71304906 Protocol Rev 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 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


Morris Corporate Center III

400 Interpace Parkway, Parsippany, NJ 07054

Tel: 862-261-7548

Fax: 862-261-9711

Email: [email protected]

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


Medical Monitor:

Darin B. Brimhall, DO, FACP,CPI

Medical Monitor


3760 Pecos McLeod

Las Vegas, NV 89121

Tel: 702-435-3739 x370

Fax: 412-291-3171


Biostatistician:

Jianhua Liu, MSc

Senior Biostatistician


5900 Penn Ave.

Pittsburgh, PA 15206

Tel: 647-779-6883

Fax: 412-924-0522








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







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







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







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







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).







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







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.







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







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







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).







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







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


90%CI Ninety Percent Confidence Interval







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







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.







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







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







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.







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).







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.







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







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







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.







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







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







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.







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.



medication since Visit 1.


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







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.



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


2. Collect Dosing Diary: Review for dosing compliance.








medication since Visit 2.

4. Adverse Events: Review any adverse events reported by patient since

Visit 2.


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.



14. Release: Discharge patient from study.







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.

71304906 Protocol Rev 1

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