QLT Inc. - CONFIDENTIAL
`
`Clinical Study Report -- ACZ ROS 01
`AczoneTM (dapsone) Gel, 5%
`
`1
`
`A Phase II, Randomized, Partial-Blind, Parallel-Group, Active-
`and Vehicle-Controlled, M ulticenter Study of the Safety and
`Efficacy of AczoneTM (Dapsone) Gel, 5% in Subjects With
`Papulopustular Rosacea
`
`Date of Report: 05 February 2007
`
`This Study Report is written as an accurate record of the conduct and the results of the study
`by:
`
`Study Director:
`
`~- z --,z/ /_ __
`Steve Garrett, MS, DDS, FACD
`QLT USA, Inc.
`
`Date
`
`Study Biostatistieian: ,-1~ ~- ~ I, _:/,,,
`
`!
`
`Craig Wesselman, MS
`QLT USA, Inc.
`
`Approvedby"
`
`~
`Sean Moriarty
`President, QLT USA, inc.
`
`-~ ~L~ta 5 ) i2~/~----
`Date
`
`7
`
`Date
`
`z.oa 7
`
`The study was conducted in accordance with the ICH GCP guidelines; Division 5 of the Canadian Food and
`Drug Regutations; US 21 CFR Parts 50, 54, 56, and 312; and the principles enunciated in the Declaration of
`Helsinki.
`
`QLT Inc.
`887 Great Northern Way
`Vancouver, British Columbia
`Canada VST 4T5
`
`QLT USA, Inc.
`2579 Midpoint Drive
`Fort Collins, Colorado
`USA 80525
`
`1 of 83
`
`Almirall EXHIBIT 2043
`Amneal v. Almirall
`IPR2018-00608
`
`

`

`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`Study Number and Title: ACZ ROS 01. A Phase II, Randomized, Partial-Blind, Parallel-
`Group, Active- and Vehicle-Controlled, Multicenter Study of
`the Safety and Efficacy of AczoneTM (dapsone) Gel, 5% in
`Subjects with Papulopustular Rosacea
`
`This Study Report is written as an accurate record of the conduct and the results of the study
`by:
`
`~" ~ "2Z_3~’3¢~
`Medical Writer: ~ 9 ~"~ /TJ
`
`D e n i s’U’G a"ff~l p e a u ,-’~I S c ~ - Date
`QLT Inc.
`
`QUALITY ASSURANCE REVIEW STATEMENT
`
`The content of this report has been reviewed against the data listings, summary tables,
`references, protocol, and amendments for accuracy and completeness by:
`
`Reviewed by:
`
`~ fd~’U~> ~-
`~6"a~C a ~
`Date
`ble, RCT (A)
`Senior Manager, Clinical Quality
`~QLT Inc.
`
`05 February 2007
`
`2
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`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`TABLE OF CONTENTS
`
`ABBREVIATIONS AND DEFINITIONS ............................................................................. 6
`
`1
`
`INTRODUCTION ........................................................................................................ 7
`
`INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ............... 8
`2
`Study Investigators ...................................................................................................... 8
`2.1
`Study Administrative Structure ................................................................................. 9
`2.2
`Contract Services ......................................................................................................... 9
`2.3
`23 1 Randomization and Clinical Trial Supplies ................................................................... 9
`23 2 Laboratory Analyses ...................................................................................................... 9
`
`3
`3.1
`3.2
`
`3.3
`
`4
`
`STUDY ETHICAL CONSIDERATIONS ............................................................... 10
`Ethical Conduct of Study .......................................................................................... 10
`Institutional Review Board, Ethics Committee, or Research Ethics Board
`(II~) ............................................................................................................................ 10
`Subject Information and Consent ............................................................................ 10
`
`STUDY OBJECTIVES .............................................................................................. 10
`
`5
`STUDY DESCRIPTION (METHODS AND INVESTIGATIONAL PLAN) ...... 11
`Overall Study Design ................................................................................................. 11
`5.1
`Discussion of Study Design ........................................................................................ 11
`5.2
`Study Population ........................................................................................................ 12
`5.3
`5 3 1 Number of Subj ects ...................................................................................................... 12
`53 2
`Inclusion Criteria ......................................................................................................... 12
`5 3 3 Exclusion Criteria ........................................................................................................ 13
`5.3.4 Withdrawal of Subjects From Treatments or Assessments ......................................... 14
`5 3 5 Special Restrictions ...................................................................................................... 15
`5.4
`Study Treatments ....................................................................................................... 15
`5 4 1 Treatments Administered ............................................................................................. 15
`5 42 Rationale for Dose Selection ....................................................................................... 16
`Identity of Investigational Products ............................................................................. 16
`5 43
`5 44 Assignment to Treatment and Blinding ....................................................................... 17
