A Multicenter, Randomized, Double-Blind, Parallel-Group, Active and Placebo Controlled Study to Assess the Safety, Efficacy and Tolerability of Oral DFD-29 Extended Release Capsules for the Treatment of Inflammatory Lesions of Rosacea Over 16 Weeks.
Phase: PHASE3
Conditions: Papulopustular Rosacea
Sponsor: Journey Medical Corporation

Dr. Reddy’s/Journey Medical 
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DFD-29-CD-004 
Version: 2.0 
MVOR-1 
23 June 2022  
Protocol Template 
Confidential 
MW501.T01 Version 2019OCT11 
1 
TITLE PAGE 
 
Title: 
A Multicenter, Randomized, Double-Blind, Parallel-Group, 
Active and Placebo-Controlled Study to Assess the Safety, 
Efficacy, and Tolerability of Oral DFD-29 Extended Release 
Capsules for the Treatment of Inflammatory Lesions of 
Rosacea Over 16 Weeks 
 
Protocol No.: 
DFD-29-CD-004 
Acronym:  
MVOR-1 
Co-Sponsors: 
Dr. Reddy’s Laboratories Ltd.,  
8-2-337, Road No. 3 
Banjara Hills, Hyderabad 
Telangana 500034, India 
Phone: +91-40-4900 2900 
Journey Medical Corporation 
9237 E. Via De Ventura Blvd., Suite 105    
Scottsdale, AZ 85258, USA 
Phone: +1 480-434-6675 
 
 
Phase: 
3 
Protocol Version: 
2.0  
Amendment No:  
01 
Current Protocol Version 
Date:  
 23 June 2022 
Previous Version of the    
Protocol: 
Version 1.0 dated 02 December 2021 
 
The information contained in this document is privileged and confidential and is the property of 
Dr. Reddy’s Laboratories Ltd. and Journey Medical Corporation. Nothing herein is to be 
reproduced, published or disclosed to others, in any form, without the prior express written consent 
of Dr. Reddy’s Laboratories Ltd. and/or Journey Medical Corporation. Persons to whom this, or 
any information related to the contents of this document, is to be disclosed must be informed that 
the information is privileged and confidential and must not be further disclosed by them. 
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DFD-29-CD-004 
Version: 2.0 
MVOR-1 
23 June 2022  
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Confidential 
MW501.T01 Version 2019OCT11 
2 
SPONSOR/CRO SIGNATURE PAGE 
 
PROTOCOL NUMBER: 
DFD-29-CD-004 
PROTOCOL VERSION: 
2.0  
AMENDMENT NO.: 
01 
PROTOCOL DATE: 
23 June 2022   
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Parallel-Group, 
Active and Placebo-Controlled Study to Assess the Safety, 
Efficacy, and Tolerability of Oral DFD-29 Extended Release 
Capsules for the Treatment of Inflammatory Lesions of 
Rosacea Over 16 Weeks 
 
Signatures of the following individuals indicate that all agree this version is final. 
 
 
 
 
 
 
Srinivas Shenoy B., M.D. 
 
Date 
Director- Clinical Development  
Dr. Reddy´s Laboratories Ltd. 
 
 
 
 
 
 
Srinivas Sidgiddi, M.D.                                                                               Date 
Vice President 
Clinical Development & Medical Affairs 
Journey Medical Corporation 
 
 
 
 
 
 
 
 
 
 
Debra A. Dow, PharmD 
 
Date 
Vice President, Scientific Affairs  
Symbio, LLC 
 

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
Debra Dow
Digitally signed by Debra Dow 
Date: 2022.07.25 10:38:25 
-07'00'

