
visits will include: Visit 1 (Baseline Visit, Day 0), Visit 2 (Day 28 ± 4 days), Visit 3 (Day 56 
± 4 days), and Visit 4 (End of Treatment, Day 84 ± 4 days).  A window of ± 4 days will be 
considered acceptable for each scheduled visit following the baseline visit. 
If the Principal Investigator determines that the patient’s condition has worsened to the degree 
that it is unsafe for the patient to continue in the study, the patient may be discontinued from 
the study as a treatment failure and the patient may be treated using the standard care.    
An Unscheduled Visit is allowed at any time, for any reason, if in the Principal Investigator’s 
opinion, it is warranted. If a patient is discontinued from the study during an Unscheduled 
Visit, the Unscheduled Visit will be referred to as an Early Discontinuation Visit and all 
procedures scheduled for Visit 4 will be performed.  If the Unscheduled Visit is not an Early 
Discontinuation Visit (i.e., the patient will continue to take part in the study), then the 
activities performed will depend on the reason for the unscheduled visit and will be left to the 
discretion of the Investigator.  The Investigator should perform any activities necessary to 
appropriately evaluate the patient at this Unscheduled Visit.  If the Unscheduled Visit is due to 
an AE, the Investigator will determine whether additional visits are needed.  
At Visit 1, an informed consent will be obtained from the potential study patient before any 
study procedures take place.  After the patient has been consented, the patient’s medical 
history will then be documented, including the patient’s concomitant medications.  A urine 
pregnancy test will be performed for all female patients of child-bearing potential.  A baseline 


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facial rosacea grade will be assigned to the patient using the Investigator’s Global Evaluation 
(IGE) and a baseline lesion count will be performed. The patient will undergo a physical 
examination, including the recording of vital signs.  The patient will be evaluated for signs 
and/or symptoms of erythema and telangiectasia.  The patient will be reviewed against the 
inclusion/exclusion criteria.  Blinded IP will be dispensed to patients who meet all of the 
inclusion and exclusion criteria.  Patients will be instructed on the application of IP and 
completion of patient diaries. 
Patients will return to the study site for Visit 2, Visit 3, and Visit 4.  The patient’s concomitant 
medications will be reviewed and documented.  A urine pregnancy test will be performed for 
female patients of child-bearing potential.  The patient’s facial rosacea will be assessed using 
the IGE, the patient’s lesions will be counted and all results will be documented.  The signs 
and/or symptoms of local irritation will be evaluated for the patient and any other adverse 
events will be documented.  The patient will bring their used IP and their study diaries to each 
study visit after the baseline visit.  Compliance with drug applications will be assessed at each 
visit after the baseline visit.  New can(s) of IP will be dispensed during Visit 2 and Visit 3. In 
addition, all IP and diaries will be collected from the patient during each scheduled visit or the 
Early Discontinuation Visit. 
3.2 
Sample Size  
The sample size for this protocol is based on published data (Finacea® Summary Basis of 
Approval); Finacea® produced a percent reduction for inflammatory lesions of approximately 
55% and the Vehicle had a percent reduction of 40% after 12 weeks of treatment.   
The anticipated standard deviation for inflammatory lesions is < 47%.  A sample size of  
n1 = 280, n2 = 280, and n3 = 280 evaluable mITT patients (1:1:1 ratio) to provide at least 
224 PP patients in each of the Test and Reference treatment groups should provide at least an 
 of showing that, the 90% confidence interval on the Test/Reference ratio of 
percent reduction from baseline is contained within the interval 0.800 to 1.250 in the PP 
population and at the same time demonstrating that the Test and Reference products are 
superior to the vehicle in the mITT population.  


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In this study, enrolled patients will be randomized in the ratio of 1:1:1 to test, reference and 
vehicle treatments.  It is anticipated that 75% of the mITT patients will qualify for the PP 
population.  Accordingly, approximately 924 patients will be randomized in the study to 
obtain at least 840 mITT patients in a 1:1:1 ratio (280:280:280 patients, respectively) to each 
treatment group. 
3.3 
Randomization and Unblinding Procedures  
Patients will be randomly assigned in a 1:1:1 ratio to receive the Test product, the Reference 
product, or the Vehicle control, respectively.  The randomization assignment will be a block 
randomization, with 3 sequential patient numbers in each block. 
An independent third party will generate the randomization code using SAS and hold it 
throughout the conduct of the study in order to minimize bias.  A sealed copy of the 
randomization scheme will be retained at each study site. 
The treatment assignments will remain blinded until the final database is locked.  The contents 
of the cans of IP may not be viewed by the PI, any Sub-investigator, evaluator or any other 
(blinded) member of the site staff. 
In the event of an emergency, the patient-specific treatment may be identified; however, every 
effort should be made to maintain the blind.  
In the event of unblinding, the patient should be excluded from the PP population.  The 
Sponsor or designee must be notified in the event the blind is broken. 
4. 
STUDY ENDPOINTS/OUTCOMES 
Primary Efficacy Endpoint 
The primary efficacy endpoints are the percent change from Baseline to Week 12 in the 
inflammatory (papules and pustules) lesion count.  
Secondary Efficacy Endpoint 
The secondary endpoint is the clinical response of "success" or "failure" at Week 12 on the 
IGE.  Success is defined as an IGE score of 0 (clear) or 1 (almost clear).  Any patient who is 
not considered to be a success will be considered to be a failure.  