`5.4.5 Prior and Concomitant Treatment ................................................................................ 18
`5 46 Assessment of Treatment Compliance ......................................................................... 18
`5.5
`Study Procedures ....................................................................................................... 19
`5 5 1 Schedule of Events ....................................................................................................... 19
`5 5 2 Screening and Day 0 Procedures (Baseline) ................................................................ 19
`5.5.3 Procedures During Treatment (Weeks 2 to 12) ........................................................... 20
`5.5.4 Follow-up Procedures (Week 13) ................................................................................ 21
`5.6
`Efficacy, Pharmacokinetic, and Safety Variables ................................................... 21
`5 6 1 Efficacy Variables ........................................................................................................ 21
`5.6.2 Safety Variables ........................................................................................................... 23
`5.6.3 Other Variables ............................................................................................................ 28
`5.7
`Data Quality Assurance ............................................................................................. 29
`5 7 1 Standardization of Study Procedures ........................................................................... 29
`
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`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`5.7.2 Study Monitoring ......................................................................................................... 29
`5.7.3 Study Database ............................................................................................................. 29
`5.7.4 Quality Assurance Audits ............................................................................................ 29
`5.8
`Statistical Methods ..................................................................................................... 30
`5.8.1 Sample Size .................................................................................................................. 30
`5.8.2 Statistical Analysis ....................................................................................................... 30
`5.9
`Study Modifications ................................................................................................... 33
`5 9 1 Protocol Amendments .................................................................................................. 33
`5.9.2 Other Changes in the Conduct of the Study or Planned Analyses ............................... 33
`
`STUDY SUBJECTS: DISPOSITION AND DEMOGRAPHY .............................. 34
`6
`Disposition of Subjects ............................................................................................... 34
`6.1
`Extent of Treatment ................................................................................................... 35
`6.2
`Data Sets Analyzed .................................................................................................... 36
`6.3
`63 1 Efficacy: Intentto Treat ............................................................................................... 36
`63 2 Efficacy: Per Protocol .................................................................................................. 37
`63 3 Safety ........................................................................................................................... 37
`6.4
`Demographics and Baseline Characteristics ........................................................... 37
`64 1 Subject Demographic and Baseline Disease Characteristics ....................................... 37
`6.4.2 Subject Medical History and Underlying Conditions .................................................. 41
`
`7
`7.1
`7.2
`
`PROTOCOL DEVIATIONS .................................................................................... 42
`Protocol Deviations That Led to Exclusion From the Analysis ............................. 42
`Other Protocol Deviations ......................................................................................... 42
`
`EFFICACY RESULTS AND DISCUSSION .......................................................... 44
`8
`Efficacy Results .......................................................................................................... 44
`8.1
`Intent-to-Treat Analysis ............................................................................................... 44
`8 1 1
`8 1 2 Per Protocol Analysis ................................................................................................... 49
`8 1 3 Subgroup Analysis: Subjects With >20 Lesions .......................................................... 49
`Discussion of Efficacy Results ................................................................................... 53
`8.2
`
`SAFETY RESULTS AND DISCUSSION ............................................................... 54
`9
`Extent of Exposure ..................................................................................................... 55
`9.1
`9 1 1 Exposure to Trial Treatment(s) .................................................................................... 55
