Post on 22-Nov-2015
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 2 of 51
2.0 KEY STUDY PERSONNEL AND FACILITIES
Sponsor:
Watson Laboratories, Inc., USA
400 Interpace Parkway
Parsippany, NJ 07054
CRO:
Novum Pharmaceutical Research Services (Novum)
5900 Penn Avenue
Pittsburgh, PA 15206
Sponsors Representative:
Nageshwar R. Thudi, PhD
Director, Biopharmaceutics
Watson Laboratories, Inc., USA
Morris Corporate Center III
400 Interpace Parkway, Parsippany, NJ 07054
Tel: 862-261-7548
Fax: 862-261-9711
Email: nageshwar.thudi@actavis.com
CRO representative:
Gail Gongas
Vice President, Clinical Trials
Novum Pharmaceutical Research Services
5900 Penn Ave., Pittsburgh, PA 15206
Tel: 412-363-3300 x 522
Fax: 412-362-5783
Email: gdgongas@novumprs.com
Medical Monitor:
Darin B. Brimhall, DO, FACP,CPI
Medical Monitor
Novum Pharmaceutical Research Services
3760 Pecos McLeod
Las Vegas, NV 89121
Tel: 702-435-3739 x370
Fax: 412-291-3171
Email: dbrimhall@novumprs.com
Biostatistician:
Jianhua Liu, MSc
Senior Biostatistician
Novum Pharmaceutical Research Services
5900 Penn Ave.
Pittsburgh, PA 15206
Tel: 647-779-6883
Fax: 412-924-0522
Email: JLiu@novumprs.com
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 4 of 51
PRINCIPAL INVESTIGATORS SIGNATURE
I _______________________________________, agree to conduct protocol 71304906 A Randomized,
Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to
Reference Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in
Patients with Moderate to Severe Facial Erythema Associated with Rosacea in accordance with FDA
regulations, ICH guidelines and Good Clinical Practice. I understand that no deviations from the protocol
may be made without the prior permission of the Sponsor (Watson Laboratories, Inc., USA) or Novum
Pharmaceutical Research Services, the company managing the study.
___________________________________ __________
Principal Investigator Date
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 5 of 51
3.0 TABLE OF CONTENTS
1.0 TITLE PAGE ................................................................................................................................... 1
2.0 KEY STUDY PERSONNEL AND FACILITIES ............................................................................ 2
3.0 TABLE OF CONTENTS ................................................................................................................. 5
4.0 SYNOPSIS ....................................................................................................................................... 8
5.0 STUDY SCHEMATIC ................................................................................................................... 14
6.0 LIST OF ABBREVIATIONS AND TERMS ................................................................................. 15
7.0 INTRODUCTION ......................................................................................................................... 16
7.1 Disease Being Treated ................................................................................................................ 16
7.2 Availability and Efficacy of Already Approved Therapies ........................................................ 16
7.3 Scientific and Statistical Considerations ..................................................................................... 16
7.4 Justification for use of Placebo ................................................................................................... 18
7.5 Risks and Benefits ....................................................................................................................... 18
8.0 STUDY OBJECTIVES ................................................................................................................... 18
9.0 INVESTIGATIONAL PLAN ......................................................................................................... 19
9.1 Study Design and Plan Description ............................................................................................ 19
9.2 Selection of Study Design ........................................................................................................... 20
9.3 Selection of Study Population ..................................................................................................... 20
9.3.1 Inclusion Criteria................................................................................................................. 20
9.3.2 Exclusion Criteria ............................................................................................................... 21
9.3.3 Restrictions During The Study ............................................................................................ 23
9.3.4 Removal of Patients from the Study ................................................................................... 25
9.4 Treatments ................................................................................................................................... 25
9.4.1 Treatments Administration ................................................................................................. 25
9.4.2 Identity of Study Products ................................................................................................... 26
9.4.3 Method of Assigning Patients to Treatment Groups ........................................................... 27
9.4.4 Study Blind ......................................................................................................................... 27
9.4.5 Compliance ......................................................................................................................... 28
9.5 Study Conduct ............................................................................................................................. 28
9.5.1 Visit 1 (Day -14 to 1): Screening ........................................................................................ 28
9.5.2 Visit 2 (Day 1): Randomization .......................................................................................... 29
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 6 of 51
9.5.3 Visit 3 (Day 7 1): Study Completion or Early Discontinuation ....................................... 30
9.6 Study Procedures ........................................................................................................................ 32
9.6.1 Informed Consent ................................................................................................................ 32
9.6.2 Demographics ..................................................................................................................... 32
9.6.3 Medical History................................................................................................................... 32
9.6.4 Vital Signs ........................................................................................................................... 32
9.6.5 Lesion Count ....................................................................................................................... 32
9.6.6 Concomitant Medication Use .............................................................................................. 32
9.6.7 Pregnancy Test .................................................................................................................... 32
9.6.8 Dispensing Study Drug ....................................................................................................... 33
9.6.9 Collecting Study Drug ........................................................................................................ 33
9.6.10 Dosing Instructions and Diary ............................................................................................ 33
9.6.11 Dosing Compliance ............................................................................................................. 34
9.6.12 Clinical Assessments............................................................................................................ 34
9.7 Adverse Events ........................................................................................................................... 34
9.7.1 Definitions ........................................................................................................................... 35
9.7.2 Severity of Adverse Events .................................................................................................. 35
9.7.3 Causality Assessment ........................................................................................................... 35
9.8 Serious Adverse Events ................................................................................................................. 36
9.8.1 Definition of a Serious Adverse Event ................................................................................. 36
9.8.2 Reporting Serious Adverse Events ..................................................................................... 36
10.0 STATISTICAL METHODS ........................................................................................................... 37
10.1 Statistical Plan ............................................................................................................................. 37
10.2 Determination of Sample Size .................................................................................................... 37
10.3 Study Populations ....................................................................................................................... 38
10.3.1 Per Protocol (PP) Population .............................................................................................. 38
10.3.2 Modified Intent-to-Treat (mITT) Population ...................................................................... 39
10.3.3 Safety Population ................................................................................................................ 39
10.4 Baseline Comparability ............................................................................................................... 39
10.5 Efficacy Endpoints ...................................................................................................................... 40
10.6 Bioequivalence ............................................................................................................................ 40
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 7 of 51
10.7 Superiority to Placebo Analysis ................................................................................................. 40
10.8 Safety Analysis ........................................................................................................................... 40
11.0 REGULATORY OBLIGATIONS .................................................................................................. 41
11.1 Institutional Review Board ......................................................................................................... 41
11.2 Study Documentation .................................................................................................................. 41
11.2.1 Protocol ............................................................................................................................... 41
11.2.2 Informed Consent ................................................................................................................ 41
11.2.3 Protocol and Informed Consent Changes ............................................................................ 42
11.2.4 Source Documents and Case Report Forms ........................................................................ 42
11.2.5 Drug Accountability ............................................................................................................ 42
11.2.6 Drug Storage ....................................................................................................................... 42
11.2.7 Retention of Reserve Samples ............................................................................................ 42
11.2.8 Return of Clinical Supplies ................................................................................................. 43
11.2.9 Pregnancies ......................................................................................................................... 43
11.2.10 Withdrawals due to Adverse Events ................................................................................... 43
11.2.11 Reporting Safety Information to the IRB ........................................................................... 43
11.2.12 Record Retention................................................................................................................ 44
11.2.13 Study Monitoring and Auditing.......................................................................................... 44
11.2.14 End of the Trial ................................................................................................................... 44
11.2.15 Clinical Study Report ......................................................................................................... 44
11.2.16 Termination of the Study .................................................................................................... 45
12.0 REFERENCES ............................................................................................................................... 46
13.0 APPENDICES ................................................................................................................................ 48
13.1 Appendix A ..................................................................................................................................... 48
13.2 Appendix B ..................................................................................................................................... 49
13.3 Appendix C ..................................................................................................................................... 50
13.4 Appendix D ..................................................................................................................................... 51
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 8 of 51
4.0 SYNOPSIS
Protocol
Number
71304906
Title A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design
Study to Evaluate the Safety and Therapeutic Equivalence of Brimonidine Topical
Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference Product Mirvaso
(brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with
Moderate to Severe Facial Erythema Associated with Rosacea
Objectives 1. Evaluate therapeutic equivalence and safety of the test formulation Brimonidine
Topical Gel, 0.33%, 30 gram fill (Watson Laboratories, Inc., USA) and the RLD
Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in
the treatment of moderate to severe facial erythema associated with rosacea.