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5. 
HYPOTHESES TESTING 
Hypothesis of Equivalence (Primary Endpoint) 
A two-sided, 90% confidence interval on the test/reference ratio for mean percent change 
from Baseline in the inflammatory lesion count will be constructed using Fieller’s method.  
The estimates of treatment means and standard errors will be obtained from a two-way 
Analysis of Variance of the Test and Reference results, using a statistical model containing 
terms for treatment and center.  Non-parametric methods will be used if the skewness factor 
for the residuals from the Analysis of Variance (ANOVA) model is outside the range -2 to +2.  
Bioequivalence will be established if the 90% confidence interval for the ratio of 
test/reference means is contained within the interval [0.80, 1.25]. 
Hypothesis of Equivalence (Secondary Endpoint) 
A two-sided, continuity-corrected, 90% confidence interval on the Test-to-Reference 
difference for the proportion of patients with treatment success on the IGE will be constructed.  
Bioequivalence will be established if the 90% confidence interval for the difference is 
contained within the interval [-0.20, +0.20]. 
Hypothesis of Superiority (Primary Endpoint) 
The null hypothesis to be tested is that there is no difference in the mean percent change 
(reduction) from baseline in the inflammatory lesion count between the active treatment and 
the Vehicle treatment.  The hypothesis testing will be performed separately for the Test 
treatment versus the Vehicle treatment and for the Reference treatment versus the Vehicle 
treatment using ANOVA under assumption of normal error and homogeneity of variance.  
Only data for the relevant two treatment arms will be included in each ANOVA.  Similarly, to 
bioequivalence, non-parametric methods will be used if the skewness factor for the residuals 
from the ANOVA model is outside the range -2 to +2. 
Superiority will be established if the mean percent change (reduction) from Baseline in the 
inflammatory lesion count for each active treatment is greater than, and statistically different 
from (p < 0.05, two-sided), that for the Vehicle. 


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Hypothesis of Superiority (Secondary Endpoint) 
The null hypothesis to be tested is that there is no difference in the proportions of patients with 
treatment success on the IGE.  The evaluation of superiority will be conducted separately for 
the Test treatment versus the Vehicle treatment and for the Reference treatment versus the 
Vehicle treatment.  The analysis will be conducted using two-sided, α = 0.05, Fisher’s exact 
test.  
Superiority will be established if the success proportion for each active treatment is greater 
than, and statistically different from, that of the Vehicle. 
6. 
ANALYSIS SUBSETS 
6.1 
Safety Population 
The safety population includes any individual who was randomized into the study and has 
evidence of usage of at least one dose of IP according to subject's diary.  For patients who are 
randomized but fail to return their diary card and for whom no evidence of study drug use is 
available, the following conservative approach will be applied: 
• if some safety or efficacy data for these patients is available after Visit 1, they will be 
included in the Safety population; 
• if no safety or efficacy data for these patients is available after Visit 1, they will be 
considered lost to follow-up and excluded from the Safety population.  
The Safety population will be the primary population for the safety analysis. 
6.2 
Modified Intent to Treat Population (mITT Population) 
The mITT population includes all Safety population patients who met all inclusion/exclusion 
criteria and return for at least one post-baseline efficacy evaluation.  This population will be 
considered as supportive for testing the clinical equivalence and as definitive while testing the 
superiority. 
6.3 
Per Protocol Population (PP Population) 
The PP population includes all mITT patients who apply 75% to 125% of the scheduled 
applications of the assigned product for 12 weeks, do not miss more than 6 consecutive 
applications, return for the 12-week evaluation within +/- 4 days OR have discontinued from 
the study due to lack of treatment effect (after completing at least 8 weeks of compliant study 
medication use), and have no protocol major violations. 


