Clinical trial NCT02385240
Conditions: Rosacea
Sponsor: Padagis LLC
Start date: 2015-03-01; Completion date: 2015-12-01
Enrollment: 552 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To compare safety and efficacy of Perrigo's rosacea drug product compared to an FDA approved rosacea drug product in the treatment of facial erythema of rosacea.

Detailed description:

Arms: arm 1: Brimonidine Topical Gel, 0.33 percent arm 2: Brimonidine Topical Gel, 0.33 percent (Reference) arm 3: Placebo
Interventions: intervention 1: Brimonidine Topical Gel, 0.33 percent (Perrigo) intervention 2: Brimonidine Topical Gel, 0.33 percent (Reference) intervention 3: Placebo gel
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_001.pdf: 
 
 
NCT02385240 
 
03-19-2015 


Protocol No.: PRG-NY-14-022 
 
 
1 
 
 
 
A Multi-Center, Double-Blind, Randomized, Vehicle-Controlled, Parallel-
Group Study to Compare Perrigo UK FINCO’s Brimonidine Topical Gel 
0.33% to Mirvaso® (Brimonidine) Topical Gel 0.33%, and Both Active 
Treatments to a Vehicle Control in the Treatment of Persistent (nontransient) 
Facial Erythema of Rosacea 
 
 
 
Protocol No.: PRG-NY-14-022 
 
 
 
 
 
 
 
 
 
Confidential 
 
The confidential information provided in this document is for use by parties directly 
involved in this investigation.  By accepting this document, you agree that the information 
contained herein will not be disclosed to any person not directly involved in this 
investigation without written authorization from Perrigo. 
 
 
 
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Protocol No.: PRG-NY-14-022 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 3 
1. 
BACKGROUND ............................................................................................................. 8 
2. 
STUDY OBJECTIVES ................................................................................................... 8 
2.1 
Endpoints ............................................................................................................................... 8 
2.2 
Safety ..................................................................................................................................... 8 
3. 
STUDY DESIGN ............................................................................................................. 8 
3.1 
Type/Design of Study ............................................................................................................ 8 
3.2 
Study Population .................................................................................................................... 9 
4. 
SELECTION AND WITHDRAWAL OF STUDY SUBJECTS ................................. 9 
4.1 
Inclusion Criteria ................................................................................................................... 9 
4.2 
Exclusion Criteria ................................................................................................................ 10 
4.3 
Precautions ........................................................................................................................... 12 
5. 
PROCEDURES ............................................................................................................. 12 
5.1 
Subject Screening and Enrollment ....................................................................................... 12 
5.2 
Assignment of Subject Number ........................................................................................... 12 
5.3 
Demographics/Medical History ........................................................................................... 12 
5.4 
Concomitant Medications .................................................................................................... 12 
5.5 
Physical Examination .......................................................................................................... 13 
5.6 
Urine Pregnancy Test ........................................................................................................... 13 
5.7 
Investigator Assessments ..................................................................................................... 13 
5.7.1 
Investigator‘s Global Assessment (IGA) of Lesions .....................................................13 
5.7.2 
Clinician‘s Erythema Assessment (CEA) ......................................................................14 
5.7.3 
Fitzpatrick Classification Scale ......................................................................................14 
5.8 
Patient Self-Assessment (PSA) ............................................................................................ 15 
5.9 
Diagnosis/ Enrollment Eligibility ........................................................................................ 15 
5.10 
Study Medication Use, Subject Instructions and Diary ....................................................... 15 
5.11 
Visit Specific Procedures ..................................................................................................... 16 
5.11.1 
Visit 1/Day 1 (Baseline) .................................................................................................16 
5.11.2 
Visit 2/End of study /treatment / Early Termination Visit /Day 15 (±2 days) ...............17 
5.11.3 
Unscheduled Visit ..........................................................................................................17 
5.12 
Summary of Assessments .................................................................................................... 18 
5.13 
Screen Failures ..................................................................................................................... 19 
5.14 
Protocol Deviations/Violations ............................................................................................ 19 
5.15 
Subject/Treatment Compliance ............................................................................................ 19 
5.16 
Discontinuation/Withdrawal of Study Subjects ................................................................... 19 
6. 
MATERIALS AND SUPPLIES ................................................................................... 20 
6.1 
Study Medication ................................................................................................................. 20 
6.2 
Medication Management ..................................................................................................... 21 
6.2.1 
Labeling, Packaging, Distribution and Randomization .................................................21 
6.2.2 
Retention Samples .........................................................................................................21 
6.2.3 
Storage and Study Medication Accountability ..............................................................22 
6.2.4 
Procedure for Breaking the Blind ..................................................................................22 
7. 
ADVERSE REACTIONS ............................................................................................. 22 
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Protocol No.: PRG-NY-14-022 
 