2. Demonstrate the superiority of the efficacy of the test and reference products over
a placebo (vehicle) gel in the treatment of moderate to severe facial erythema
associated with rosacea.
3. Compare the safety of test, reference and placebo treatments in patients with facial
erythema associated with rosacea.
Sponsor Watson Laboratories, Inc., USA
400 Interpace Parkway
Parsippany, NJ 07054
Study Products Test (A): Brimonidine Topical Gel, 0.33%, 30 gram fill (Watson Laboratories,
Inc., USA)
Reference (B): Mirvaso (brimonidine) topical gel, 0.33% (Galderma
Laboratories, L.P., USA)
Placebo (C): Topical gel base only (Watson Laboratories, Inc., USA)
Route of
Administration Topical application to the face
Treatment
Randomization 3:3:1 (Test: Reference: Placebo)
Patient
Population
Up to 462 patients 18 years of age and older, with confirmed clinical diagnosis of
rosacea will be enrolled to have 413 in the modified intent-to-treat (mITT) population
and 371 in the per-protocol (PP) population. Patients should have fewer than 3 facial
inflammatory lesions, and moderate to severe erythema according to both Clinicians
Erythema Assessment (CEA) and Patients Self-Assessment (PSA).
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 9 of 51
Study Design Patients will complete 3 visits:
Visit 1 Screening (Day -14 to Day 1): Erythema severity will be assessed.
Visit 2 Randomization (Day 1): Eligible patients will receive randomized study
medication; first dose will be applied in the clinic; clinical assessment for
erythema will occur prior to dosing (pre-dose) and 6 hours ( 10 minutes) post-
dose.
Visit 3 End of Treatment (Day 7 1): The last dose will be applied in the clinic
on Day 7 ( 1); clinical assessment for erythema will occur prior to dosing (pre-
dose) and 6 hours ( 10 minutes) post-dose.
Patients will apply the study medication once-daily at home on non-clinic visit days
(Days 2-6). Erythema severity will be assessed on Day 1 (pre- and post-application)
and Day 7 (pre- and post-application), using CEA and PSA scores. Post-application
assessments will be relative to baseline (pre-dose) assessments on the application day.
Inclusion
Criteria 1. Male or non-pregnant, non-lactating female, 18 years of age or older.
2. Signed informed consent form, which meets all criteria of current FDA
regulations.
3. Females of child bearing potential must not be pregnant or lactating at
Screening and Randomization (as confirmed by a negative urine pregnancy
test with a sensitivity of less than 25 mlU/mL or equivalent units of human
chorionic gonadotropin). Women of childbearing potential must agree to the
use of a reliable method of contraception (e.g., total abstinence, IUD, a
double-barrier method [such as condom plus diaphragm with spermicide],
oral, transdermal, injected or implanted non- or hormonal contraceptive),
throughout the study. A sterile sexual partner is not considered an adequate
form of birth control.
All females will be considered to be of childbearing potential unless they:
Are post-menopausal, defined as women who have been amenorrheic
for at least 12 consecutive months, without other known or suspected
primary cause.
Have been sterilized surgically or who are otherwise proven sterile
(i.e., total hysterectomy, or bilateral oophorectomy) with surgery at
least 4 weeks prior to Screening. Tubal ligation will not be considered
a surgically sterile method.
Female patients of childbearing potential are defined as:
Women without prior hysterectomy, or who have had any evidence of
menses in the past 12 months.
Females who have been amenorrheic for 12 months, but the
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 10 of 51
amenorrhea is possibly due to other causes, including prior
chemotherapy, anti-estrogens, or ovarian suppression.
4. Have a clinical diagnosis of facial rosacea and fewer than 3 inflammatory
lesions on the face at Screening and at Randomization (before drug
application on Day 1).
5. Have moderate to severe facial erythema according to both CEA and PSA
(i.e., an erythema score of 3 or more for each of the CEA and PSA) at
Screening and at Randomization (before drug application on Day 1).
6. Free from any systemic or dermatologic disorder (other than rosacea) that, in
the opinion of the Investigator, will interfere with the study evaluations or
increase the risk of AEs.
7. Willing to minimize external factors that might trigger rosacea flare-ups (e.g.,
hot environments, prolonged sun exposure, strong winds and emotional stress)
within 24 hours of the Screening and Randomization visit.
8. Any skin type or race, providing the skin pigmentation will allow discernment
of erythema.
9. Willingness and capability to cooperate to the extent and degree required by
the protocol.
Exclusion
Criteria 1. Patients with particular forms of rosacea (rosacea conglobata, rosacea
fulminans, isolated rhinophyma, isolated pustulosis of the chin) or other
concomitant facial dermatoses similar to rosacea, such as peri-oral dermatitis,
demodicidosis, facial keratosis pilaris, seborrheic dermatitis, acute lupus
erythematosus, or actinic telangiectasia, that are present on the face (i.e., 5
areas: chin, nose, both cheeks, and forehead), that in the opinion of the
Investigator would interfere with study evaluations.
2. Have 3 or more facial inflammatory lesions of rosacea.
3. Have an erythema score of 2 (mild), 1 (almost clear), or 0 (clear) on the CEA
and/or the PSA at Screening and at Randomization (before drug application
on Day 1).