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Patients who are discontinued prematurely from the study due to lack of treatment effect after 
completing at least 8 weeks of compliant study medication use and without major protocol 
violations will be included in the PP population as treatment failures (i.e., non-responders) 
even if they do not have Week 12 evaluation within the visit window or at all.  An LOCF 
approach will be used for imputing missing lesion counts in these PP patients and they will be 
considered as failures in the IGE evaluations. 
Patients discontinued prematurely for other reasons (including those who discontinue due to 
lack of treatment effect with less than 8 weeks of treatment) will be excluded from the PP 
population, but included in the mITT population, using LOCF. 
Patients can be additionally excluded from the PP population due to non-compliance, if the 
Investigator's and Sponsor's review of their dosing times suggests a clinically meaningful 
departure from a twice-daily dosing pattern. 
For the purpose of determining the PP status of the patient, a "major protocol violation" is any 
patient or investigator activity that could have possibly interfered with the therapeutic 
administration of the treatment or the precise evaluation of the treatment efficacy. 
The PP population will be considered as definitive for testing the clinical equivalence and as 
supportive while testing the superiority. 
7. 
STATISTICAL METHODS OF ANALYSIS 
7.1 
General Principles 
The statistical analyses will be performed by 
, under the direction of the 
Sponsor, Actavis Laboratories UT, using SAS Version 9.3(or higher). All tables, figures, and 
listings will be produced in the landscape format.  
In general, all data will be listed by treatment group, patient and visit/time point where 
appropriate.  The summary tables will also be stratified by, or have columns corresponding to, 
treatment group. 
All patients will be identified by their unique patient numbers.  Data from the screen failures 
will not be included in tables, listings, or figures. 


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The total number of patients in the study group (N) under the stated population will be 
displayed in the header of summary tables. 
Data will be summarized using descriptive statistics for continuous variables.  Unless 
otherwise stated, descriptive statistics will include number of patients, mean, standard 
deviation, minimum, median, and maximum.  The minimum and maximum statistics will be 
presented to the same number of decimal places as the original data.  The mean and median 
will be presented to one more decimal place than the original data.  The standard deviation 
will be presented to two more decimal places than the original data.  The number of missing 
observations will be presented only if non-zero. 
In summary tables of categorical variables, counts, and percentages will be used.  The count 
[n] indicates the actual number of patients in a particular category, which should always be 
less than or equal to the total number of patients in the respective study group with known 
(non-missing) category [N].  Percentage will be obtained by: % = n/N*100.  Unless otherwise 
stated, all percentages will be expressed to one decimal place. 
All statistical tests will be two-sided at a significance level of α = 0.05, unless otherwise 
indicated.  No adjustment will be made for multiplicity. 
Relative days will be calculated relative to date of first dose of study medication.  In general, 
relative days will be calculated as follows only when the full assessment date is known (i.e., 
partial dates will have missing relative days). 
For assessment on or after the day of first dose of study drug: 
Relative Day = Date of Assessment – Date of First Dose of study Drug+1. 
For assessment before the day of first dose of study drug: 
Relative Day = Date of Assessment – Date of First Dose of study Drug. 
All dates will be displayed in DD/MMM/YYYY format. 
7.2 
Patient Disposition 
The number of patients enrolled in the study, randomized to treatment, included in the Safety, 
PP, mITT populations, prematurely discontinued from the study (along with the reasons for 
discontinuation) will be calculated.  The percentages will be based on the number of patients 


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randomized to each treatment group.  Percentages for discontinuation reasons will be based on 
the sub-population of patients who discontinued from the study. 
Number and percentage of patients enrolled by site will be tabulated for all enrolled patients, 
Safety, mITT, and PP populations. 
7.3 
Demographic and Baseline Characteristics 
Demographic characteristics will include: 
• age;  
• gender;  
• race;  
• ethnicity; 
• Rosacea history including time since diagnosis (years). 
Baseline characteristics include: 
• Baseline inflammatory lesion count; 
• Baseline telangiectasia assessment; 
• Vital signs: systolic and diastolic blood pressure, heart rate, respiratory rate, oral body 
temperature; 
• Physical examination: height, weight; 
• Medical history other than rosacea history. 
Descriptive statistics will be presented for age (years), height, weight, body mass index 
(BMI), time since diagnosis (years), lesion count.  Frequency counts and percentages will be 
presented for race, ethnicity, and baseline telangiectasia grade.  Height will be reported in 
centimeters and weight in kilograms. 
Age will be derived from Informed Consent Signed Date (INFCSD) and Date of Birth (DOB) 
as the number of whole years between those two dates. 
Demographic and baseline/randomization characteristics will be evaluated for comparability 
across treatment groups in the following manner.  Continuous variables (age, height, and 
weight) will be analyzed with an ANOVA with factors of treatment and investigational site.  
Overall p-value for the global null hypothesis of all groups being equal will be displayed.  
Categorical variables (gender, ethnicity, and race) will be analyzed with a Cochran-Mantel-
Haenszel general association test, stratified by investigational site. 