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DFD-29-CD-004 
Version: 2.0 
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3 
SYNOPSIS AND STUDY FLOW CHART 
3.1 
Synopsis 
Title of Study: A Multicenter, Randomized, Double-Blind, Parallel-Group, Active and 
Placebo Controlled Study to Assess the Safety, Efficacy and Tolerability of Oral DFD-29 
Extended Release Capsules for the Treatment of Inflammatory Lesions of Rosacea Over 
16 Weeks 
Name of Sponsor: Dr. Reddy’s Laboratories Ltd., India 
Name of Finished Product: DFD-29 Extended Release Capsules 
Name of Active Ingredient: Minocycline HCl 
Objectives 
Primary: To evaluate the safety, efficacy, and tolerability of oral DFD-29 (Minocycline HCl 
Extended Release Capsules), 40 mg (hereafter referred to as DFD-29) compared to placebo in 
the treatment of papulopustular rosacea for 16 weeks 
Secondary: To evaluate the safety, efficacy, and tolerability of DFD-29 compared to  
Doxycycline capsules 40 mg (an authorized generic of Oracea® in the United States) in the 
treatment of papulopustular  rosacea for 16 weeks 
Study Design: This is a 16-week, multicenter, randomized, parallel-group, double-blind, 
controlled study. After assessing eligibility during a screening period of up to 30 days, 
approximately 320 subjects at least 18 years old who are diagnosed with moderate to severe 
papulopustular rosacea will be randomized in a 3:3:2 ratio to DFD-29 (40 mg), Doxycycline 
capsules 40 mg, or Placebo once daily for 16 weeks. 
Subject visits are scheduled at Screening, Baseline (Day 1), and Weeks 2, 4, 8, 12, and 16. 
Clinical assessments of efficacy will be conducted based on Investigator’s Global Assessment 
modified scale without erythema (IGA), Clinician’s Erythema Assessment (CEA), and total 
inflammatory lesion count at Weeks 2, 4, 8, 12, and 16 compared to Baseline.  
Laboratory assessments of blood (hematology and biochemistry) and urine (routine tests) will 
be conducted at Screening and Week 16 (end of study [EOS] or early termination) to assess for 
any changes in the safety parameters. Other safety assessments include vital signs, physical 
examination, urine pregnancy tests (for females of childbearing potential), and collection of AE 
data. 
The impact of the treatment on the quality of life (QoL) of the subjects will be assessed using 
the rosacea-specific tool RosaQoL in addition to the Dermatology Life Quality Index (DLQI) at 
Baseline and Weeks 2, 4, 8, 12, and 16. 
Number of Study Centers: Approximately 29 study centers in the United States (US) to enroll 
a total of approximately 320 subjects. 
Duration of Participation: Each subject will participate in the study for approximately 
20 weeks from the time the subject signs the informed consent form (ICF) through the final 
contact. The screening period is up to 30 days and duration of treatment is 16 weeks. 
Duration of Study: The study will require approximately 10 months from the beginning to the 
end of the study (first subject signing the ICF to last contact with last subject). 
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DFD-29-CD-004 
Version: 2.0 
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23 June 2022  
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Key Inclusion/Exclusion Criteria: Male and female subjects at least 18 years of age in good 
general health with a clinical diagnosis of papulopustular rosacea, IGA grade 3 (moderate) or 
grade 4 (severe) at Baseline will be selected to participate in the study. Subjects must have 15 
to 60 (both inclusive) inflammatory lesions (papules and pustules) of rosacea over the face and 
not more than 2 nodules or cysts at Baseline. 
Investigational Product, Dose, Route of Administration, and Regimen: 
To maintain the double-blind design, all 3 study medications will be over-encapsulated with the 
original capsules enclosed within a second, larger (size 0) capsule shell. 
Investigational product: DFD-29 (Minocycline Hydrochloride Extended Release Capsules), 
40 mg (Dr. Reddy’s Laboratories, Ltd.) 
Active control: Doxycycline Capsules 40 mg [an authorized generic of Oracea® in the United 
States (marketed by Prasco Laboratories, Mason OH 45040 USA)] 
Placebo: Capsules matching DFD-29 with same excipients but without minocycline HCl (Dr. 
Reddy’s Laboratories Ltd.) 
The study medication will be taken at a fixed time of the day once a day for 16 consecutive 
weeks. The preferred time of administration will be in the morning, after an overnight fast. 
Statistical Methods:  
Analysis Populations:  
x Intent-to-treat (ITT) population includes all randomized subjects (i.e., assigned to a 
treatment group). The ITT population will be the primary population for the efficacy 
analysis. 
x Safety population includes subjects who received at least one dose of study medication 
and had at least one safety assessment post-Baseline. The safety population will be used 
for analysis of tolerability and safety variables.  
x Per-protocol population (PP) comprises all subjects who did not violate the protocol in 
a way that might affect the evaluation of the effect of the study medication on the primary 
endpoint (without major protocol violations or deviations). Key protocol deviation 
categories that would influence the decision to include a subject in the PP population at 
time of final review before study database lock will be pre-specified in the Statistical 
Analysis Plan (SAP).   
Sample Size: The sample size was calculated based on results of a Phase 2 study with orally 
administered DFD-29 (40 mg) in the treatment of inflammatory lesions of papulopustular 
rosacea. Based on the sample size calculations and an assumed dropout rate of 20%, the final 
planned sample size is 120 subjects each in the DFD-29 and Doxycycline capsules 40 mg groups 
and 80 subjects in the placebo group for a total of 320 subjects. This sample size will provide 
adequate power to assess the superiority of DFD-29 against both placebo and Doxycycline 
capsules 40 mg in terms of efficacy on both co-primary endpoints. 
 