4. Patients with excessive facial hair (beards, sideburns, moustaches, etc.) that
would interfere with the diagnosis or assessment of rosacea.
5. Patients with moderate to severe telangiectasial masses in the 5 areas of the
entire face: forehead, chin, nose and each cheek, that would interfere with
study evaluations.
6. History of hypersensitivity or allergy to Mirvaso including the active
ingredient brimonidine tartarate or other component within the formulation.
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 11 of 51
7. Facial laser surgery for telangiectasia (or other conditions) within 6 weeks
prior to randomization.
8. Exposed to excessive ultraviolet (UV) radiation within 1 week before
Screening or Randomization visit and/or patient was unwilling to refrain from
excessive exposure to UV radiation during the course of the study.
9. History of blood dyscrasia.
10. Current diagnosis of Raynauds syndrome, thromboangiitis obliterans,
orthostatic hypotension, severe cardiovascular disease, cerebral or coronary
insufficiency, renal or hepatic impairment, scleroderma, Sjgrens syndrome,
or depression, or any other condition causing uncontrolled blood flow or
blood pressure.
11. Females who are pregnant, lactating or likely to become pregnant during the
study.
12. Significant history or current evidence of chronic infectious disease, system
disorder, organ disorder or other medical condition that in the Investigators
opinion would place the study patient at undue risk by participation.
13. Patients with severe, unstable or uncontrolled cardiovascular disease.
14. Patients who meet study restrictions at Screening and Randomization and/or
unwillingness to comply with all restricted treatments as detailed in section
9.3.3 of this protocol.
15. Receipt of any drug as part of a research study within 30 days before dosing.
16. Employees of the research center or Investigator.
17. Previous participation in this study.
18. Patients who are unable and/or unwilling to follow the study requirements,
and procedures.
Treatment
Administration
The patients will wash their face with Dove facial soap and gently dry before each
study gel application. At Randomization (Visit 2), a designated site staff member will
administer the first dose of randomized study medication with a gloved hand (a thin
application of pea-sized amount to each of the 5 areas of the entire face: forehead,
chin, nose and each cheek), preferably in the morning or early afternoon.
Patients will be asked to dose at home for non-clinic visit days (Days 2-6), one
application daily, at approximately the same time each day (preferably in the morning
or early afternoon), as per provided dosing instructions. Patients will return to the
clinic on Day 7 ( 1) for application of the last treatment by a designated gloved site
staff member.
Clinical
Assessments
Erythema will be assessed based on a 5-point scoring scale in the clinic by an
Investigator (CEA) and a patient (PSA) at baseline (pre-dose) and at 6 hours ( 10
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 12 of 51
minutes) post-dose on Days 1 and 7 ( 1). Refer to Appendix A.
Confinement Patients will enter the clinic on Days 1 and 7 and will remain confined for 6 hours
post dose. While in confinement the patients will remain in the ambulatory
sitting/standing position. No strenuous activities will be permitted during
confinement.
Efficacy
Endpoints
Primary Endpoint:
Proportion of patients with a clinical response of treatment success on Day 7 ( 1).
Treatment success is defined as at least a 2-grade improvement on both CEA and PSA
scores from baseline (pre-dose) on Day 7 ( 1) to 6 hours post-application on Day 7
( 1).
Secondary Endpoint:
Proportion of patients with a clinical response of treatment success on Day 1.
Treatment success is defined as at least a 2-grade improvement on both CEA and PSA
scores from baseline (pre-dose) on Day 1 to 6 hours post-application on Day 1.
Safety
Parameters
The frequency, severity and relationship to the study drug for adverse events will be
monitored. Localized AEs (identified in the treatment areas) and systemic AEs will be
tabulated per patient.
Evaluation of
Therapeutic
Equivalence
and Superiority
Therapeutic equivalence of the test product to the reference product will be evaluated
in the PP population. If the 90% confidence interval (calculated using Yates
continuity correction) for the absolute difference between the proportion of patients
considered a treatment success (at least a 2-grade improvement on CEA and PSA over
6 hours) in the test and reference groups is contained within the range [-20%, +20%]
then bioequivalence of the test product to the reference product will be considered to
have been demonstrated.
Superiority of the test and reference gels against the placebo will be tested at the 5%
significance level (p < 0.05; using two-sided, continuity-corrected Z-test) in the mITT
population using last observation carried forward.
Determination
of Sample Size
The primary statistical analysis of interest is the proportion of patients in the PP
population with a clinical response of treatment success (at least a 2-grade
improvement on CEA and PSA over 6 hours) at study Day 7 ( 1) (end of 7-day
treatment period).
The treatment success rate for the reference treatment group at the end of the 7-day
treatment period is assumed to be 45% in the PP population. Assuming that the
treatment success rate for the test treatment group will be an absolute difference of 5%
higher than the reference success rate in this study, a sample size of 159 patients per
active group will provide at least 82% power to demonstrate bioequivalence (i.e., the
90% confidence interval (Yates continuity-corrected) of the absolute difference
between the test and reference composite success rate rates is within a defined
equivalence range [-20%, +20%]).
The rates of treatment success for the placebo and active treatment groups at the end
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 13 of 51
of the 7-day treatment period are assumed to be 10% and at least 40%, respectively, in
the mITT population. Therefore, one-third of the number of patients will be enrolled
in the placebo group as in each of the two active treatment groups to maintain an
adequate sample size in the placebo treatment group. Assuming the conversion rate
from mITT to PP will be about 90%, 177 patients in each of active groups and 59
patients in the placebo group of the mITT population will provide at least 98% power
to demonstrate superiority of active over placebo. Under the above assumptions, the
overall study power to demonstrate bioequivalence and superiority is estimated to be
at least 80% (0.82 x 0.98), assuming 100% correlation between the two superiority
tests. To allow for about 10% of patients who may drop out from the study or are
otherwise non-evaluable, up to 462 patients may be enrolled (198 in each active group
and 66 in the placebo group).
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 14 of 51
5.0 STUDY SCHEMATIC
*Clinical assessments (both CEA and PSA): conducted at Screening and before application (pre-application) and at 6 hours post-application on
Days 1 and 7 ( 1). Assessments conducted 6 hours post-application will allow for a 10 minute window at each interval. Patients will be
administered first and last doses of blinded and randomized medication in the clinic on Day 1 and Day 7 ( 1), respectively. On these two study
days, patients will remain in the clinic during the time interval between their pre- and post-dose erythema evaluations.