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Separately, a categorical summary will be created for physical examination results and vital 
signs results (normal, abnormal not clinically significant, and abnormal clinically significant).  
Medical history other than rosacea history will be summarized by Medical Dictionary for the 
Drug Regulatory Activities (MedDRA) System Organ Class and Preferred Term.  Baseline 
vital signs and physical examination will be listed. 
These analyses will be performed for Safety, mITT, and PP populations. 
All parameters reported during screening or baseline phase (including informed consent 
information, inclusion/exclusion criteria, randomization information, method of contraception, 
etc.) will be presented in the by-patient listings. 
7.4 
Protocol Deviations 
Protocol deviations will be derived algorithmically.  The following deviation categories will 
be derived: 
1. Use of prohibited medication: use of any concomitant medication identified by the 
clinical review as critical and influencing the efficacy outcomes (major deviation). 
2. Concomitant Medication – not critical: use of any other concomitant medication 
(minor deviation). 
3. Diary accountability: subjects failing to return their diary at at least one scheduled visit 
(minor deviation). 
4. Missed > 6 consecutive doses (major deviation). 
5. IP compliance < 75% or > 125% (major deviation). 
6. Dosing – Missed Doses(s): subjects who missed at least one dose, but do not fall under 
the previous two items (minor deviation). 
7. IP Accountability: subjects who failed to return the IP at at least one scheduled visit 
(minor deviation). 
8. Visit 4 out of window: subjects who attended Week 12 visit outside of ± 4-day 
window (major deviation). 


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9. Failed to return to Visit 4: subjects who do not attend Visit 4 at all. This deviation will 
not apply to subjects who discontinued from study due to lack of treatment effect after 
at least 8 weeks of treatment (major deviation). 
10. Inclusion/Exclusion criteria violated: subjects who were enrolled despite violating 
inclusion/exclusion criteria (major deviation). 
11. Pregnancy: subjects with positive pregnancy test results at any time during the study or 
adverse event with preferred term "Pregnancy" or discontinuing from the study with 
reason "Pregnancy" (major deviation). 
12. Urine Pregnancy Test not done: subject is female and of child-bearing potential, but 
UPT was not performed at Visits 2, 3, or 4 (minor deviation). 
13. Facial lesion count not done at Visits 2 or 3 (minor deviation); 
14. Facial lesion count not done at Visit 4 (major deviation); 
15. IGE not done at Visits 2, 3, or 4 (minor deviation); 
16. Sign and symptoms of local irritation not done at Visits 2, 3, or 4 (minor deviation). 
Additional deviations may be reported by sites classified into deviation categories and graded 
as major or minor. 
Protocol deviations will be summarized by deviation type and treatment group.  This analysis 
will be performed for Safety, mITT, and PP populations. 
7.5 
Efficacy Analyses  
7.5.1 
Center pooling 
To eliminate potential effect of random fluctuations at small site on the primary endpoints 
small centers will be pooled.  A study center will be pooled if it doesn't meet both of the 
following conditions: 
• It has at least 10 patients in the PP population; 
• It has at least one patient in each treatment group in the PP population. 
The smallest center that does not meet the above requirements will be pooled with the next 
smallest center.  The procedure will be repeated until all pooled centers meet the above two 
requirements. 
Pooled center will be used in all the efficacy analyses. 


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7.5.2 
Analyses of Primary Endpoint  
At each visit, an Investigator will assess the patient’s facial rosacea by counting the number of 
pustules, papules, and nodules.  The number of pustules, papules, total number of 
inflammatory lesions (pustules and papules) and nodules will be reported on the CRF.  
Missing Week 12 assessments will be imputed as follows.  In the mITT analysis, if a patient 
discontinues the study prior to Week 12 or misses the Week 12 assessment for any other 
reason, the LOCF rule will be used to impute the number of lesions.  In the PP analysis, if a 
patient discontinues the study prior to Week 12, due to lack of treatment effect, after at least 8 
weeks of treatment, the LOCF rule will be used to impute the number of lesions.  If a patient 
is missing the Week 12 assessment for any other reason, the patient will be excluded from the 
PP population. 
The baseline lesion count will be defined as the results from the latest examination prior to the 
start of study drug therapy.  For each post-baseline visit the change from Baseline and percent 
change from Baseline in the total number of inflammatory lesions will be calculated.  The 
baseline value, timepoint value, change from baseline, and percent change from baseline at the 
timepoint will be analyzed using descriptive statistics and will be tabulated by site, visit, and 
treatment group. 
7.5.2.1 
Analysis of clinical equivalence of test and reference treatments 
To show the clinical equivalence, estimates of mean percent change from Baseline in the 
inflammatory lesion count will be calculated for the Test and Reference treatment, and then 
the 90% CI for the mean ratio will be constructed using Fieller’s method.  Bioequivalence will 
be established if the 90% confidence interval for the ratio of Test/Reference means is 
contained within the interval [0.80, 1.25] for the PP population. 
To this end, first an ANOVA model will be fit with percent change from Baseline in lesion 
count as outcome and treatment, center and treatment-by-center interaction, as factors on the 
data from Test and Reference treatments only (excluding Vehicle patients).  If the treatment-
by-center interaction factor is not significant at the 0.05 level, the model will be rerun without 
the interaction term.  Treatment means and standard errors will be estimated from this model. 