 
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DFD-29-CD-004 
Version: 2.0 
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23 June 2022  
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MW501.T01 Version 2019OCT11 
Safety/Tolerability Endpoints: 
The following parameters have been defined as endpoints regarding safety and tolerability: 
x Change from Baseline to each scheduled time point up to End of Study (EOS) for vital 
signs, physical examination and clinical laboratory tests. The clinical laboratory tests 
obtained at screening visit will be defined as baseline assessments.   
x Treatment-emergent AEs up to EOS. 
x Treatment-emergent AEs leading to premature discontinuation of study drug. 
x Treatment-emergent SAEs up to EOS. 
For pre-existing conditions, any event that worsens during treatment will be considered 
treatment emergent. 
Efficacy Endpoints: 
Co-Primary Efficacy Endpoints: 
 
x Proportion of subjects with IGA (modified scale without erythema) ‘treatment success’ 
– Grade 0 or 1 at Week 16 with at least 2 grade reduction from Baseline to Week 16, in 
the DFD-29 group compared to Placebo 
x Total inflammatory lesion count (sum of papules, pustules, and nodules) reduction from 
Baseline to Week 16, in the DFD-29 group compared to Placebo 
Secondary Efficacy Endpoints: 
x Percentage Change in Total inflammatory lesion count (sum of papules, pustules, and 
nodules) from Baseline to Week 16, in the DFD-29 group compared to Placebo 
x Proportion of subjects with IGA treatment success at week 16 in the DFD-29 group 
compared to Doxycycline capsules 40 mg. 
x Total inflammatory lesion count reduction from Baseline to week 16 in the DFD-29 
group compared to Doxycycline capsules 40 mg. 
x Proportion of subjects with at least 2-grade reduction in CEA score from Baseline to 
Week 16 in the DFD-29 group compared to Placebo. 
x Change in DLQI score from Baseline to Week 16 in the DFD-29 group compared to 
Placebo. 
Exploratory Efficacy Endpoints: 
All the following endpoints for DFD-29 will be compared against Placebo and Doxycycline 
capsules 40 mg 
x Proportion of subjects with IGA ‘treatment success’ from Baseline to Weeks 2, 4, 8 and 
12. 
x Total inflammatory lesion count (sum of papules, pustules, and nodules) reduction from 
Baseline to Weeks 2, 4, 8 and 12. 
x Percentage Change in Total inflammatory lesion count (sum of papules, pustules, and 
nodules) from Baseline to Weeks 2, 4, 8, 12 (and 16, in case of DFD-29 vs Doxycycline 
capsules 40 mg comparison).  
x Proportion of subjects with at least 2-grade reduction in IGA score from Baseline to 
Weeks 2, 4, 8 12 and 16. 
x Change in RosaQoL score from Baseline to Weeks 2, 4, 8, 12 and 16. 
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x Change in DLQI score from Baseline to Weeks 2, 4, 8, 12 (and 16, in case of DFD-29 
vs Doxycycline capsules 40 mg comparison). 
x Proportion of subjects with at least 2-grade improvement in the CEA score at Weeks 2, 
4, 8, 12 (and 16, in case of DFD-29 vs Doxycycline capsules 40 mg comparison). 
Safety and Tolerability Analysis 
Safety and tolerability data will be listed individually and summarized using descriptive 
statistics and frequency tables. 
Efficacy Analysis 
Co-Primary Endpoints: 
x The proportion of subjects with IGA treatment success (DFD-29 versus placebo) will be 
investigated with a Cochran-Mantel-Haenszel (CMH) test for general association 
adjusted for site. Treatment success is defined as having at least a 2-grade reduction from 
Baseline with Grade 0 or 1 at Week 16. 
x The difference between the treatments (DFD-29 versus placebo) in terms of the change 
from Baseline in the total inflammatory lesion count at Week 16 will be tested using an 
Analysis of Covariance (ANCOVA) model with treatment and site included in the model 
as fixed effects, and Baseline total inflammatory lesion count as a covariate. 
Secondary Endpoints: 
x Percentage Change in Total inflammatory lesion count (sum of papules, pustules, and 
nodules) from Baseline to Week 16, in the DFD-29 group compared to Placebo will be 
tested using an ANCOVA model with treatment and site included as fixed effects, and 
Baseline total inflammatory lesion count as a covariate. 
x Proportion of subjects with IGA treatment success (DFD-29 versus Doxycycline 
capsules 40 mg) at Week 16 will be investigated with a CMH test for general association 
adjusted for site.  
x The difference between treatments (DFD-29 versus Doxycycline capsules 40 mg) in 
change from Baseline in the total inflammatory lesion count at Week 16 will be tested 
using an ANCOVA model with treatment and site included as fixed effects, and Baseline 
total inflammatory lesion count as a covariate. 
x Proportion of subjects with at least a 2-grade reduction in CEA score from Baseline to 
Week 16 will be investigated with a CMH test for general association adjusted for site 
(DFD-29 versus placebo).  
x Change in DLQI score from Baseline to Week 16 will be investigated using an 
ANCOVA model with treatment and site included as fixed effects, and Baseline DLQI 
score as a covariate (DFD-29 versus placebo). 
 