 
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7.1 
Deviation from the Protocol for Individual Subjects ........................................................... 23 
7.2 
Definitions ........................................................................................................................... 23 
7.3 
Eliciting and Reporting of Adverse Events ......................................................................... 24 
7.3.1 
Expedited Reporting Responsibilities of the Study Center ............................................25 
7.3.2 
Submitting an Expedited Safety Report to the IRB .......................................................26 
7.3.3 
SAE & AEs Requiring Discontinuation of Study Medication, including Pregnancies .26 
7.3.4 
Pregnancy .......................................................................................................................27 
7.4 
Post Study Adverse Events .................................................................................................. 28 
7.5 
Non-serious Adverse Events ................................................................................................ 28 
7.6 
Serious Adverse Events ....................................................................................................... 28 
8. 
STATISTICAL ANALYSIS ......................................................................................... 28 
8.1 
General Considerations ........................................................................................................ 28 
8.2 
Analysis Populations ............................................................................................................ 28 
8.3 
Planned Analysis .................................................................................................................. 29 
8.3.1 
Sample Size Considerations ...........................................................................................30 
8.3.2 
Efficacy Measures and Analysis ....................................................................................30 
8.3.3 
Safety and Adverse Events Analysis .............................................................................31 
8.4 
Comparability of Subjects at Baseline ................................................................................. 31 
9. 
CONSENT/ASSENT CONSIDERATIONS AND PROCEDURES ......................... 31 
9.1 
Subject Confidentiality ........................................................................................................ 32 
10. 
CONDUCT OF STUDY ............................................................................................... 33 
10.1 
Completion of Study ............................................................................................................ 33 
10.2 
Protocol Amendments .......................................................................................................... 33 
11. 
RECORDS MANAGEMENT ...................................................................................... 33 
11.1 
Data Collection .................................................................................................................... 33 
11.2 
Source Documents ............................................................................................................... 34 
11.3 
File Management at the Study Site ...................................................................................... 34 
11.4 
Records Retention at the Study Site ..................................................................................... 34 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 35 
12.1 
Monitoring ........................................................................................................................... 35 
12.2 
Auditing ............................................................................................................................... 35 
13. 
ETHICS AND RESPONSIBILITY ............................................................................. 35 
14. 
USE OF INFORMATION AND PUBLICATION ..................................................... 35 
15. 
APPENDICES ............................................................................................................... 38 
15.1 
Appendix A: Study Personnel Contacts ............................................................................... 38 
15.2 
Appendix B:  Instructions for the Subject ............................................................................ 39 
16. 
REFERENCES .............................................................................................................. 41 
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Protocol No.: PRG-NY-14-022 
 
 
5 
 
STUDY SYNOPSIS 
 
Title: 
A Multi-Center, Double-Blind, Randomized, Vehicle-Controlled, Parallel-
Group Study to Compare Perrigo UK FINCO‘s  Brimonidine Topical Gel 
0.33% to Mirvaso® (Brimonidine) Topical Gel 0.33%, and Both Active 
Treatments to a Vehicle Control in the Treatment of Persistent (nontransient) 
Facial Erythema of Rosacea 
Study Period: 
15 Days  
Study Medication: 
1. Brimonidine Topical Gel 0.33%, Perrigo Israel Pharmaceuticals, Ltd. 
2. Mirvaso® (Brimonidine) Topical Gel 0.33%, Galderma Laboratories, 
L.P. 
3. Vehicle of test product, Perrigo Israel Pharmaceuticals, Ltd. 
Study Objectives: 
To compare the safety and efficacy of Perrigo UK FINCO‘s Brimonidine 
Gel 0.33% to Mirvaso® (Brimonidine) Topical Gel 0.33% and to 
demonstrate the superior efficacy of the two active formulations over that of 
the vehicle in the treatment of persistent (nontransient) facial erythema of 
rosacea. 
Study Design: 
Subjects in this multi-center, double-blind, randomized, vehicle-controlled, 
parallel-group study will be admitted into the study only after written 
informed consent has been obtained and after all inclusion/exclusion criteria 
have been met.  Male and female subjects ≥ 18 years of age with persistent 
(nontransient) facial erythema of rosacea will be eligible for enrollment. 
Study Population: 
 healthy males and females, ≥ 18 years of age who meet 
the inclusion/exclusion criteria, will be enrolled to obtain 
 
modified intent-to-treat (mITT) subjects and 
 per-protocol (PP) subjects. 
Dosing: 
Subjects will be randomized 
 to either the test product, 
reference product or vehicle treatment group, respectively, and will apply 
 to each of the five areas of the face 
avoiding contact with the eyes and lips once daily for 15 days. 
Study Visits: 
Clinical Evaluations will be performed at: 
1. Visit 1/Day 1 (Baseline) 
2. Visit 2/Day 15 (±2 days)(End of Study/Treatment) 
Safety will be assessed by monitoring adverse events at each visit.  
Evaluations: 
 The Clinician‘s Erythema Assessment (CEA) will be administered at 
Visit 1/Day 1 and Visit 2/Day 15.  
 The Patient Self-Assessment (PSA) will be performed at Visit 1/Day 
1 and Visit 2/Day 15. 
 Investigator‘s Global Assessment (IGA) will be administered on 
Visit 1/Day 1 and Visit 2/Day 15 prior to study medication 
application. 
 The Fitzpatrick Classification Scale will be administered on Visit 
1/Day 1 prior to study medication application. 
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Protocol No.: PRG-NY-14-022 
 
 
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Endpoints: 
The primary efficacy endpoint will be the proportion of subjects with 
composite success on Day 15 at hour 6 post study medication application, 
where composite success is defined as at least a 2-grade improvement from 
Visit 1/Day 1 prior to the first application of study medication on both the 
Clinician‘s Erythema Assessment (CEA) and the Patient Self-Assessment 
(PSA) scales. 
 