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Then Fieller’s formula will be applied; covariance between the treatment means will be 
assumed to be 0.  See Appendix 11.4 for complete description of the Fieller’s formula. 
A non-parametric rank based ANOVA will be considered when the data is highly skewed.  
The evaluation of skewness, (using SAS® PROC UNIVARIATE) will be performed using the 
residuals from ANOVA and if the skewness statistic is less than -2 or greater than +2, the 
analysis will be performed on the ranks of the percent change in the inflammatory lesion count 
values. 
Analysis of bioequivalence will be performed both on the PP population and on the mITT 
population.  The results on the PP population will be considered definitive and the results on 
the mITT population will be considered supportive. 
7.5.2.2 
Analysis of superiority to vehicle control 
The analysis of superiority will be performed separately for the Test treatment versus the 
Vehicle treatment and for the Reference treatment versus the Vehicle treatment.  Each of these 
analyses will be performed using an ANOVA model with percent change from baseline in the 
lesion count as outcome and treatment, center and treatment-by-center interaction as factors.  
If the treatment-by-center interaction factor is not significant at the 0.05 level, the model will 
be rerun without the interaction term.  The model will be fit on data from the Test and Vehicle 
treatment for analysis of superiority of the Test treatment and separately on data from the 
Reference and Vehicle treatment for analysis of superiority of the Reference treatment.  From 
this model, the least square (LS) mean estimate for each treatment group with the 95% CI will 
be calculated; further, an estimate of the LS mean difference between the active treatment 
(Test or Reference) and Vehicle with 95% CI and the p-value for test of no difference will be 
calculated. 
Superiority will be established if the mean percent change from Baseline (reduction) for each 
active treatment is estimated to be greater than, and statistically significantly different from 
(p < 0.05 for test of no difference) that for the Vehicle, for the mITT population. 


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Analysis of superiority will be performed both on the PP population and on the mITT 
population.  The results on the mITT population will be considered definitive and the results 
on the PP population supportive. 
A non-parametric rank based ANOVA will be considered under the same circumstances as for 
the analysis of bioequivalence. 
7.5.3 
Analyses of Secondary Endpoint Outcome 
The secondary endpoint is the IGE score (see Appendix 11.2), expressed in terms of treatment 
success or failure.  Success is defined as an IGE score at Week 12 of 0 (clear) or 1 (almost 
clear).  Any other outcome will be considered a failure. Patients who are discontinued 
prematurely from the study due to lack of treatment effect after at least 8 weeks of compliant 
treatment will be considered as treatment failures both in the PP and mITT analyses.  Patients 
who do not have a valid Week 12 assessment for any other reason will be excluded from the 
PP analysis, but included in the mITT analysis using LOCF approach to impute the response. 
7.5.3.1 
Analysis of clinical equivalence of test and reference treatments 
A two-sided, continuity-corrected, 90% confidence interval on the Test-to-Reference 
difference for the proportion of patients with treatment success on the IGE will be constructed.  
Bioequivalence will be established if the 90% confidence interval for the difference is 
contained within the interval [-0.20, +0.20] for the PP population. 
Analysis of bioequivalence will be performed both on the PP population and on the mITT 
population.  The results on the PP population will be considered definitive and the results on 
the mITT population supportive. 
7.5.3.2 
Analysis of superiority to vehicle control 
The evaluation of superiority will be conducted separately for the Test treatment versus the 
Vehicle treatment and for the Reference treatment versus the Vehicle treatment, comparing 
the proportions of patients with treatment success on the IGE.  The analysis will be conducted 
using two-sided Fisher’s exact test.  
Superiority will be established if the success proportion for each active treatment is greater 
than, and statistically significantly different from (p < 0.05 for the Fisher’s test) that of the 