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DFD-29-CD-004 
Version: 2.0 
MVOR-1 
23 June 2022  
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MW501.T01 Version 2019OCT11 
Exploratory Endpoints: 
All the following endpoints for DFD-29 will be compared against Placebo and Doxycycline 
capsules 40 mg 
x Proportion of subjects with IGA treatment success from Baseline to Weeks 2, 4, 8 and 
12 will be investigated with a CMH test for general association adjusted for site. 
Treatment success is defined as having at least a 2-grade reduction from Baseline with 
Grade 0 or 1. 
x The difference between treatments in terms of the change from Baseline in the total 
inflammatory lesion count at Weeks 2, 4, 8 and 12 will be tested using mixed model 
repeated measures (MMRM) with treatment, site, visit, and treatment-by-visit 
interaction included in the model as fixed effects, Baseline total inflammatory lesion 
count as a covariate, and the subjects as a random factor 
x Percentage Change in Total inflammatory lesion count (sum of papules, pustules, and 
nodules) from Baseline to Weeks 2, 4, 8, 12 (and 16, in case of DFD-29 vs Doxycycline 
capsules 40 mg comparison) will be tested using MMRM with treatment, site, visit, and 
treatment-by-visit interaction included in the model as fixed effects, Baseline total 
inflammatory lesion count as a covariate, and the subjects as a random factor 
x The proportion of subjects with at least 2-grade reduction in IGA score from Baseline to 
Weeks 2, 4, 8, 12 and 16 will be investigated with a CMH test for general association 
adjusted for site. 
x Change in total RosaQoL score from Baseline to Weeks 2, 4, 8, 12 and 16 will be 
investigated using MMRM with treatment, site, visit, and treatment-by-visit interaction 
included in the model as fixed effects, Baseline RosaQoL as a covariate, and the subjects 
as a random factor. 
x Change in DLQI score from Baseline to Weeks 2, 4, 8, 12 (and 16, in case of DFD-29 
vs Doxycycline capsules 40 mg comparison) will be investigated using MMRM with 
treatment, site, visit, and treatment-by-visit interaction included in the model as fixed 
effects, Baseline DLQI as a covariate, and the subjects as a random factor. 
x Proportion of subjects with at least a 2-grade improvement in the CEA score from 
Baseline to Weeks 2, 4, 8, 12 (and 16, in case of DFD-29 vs Doxycycline capsules 40 
mg comparison) will be investigated with a CMH test for general association adjusted 
for site. 
Exploratory analyses for the following subgroups will be performed with respect to the primary 
endpoints: 
x Males versus females. 
x Baseline Moderate (IGA 3) versus severe (IGA 4). 
x Baseline Inflammatory lesion count below versus above Median count. 
x Fitzpatrick skin types I-III versus IV-VI 
 
 
Interim Analysis: No formal interim analysis is planned.  
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3.2 
Study Flow Chart 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Screening Baseline 
Week 2 
Week 4 
Week 8 
Week 12 Week 16 EOS/ET 
Study Day 
Day -30 to 
Day -3 
Day 1 
Day 14 
(± 3 days) 
Day 29 
(± 3 days) 
Day 57 
(± 5 days) 
Day 85 
(± 5 days) 
Day 113  
(± 5 days) 
Informed Consent 
X 
 
 
 
 
 