The secondary endpoints will be: 
 
 The proportions of subjects with composite success on Day 15 at 
hours 3 and 9 post study medication application. 
Safety: 
The incidence of all adverse events reported during the study will be 
summarized by treatment group.  Equivalence of the test and reference with 
regard to safety will be evaluated by comparing the nature, severity and 
frequency of their adverse event profiles.   
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Protocol No.: PRG-NY-14-022 
 
 
7 
 
ABBREVIATIONS 
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
CEA 
Clinician‘s Erythema Assessment 
CMH 
Cochran–Mantel–Haenszel Test 
CRF 
Case Report Form 
DCF 
Data Correction Form 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IGA 
Investigator‘s Global Assessment 
IRB 
Institutional Review Board 
ITT 
Intent to Treat Population 
IUD 
Intra-Uterine Device 
LPN 
Licensed Practical Nurse 
LVN 
Licensed Vocational Nurse 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent To Treat population 
NP 
Nurse Practitioner  
OTC 
Over the Counter 
PA  
Physician‘s Assistant 
PI 
Principal Investigator 
PP 
Per Protocol Population 
PSA 
Patient Self-Assessment 
RN 
Registered Nurse 
Rx 
Prescription 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SPF 
Sun Protection Factor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: PRG-NY-14-022 
 
 
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5.8 
Patient Self-Assessment (PSA) 
Each subject‘s initial condition and course of erythema of rosacea will be assessed using the 
PSA. The patient will evaluate their facial erythema by performing a static evaluation of 
erythema severity using the PSA and report the number that best describes overall severity of 
their facial redness as seen in a mirror at the time of the evaluation. The PSA will be performed 
at Visit 1/Day 1 (Baseline) and Visit 2/Day 15 (End of Study/Treatment) prior to the application 
of study medication and at hours 3 (+15 minutes), 6 (+15 minutes) and 9 (+15 minutes) post 
study medication application for each visit. 
 
 
 
Study staff will instruct the subject on how to correctly perform the PSA at Visit 1/Day 1 
(Baseline) prior to the first application of study medication and as needed thereafter. 
 
Grade 
Description 
0 
No redness 
1 
Very mild redness 
2 
Mild redness 
3 
Moderate redness 
4 
Severe redness 
 
 
5.9 
Diagnosis/ Enrollment Eligibility 
At Visit 1/Day 1 (Baseline), prior to the first application of study medication, the investigator 
will examine the subject to establish the clinical diagnosis of persistent (nontransient) facial 
erythema of rosacea using the CEA scale. Each subject will also evaluate their facial erythema of 
rosacea using the PSA scale.  
 
Both the investigator (CEA) and subject (PSA) assessments should each yield a score of at least 
3 (moderate erythema) or 4 (severe erythema) in order for the subject to be enrolled in the study. 
 
5.10 
Study Medication Use, Subject Instructions and Diary 
At Visit 1/Day 1 (Baseline), study staff will dispense one 
 tube of study medication from 
the subject kit box to eligible subjects along with a diary card.  Each subject will also receive a 
copy of usage instructions and study precautions (Appendix B).  
 
The initial/first application on Visit 1/Day 1 (Baseline) will be applied by the subject at the site 
under the supervision of study staff not conducting clinical evaluations. The time of first 
application will be noted as Hour 0. The study staff will instruct the subject to apply all 
subsequent doses of the study medication (starting on Day 2 of study treatment period) similarly 
and to record each application in their study diary. On Visit 2/Day 15 (End of Study/Treatment) 
V 
Dark Brown; 
 
 
VI 
Black 
 
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Protocol No.: PRG-NY-14-022 
 
 
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4. The subject‘s medication code is unblinded. 
5. An adverse event occurs for which the study staff determines that it is in the subject‘s 
best interest to be discontinued. 
6. The subject is lost to follow-up.  The study staff will document efforts to attempt to reach 
the subject twice by telephone and will send a certified follow-up letter before 
considering that subject lost to follow-up. All attempts must be thoroughly recorded. 
7. The subject becomes pregnant during the course of the trial. 
8. Non-compliant use of the study medication  
9. Significant protocol violation or non-compliance with the study protocol that could 
interfere with the effect or accurate assessment of the assigned study treatment.  
 
 
After a subject has been enrolled, he/she will not be allowed to re-enroll in the study. 
 
In the event that a subject discontinues from the study at any time due to an adverse event, the 
reason for discontinuation, the nature of the event and its clinical course must be fully 
documented.  For such a subject, the investigator must strive to follow the subject until the 
adverse event has resolved, become clinically insignificant, is stabilized, or the subject is lost to 
follow-up.  
 
If the investigator assesses the subject‘s condition and determines that the subject‘s condition has 
worsened to the degree that it is unsafe for the subject to continue in the study, the subject may 
be discontinued from the study as a treatment failure, and a standard of care treatment may be 
advised at the investigator‘s discretion.  
 
The reason for a subject‘s discontinuation will be documented in the subject‘s source documents, 
case report form and the enrollment log.  
 
If a subject is discontinued from the study for any reason, the Day 15/End of Study Visit/Early 
Termination Visit procedures should be completed and any outstanding data and study 
medication should be collected.  Data, in addition to the reason for discontinuation and the date 
of removal, will be recorded on the End of Study Case Report Form. 
 
6. 
MATERIALS AND SUPPLIES 
 
6.1 
Study Medication 
The study medication supplied by Perrigo will consist of: 
 
Test Product: Brimonidine Topical Gel 0.33% - 
 
 
 
Reference Product: Mirvaso® (Brimonidine) Topical Gel 0.33%, - manufactured by 
Galderma Laboratories, L.P.  
 
Vehicle: Vehicle of test product - 
. 
 
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Protocol No.: PRG-NY-14-022 
 
 
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under conditions consistent with product labeling and in an area segregated from the area where 
testing is conducted and with access limited to authorized personnel. Each reserve sample shall 
be retained for a period of at least 5 years following the date on which the application or 
supplemental application is approved, or, if such application or supplemental application is not 
approved, at least 5 years following the date of completion of the bioavailability study in which 
the sample from which the reserve sample was obtained was used.‖ The investigator will store 
the retention sample study medication until such time as notification is received from Perrigo 
that the samples are no longer required. 
 