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Vehicle for the mITT population.  Analysis of superiority will be performed both on the PP 
population and on the mITT population.  The results on the mITT population will be 
considered definitive and the results on the PP population supportive. 
7.5.4 
Analyses of IGE 
Investigator Global Evaluation (IGE) expressed as severity grade 0 to 4 will be performed at 
each visit.  For study enrollment, the patient must have an IGE rosacea severity score of 3 at 
Baseline visit. 
Number and percentage of patient at each IGE severity grade will be tabulated by visit.  In 
addition, a shift table for changes in IGE grades from Baseline to each post-baseline visit will 
be created.  This analysis will be performed for both mITT and PP populations. 
7.6 
Safety Analyses 
7.6.1 
Adverse Events  
Adverse Events will be coded using the MedDRA, Version 18.0, AE coding system for 
purposes of summarization. 
Only Treatment Emergent Events (TEAEs) will be used for the summary analysis.  An AE 
will be considered as treatment-emergent if the time of onset is after the time of the first study 
drug administration or if it increased in severity during the study period.  AEs with unknown 
start dates will be counted as treatment-emergent unless the AE resolution date is prior to the 
study drug start date.  If the start date is partially missing, then month and year (when 
available) will be used to determine if the event occurred prior to or post dosing. 
A summary of the frequencies (number and percentage of patients) of TEAEs, serious TEAEs 
(AEs with missing seriousness will be treated as serious), treatment-related TEAEs will be 
presented by system organ class and preferred term.  Adverse events will also be analyzed by 
their severity (Mild, Moderate, Severe).  In case the severity was not assessed, the most 
conservative result – severe will be chosen for the analysis.  
A TEAE is termed as treatment-related if it is recorded as definitely, probably, or possibly 
related to the study medication on the CRF.  In case the relatedness was not assessed, the most 
conservative result – related will be chosen for the analysis.  


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A patient experiencing the same AE multiple times will only be counted once for that 
preferred term.  Similarly, if a patient experiences multiple AEs within the same system organ 
class, that patient will be counted only once in that system organ class.  All AEs will be listed 
in alphabetical order of SOC and preferred terms. 
An overall summary will include, by treatment group and overall, the number of TEAEs and 
the number and percentage of patients reporting at least 1 TEAE in the following categories: 
• Any TEAE, 
• Treatment-related TEAE, 
• Serious TEAE, 
• TEAE leading to discontinuation of the study medication. 
The following TEAE frequency tables will be prepared summarizing the overall number of 
TEAEs, the number and percentage of patients reporting at least one TEAE by MedDRA SOC 
and PT: 
• All TEAEs, 
• TEAEs by Severity, 
• TEAEs by Relationship to Study Medication. 
Additionally, TEAEs will be summarized by the preferred terms in the descending order of 
frequency in the total treatment group.  In this table a p-value from Fisher's exact test 
comparing event rates between the Test and the Reference treatment groups will be provided 
for those preferred terms that have frequency > 1% in either Test or Reference group. 
All information pertaining to adverse events noted during the study will be listed by patient, 
detailing verbatim, preferred term, system organ class, start date, stop date, intensity, outcome, 
action taken, and causal relationship to the study drug.  The adverse event onset will also be 
shown relative (in number of days) to the date of first administration of the study medication.  
In addition, the adverse event duration (if AE Stop Date is available) will be evaluated as 
below and presented (in number of days). 
                          AE Duration = AE Stop Date – AE Start Date + 1 
 


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7.6.2 
Signs/Symptoms of Local Irritation  
At each study visit, beginning with Visit 1, patients will be evaluated for any signs and 
symptoms of local irritation (application site reactions), including erythema, dryness, scaling, 
pruritus, burning/stinging and edema.  Baseline values will be used for comparative purposes 
against the scores documented at subsequent visits for each treatment group.  Each patient will 
be assigned a severity score by an Investigator based on the scale as presented in 
Appendix 11.3.  
Number and percentage of subjects with each severity will be presented by visit and by 
symptom. Additionally, the shifts from baseline in irritation score will be tabulated by site, 
treatment, symptoms and scheduled post-baseline visits. The denominator for the proportions 
will be the number of patients with evaluated signs and symptoms both at baseline and at 
given visit. 
7.6.3 
Exposure to Product 
The patients will be instructed to use the diary to document all doses taken by checking the 
yes or no box for the appropriate date and am/pm time.  The date(s) and reason for each 
dosing noncompliance must be recorded. 
Compliance with scheduled application of IP will be determined from the patient’s diary as 
[Number of recorded applications] / [Planned number of applications] * 100%, where Planned 
number of applications is 168. 
Number of missed doses will be calculated as follows.  The number of doses missed in the 
dosing period (between the first and the last study drug application) will be taken directly 
from the CRF.  Additionally, number of doses missed outside of the dosing period is the 
number of missed dosing times between the date and time (AM/PM) of the last dose and the 
date and time when the subject would have reached the required 168 doses (i.e. the date and 
time (AM/PM) of the first dose plus 84 days, inclusive).. 
Patients who have more than 6 consecutive missed doses will be considered non-compliant 
and will be excluded from the PP population. For the dosing period >6 consecutive 
applications will be collected directly on the eCRF. Additionally, patients will be considered 
having >6 consecutive missed doses if after the dosing period patients missed more than 6 