`9 1 2 Exposure to Concomitant Treatment ........................................................................... 57
`9.2
`Overview of Adverse Events ..................................................................................... 57
`92 1 Common Treatment-Emergent Adverse Events .......................................................... 59
`9.2.2 All Associated Adverse Events .................................................................................... 61
`9.2.3 Special Safety Issues: Glucose-6-Phosphate Dehydrogenase Deficiency ................... 63
`9.3
`Deaths, Withdrawals, and Serious or Clinically Significant Adverse Events ...... 64
`93 1 Deaths .......................................................................................................................... 64
`93 2 Withdrawal Due to Adverse Events ............................................................................. 64
`93 3 Serious Adverse Events ............................................................................................... 70
`9.4
`Laboratory Data ......................................................................................................... 70
`94 1 Laboratory Values Over Time ..................................................................................... 70
`Individual Subject Changes ......................................................................................... 72
`9.4.2
`
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`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`9.4.3 Clinically Significant Abnormalities ........................................................................... 75
`9.5
`Vital Signs and Other Physical Findings ................................................................. 75
`9.6
`Local Symptom Scores .............................................................................................. 75
`Discussion of Safety Results ...................................................................................... 78
`9.7
`
`10
`
`11
`
`DISCUSSION AND OVERALL CONCLUSIONS ................................................ 79
`
`REFERENCES ........................................................................................................... 80
`
`APPENDICES (FULL LIST APPEARS AT END OF REPORT)
`
`APPENDIX A -- SUMMARY TABLES AND GRAPHS
`
`A 1 Disposition Summary Tables
`A2 Demographic and Baseline Data Summary Tables
`Efficacy Summary Tables
`A3
`A4
`Safety Summary Tables
`
`APPENDIX B -- STATISTICAL OUTPUT
`
`APPENDIX C -- SUBJECT NARRATIVES
`
`C 1 Withdrawals Due to an Adverse Event
`C2 Serious Adverse Events
`
`APPENDIX D -- STUDY INFORMATION
`
`Protocol and Protocol Amendments
`D 1
`Sample Case Report Form (unique pages only)
`D2
`List of Investigators and Other Essential Study Personnel
`D3
`Ethical Considerations
`D4
`Randomization Scheme and Codes
`D5
`Statistical Analysis Plan
`D6
`D7 Data Conventions
`Interlaboratory Standardization Methods
`D8
`Important Publications Referenced in the Report
`D9
`
`APPENDIX E -- INDIVIDUAL DATA LISTINGS
`
`E 1
`E2
`E3
`E4
`E5
`
`Disposition and Baseline Data Listings
`Demographic and Baseline Data Listings
`Efficacy Data Listings
`Treatment Exposure
`Safety Data Listings
`
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`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`ABBREVIATIONS AND DEFINITIONS
`
`AE
`Aczone
`ALA
`ALT
`AST
`BUN
`CFR
`CRF
`ET
`G6PD
`GCP
`ICF
`ICH
`IGA
`IRB
`ITT
`IUD
`LDH
`LOCF
`MCH
`MCV
`MedDRA
`MetroGel
`N
`NOS
`NSAIDS
`PP
`PUVA
`RBC
`ROS
`SAE
`SD
`USP
`VC
`WHO DD
`
`Adverse event
`AczoneTM (dapsone) Gel, 5%
`5-aminolenulinic acid
`Alanine aminotransferase
`Aspartate aminotransferase
`Blood urea nitrogen
`Code of Federal Regulations
`Case report form
`Early termination
`Glucose-6-phosphate dehydrogenase
`Good Clinical Practice
`Informed consent form
`International Conference on Harmonization
`Investigator’s Global Assessment (5-point scale of disease severity)
`Institutional Review Board
`Intent-to-treat
`Intrauterine Device
`Lactate dehydrogenase
`Last observation carried forward
`Mean corpuscular hemoglobin
`Mean corpuscular volume
`Medical Dictionary for Regulatory Activities
`MetroGel® (metronidazole gel), 1%
`Number
`Not otherwise specified
`Nonsteroidal anti-inflammatory drugs
`Per protocol
`Psoralen ultraviolet A
`Red blood cell
`Rosacea
`Serious adverse event
`Standard deviation
`United States Pharmacopeia
`Vehicle Control
`World Health Organization Drug Dictionary
`
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`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`1
`
`INTRODUCTION
`
`Rosacea is a multifactorial chronic skin disorder that most often affects the central face
`including the nose, forehead, cheeks, and chin. Rosacea usually affects fair-skinned people
`30 to 50 years of age who tend to blush or flush easily. Four subtypes of rosacea are
`described: papulopustular, erythematotelangiectatic, phymatous, and ocular [1]. In a recent
`study of clinical patterns of rosacea, papules and pustules were found in 83% and 67% of a
`sample of 108 rosacea patients, respectively [2]. In the papulopustular subtype of rosacea,
`patients typically present with persistent central facial erythema with transient papules or
`pustules or both. Symptoms of burning, stinging, and dry skin are common [1,3]. Other
`symptoms include flushing, erythema, and telangiectasia. While the exact pathogenesis of
`rosacea is unknown, inflammatory and vascular components are believed to be important in
`its pathogenesis.