6.2.3 Storage and Study Medication Accountability 
Study medication used to conduct this study will be maintained under adequate security by the 
investigator.  Study test articles will be stored between 20-25°C (68-77°F) with excursions 
permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature] in 
a secured area with limited access.  Each investigative site will ensure that the temperature of 
study medication is monitored and recorded throughout the study. The medication should not be 
frozen, should be protected from heat and kept tightly closed. The investigator will not supply 
study test articles to any person not enrolled in this study, or to any physician or scientist except 
those named as sub-investigators.  
 
The study staff will keep a running inventory of study medication dispensed that will include 
subject numbers assigned and the date each is dispensed and used.  A study medication 
accountability form will be provided to the investigator to document all medications received, 
dispensed by and used by each subject.  At the conclusion of the study all unused, partially used, 
and empty containers must be inventoried by the monitor and returned to Perrigo, or designee, 
for destruction. 
 
6.2.4 Procedure for Breaking the Blind 
The investigator, staff at the study site, study monitors, and data analysis/management personnel 
are blinded to the subject assignment. In the event of an emergency, the specific subject 
treatment may be identified by removing the overlay of the blinded label, which is attached to 
the study medication log; however, every effort should be made to maintain the blind.  The 
investigator must not scratch off the occluding layer of the label unless absolutely necessary 
to provide medical treatment to a subject in an emergency situation only and should seek 
prior authorization by Perrigo or designee when possible. The reason for breaking the blind 
must be clearly documented in the source documentation and CRF and the subject must be 
discontinued from the study. Perrigo must be notified immediately upon all unblinding 
situations.  
 
7. 
ADVERSE REACTIONS 
The potential adverse reactions of generic Brimonidine Topical Gel 0.33% are anticipated to be 
similar to those observed in Mirvaso® (Brimonidine) Topical Gel 0.33%.  
 
In studies with Mirvaso® (Brimonidine) Topical Gel for 29 days, adverse reactions related to 
treatment reported by at least 1% of subjects treated for 29 days included erythema, flushing, 
skin burning sensation, contact dermatitis, dermatitis, warm skin, parasthesia, acne, skin pain, 
blurred vision, nasal congestions. 
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Protocol No.: PRG-NY-14-022 
 
 
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In an open label study with Mirvaso® (Brimonidine) Topical Gel for one year where other 
rosacea therapies were allowed, adverse reactions related to treatment included flushing, 
ertythema, rosacea, nasopharyngitis, burning skin sensation, increased intraocular pressure and 
headache. 
 
Allergic contact dermatitis to Mirvaso® (Brimonidine) Topical Gel was reported in 
approximately 1% of subjects across the clinical development program. One subject was found 
to be sensitive to brimonidine tartrate and one was subject was sensitive to a preservative 
phenoxyethanol. 
 
7.1 
Deviation from the Protocol for Individual Subjects 
When an emergency occurs requiring a subject‘s departure from the protocol this shall apply 
only for that subject.  In such circumstances, the investigator or other physician in attendance 
shall notify the Medical Monitor or Perrigo by telephone and follow up with a written 
description within one day. The overseeing IRB should also be notified. 
 
7.2 
Definitions 
An adverse event (AE) is defined as any untoward medical occurrence in a subject administered 
a medicinal product and which does not necessarily have to have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (for example, 
an abnormal laboratory finding), symptom, or disease temporally of the use of a medicinal 
product, whether or not considered related to this medicinal product.  
 
A serious adverse event (SAE) is an adverse event that results in any of the following outcomes: 
 death 
 life-threatening event (i.e., the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred.  It does not include an event that, had it 
occurred in a more severe form, might have caused death 
 requires in-subject hospitalization or prolongs hospitalization 
 a persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions 
 congenital anomaly/birth defect 
 Other adverse events that may be considered serious based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above, e.g. allergic bronchospasm requiring intensive 
treatment in an emergency room or home, blood dyscrasias or convulsions that do not 
result in hospitalization, or the development of drug dependency or drug abuse 
 
Immediately Reportable Adverse Events (IRAE): Any serious AE or any AE that necessitates 
discontinuation of study medication, including pregnancy. 
 
Unexpected Adverse Event: An unexpected event is any adverse drug experience, the specificity 
or severity of which is not consistent with the current approved product labeling (package insert) 
for the study medication, the Investigator‘s Brochure, or as described in the clinical protocol and 
consent materials.    
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Protocol No.: PRG-NY-14-022 
 
 
24 
 
 
Intensity of Adverse Events:  The maximum intensity of an AE during a day should be recorded 
on the CRF. If the intensity of an AE changes over a number of days, then separate entries 
should be made having distinct onset dates for the changes in severity. 
 
Mild - AEs are usually transient, requiring no special treatment, and do not interfere with 
subject‘s daily activities. 
 
Moderate - AEs typically introduce a low level of inconvenience or concern to the subject and 
may interfere with daily activities, but are usually ameliorated by simple therapeutic measures. 
 
Severe - AEs interrupt a subject‘s usual daily activity and traditionally require systemic drug 
therapy or other treatment. 
 
Causal Relationship to Study Medication: The following criteria should be used in assessing the 
apparent causal relationship of an AE to study medication.  
 
Definitely - The AE: 
• 
follows a reasonable temporal sequence from study medication administration. 
• 
abates upon discontinuation of the study medication (dechallenge). 
• 
is confirmed by reappearance of the reaction on repeat exposure. 
 
Probably - The AE: 
• 
follows a reasonable temporal sequence from study medication administration. 
• 
abates upon discontinuation of the study medication (dechallenge). 
• 
cannot be reasonably explained by the known characteristics of the subject‘s state. 
 