 
Demographic Data including 
Fitzpatrick Skin Type 
X 
 
 
 
 
 
 
Inclusion and Exclusion Criteria 
X 
X 
 
 
 
 
 
Eligibility Conclusion 
X 
X 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
Medical History/Prior Medications 
X 
X 
 
 
 
 
 
Vital Signs (blood pressure, pulse 
rate)  
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test (for females 
of childbearing potential) 
X 
X 
X 
X 
X 
X 
X 
IGA 
X 
X 
X 
X 
X 
X 
X 
CEA 
X 
X 
X 
X 
X 
X 
X 
Lesion count 
X 
X 
X 
X 
X 
X 
X 
RosaQoL & DLQI Score 
 
X 
X 
X 
X 
X 
X 
Physical Examinationa 
X 
 
 
 
 
 
X 
Laboratory assessments (Blood & 
Urine tests) 
X b 
 
 
 
 
 
Xc 
Photographyd 
 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
Dispense/ Re-dispense Study Drug 
 
X 
Xe 
X 
X 
X 
 
Dispense/Review/Collect Study 
Diary 
 
X 
X 
X 
X 
X 
X 
Discussion of Subject Instructions 
 
X 
X 
X 
X 
X 
 
Collect Study Drug 
 
 
Xe 
X 
X 
X 
X 
Evaluate Study Drug Compliance 
 
 
X 
X 
X 
X 
X 
Adverse Event 
(Assessment/Collection) 
 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
 
 
X 
X 
X 
X 
X 
CEA = Clinician’s Erythema Assessment; DLQI = Dermatology Life Quality Index; EOS = end of study; 
IGA = Investigator’s Global Assessment modified scale without erythema; RosaQoL = Rosacea Quality of Life 
 