`
`Dapsone has been recognized as being effective orally against a number of non-infectious
`inflammatory diseases, of which dermatitis herpetiformis is best known. A number of other
`inflammatory, as well as bullous, diseases have been reported to respond in varying degrees
`to dapsone [4]. Anecdotal case reports of the use of oral dapsone in treating patients with
`various forms of rosacea support the hypothesis that dapsone may have activity in treating
`papulopustular rosacea [5,6,7]. Topical administration of dapsone may be more appropriate
`than oral administration for the treatment of rosacea since it can be delivered directly to the
`skin, with lower systemic exposure and less risk of systemic toxicity.
`
`AczoneTM (dapsone) Gel, 5% is a new topical formulation of dapsone that is approved for the
`treatment of acne vulgaris in the US and Canada. In previous clinical studies for acne
`vulgaris, Aczone significantly reduced inflammatory and non-inflammatory lesion counts. In
`2 vehicle-controlled studies (Studies DAP0203 and DAP0204), inflammatory lesion counts
`were reduced by 46% and 48% in Aczone-treated groups compared with 42% and 40% for
`the vehicle-treated groups, respectively. The percentage reduction in non-inflammatory
`lesion counts were 31% and 30% for Aczone compared with 24% and 21% for vehicle. An
`important component of the Aczone effects observed in these trials was anti-inflammatory.
`Since inflammation is a component of papulopustular rosacea and anti-inflammatory
`properties are a common characteristic of systemic and topical therapies used for rosacea
`[8,9,10], Aczone may also have potential treatment effects on the signs and symptoms of
`papulopustular rosacea.
`
`This report presents the results of a phase II study to evaluate the safety and preliminary
`efficacy of Aczone in the treatment of papulopostular rosacea. It was conducted as a
`randomized, partial-blind, parallel-group study with both an active and vehicle control. This
`was the first study of Aczone in this patient population and was designed to provide an
`estimate of safety and efficacy to guide the design of any potential future trials.
`
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`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`2
`
`INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
`
`2.1 Study Investigators
`
`The study enrolled a total of 400 subjects across 27 study centers in the United States.
`Following is a list of study investigators, centers, and the number of subjects enrolled at each
`center. A list of other essential study personnel is provided in Appendix D.3.
`
`Center
`Number
`
`01
`
`02
`03
`
`04
`05
`06
`07
`08
`
`09
`10
`11
`12
`13
`
`14
`15
`16
`17
`18
`
`19
`
`20
`
`21
`22
`23
`
`24
`
`25
`
`26
`27
`28
`
`Investigator
`
`Paul Yamauchi, MD
`
`Hector Wiltz, MD, CCTI
`Pranav Sheth, MD
`
`Stacy R. Smith, MD
`Harry Sharata, MD
`Joel Schlessinger, MD
`Ronald C Savin, MD
`Janet L Roberts, MD
`
`Lawrence C Parish, MD
`Jeffrey Moore, MD
`Robert Matheson, MD
`J Michael Maloney, MD
`Anne Lucky, MSa
`
`Mark R Ling, MD, PhD
`Terry M Jones, MD
`Michael T Jarratt, MD
`Jolynne Herzog, MD
`Lynn A Cornelius, MD
`
`William B Harwell, MD
`
`Larry I Gilderman, DO
`
`David Fried, MD
`Frank Dunlap, MD
`Zoe Draelos, MD
`
`Sunil S Dhawan, MD
`
`Alicia Bucko, DO
`
`Steven Bowman, MD
`Keith Aqua, MD
`Anne Lucky, MSb
`
`Study Center
`
`Number of
`Subjects
`
`Clinical Research Specialists, Inc., Santa
`Monica, CA
`FXM Research, Miami FL
`University Dermatology Consultants, Inc.