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dosing times after their last dose and prior to the morning of Visit 4 date or the date and time 
(AM/PM) when they would have reached the required 168 doses, whichever occurs earlier. 
Patients can be additionally excluded from the PP population due to non-compliance, if the 
Investigator's and Sponsor's review of their dosing times suggests a clinically meaningful 
departure from a twice-daily dosing pattern.   
Patients will be considered compliant if they apply at least 75% and not more than 125% of 
doses, with no more than 6 consecutive missed doses.  The compliance will be analyzed using 
the descriptive statistics by treatment group.  The proportion of compliant vs. non-compliant 
patients will be tabulated for each treatment. 
Duration of exposure will be calculated as Date of last use of study medication – Date of first 
use of study medication + 1.  Duration of exposure will be summarized descriptively by 
treatment group. 
Compliance and duration of exposure will be summarized for the Safety and mITT 
populations. 
7.6.4 
Exposure to Concomitant Medication 
Prior and concomitant medications and concomitant non-drug therapies, including the use of 
sunscreen, in addition to the reason for the medication use, will be assessed at baseline and at 
each subsequent study visit.  The start and stop date of concomitant medication use during the 
study will be provided in the data set, in addition to the reason for the medication use.  
Medication or non-drug therapy will be classified as prior, if the end date is known and is 
prior to the first use of the study medication.  Medications and non-drug therapies that are 
ongoing or ended after the first use of the study medication will be classified as concomitant.  
If the end date of the medication or non-drug therapy is unknown, it will also be considered 
concomitant. 
The concomitant medications will be summarized by preferred term for each treatment group 
as coded by the World Health Organization Drug (WHODRUG) dictionary Sept-2015 B2 and 
be listed in a by patient listings.  Prior medications will be listed only. 
8. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES  
There are no changes from the protocol-specified analyses. 


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9. 
LIST OF PLANNED TABLES, FIGURES, AND LISTINGS 
See separate document with the table, figure and listing shells. 
10. 
LITERATURE CITATIONS / REFERENCES 
1. Study Protocol: A Multicenter, Double-blind, Randomized, Parallel-group, Vehicle-
Controlled Study to Evaluate the Safety and Clinical Equivalence of a Generic Azelaic 
Acid Foam, 15% and the Reference Listed Finacea® (azelaic acid) Foam, 15% in 
Patients with Moderate Facial Rosacea. 
 


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11. 
APPENDICES 
11.1 
Study visit Schedule 
 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit Day 
Day 0 
Day 28±4 
Day 56±4 
Day 84±4 
Visit Name 
Baseline 
Interim 
Interim 
End of 
Treatment/ 
Early 
Termination 
Informed Consent  
X 
 
 
 
Demographics   
X 
 
 
 
Medical History 
X 
 
 
 
Inclusion/Exclusion Criteria  
X 
 
 
 
Physical Exam including Vital 
Signs  
X 
 
 
 
Pregnancy Test *   
X 
X 
X 
X 
Concomitant Medication  
X 
X 
X 
X 
Adverse Event  
 
X 
X 
X 
Inflammatory Lesion Counts   
X 
X 
X 
X 
Investigator’s Global 
Evaluation (IGE) 
X 
X 
X 
X 
Telangiectasia Assessment  
X 
 
 
 
Irritation Assessment   
X 
X 
X 
X 
Subject Instruction/Compliance 
Review  
X 
X 
X 
X 
Dispense Study Medication and 
Diary **  
X 
X 
X 
 
Collect Study Medication and 
Diary (Accountability)  
 
X 
X 
X 
 
* Urine pregnancy test for all females of childbearing potential enrolled in study. 
** Day 1 will occur the date patient begins dosing. This may be the evening of Visit 1 or the following day. 
 
11.2 
IGE Scale  
Score  
Grade 
Description  
0  
Clear 
No inflammatory lesions present; at most, mild erythema   
1  
Almost Clear 
Very mild erythema present. Very few small papules/pustules.  
2  
Mild 
Mild erythema. Several small papules/pustules. 


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3  
Moderate 
Moderate erythema. Several small or large papules/pustules, and 
up to 2 nodules. 
4 
Severe 
Severe erythema. Numerous small and/or large papules/pustules, 
up to several nodules.  
 