** Scheduled AE assessment: conducted before release from confinement. AEs will be assessed throughout the study.
PROCEDURE
Visit 1
Screening
Days -14 to 1
Visit 2
Randomization
Day 1
Visit 3
End of
Treatment
Day 7 1
Informed Consent X
Demographics X
Medical History X X
Inclusion/Exclusion X X
Vital Signs X X X
Pregnancy Test X X X
Lesion Count X X X
Dispense Medication X
Collect Medication X
Dispense Dosing Diary X
Collect Dosing Diary X
Dose Application in Clinic X X
Clinicians Erythema Assessment
X* X* X*
Concomitant Medication X X X
Patients Self Assessment X* X* X*
Adverse Events X** X**
Discharge and End of Study
Procedures
X
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 15 of 51
6.0 LIST OF ABBREVIATIONS AND TERMS
ADR Adverse Drug Reaction
AE Adverse Event
C Celsius
CEA Clinicians Erythema Assessment
CRF Case Report Form
CRO Clinical Research Organization
eCTD electronic Common Technical Document
F Fahrenheit
FDA
Galderma
Food and Drug Administration
Galderma Laboratories, L.P., USA
ICF Informed Consent Form
ICH International Conference on Harmonization
IND Investigational New Drug
IRB Institutional Review Board
IUD Intrauterine Device
LOCF
mg
Last Observation Carried Forward
Milligram
mITT Modified Intent-to-Treat
NDA New Drug Application
OGD Office of Generic Drugs
OHRP Office of Human Rights Protection
OTC Over-the-Counter
PP Per Protocol
PSA Patients Self Assessment
RLD Reference Listed Drug
SAE Serious Adverse Event
SDTM Study Data Tabulation Model
USA
Watson
United States of America
Watson Laboratories, Inc., USA
90%CI Ninety Percent Confidence Interval
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 16 of 51
7.0 INTRODUCTION
7.1 Disease Being Treated
Rosacea is a chronic, inflammatory and vascular disorder affecting the face in adults aged
30 to 60 years. Rosacea affects an estimated 16 million Americans.1 The condition is
characterized by flushing and persistent erythema in the central facial area. Other
cutaneous signs such as telangiectasia, papules, and pustules are typically present on the
central portion of the face.2, 6
The clinical appearance of rosacea can range from very
mild (mild erythema on the cheeks) to severe (large numbers of inflamed lesions and
nodular cysts overlying erythema and telangiectasia on the face, neck, and upper trunk).
Triggers for the condition may include spicy foods, alcohol, emotional stress, sun
exposure, and hot baths.3 The physical manifestation of rosacea on the face can result in
embarrassment4, anxiety and frustration and can have a negative impact on the patients
social life.5 Patients selected for this study will be considered to have persistent moderate
to severe facial erythema of rosacea, with fewer than 3 facial inflammatory lesions.
7.2 Availability and Efficacy of Already Approved Therapies
There are a number of medications including topical metronidazole (Noritate), azelaic
acid (Finacea), doxycycline, and oral antibiotics that are approved by the FDA for
treatment of lesions (papules and pustules) in rosacea. However, their effectiveness in
significantly reducing erythema has not been successfully demonstrated.7 In the absence
of effective treatment, patients are frequently advised to avoid environmental and
lifestyle triggers that can exacerbate erythema.8-10
Mirvaso (brimonidine) topical gel
0.33% (Galderma Laboratories) received FDA approval in August 2013. The active
ingredient, brimonidine tartrate (BT) is a highly selective alpha-2 adrenergic receptor
agonist, with potent vasoconstrictive activity. Clinical studies in support of the NDA for
Mirvaso have shown that it can effectively and rapidly reduce erythema in rosacea, with
effects lasting for up to 12 hours after application.11
7.3 Scientific and Statistical Considerations
Facial erythema of rosacea is thought to result from dysregulation in the cutaneuous
vasomotor responses, which leads to abnormal, involuntary, and persistent dilation of
facial blood vessels12-14
. Alpha-2 receptor agonists have been reported to induce
cutaneous vasoconstriction, and hence are considered strong candidates for treatment of
erythema in rosacea.
Clinical studies of Mirvaso
evaluated treatment effects in adult patients with moderate to
severe erythema associated with rosacea. These studies revealed that Mirvaso treatment
exhibited a significantly higher rate of treatment success (2-grade improvement on both
the Clinicians Erythema Assessment (CEA) and Patients Self-Assessment (PSA) over
baseline at various times over 12 hours post-application on Days 1, 15 and Day 29 of
treatment) compared to placebo (vehicle gel).11, 15-17
In clinical studies supporting the
NDA for the reference drug, Mirvaso, maximal treatment success was observed about 6
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 17 of 51
hours following drug application, and the post-treatment success rates of Mirvaso were
similar from first to last dose over the 4-week treatment period whereas those of the
vehicle gel increased with duration of treatment.11, 16, 17
Composite (treatment) success
rates of 23%-30% and 3%-10% were observed for Mirvaso and vehicle gel,
respectively, at the 6-hour post-application evaluation time on Days 1, 15 and 29 of
treatment (see Figures 1-2 below).11
The Office of Generic Drugs (OGD) recommends a clinical endpoint bioequivalence
study in the treatment of moderate to severe rosacea.18-19
NDA studies conducted for Mirvaso indicated that a similar treatment response was
observed on Days 1, 15 or 29, based on 12 hour erythema assessments. Based on this
information and discussions with Sponsor, a Day 1 and Day 7 treatment assessment was
sought for this study.
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 18 of 51
The pivotal efficacy studies that supported the Mirvaso NDA showed similar rates of
treatment success on Days 1, 15 and 29, with maximal success rates observed at about 6
hours post-application of the gel. 11, 16, 17
Based on data from these studies, additional
evidence from a single-dose pilot study (71304909) conducted by Watson Laboratories
Inc., USA for a generic formulation of Brimonidine Topical Gel, 0.33%, and discussions
with the Sponsor, a clinical endpoint study evaluating responder rate at the start and end
of a 7-day treatment period, with clinical assessments conducted at pre-dose and at 6
hours post-application on each study day, was considered the optimal approach to
minimize drug exposure to patients and to increase chance of demonstrating superiority
of active treatments over placebo.11, 16, 17, 24
7.4 Justification for use of Placebo
To confirm the sensitivity of a clinical endpoint study to differentiate between two
possibly bio-inequivalent products (i.e., to prevent a false positive result of
bioequivalence) OGD/FDA recommends that a placebo group be included in such
studies. In addition to the test product demonstrating therapeutic equivalence to the
reference product, both the test and reference products should demonstrate statistical
superiority to the placebo group.18-19
7.5 Risks and Benefits
The risks and benefits to patients enrolled in clinical research studies that include a
placebo treatment group must be carefully considered based on three main criteria,
namely: the disease being treated, the availability, efficacy and safety of already
approved therapies and the scientific and statistical requirements of the desired outcome
of the research study. The Office of Human Rights Protection (OHRP), a Division of the
USA Federal Governments Department of Health and Human Services, has issued a
detailed guidebook to Institutional Review Boards (IRBs) that includes discussion on the
use of placebos in clinical studies.20
Qualifying patients entering the active treatment period have a 14% chance they may be
treated with placebo. Although the potential for any drug-related side effects of
significance occurring during the study are low, the risk is higher in the two active
treatment groups than in the placebo group.