Possible - The AE: 
• 
follows a reasonable temporal sequence from study medication administration  
but that could readily be produced by a number of other factors. 
 
Unlikely - The AE: 
• 
follows a reasonable temporal sequence from study medication administration. 
• 
could have been produced by either the subject‘s clinical state or by study 
medication administration. 
 
Not related - The AE: 
• 
does not have a reasonable temporal association with the administration of study 
medication.  
• 
has some other obvious explanation for the event. 
 
7.3 
Eliciting and Reporting of Adverse Events 
The investigator will periodically assess subjects for the occurrence of adverse events.  In order 
to avoid bias in eliciting adverse events, the subject or parent/legally authorized representative 
should be asked a non-specific question (e.g., ―How have you been feeling since your last 
visit?‖) to assess whether any AE has been experienced since the last visit. All adverse events (as 
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Protocol No.: PRG-NY-14-022 
 
 
26 
 
should be sought (hospital discharge summaries, operative reports etc.) and a follow up SAE 
report form submitted.  A designation of causality from the study medication should always be 
included with a follow up report.  Assess and report the causality of the event. 
 
7.3.2 Submitting an Expedited Safety Report to the IRB 
Once 
 receives all supporting documentation for the reported event, the Medical Monitor, 
in conjunction with Perrigo, will determine if the safety report is eligible for expedited review. 
 will log the initial event and will notify Perrigo that an event has been reported within 1 
business day after initial receipt. 
 will complete the review of the event, enter information 
into their safety database and generate the report. This form, as well as other supporting 
documentation, will be forwarded to 
s Medical Monitor for review. 
 will finalize 
the report and distribute it to Perrigo within 2 days after initial receipt. When expedited safety 
reporting to regulatory authorities is indeed required, the Investigator should review and update 
any newly available materials at once. Follow-up queries may be sent to the study center to 
further clarify the event. 
 
Each expedited safety report will routinely include a brief cover memorandum, the completed 
report, and any additional pertinent information recommended by 
 Perrigo, or study 
Medical Monitor. Once the report is assembled, the Principal Investigator must submit the 
expedited safety report to the IRB within the required reporting timeframe. Follow-up reports 
should be submitted when requested or when pertinent information becomes available.  
 
When a Principal Investigator receives an expedited safety report from 
 or Perrigo 
detailing adverse events occurring at other study centers under this protocol, it must be promptly 
submitted to the study center‘s IRB.  The Principal Investigator must retain a copy of such 
reports as submitted to their IRB in the site‘s study Regulatory Binder. 
 
7.3.3 SAE & AEs Requiring Discontinuation of Study Medication, including Pregnancies 
ANY SAE, WHICH OCCURS AFTER A SUBJECT HAS ENTERED THE STUDY, 
WHETHER OR NOT RELATED TO STUDY MEDICATION, MUST BE REPORTED TO 
 AND/OR PERRIGO IMMEDIATELY (WITHIN 24 HOURS) VIA TELEPHONE OR 
FACSIMILE. IF INITIALLY REPORTED VIA TELEPHONE, THIS MUST BE FOLLOWED-
UP BY A FACSIMILE OF THE WRITTEN SAE REPORT WITHIN 24 HOURS OF THE 
CALL TO 
. 
 
Non-serious events that require discontinuation of study medication (including laboratory 
abnormalities) should be reported to Perrigo immediately and within 1 working day. 
Subjects who discontinue due to experiencing adverse events should be followed clinically until 
their health has returned to baseline status, or until all parameters have returned to normal. It is 
expected that the investigator will provide or arrange appropriate supportive care for the subject. 
 
A subject who experiences a severe adverse event related to study medication will be 
discontinued from the study. 
 
The notification about any serious adverse event should be directed to: 
 
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Protocol No.: PRG-NY-14-022 
 
 
28 
 
the event by phone and by faxing a completed SAE report form to 
 within one working 
day of being notified of the pregnancy report. 
 
If 
s responsibilities for the trial are completed before the outcome of the pregnancy is 
known, they must have a plan in place to conduct pregnancy outcome follow-up and notify 
Perrigo. 
 
7.4 
Post Study Adverse Events 
 
7.5 
Non-serious Adverse Events 
Adverse events that are identified at the last assessment visit (or the early termination visit) must 
be recorded on the AE case report form (CRF) with the status of the AE noted.   
 
7.6 
Serious Adverse Events 
Serious adverse events that are identified on the last assessment visit (or the early termination 
visit) must be recorded on the AE case report form (CRF) page and reported to Perrigo according 
to the procedures outlined above. Subjects with unresolved previously reported serious adverse 
events, or any new serious adverse events identified on the last assessment visit, should be 
followed by the investigator until the events are resolved, or the subject is lost to follow-up.  
Resolution means the subject has returned to the baseline state of health, or the investigator does 
not expect any further improvement or worsening of the adverse event.  The investigator should 
continue to report any significant follow-up information to Perrigo up to the point that the event 
has resolved.  Any serious adverse event reported by the subject to the investigator that occurs 
after the last assessment, and are determined by the investigator to be reasonably of the use of the 
study medication, should be reported to Perrigo. 
 
8. 
STATISTICAL ANALYSIS 
 
8.1 
General Considerations 
Statistical analyses will be conducted by the Sponsor‘s designee. The sections that follow 
highlight sample size determination and the planned analyses for this study. A statistical analysis 
plan (SAP) will be prepared separately from this protocol which gives descriptions of the 
statistical methods, models, hypotheses and subject populations to be analyzed. The SAP will be 
completed and finalized / approved before locking the database and unblinding the study and will 
serve as a companion to the protocol and the de facto documentation of the proposed statistical 
evaluation.   
 