11.3 
Application Site Reactions Scores  
Erythema: 
Score  
Grade 
Definition  
0  
None 
No redness present.  
1  
Very Mild 
Slight pinkness.  
2  
Mild 
Pink to light red.  
3  
Moderate 
Definite redness, easily recognized.  
4 
Severe 
Marked erythema; fiery red.  
Dryness: 
Score  
Grade 
Definition  
0  
None 
No dryness.  
1  
Mild 
Slight but definite roughness.  
2  
Moderate 
Moderate roughness.  
3 
Severe 
Marked roughness.  
Scaling: 
Score  
Grade 
Definition  
0  
None 
No scaling.  
1  
Mild 
Barely perceptible shedding, noticeable only on light scratching 
or rubbing.  
2  
Moderate 
Obvious but not profuse scaling.  
3 
Severe 
Heavy scale production.  


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Pruritus: 
Score  
Grade 
Definition  
0  
None 
No itching.  
1  
Mild 
Slight itching but not bothersome.  
2  
Moderate 
Definite itching, somewhat bothersome without loss of sleep.  
3 
Severe 
Intense itching that has caused pronounced discomfort; 
interrupted sleep and excoriation of the skin may be present.  
Stinging/Burning: 
Score  
Grade 
Definition  
0  
None 
No stinging/burning.  
1  
Mild 
Slight warm tingling sensation but not bothersome.  
2  
Moderate 
Definite warm tingling/stinging sensation somewhat bothersome.  
3 
Severe 
Hot tingling/stinging sensation that has caused definite 
discomfort 
Edema: 
Score  
Grade 
Definition  
0  
None 
No swelling.  
1  
Mild 
Slightly or barely perceptible swelling.  
 
2  
Moderate 
Distinct presence of swelling.  
3 
Severe 
Marked or intense swelling.  
 
11.4 
Code Fragments  
ANOVA model for superiority analysis in primary endpoint 
proc glm data=<datasets name>; 
class <treatment> <center>; 
model <Percent change from baseline in lesion count at week 12> = <treatment> <center> 
<treatment>*< center>/ ss3; 
lsmeans <treatment> / pdiff cl; 


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output out=residuals residual=residual; 
run; 
quit; 
 
Note: this analysis needs to be performed separately for test and reference treatments on a 
dataset containing only test and vehicle or reference and vehicle treatment patients. If 
treatment-by-center interaction term is not significant at 0.05 level, the model will be rerun 
without this term. 
 
Superiority analysis in secondary endpoint 
proc freq data=<dataset> 
tables <treatment>*<success> / fisher; 
run; 
 
Note: this analysis needs to be performed separately for test and reference treatments on a 
dataset containing only test and vehicle or reference and vehicle treatment patients. 
 
Analysis of clinical equivalence in primary endpoint 
ANOVA model: 
proc glm data=<datasets name>; 
class <treatment> <center>; 
model <Percent change from baseline in each type of lesions at week 12> = <treatment> 
<center> <treatment>*<center>/ ss3; 
lsmeans <treatment> / stderr; 
output out=residuals residual=residual; 
run; 
quit; 
 
Here dataset contains test and reference treatment patients only. 
Note: if the treatment-by-center interaction term is not significant at the 0.05 level, the model 
will be rerun without this term. 
 
Fieller’s method.  
Generally, Fieller's formula allows to calculate the confidence interval for the ratio of two 
(possibly correlated) means of two samples a and b with expectations 
 and 
, and 
variances 
 and 
 and covariance 
. If 
 are all known, then a 
(1 − 2α) confidence interval (mL, mU) for 
 is given by 
 
where 


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Here 
 is an unbiased estimator of 
 based on r degrees of freedom, and 
 is the -level 
deviate from the Student's t-distribution based on r degrees of freedom. 
In the case of this study the two samples are independent (different patients), thus covariance 
can be assumed to be zero, and the formula simplifies to: 
 
 
where 
 
Here mt and set are mean and standard error estimate for test treatment and mr and ser for 
reference treatment correspondingly obtained from the above model. The degrees of freedom r 
can be obtained from the model as degrees of freedom for the error term in the overall 
ANOVA table, α = 0.05 (for the 90% confidence interval). The term tr,α can be calculated in 
SAS as tinv(α, r). 
Clinical equivalence analysis in secondary endpoint 
proc freq data=<dataset> 
tables <treatment>*<success> / riskdiffc; 
run; 
 
Note: this analysis needs to be performed on a dataset containing test and reference treatment 
patients only. 
 
Evaluation of skewness 
This evaluation will be performed on the residuals output by the "output" statement in 
PROCGLM above: 
proc univariate data=residuals; 
var residual; 
run; 
Non-parameteric rank ANOVA 
If decision to use the rank ANOVA is taken, the data will be ranked first: 


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proc rank data=<dataset> 
var <change_from_baseline>; 
ranks rank; 
run; 
After that the analysis will proceed using the same SAS code as described above but using 
rank variable instead of the original change from baseline.