All patients enrolled in this study will receive the benefit of free specialized medical care
beyond standard medical treatment that would be expected through most health insurance
plans. In addition, the patient will receive a stipend for participation to cover costs and
expenses associated with trips to the medical facility.
8.0 STUDY OBJECTIVES
The objectives of this study are to 1) evaluate the therapeutic equivalence and safety of the test
product Brimonidine Topical Gel, 0.33%, 30 gram fill (Watson Laboratories, Inc., USA) and the
marketed reference product, Mirvaso
(brimonidine) topical gel, 0.33% (Galderma Laboratories
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 19 of 51
L.P., USA) in treatment of facial erythema associated with rosacea, 2) demonstrate the superiority
of the test and reference (active) treatments over placebo (vehicle) gel in the treatment of
moderate to severe facial erythema associated with rosacea, and 3) compare the safety of test,
reference and placebo treatments in patients with facial erythema associated with rosacea
9.0 INVESTIGATIONAL PLAN
9.1 Study Design and Plan Description
This double-blind, randomized, placebo-controlled, parallel-design, multiple-site study
has been designed to evaluate the therapeutic equivalence and safety of a generic product
brimonidine topical gel, 0.33%, 30 gram fill (Watson Laboratories, Inc., USA) and the
FDA Reference Listed Drug, Mirvaso
(brimonidine) topical gel, 0.33% (Galderma
Laboratories L.P., USA), in the relief of moderate to severe facial erythema associated
with rosacea. Additionally, both the test and the RLD products will be tested for
superiority against a placebo.
At least 462 adult patients with moderate to severe facial erythema associated with
rosacea will be randomized. To qualify for inclusion in the study, patients must be at least
18 years of age, with a, diagnosis of facial rosacea. Please refer to section 9.3 for a
comprehensive list of inclusion/exclusion criteria for the study. Before any study-specific
procedures are performed, all patients will read and sign the IRB-approved informed
consent form.
Plan Description
Screening, Visit 1 (Days -14 to 1)
Patients will be screened for all inclusion/exclusion criteria prior to study
enrollment.
Randomization, Visit 2 (Day 1)
Randomization: Patients will be assigned randomization numbers in a 3:3:1
scheme for Test: Reference: Placebo.
Baseline: Before dosing, patients will be assessed for facial erythema severity
based on a 5-point scoring system (Refer to section 9.6.12 Clinical Assessments
and Appendix A). Assessments will be carried out by Investigator (CEA) and
patient (PSA), both of which will determine a baseline score.
Randomized Treatment: Patients will be dispensed randomized study
medication with instructions for dose application at home, once daily during non-
clinic visit days. Patients will be administered the first application of blinded
study medication in the clinic by a designated site staff member. Patients will be
instructed not to apply the last dose until they arrive at the clinic for Visit 3.
Post-Treatment Clinical Assessment: 6 ( 10 minutes) hours following first
dose application, patients will be assessed for facial erythema as per baseline
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 20 of 51
evaluation. Patients will remain in the clinic during the time interval between
their pre- and post-dose erythema evaluations.
End of Treatment, Visit 3 (Day 7 1)
Baseline: Patients will return to the clinic before dosing to be assessed for facial
erythema as per Day 1 baseline assessments.
Randomized Treatment: Patients will be administered the last application of
blinded study medication in the clinic by a designated site staff member.
Post-Treatment Clinical Assessment: 6 ( 10 minutes) hours following last
dose application, patients will be assessed for facial erythema as per baseline
evaluation. Patients will remain in the clinic during the time interval between
their pre- and post-dose erythema evaluations.
All other Visit 3 procedures (refer to section 9.5.4) will be conducted for all
patients who completed the study or terminated early.
9.2 Selection of Study Design
This study has been designed after a thorough review of a large number of clinical studies
in rosacea including those conducted as a part of the NDA for the Reference Listed Drug
(RLD) used in this study, Mirvaso
(brimonidine) topical gel, 0.33% (Galderma
Laboratories), draft guidances for rosacea therapies (including those that treat erythema)
and results from a pilot study for the test formulation used in this study. 1-19, 24
9.3 Selection of Study Population
9.3.1 Inclusion Criteria
1. Male or non-pregnant, non-lactating female, 18 years of age or older.
2. Signed informed consent form, which meets all criteria of current FDA regulations.
3. Females of child bearing potential must not be pregnant or lactating at Screening and
Randomization (as confirmed by a negative urine pregnancy test with a sensitivity of
less than 25 mlU/mL or equivalent units of human chorionic gonadotropin). Women
of childbearing potential must agree to the use of a reliable method of contraception
(e.g., total abstinence, IUD, a double-barrier method [such as condom plus
diaphragm with spermicide], oral, transdermal, injected or implanted non- or
hormonal contraceptive), throughout the study. A sterile sexual partner is not
considered an adequate form of birth control.
All females will be considered to be of childbearing potential unless they:
Are post-menopausal, defined as women who have been amenorrheic for at
least 12 consecutive months, without other known or suspected primary
cause.
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 21 of 51
Have been sterilized surgically or who are otherwise proven sterile (i.e., total
hysterectomy, or bilateral oophorectomy) with surgery at least 4 weeks prior
to Screening. Tubal ligation will not be considered a surgically sterile
method.
Female patients of childbearing potential are defined as:
Women without prior hysterectomy, or who have had any evidence of
menses in the past 12 months.
Females who have been amenorrheic for 12 months, but the amenorrhea is
possibly due to other causes, including prior chemotherapy, anti-estrogens, or
ovarian suppression.
4. Have a clinical diagnosis of facial rosacea and fewer than 3 inflammatory lesions on
the face at Screening and at Randomization (before drug application on Day 1).
5. Have moderate to severe facial erythema according to both CEA and PSA (i.e., an
erythema score of 3 or more for both CEA and PSA) at Screening and at
Randomization (before drug application on Day 1).
6. Free from any systemic or dermatologic disorder (other than rosacea) that, in the
opinion of the Investigator, will interfere with the study evaluations or increase the
risk of AEs.
7. Willing to minimize external factors that might trigger rosacea flare-ups (e.g., hot
environments, prolonged sun exposure, strong winds and emotional stress) within 24
hours of the Screening and Randomization visits.
8. Any skin type or race, providing the skin pigmentation will allow discernment of
erythema.
9. Willingness and capability to cooperate to the extent and degree required by the
protocol.
9.3.2 Exclusion Criteria
1. Patients with particular forms of rosacea (rosacea conglobata, rosacea fulminans,
isolated rhinophyma, isolated pustulosis of the chin) or other concomitant facial
dermatoses similar to rosacea, such as peri-oral dermatitis, demodicidosis, facial
keratosis pilaris, seborrheic dermatitis, acute lupus erythematosus, or actinic
telangiectasia, that are present on the face (i.e., 5 areas: chin, nose, both cheeks, and
forehead), that in the opinion of the Investigator would interfere with study
evaluations.