8.2 
Analysis Populations 
The following populations are defined for the purpose of analyses: 
 Intent-to-Treat (ITT) (safety population):  Any subject who was randomized, received 
and used study medication. 
 
 Modified Intent-to-Treat (mITT):  Any subject, who met the inclusion/exclusion criteria, 
was randomized, received and used the study medication, and returned for at least one 
post-baseline efficacy assessment. 
 
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Protocol No.: PRG-NY-14-022 
 
 
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documented on a written informed consent/assent form, which shall be approved by the same 
Institutional Review Board (IRB) responsible for approval of this protocol. Each informed 
consent/assent form shall include the elements required by FDA regulations in 21 CFR Part 50.  
The investigator agrees to obtain approval from Perrigo of any written informed consent/assent 
form used in the study, preferably prior to submission to the IRB. 
 
Once the appropriate essential information has been provided to the subject and fully explained 
by the investigators (or a qualified designee) and it is felt that the subject understands the 
implications of participating, the IRB-approved written informed consent/assent form shall be 
signed by the subject (or their parent/legally authorized representative) and the person obtaining 
consent/assent (investigator or designee).  The subject shall be given a copy of the signed 
informed consent/assent form and the investigator shall keep the original on file. 
 
If the subject fails to meet the inclusion/exclusion criteria at the conclusion of the screening 
phase, the subject will be withdrawn from screening.  In the event that the subject is re-screened 
for study participation, a new informed consent/assent form must be signed. 
 
9.1 
Subject Confidentiality 
All study participants are concerned for the individual subject‘s privacy and, therefore, all 
subject data will be identified only by a subject identification number and subject initials. 
However, in compliance with federal guidelines regarding the monitoring of clinical studies and 
in fulfillment of his/her obligations to sponsor, it is required that the investigator permit the study 
monitor, any Sponsor authorized representative, and/or FDA representative to review that 
portion of the subject‘s medical record that is directly related to the study.  This shall include all 
study relevant documentation including subject medical histories to verify eligibility, laboratory 
test result reports to verify transcription accuracy, admission/discharge summaries for hospital 
stays occurring while the subject is enrolled in the study and autopsy reports for deaths occurring 
during the study. 
 
As part of the required content of informed consent, the subject must be informed that his/her 
medical chart may be reviewed by sponsor or their authorized representative, or a representative 
of the FDA.  Should access to the medical record require a separate waiver or authorization, it is 
the investigator‘s responsibility to obtain such permission from the subject in writing before the 
subject is entered into the study. 
 
To preserve the subject's confidentiality, the data collected will be available only to the 
investigators of the study, their support staff, sponsor or their authorized representative and 
possibly the FDA. 
 
All reports and communications relating to the subject in the study will identify each subject 
only by the subject‘s initials and by the subject number. The investigator agrees to furnish 
Perrigo with complete subject identification, if necessary on a confidential follow-up form, 
which will be used for the purpose of a long-term follow-up, if needed.  This will be treated with 
strict adherence to professional standards of confidentiality and will be filed at Perrigo under 
adequate security and restricted accessibility. 
 
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Protocol No.: PRG-NY-14-022 
 
 
33 
 
10. 
CONDUCT OF STUDY 
The investigational site is to maintain complete documentation of all events and the times at 
which they occur. 
 
10.1 
Completion of Study 
The investigational site will complete the study and complete all documentation required, in 
satisfactory compliance with the protocol. 
 
It is agreed that, for reasonable cause, either the investigator or sponsor may terminate this study 
before completion provided written notice is submitted at a reasonable time in advance of 
intended termination.  Any extension of this study must be mutually agreed upon in writing by 
both the investigator and Perrigo. 
 
10.2 
Protocol Amendments 
The Investigator will not make any changes to this protocol without prior written consent from 
sponsor and subsequent approval by the IRB.  Any permanent change to the protocol, whether it 
is an overall change or a change for specific study center(s), must be handled as a protocol 
amendment. Any amendment to the protocol that appears indicated as the study progresses will 
be fully discussed between CRO and sponsor. If agreement is reached regarding the need for an 
amendment, the amendment will be written by sponsor. The written amendment must be 
submitted to the chairman of the IRB identified with this responsibility. Except for 
‗administrative amendments‘, investigators must await IRB approval of protocol amendments 
before implementing the change(s). Administrative amendments are defined to have no effect on 
the safety of the research subjects, scope of the investigation, or quality of the trial.  However, a 
protocol change intended to eliminate an apparent immediate hazard to subjects should be 
implemented immediately, and the IRB notified within five days.  Sponsor will submit protocol 
amendments to the FDA or other regulatory agencies. 
 
When, in the judgment of the reviewing IRB, the investigators and/or sponsor, the amendment to 
the protocol substantially alters the study design and/or increases the potential risk to the subject, 
the currently approved written informed consent form will require similar modification.  In such 
cases, repeat informed consent will be obtained from subjects enrolled in the study before 
expecting continued participation. 
 
11. 
RECORDS MANAGEMENT 
 
11.1 
Data Collection 
All data collected in this study will be entered onto case report forms (CRFs), verified by 
monitoring, and submitted for statistical evaluation as described below.  Checks will be run on 
the data and queries issued as needed. Once all data is cleaned, full quality control verification 
will be done prior to breaking the blind. After all data are correctly entered, the database will be 
locked and submitted for appropriate Quality Assurance verifications before the treatment 
assignment code is broken.  All data collected in the CRFs will be documented in subject data 
listings and summarized in tables, as appropriate. 
 