`Cincinnati, OH
`Therapeutics Clinical Research, San Diego, CA
`Madison Skin & Research, Inc., Madison, WI
`Skin Specialists, PC, Omaha, NE
`Savin Center, PC, New Haven, CT
`Northwest Dermatology and Research, Portland,
`OR
`Paddington Testing Clinic, Philadelphia, PA
`Welborn Clinic, Evansville, IN
`Oregon Medical Research Center, Portland, OR
`Cherry Creek Research, Inc., Denver, CO
`Dermatology Research Associates, Inc.,
`Cincinnati, OH
`MedaPhase, Inc., Newnan GA
`J&S Studies, Inc., Bryan, TX
`DermResearch, Inc., Austin, TX
`Radiant Research, Inc., Birmingham, AL
`Dermatology Clinical Trials Unit, Washington
`University, St. Louis, MO
`Dermatology Research Associates, Nashville,
`TN
`University Clinical Research, Pembroke Pines,
`FL
`Omega Medical Research, Warwick, RI
`Radient Research, Tuscon, AZ
`Dermatology Consulting Services, High Point,
`NC
`East Bay Dermatology Medical Group, Inc.,
`Fremont, CA
`Academic Dermatology Associates,
`Albuquerque, NM
`Tampa Bay Medical Research, Clearwater, FL
`Visions Clinical Research, Boynton Beach, FL
`Dermatology Research Associates, Inc.,
`Cincinnati, OH
`
`15
`
`28
`25
`
`16
`14
`30
`3
`25
`
`10
`14
`9
`20a
`4
`
`17
`7
`19
`20
`5
`
`14
`
`15
`
`0
`10
`13
`
`5
`
`20
`
`30
`7
`5
`
`a
`
`One subject was randomized in error at Center 12. Data were collected from only 19 subjects at this center.
`b Dr. Lucky enrolled subjects at 2 different clinic locations in Cincinnati, which had separate randomization
`sequences and were therefore assigned separate center identification numbers.
`
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`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`2.2 Study Administrative Structure
`
`The following Sponsor individuals were involved in the design, conduct, analysis, and/or
`reporting of the study:
`
`Individual
`
`Title
`
`Responsibility
`
`QLTUSA, Inc.
`Steve Garrett, MS, DDS, FACD
`Craig Wesselman, MS
`Cynthia Strock, MPH
`Mary McManus, CCRA
`Adam James, CCRA
`QLT, Inc.
`Denise Galipeau, MSc
`Jane Liu, MS
`Gina Briggs
`Sheryl Myers, RN, CCRA
`Wendy Wilson, RN
`
`Other
`Mary Beth McClain, RN, MBA,
`CCRA
`Stephanie Costa, RT
`
`Senior Vice President, Dermatology
`Biostatistician
`Senior Manager, Clinical Operations
`Clinical Research Associate
`Senior Clinical Research Associate
`
`Overall study responsibility
`Statistical analyses and design
`Study operations
`Lead CRA, study monitoring
`Study monitoring
`
`Medical Writer
`Medical writing
`Clinical Data & Application Manager Study database and CRF
`Clinical Research Associate
`Study monitoring
`Senior Clinical Research Associate
`Study monitoring
`Clinical Research Associate
`Study monitoring
`
`Contract Monitor
`
`Study monitoring
`
`Contract Monitor
`
`Study monitoring
`
`2.3 Contract Services
`
`2.3.1 Randomization and Clinical Trial Supplies
`
`Labeling, distribution, and tracking of study treatment supplies and randomization services
`were provided by:
`
`Fisher Clinical Services
`7554 Schantz Road
`Allentown, PA
`18106
`
`2.3.2 Laboratory Analyses
`
`The following was the central laboratory for the study:
`
`Quintiles Laboratories, Ltd.