2. Have 3 or more facial inflammatory lesions of rosacea.
3. Have an erythema score of 2 (mild), 1 (almost clear), or 0 (clear) on the Clinicians
Erythema Assessment (CEA) and/or the Patients Self-Assessment (PSA) at
Screening and at Randomization (before drug application on Day 1).
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 22 of 51
4. Patients with excessive facial hair (beards, sideburns, moustaches, etc.) that would
interfere with the diagnosis or assessment of rosacea.
5. Patients with moderate to severe telangiectasial masses in the 5 areas of the entire
face: forehead, chin, nose and each cheek, that would interfere with study
evaluations.
6. History of hypersensitivity or allergy to Mirvaso including the active ingredient
brimonidine tartarate or other component within the formulation.
7. Facial laser surgery for telangiectasia (or other conditions) within 6 weeks prior to
randomization.
8. Exposed to excessive ultraviolet (UV) radiation within 1 week before Screening or
Randomization visit and/or patient was unwilling to refrain from excessive exposure
to UV radiation during the course of the study.
9. History of blood dyscrasia.
10. Current diagnosis of Raynauds syndrome, thromboangiitis obliterans, orthostatic
hypotension, severe cardiovascular disease, cerebral or coronary insufficiency, renal
or hepatic impairment, scleroderma, Sjgrens syndrome, or depression or any other
condition causing uncontrolled blood flow or blood pressure.
11. Females who are pregnant, lactating or likely to become pregnant during the study.
12. Significant history or current evidence of chronic infectious disease, system disorder,
organ disorder or other medical condition that in the Investigators opinion would
place the study patient at undue risk by participation.
13. Patients with severe, unstable or uncontrolled cardiovascular disease.
14. Patients who meet study restrictions at screening and/or unwillingness to comply
with all restricted treatments as detailed in section 9.3.3 of this protocol.
15. Receipt of any drug as part of a research study within 30 days before dosing.
16. Employees of the research center or Investigator.
17. Previous participation in this study.
18. Patients who are unable and/or unwilling to follow the study requirements, and
procedures.
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 23 of 51
9.3.3 Restrictions During The Study
The following will not be allowed before or during study participation as per the below
schedule:
Treatments Examples (not all inclusive)
Restriction
Period/Washout
Topical
Treatments
Prescription
medications for the
treatment of rosacea azelaic acid, metronidazole 4 weeks before Visit 1
Topical
Immunomodulators Tacrolimus, Pimecrolimus 4 weeks before Visit 1
Topical
Corticosteroids
Betamethasone, Clobetasol,
Fluocinonide, Triamcinolone,
Fluticasone, Hydrocortisone,
Alclomethasone 4 weeks before Visit 1
Topical Prescription
and OTC
medication treating
erythema and
inflammation Diclofenac, Indomethacin Within 24 hours of Visit 1
Topical antibiotics Neosporin, sulfacetamide sodium 2 weeks before Visit 1
OTC facial cosmetic
products
Make-up, lotion, oil, creams,
powder
12 hours before Clinic
Visits. Allowed on non-
visit days, if only applied
after study drug
application
OTC topical
medications for
treatment of acne
Benzoyl peroxide, salicylic acid
creams, face washes 1 week before Visit 1
Astringents or
abrasives Proactiv
, witch hazel lotion 2 days before Visit 1
Systemic
Treatments
Prescription
medications for the
treatment of rosacea
doxycycline, tetracycline,
macrolides 4 weeks before Visit 1
Prescription
medications for
treatment of acne corticosteroids 4 weeks before to Visit 1
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 24 of 51
Treatments Examples (not all inclusive)
Restriction
Period/Washout
Systemic
Treatments
Corticosteroids,
Immunomodulators
Prednisone,
Methylprednisolone,
Hydrocortisone, Dexamethasone 12 weeks before Visit 1
Retinoids Isotretinoin 6 months before Visit 1
Antibiotics (effecting
Rosacea) Tetracycline 4 weeks before Visit 1
OTC anti-
inflammatory drugs
(excluding low-dose,
e.g., 81 mg) Ibuprofen, Naproxen, Aspirin 1 week before Visit 1
Prescription anti-
inflammatory drugs
Ibuprofen, Naproxen, Aspirin,
Ketorolac, Celecoxib,
Indomethacin, Diclofenac,
Meloxicam 2 weeks before Visit 1
Cardiac glycosides,
alpha and beta
adrenergic blockers or
other antihypertensive
agents
Oxymetazoline, Nadolol,
Propranolol, Prazosin,
Doxazosin, Digoxin
Patients will be excluded,
if started these within
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 25 of 51
Patients will be asked to abstain from the following items 24 hours before clinic visits:
Caffeine (e.g., tea, coffee, caffeinated soft drinks including Pepsi, Coke)
Rosacea trigger foods (refer to Appendix B)
Patients will be allowed to consume these items on non-clinic visit days during the study,
but will be asked to minimize exposure in order to prevent rosacea flare-ups.
Patients will be questioned about all prescription and OTC concomitant medication use
(including vitamins or nutritional supplements) at each study visit. All concomitant
medications will be recorded in the patients source documents. Anyone who violates any
listed restrictions may be dropped from continued participation in the study by the
Investigator.
During confinement, patients will be required to remain in the ambulatory sitting and/or
standing position. No strenuous activities will be permitted during confinement.
9.3.4 Removal of Patients from the Study
Patients will be advised that they are free to withdraw from the study at any time for any
reason or, if necessary, the Investigator may withdraw a patient from the study to protect
the health of that patient. A patient may also be withdrawn for not complying with study
procedures. The clinical report will include all reasons for early withdrawals.
All patients who are randomized will be included in the safety monitoring tabulating all
adverse events experienced after dosing. If a randomized patient terminates from the
study early, all procedures performed up to that point will be used. In case of early
termination the Investigator shall fully document the reason for early termination.
9.4 Treatments
9.4.1 Treatments Administration
Patients will be instructed to apply study medication once a day, preferably in the
morning or early afternoon, at approximately the same time, each day of the study
duration.
The first and last doses will be applied in the clinic at Visit 2 and Visit 3, respectively, by
a blinded doser as outlined in steps below:
The patients will wash their face with Dove facial soap and gently dry before
study gel application. Each treatment will be administered by a designated site
staff, Blinded Doser. The Blinded Doser will apply the study drug to the
patients entire face (i.e., chin, nose, forehead, and both cheeks) at Visits 2 and 3.
The Blinded Doser using gloves will gently and smoothly apply the gel in a thin
even layer to the entire face, avoiding contact with the eyes and lips. In order to
maintain consistency these application procedures will be followed for all
patients.
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 26 of 51
The Blinded Doser will not be involved in any clinical assessments (i.e. CEA
assessment) and will be instructed not to discuss the appearance of the study drug
with any study personnel conducting evaluations. The Blinded Doser can be the
Independent Dispenser.