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Protocol No.: PRG-NY-14-022 
 
 
34 
 
During each subject‘s visit to the clinic, a designee participating in the study will record progress 
notes to document all significant observations.  At a minimum, these notes will contain: 
 
a) Documentation of the informed consent process; 
b) The date of the visit and the corresponding Visit Day in the study schedule; 
c) General subject status remarks, including any significant medical findings.  The severity 
and duration of any adverse events and the investigator's assessment of relationship to 
study medication must also be recorded. 
d) Any changes in concomitant medications or dosages; 
e) A general reference to the procedures completed; and 
f) The signature (or initials) and date of all clinicians who made an entry in the progress 
notes. 
 
In addition, any contact with the subject via telephone or other means that provides significant 
clinical information will also be documented in the progress notes as described above. 
 
Any changes to information in the study progress notes and other source documents, will be 
entered in black ink, initialed and dated by the authorized person making the 
correction/addition.  Changes will be made by striking a single line through erroneous data, and 
clearly entering the correct data.  (e.g., wrong data right data).  Entries may not be erased or 
masked with white-out fluid.  If the reason for the change is not apparent, a brief explanation for 
the change will be written adjacent to the change by the clinician. 
 
For transmission to sponsor, information from the study progress notes and other source 
documents will be promptly entered into the CRF/database.  The database also contains a 
complete audit trail which will automatically generate a time-stamped audit trail including the 
date, time, login ID of the initial entry as well as any subsequent change, addition, or deletion of 
database information. 
 
11.2 
Source Documents 
Source documents are defined as the results of original observations and activities of a clinical 
investigation.  Source documents will include, but are not limited to, progress notes and 
screening logs.  All source documents pertaining to this study will be maintained by the 
investigators and made available for inspection by authorized persons.  The original signed 
informed consent form for each participating subject shall be filed with records kept by the 
investigators and a copy given to the subject. 
 
11.3 
File Management at the Study Site 
It is the responsibility of the investigator to ensure that the study center file is maintained in 
accordance with Section 8 of the International Conference on Harmonization (ICH) Guideline 
for Good Clinical Practices (GCP). 
 
11.4 
Records Retention at the Study Site 
FDA regulations require all investigators participating in clinical drug studies to maintain 
detailed clinical data for one of the following periods: 
 
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Protocol No.: PRG-NY-14-022 
 
 
35 
 
a) A period of at least two years following the date on which a New Drug Application is 
approved by the FDA; 
b) A period of two years after sponsor notifies the investigator that no further application is 
to be filed with the FDA. 
 
The investigator must not dispose of any records relevant to this study without either (1) written 
permission from sponsor or (2) providing an opportunity for sponsor to collect such records.  The 
investigator shall take responsibility for maintaining adequate and accurate electronic or hard 
copy source documents of all observations and data generated during this study, including any 
data correction forms (DCFs) received from CRO. Such documentation is subject to inspection 
by sponsor and the FDA. 
 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
12.1 
Monitoring 
Perrigo has ethical, legal and scientific obligations to carefully follow this study in a detailed and 
orderly manner in accordance with established research principles and FDA regulations.  All 
medical records (source documents) of the subjects participating in this study must be presented 
for review and verification of CRFs. 
 
12.2 
Auditing 
Perrigo (or representative) may conduct audits at the study center(s).  Audits will include, but are 
not be limited to, drug supply, presence of required documents, the informed consent process, 
and comparison of case report forms with source documents.  The investigator agrees to 
participate with audits conducted at a reasonable time in a reasonable manner. 
 
Regulatory authorities worldwide may also audit the investigator during or after the study. The 
investigator should contact sponsor immediately if notified of such an audit, and must fully 
cooperate with the audits conducted at a reasonable time in a reasonable manner. 
 
13. 
ETHICS AND RESPONSIBILITY 
This study must be conducted in compliance with the protocol, the United States Food and Drug 
Administration (FDA) regulations, any other countries regulations, and ICH GCP Guidelines. 
 
14. 
USE OF INFORMATION AND PUBLICATION 
All information supplied by the sponsor in connection with this study and not previously 
published, is considered confidential information. This information includes, but is not limited 
to, data, materials (i.e. the clinical protocol, case report forms), equipment, experience (whether 
of a scientific, technical, engineering, operational, or commercial nature), designs, specifications, 
know-how, product uses, processes, formulae, costs, financial data, marketing plans and direct 
selling systems, customer lists and technical and commercial information relating to customers 
or business projections used by sponsor in its business. Any data, inventions, or discoveries 
collected or developed, as a result of this study is considered confidential. This confidential 
information shall remain the sole property of sponsor, shall not be disclosed to any unauthorized 
person or used in any unauthorized manner without written consent of sponsor, and shall not be 
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Protocol No.: PRG-NY-14-022 
 
 
37 
 
INVESTIGATOR AGREEMENT 
 
PROTOCOL NUMBER:  PRG-NY-14-022 
 
PROTOCOL TITLE: 
A Multi-Center, Double-Blind, Randomized, Vehicle-Controlled, 
Parallel-Group Study to Compare Perrigo UK FINCO‘s Brimonidine 
Topical Gel 0.33% to Mirvaso® (Brimonidine) Topical Gel 0.33%, and 
Both Active Treatments to a Vehicle Control in the Treatment of 
Persistent (nontransient) Facial Erythema of Rosacea 
 
 
I have carefully read the foregoing protocol and agree that it contains all the necessary 
information for conducting this study safely.  I will conduct this study in strict accordance with 
this protocol, ICH Guidelines for Good Clinical Practices, the Code of Federal Regulations, the 
Health Insurance Portability and Accountability Act (HIPAA) and any local regulatory 
requirements and will attempt to complete the study within the time designated.  I will provide 
access to copies of the protocol and all other information relating to pre-clinical and prior clinical 
experience submitted by Perrigo to all personnel responsible to me who participate in the study.  
I will discuss this information with them to assure that they are adequately informed regarding 
the drug and conduct of the study. I agree to keep records on all subject information in 
accordance with FDA regulations. 
 