`5500 Highlands Parkway
`Suite 600
`Smyrna, GA 30082
`Tel: 770-373-3500
`
`Quintiles was responsible for receipt and handling of all blood samples required for this
`study, for reporting results back to the study center, and for providing an electronic data
`
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`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`transfer to the Sponsor at the end of the study. Quintiles also performed the analysis of
`clinical chemistry and hematology. The following laboratories performed the specialized
`laboratory tests indicated:
`
`Plasma dapsone and metabolites
`CANTEST BioPharma Services
`4606 Canada Way
`Burnaby, British Columbia
`Canada V5G 1K5
`
`G6PD Activity
`ARUP Laboratories
`500 Chipeta Way
`Salt Lake City, Utah
`United States 84108-1221
`
`3 STUDY ETHICAL CONSIDERATIONS
`
`3.1 Ethical Conduct of Study
`
`The study was conducted in accordance with the International Conference on Harmonization
`(ICH) GCP guidelines; Division 5 of the Food and Drugs Regulations of Canada; the US
`21 CFR Parts 50, 54, 56, and 312; and the principles enunciated in the Declaration of
`Helsinki.
`
`3.2 Institutional Review Board, Ethics Committee, or Research Ethics Board (IRB)
`
`The protocol and informed consent form for this study were reviewed and approved by an
`Institutional Review Board, Ethics Committee, or Research Ethics Board ORB) at each study
`center prior to implementation. No subject was treated until the IRB had provided written
`approval of the study and the informed consent form to the Investigator and the Sponsors.
`The IRB regulations in each country were followed at respective centers. Appendix D.4.1
`contains a list of the names and addresses of each IRB and their corresponding approval
`letters.
`
`3.3 Subject Information and Consent
`
`The Informed Consent form used for each study center complied with the Declaration of
`Helsinki, federal regulations (US 21 CFR 50 and other national requirements), and ICH GCP
`guidelines and was approved by the Sponsor and the Investigator’s IRB. The Investigator
`explained orally and in writing the medical aspects of the study, including the nature of the
`study and the treatment, in such a manner that each subject was aware of potential benefits
`and risks. Other elements of the informed consent process may have been delegated by the
`Investigator. After having been informed that participation was voluntary and that subjects
`may withdraw from the study at any time, without prejudice, each subject signed the IRB-
`approved informed consent form prior to enrollment in the study. A sample informed consent
`form, including information for subj ects, is provided in Appendix D.4.2.
`
`4 STUDY OBJECTIVES
`
`The objective of this study was to evaluate the safety and preliminary efficacy of Aczone in
`subj ects with papulopustular rosacea.
`
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`CR-06009
`AczoneTM (dapsone) Gel, 5%
`Clinical Study Report ACZ ROS 01
`
`5 STUDY DESCRIPTION (METHODS AND INVESTIGATIONAL PLAN)
`
`This section describes the design and conduct of the study, as outlined in the protocol. The
`protocol is provided in Appendix D. 1. There were no amendments or changes to the study
`design described in the protocol.
`
`5.1 Overall Study Design
`
`This was a multicenter, randomized, partial-blind, parallel-group study in male and female
`adult subjects with papulopustular rosacea. Subjects were randomly assigned to 1 of the
`following 5 treatment groups, in an equal ratio, according to a computer-generated
`randomization scheme:
`
`¯ Vehicle Control (VC), 2x/day.
`
`¯ Aczone (dapsone) Gel, 5%, 2x/day.
`
`¯ Aczone (dapsone) Gel, 5%, ix/day.
`
`¯ MetroGel® (metronidazole gel), 1%, lx/day.
`
`¯ Aczone (dapsone) Gel, 5% lx/day + MetroGel (metronidazole gel), 1%, lx/day.
`
`Subjects were instructed to apply the assigned study treatment to the entire face, after
`cleansing, for 12 weeks. Subjects were not blinded; however, they were not specifically told
`which treatment group they belonged to. Study personnel who dispensed the study treatment
`and the Sponsor were not blinded to treatment, but the evaluators of efficacy and safety
`variables were blinded.
`
`Efficacy assessments included monitoring inflammatory lesion counts, Investigator Global
`Assessment (IGA) scores, erythema scores, and telangiectasia scores. Plasma dapsone
`concentrations were measured to assess systemic exposure to the study treatment. Safety was
`evaluated by monitoring adverse events, hematology and serum chemistry parameters,
`concomitant medications, vital signs, and local symptoms (dryness, itching, stinging, and
`burning).