Each daily dose between Visits 2 and 3 will be applied by the patient, at home, according
to instructions provided (Refer to Sections 9.4.5 Compliance and 9.6.10 Dosing
Instructions and Diary). The last dose at home should be applied 24 ( 2) hours before
Visit 3 baseline erythema assessment.
9.4.2 Identity of Study Products
Test (A): Brimonidine Topical Gel, 0.33%, 30 gram fill (Watson Laboratories,
Inc., USA)
Reference (B): Mirvaso (brimonidine) topical gel, 0.33% (Galderma
Laboratories, L.P., USA)
Placebo (C): Topical gel base only (Watson Laboratories, Inc., USA)
All three study formulations will be supplied in 30 gram tubes with child resistant caps.
All randomized study medication will be blinded and packaged in blinded sealed boxes.
Each tube will be identified by a label bearing the protocol number, randomization
number, a statement that the study medication is for Investigational Use Only and the
Sponsors name. The delegated study staff will dispense the study medication tube only
to those patients identified by the Investigator as eligible participants. The study staff will
instruct the patients on the use and return of the study medication. The patient will be
instructed not to discuss the appearance of the study medication tube with any study
personnel conducting the study assessments i.e., the Investigator(s) or the Study
Coordinator(s).
Each study site will have at least one Independent Dispenser. The role of the
Independent Dispenser is to dispense and collect study medication to/from the patients,
maintain dispensing records, and ensure the study drug logs are complete and accurate.
Individual tubes of study medication will be packaged in blocks of 7 based on the 3:3:1
randomization (refer to section 9.4.3 of the protocol). The study medication will be
shipped to each Investigators site from a centralized location. The Principal Investigator
at each site is responsible for ensuring that all study medications are stored in a locked,
secure location, with access limited to the Investigator and his/her designee(s). An
accurate inventory of the study medication will be maintained in accordance with federal
regulations. For every study drug shipment received at the Investigator Site, the
Investigator (or designee) will randomly select at least one block of study drug for
retention, unless otherwise instructed by the Sponsor and/or Novum. The selection
process will ensure a sufficient amount of retention samples are retained as per Sponsor
requirement. These blocks will be affixed with a label provided by Novum to be clearly
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 27 of 51
marked as retention samples and are not to be used for dispensing to study patients. The
selected retention samples will be retained at a third party storage facility (BioRepository
Resources, LLC) under FDA regulations as study retention samples. 21
Once the site has been notified that they may do so, all unused study medication and
empty or partially used tubes of study medication, other than that randomly selected for
retention samples will be returned to the Sponsor (Watson) or designee. It is important
that retention samples not be returned to Novum, the Sponsor or the packaging company
during or at the end of the study. Sufficient study medication tubes must be retained
amongst the sites participating in the study to meet the sample retention requirements as
outlined by the FDA. 21
9.4.3 Method of Assigning Patients to Treatment Groups
In order to maintain the study blind, the study medication will be packaged and blinded
by an independent packaging company. The randomization will be generated in blocks of
7 (3 test medication: 3 reference medication: 1 placebo). Seven (7) patients worth of
study medication (3 tubes of test medication, 3 tubes of reference medication and 1 tube
of placebo) will be packed into a larger box. This larger box will be designated one
block of study medication. The study medication should be blinded, packaged and
delivered to the study site in blocks.
Randomization will be performed according to a computer-generated randomization
scheme. Prior to dispensing study treatment, patients will be randomized to a treatment
regimen in a blinded fashion by assigning randomization numbers in ascending
sequential order starting with the lowest available randomization number at each site.
The randomization number will consist of a 2-digit site number and 4-digit study drug kit
number. The 4-digit study drug kit number will be obtained from the individual study
drug box.
A perforated or two-part label will be attached to each of the small sized boxes of study
medication. Both pieces of the label will include the following information: Protocol
number, randomization number, space for patients initials, statement that the study
medication is for Investigational Use only, space for dispensing date and the Sponsors
name. In addition all patients will be provided with written instructions on how to use the
study medication. One part of the label shall remain attached to the box. The other part
will be removed prior to dispensing and attached to patients Source documentation.
Each patient will receive one box containing 1 x 30 gram tube of study medication; this
quantity will suffice for the entire study duration. Each patient will maintain the same
randomization number and treatment assignment throughout the study.
9.4.4 Study Blind
The Investigator, staff at the study site, study monitors, and data analysis/management
personnel will be blinded to the patient assignment. The patient will be requested not to
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 28 of 51
discuss the appearance of the study medication tube with the Investigator or study staff
outside of the Independent Dispenser.
To ensure that information that could potentially bias handling of data is not disclosed,
the packaging company will hold the randomization scheme until after database lock. For
each patient a perforated tear-off label containing the unblinding information will be
placed in the patients chart, to be unblinded in case of medical emergency only. The
patients chart containing the occluded unblinding label should be stored in a secure
location at all times.
Where possible, the Sponsor and/or Novum medical monitor should be contacted before
breaking the blind for any patient. In the event the blind is broken for any reason Sponsor
and Novum will be notified as soon as possible in writing of the details of the occurrence.
At the conclusion of the study, after the database has been locked, each site will be sent a
sealed envelope containing the full study randomization scheme that should be retained
with the study documents in the event of an FDA Inspection.
The tubes of test, reference and placebo products will be blinded with identical labels.
This will allow the treatment phase of the study to be conducted under double-blind
conditions, such that neither the patient nor the Investigator or study staff members will
know the identity of the patients treatment.
9.4.5 Compliance
Patients will be provided with dosing instructions at Visit 2. One dose is equivalent to 1
application of study product to entire face (i.e. 5 areas of the face: nose, forehead, both
cheeks and chin), once a day.
Patient compliance with respect to study medication administration will be calculated by
analyzing the doses recorded in the provided dosing diary. Compliance criteria are as
outlined in the table below.
Compliance Criteria
Study period Duration
Scheduled
doses
not more than
125% (doses)
not less than
75% (doses)
Randomized
treatment 7 days 7 8 6
9.5 Study Conduct
9.5.1 Visit 1 (Day -14 to 1): Screening
1. Informed Consent: Patients who are willing to comply with study
procedures will read and sign the informed consent form.
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 29 of 51
2. Baseline Demographics and Medical History: Confirm the patient has
a clinical diagnosis of rosacea. Review the patients demographic and
medical history.
3. Dermatological Assessment: Patients should have a clinical diagnosis
of rosacea with fewer than 3 inflammatory lesions on the face.
4. Erythema Assessment: The Investigator will perform the Clinicians
Erythema Assessment and confirm diagnosis of moderate to severe facial
erythema associated with rosacea. Patients will perform the Patients
Self-Assessment after appropriate instruction.