 
 
 
 
 
 
 
   Principal Investigator‘s Printed Name 
 
 
 
 
 
 
 
 
   Principal Investigator‘s Signature 
 
 
 
 
 
 
 
   Date 
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Protocol No.: PRG-NY-14-022 
 
 
41 
 
16. 
REFERENCES 
 
1. The Merck Manual - www.merckmanuals.com 
2. Summary Basis of Approval Mirvaso® (Brimonidine) Topical Gel, 0.33% 
3. Package insert Mirvaso® (Brimonidine) Topical Gel, 0.33% dated August-2013 
4. www.mirvaso.com 
5. Azelaic Acid Draft Guidance Bioequivalence recommendations: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM212602.pdf  
Page 42 of 42

SAP_000.pdf: 
 
 
NCT02385240 
 
03-19-2015 








Perrigo New York Inc.                                                                                                                  Protocol: PRG-NY-14-022 
                                                                                                                                                                     
 
3  
CONFIDENTIAL 
List of Abbreviations 
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
CEA 
Clinician’s Erythema Assessment 
CI 
Confidence Interval 
CMH 
Cochran–Mantel–Haenszel Test 
IGA 
Investigator’s Global Assessment 
ITT 
Intent-to-Treat (Population) 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat (Population) 
PD 
Protocol Deviation 
PP 
Per-Protocol (Population) 
PSA 
Patient Self-Assessment 
PV 
Protocol Violation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
WHO Drug 
World Health Organization Drug Dictionary 
 
 
 
 
 
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Perrigo New York Inc.                                                                                                                  Protocol: PRG-NY-14-022 
                                                                                                                                                                     
 
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5.5.2 Secondary Endpoints 
The secondary efficacy endpoints will be the proportions of subjects with composite success at 
hours 3 and 9 on Day 15, proportion of subjects with composite success at all three hours 3, 6 
and 9 on Day 15 and the proportion of subjects with composite success at all three hours: 3, 6 
and 9 on Day 1. The same analysis from the primary efficacy endpoint will be applied to 
second endpoints. 
5.5.3 Other Endpoint 
Investigator’s Global Assessment (IGA) will be evaluated on Visit 1/ Day 1 (Baseline) and 
Visit 2/Day 15 (End of Study/Treatment) prior to each visits’ application of study medication. 
They will be summarized descriptively. 
5.6 
Safety Variables and Analyses 
Duration of Treatment and Medication Compliance 
Number of applications, days of exposure, and compliance rate will be summarized by 
treatment group using descriptive statistics. For each subject, the overall duration of treatment 
(days) will be calculated using the following formula: 
(Date of last application of study medication) - (Date of first application of study medication) 
+ 1. 
Medication compliance rate (%) will be calculated for each subject as follows: 
(Total number of applications used) / (Expected number of applications) *100%. 
Subjects who complete the study are expected to have 15 applications. For prematurely 
discontinued subjects, expected number of applications will be determined based on the 
expected number of applications by the time of discontinuation, i.e. the overall duration of 
treatment. Descriptive summaries of exposure and medication compliance rate will be 
provided by treatment group for the ITT subjects 
Adverse Events 
Adverse events (AEs) will be coded in MedDRA, version 15.1. Treatment-Emergent Adverse 
Event (TEAE) is defined as any AE occurs on or after applying the first dose of study drug. 
Number and percent of subjects reporting TEAEs will be tabulated by treatment group. 
Summaries will be presented by body system and preferred term for the ITT population, and 
further by severity and relationship to study medication. 
 
 In the summaries of incidence rates 
(frequencies and percentages), severity and relationship to study drug, subjects who report 
more than one event that are mapped to the same preferred term will be counted only once 
under the strongest severity and relationship, accordingly. Fisher’s exact test will be used to 
compare the proportions of subjects of the two active treatment groups who report any TEAE. 
Treatment-Emergent Serious Adverse Events (TESAEs) will be discussed within the clinical 
study report. TESAEs and TEAEs that led to treatment interruption or discontinuation will be 
presented in data listings. 
 
Concomitant Medications 
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Perrigo New York Inc.                                                                                                                  Protocol: PRG-NY-14-022 
                                                                                                                                                                     
 
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CONFIDENTIAL 
Concomitant medications will be coded using the WHO Drug Dictionary, version September 
2014, and will be presented in data listings. 
 
. 
6 
Appendices 
6.1 
Handling of Missing or Incomplete Dates for Adverse Events and Concomitant Medications 
Adverse Events 
Handling of partial dates is only considered for the start date. An adverse event with a partial 
start date is considered treatment emergent if: 
- only the day is missing and the start month/year is the same or after the month/year of the 
first dose 
- the day and month are missing and the start year is the same or greater than the year of the 
first dose date 
- the start date is completely missing 
Concomitant Medications 
Handling of partial dates is only considered for the stop date. A medication with a partial stop 
date is considered concomitant if: 
- only the day is missing and the stop month/year is the same or after the month/year of the 
first dose 
- the day and month are missing and the stop year is the same or greater than the year of the 
first dose date 
- the stop date is completely missing or the medication is ongoing 
6.2 
Summary of Assessments 
The schedule of visits and procedures to be conducted at each visit are summarized in the 
Schedule of Study Procedures. 
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