`
`5.2 Discussion of Study Design
`
`A partial-blind study design, in which the evaluators of efficacy and safety variables are
`blinded, was chosen to avoid bias in the assessment of those variables. Subjects’ knowledge
`of their treatment assignment was not believed to affect the outcome of these assessments,
`therefore rigorous blinding of the subject was not considered necessary. Because the study
`included 2 different active treatments (Aczone and MetroGel) with different packaging and
`different treatment regimens (once-daily and twice-daily), a double-blind design was not
`considered reasonable for this phase II study.
`
`MetroGel is an approved product for the treatment of papulopustular rosacea and recent
`studies used the same efficacy assessments used in this study. A VC arm was included in
`order to compare the effects of each treatment against an inactive treatment and to establish
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`the magnitude of any potential treatment effects, since some improvement was observed in
`subj ects treated with VC alone in Aczone studies with acne vulgaris subj ects.
`
`Several measures of efficacy were included in the study. Success rates, based on a 5-point
`IGA, and changes from baseline in lesion counts, are direct indications of treatment response,
`and were used in recent studies of other rosacea therapies [11,12]. Both of these endpoints
`are considered important and clinically relevant in evaluating the efficacy of treatments for
`rosacea. Erythema and telangiectasia are signs of rosacea that were evaluated according to
`standardized 4-point scales, and treatment-induced changes in these signs were considered to
`be clinically meaningful to subj ects.
`
`The treatment period was designed to be 12 weeks, which is sufficient for any potential
`treatment benefits to become apparent, and is consistent with other studies of topical
`therapies for rosacea [12,13]. Subjects were followed for 7 days after stopping treatment to
`monitor any ongoing adverse events. This length of time was longer than or equivalent to
`5 half-lives of dapsone after topical application (tv2=27.8 + 8.31 hours [Study DAP9903]).
`
`5.3 Study Population
`
`5.3.1 Number of Subj ects
`
`As planned in the protocol, a total of 400 subjects were enrolled in this study. However, data
`were only collected from 399 subjects because there was 1 subject randomized in error who
`was never dispensed any study treatment (randomization number 7519 at center 12, which
`was not re-used).
`
`5.3.2 Inclusion Criteria
`
`To be eligible for the study, subjects had to fulfill all of the following criteria:
`
`1. Men or women >18 years of age.
`
`2. Had a diagnosis of papulopustular rosacea, with >10 inflammatory lesions (papules
`and/or pustules) above the mandibular line at baseline.
`
`3. Had an IGA score >2.
`
`Score
`0
`
`1
`
`2
`
`Description
`Severity
`Clear
`No signs or symptoms present; at most, mild erythema
`Almost Very mild erythema present. Very few small papules/pustules
`Clear
`Mild
`
`Mild erythema. Several small papules/pustules
`Moderate erythema. Several small or large papules/pustules, and up to 2
`nodules
`Severe erythema. Numerous small and/or large papules/pustules, up to several
`nodules.
`
`3 Moderate
`
`4
`
`Severe
`
`4. Was in good physical and mental health.
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`5.
`
`Signed an approved informed consent form for the study and HIPAA authorization (if
`applicable).
`
`6. Was willing to comply with the protocol.
`
`5.3.3 Exclusion Criteria
`
`Subj ects who met any of the following criteria were excluded from the study:
`
`1. A skin examination revealed the presence of another skin disease and/or condition
`(excessive facial hair, excessive scarring, sunburn, or other disfigurement) located on
`the face that, in the study physician’s opinion, would have confounded the evaluation of
`the rosacea condition.
`
`2. Current or past ocular rosacea, such as conjunctivitis, iritis, and keratitis, of sufficient
`severity to require topical or systemic antibiotics, in the opinion of the Investigator.
`
`3. Treatment with topical antibiotics, topical steroids and other topical rosacea treatments
`on the face within 14 days of Baseline and throughout the study. This included other
`topical rosacea treatments including, but not limited to, treatments containing
`metronidazole (other than the MetroGel product supplied for this study), azelaic acid,
`and treatments containing