5. Lesion Count: Perform a count of the inflammatory rosacea lesions.
6. Vital Signs: Obtain the patients vital signs (blood pressure, pulse,
respiration rate and temperature).
7. Concomitant Medications: Review the patients use of concomitant
medication within the last 6 months.
8. Pregnancy Test: All females of child-bearing potential will have a urine
pregnancy test performed. The test must be negative for the patient to be
eligible for inclusion in the study.
9. Inclusion/Exclusion Criteria: Confirm the patient meets all the
inclusion/exclusion criteria.
10. Schedule Visit 2: Patients will be instructed to return to the clinic for
Visit 2 (as per the schedule determined by the site staff and patient).
9.5.2 Visit 2 (Day 1): Randomization
1. Medical History: Review and report any changes in the patients health
status since Visit 1.
2. Dermatological Assessment: Patients should have a clinical diagnosis
of rosacea with fewer than 3 inflammatory lesions on the face.
3. Lesion Count: Perform a count of the inflammatory rosacea lesions.
4. Concomitant Medications: Review the patients use of concomitant
medication since Visit 1.
5. Pregnancy Test: All females of child-bearing potential will have a urine
pregnancy test performed. The test must be negative for the patient to be
eligible for inclusion into the treatment phase of the study.
6. Pre-dose Erythema Assessment: The Investigator (who is not the
blinded doser/independent dispenser) will perform the Clinicians
Erythema Assessment. Confirm diagnosis of moderate to severe facial
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 30 of 51
erythema associated with rosacea. Patients will perform the Patients
Self-Assessment after appropriate instruction.
7. Inclusion/Exclusion Criteria: Confirm the patient meets all the
inclusion/exclusion criteria, following which the patient may be enrolled
into the study and assigned a randomization number.
8. Dispense Study Medication and Dosing Diary: The independent
dispenser will dispense study drug. Patients will be provided their dosing
diary, and receive instruction on how to dose, and procedures for
recording doses, AEs and concomitant medications in their diary.
9. Administer First Dose: Patients will gently wash their face with a mild,
non medicated cleanser (e.g., Dove soap), rinse with warm water and
pat dry. A designated member of staff will apply the first dose of
blinded, randomized medication to patients with a gloved hand, in the
clinic.
10. 6 Hour Confinement Period: Patients will be asked to remain at the
clinic for 6 hours following first dose application. They may be provided
with a standard light meal (i.e., snacks and/or small meal) and
refreshments during this period. All food provided will be in accordance
with dietary restrictions in Appendix B.
11. Post-dose Erythema Assessment: Following 6 hours ( 10 minutes) of
the first dose, patients will undergo a post-dose erythema assessment
(CEA and PSA) in a manner similar to the pre-dose assessment.
12. Scheduled Adverse Events Assessment: Prior to release from
confinement, an assessment of changes in patients health (since the
application of the study medication) will be performed.
13. Adverse Events: Review any adverse events reported by patient during
the 6 hours after study medication application.
14. Vital Signs: Obtain the patients vital signs (blood pressure, pulse,
respiration rate and temperature).
15. Schedule Visit 3: Patients will be instructed to return to the clinic for
Visit 3 (as per the schedule determined by the site staff and patient) and
not apply the last dose until they are in the clinic. Patients will be
instructed to bring their study medication tube to the clinic for Visit 3.
9.5.3 Visit 3 (Day 7 1): Study Completion or Early Discontinuation
1. Lesion Count: Perform a count of the inflammatory rosacea lesions.
2. Collect Dosing Diary: Review for dosing compliance.
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 31 of 51
3. Concomitant Medications: Review the patients use of concomitant
medication since Visit 2.
4. Adverse Events: Review any adverse events reported by patient since
Visit 2.
5. Pregnancy Test: All females of child-bearing potential will have a urine
pregnancy test performed.
6. Pre-dose Erythema Assessment: The Investigator (who is not the
blinded doser/independent dispenser) will perform the Clinicians
Erythema Assessment. Patients will perform the Patients Self-
Assessment after appropriate instruction. CEA and PSA assessments at
baseline should not be conducted 24 ( 2) hours before last study
medication application at home (i.e., last dose before Visit 3).
7. Administer Last Dose: Patients will gently wash their face with a mild,
non medicated cleanser (e.g., Dove
soap) rinse with warm water and pat
dry. A designated member of staff will apply the last dose of blinded,
randomized medication to patients with a gloved hand, in the clinic.
8. Study Drug: Collect the study drug after the last dose has been
administered.
9. 6 Hour Confinement Period: Patients will be asked to remain at the
clinic for 6 hours following last dose application. They may be provided
with a standard light meal (i.e., snacks and/or small meal) and
refreshments during this period. All food provided will be in accordance
with dietary restrictions in Appendix B.
10. Post-dose Erythema Assessment: Following 6 hours ( 10 minutes) of
the last dose, patients will undergo a post-dose erythema assessment
(CEA and PSA) in a manner similar to the pre-dose assessment.
11. Scheduled Adverse Events Assessment: Prior to release from
confinement, an assessment of changes in patients health (since the
application of the study medication) will be performed.
12. Adverse Events: Review any adverse events reported by patient during
the 6 hours after study medication application.
13. Vital Signs: Obtain the patients vital signs (blood pressure, pulse,
respiration rate and temperature).
14. Release: Discharge patient from study.
CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso (brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea
71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 32 of 51
9.6 Study Procedures
9.6.1 Informed Consent
At Visit 1, each patient shall be required to read and sign the IRB approved Informed
Consent Form. No patient will be entered into the study without reading, understanding,
and signing an informed consent. For illiterate patients, verbal consent should be obtained
in the presence of and be countersigned by a literate witness. If any other language is
required, translation will be performed by a certified translator.
9.6.2 Demographics
At Visit 1, each patient shall be required to provide basic demographic information: date
of birth, gender, ethnicity, race, and tobacco usage.
9.6.3 Medical History
At Visit 1, patients will be questioned about their rosacea history and must provide
information on all symptoms and rosacea medications. The patients medical history,
including any acute and/or chronic medical conditions and concomitant medication use
(used within the last 6 months) will be recorded. At Visit 2 a review of the patients
medical history and concomitant medication use since the previous visit will be
performed and updates will be recorded. At Visits 1 and 2 medical history and
concomitant medication recorded will be reviewed to determine eligibility for inclusion
into the study.
9.6.4 Vital Signs
The patients vital signs will be recorded (pulse, blood pressure, temperature and
respiration rate) at all three visits.
9.6.5 Lesion Count
At Visits 1 and 2 a dermatological exam will be performed by an Investigator to count the
inflamed facial lesions of rosacea and will determine eligibility for inclusion into the
study. At Visit 3 the Investigator will continue to perform lesion counts.
9.6.6 Concomitant Medication Use
At Visit 1 patients will be questioned about current and concomitant medication use over
the previous 6 months. At Visits 2 and 3, patients will be questioned about ongoing or
new concomitant medication use.