a 
A complete physical examination will be performed. Height and weight will be measured at Screening. 
Weight will also be measured at Baseline and Visit 7 (EOS or ET) 
b 
Serology assessments will be performed only at Screening. 
c 
Laboratory assessments (except Serology) for all subjects will be done at their EOS visit (Week 16). 
d 
Photography will be done at a subset of sites. 
e 
Collect and Re-dispense at Visit 3 
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4 
TABLE OF CONTENTS 
1 
TITLE PAGE ..........................................................................................................................1 
2 
SPONSOR/CRO SIGNATURE PAGE .................................................................................2 
3 
SYNOPSIS AND STUDY FLOW CHART ..........................................................................3 
3.1 
Synopsis ..............................................................................................................................3 
3.2 
Study Flow Chart ................................................................................................................8 
4 
TABLE OF CONTENTS ........................................................................................................9 
4.1 
List of Tables ....................................................................................................................12 
5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................13 
6 
INTRODUCTION .................................................................................................................15 
6.1 
Background .......................................................................................................................15 
6.2 
Rationale for the Study and Study Design ........................................................................16 
6.2.1 
Study Rationale ..........................................................................................................16 
6.2.2 
Dose Selection ...........................................................................................................17 
7 
STUDY OBJECTIVES .........................................................................................................17 
7.1 
Primary Objective .............................................................................................................17 
7.2 
Secondary Objectives ........................................................................................................17 
8 
INVESTIGATIONAL PLAN ...............................................................................................17 
8.1 
Overall Study Design ........................................................................................................17 
8.2 
Beginning and End of Study .............................................................................................18 
8.3 
Study Population ...............................................................................................................19 
8.3.1 
Inclusion Criteria .......................................................................................................19 
8.3.2 
Exclusion Criteria ......................................................................................................20 
8.3.3 
Subject Discontinuation Criteria ................................................................................23 
8.3.4 
Replacement of Subjects ............................................................................................25 
8.4 
Treatments .........................................................................................................................25 
8.4.1 
Dosage and Formulations ..........................................................................................25 
8.4.2 
Method of Treatment Assignment, Randomization, and/or Stratification .................27 
8.4.3 
Selection and Timing of Dose for Each Subject ........................................................27 
8.4.4 
Blinding of Study Medication ....................................................................................27 
8.4.5 
Method of Packaging, Labeling, Storage, and Dispensing ........................................27 
8.4.6 
Replacement of Study Medication .............................................................................28 
8.4.7 
Study Medication Accountability ..............................................................................28 
8.4.8 
Prior and Concomitant Medications ..........................................................................29 
8.4.8.1 
Medications, Supplements, and Other Substances Prohibited Before Study Entry 
and During the Study ..................................................................................................... 29 
8.4.8.2 
Other Restrictions .......................................................................................................... 29 
8.4.8.2.1 Sun Exposure .............................................................................................................. 29 
8.4.8.2.2 Contraceptives ............................................................................................................ 29 
8.4.8.3 
Concomitant Medications, Supplements, and Other Substances Allowed During 
the Study ........................................................................................................................ 30 
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8.4.9 
Assessment of Compliance ........................................................................................30 
8.5 
Study Schedule ..................................................................................................................30 
8.6 
Study Procedures ..............................................................................................................30 
8.6.1 
Study Initiation...........................................................................................................31 
8.6.2 
Written Informed Consent .........................................................................................31 
8.6.3 
Significant Medical History/Demographic Information ............................................31 
8.6.4 
Physical Examination (Including Vital Signs) ...........................................................31 
8.6.5 
Prior Medication Review ...........................................................................................31 
8.6.6 
Laboratory Assessments ............................................................................................31 
8.6.7 
Urine Pregnancy Test and Acceptable Contraceptive Methods ................................32 
8.6.8 
Investigator’s Global Assessment (IGA) ...................................................................33 
8.6.9 
Clinician’s Erythema Assessment (CEA) ..................................................................33 
8.6.10 Total Inflammatory Lesion Count .............................................................................34 
8.6.11 Rosacea Quality of Life (RosaQoL) ..........................................................................34 
8.6.12 Dermatology Life Quality Index (DLQI) ..................................................................34 
8.6.13 Photography ...............................................................................................................34 
8.6.14 Review Inclusion/Exclusion Criteria .........................................................................34 
8.6.15 Study Medication Dispensing and Collection............................................................34 
8.6.16 Subject Instruction, Diary Card, and Compliance .....................................................35 
8.6.17 Adverse Events and Serious Adverse Events Assessment ........................................35 
8.6.18 Concomitant Medication Review ..............................................................................35 
8.6.19 Study Medication Accountability ..............................................................................35 
8.7 
Visit-Specific Procedures ..................................................................................................35 
8.7.1 
Visit 1/Day -30 to -3: Screening ................................................................................35 
8.7.2 
Visit 2/Day -1: Baseline .............................................................................................36 
8.7.3 
Visit 3/Day 14 (± 3 days), Visit 4/Day 29 (± 3 days), Visit 5/Day 57 (± 5 days), 
and Visit 6, Day 85 (± 5 days) ................................................................................................37 
8.7.4 
Visit 7/Day 113 (± 5 days): End of Study or Early Termination ...............................37 
8.7.5 
COVID-19 Considerations.........................................................................................38 
8.8 
Efficacy Assessments ........................................................................................................39 
8.8.1 
Co-Primary Efficacy Endpoints .................................................................................39 
8.8.2 
Secondary Efficacy Endpoints ...................................................................................39 
8.8.3 
Exploratory Efficacy Endpoints .................................................................................39 
8.9 
Assessment of Safety ........................................................................................................39 
8.9.1 
Safety Endpoints ........................................................................................................39 
8.9.2 
Definitions of Terms ..................................................................................................40 
8.9.2.1 
Adverse Event ................................................................................................................ 40 
8.9.2.2 
Suspected Adverse Reaction .......................................................................................... 41 
8.9.2.3 
Unexpected Adverse Event ............................................................................................ 41 
8.9.2.4 
Serious Adverse Event ................................................................................................... 41 
8.9.2.5 
Planned Hospitalization ................................................................................................. 42 
8.9.2.6 
Pregnancy ...................................................................................................................... 42 
8.9.3 
Monitoring Adverse Events and Laboratory Evaluations ..........................................42 
8.9.4 
Assessment of Adverse Events ..................................................................................43 
8.9.4.1 
Assessment of Severity .................................................................................................. 43 
8.9.4.2 
Assessment of Causality ................................................................................................ 43 
8.9.5 
Reference Safety Information for Assessing Expectedness of Adverse Events ........44 
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8.9.5.1 
Known Potential Toxicities of Investigational Product ................................................. 44 
8.9.6 
Reporting Safety Observations ..................................................................................44 
8.9.7 
Discontinuation, Treatment Interruption, and Unblinding of Blinded Treatment 
Due to Safety Observations .....................................................................................................47 
8.9.7.1 
Discontinuation .............................................................................................................. 47 
8.9.7.2 
Treatment Interruption ................................................................................................... 47 
8.9.7.3 
Modification of Dose of Study Medication ................................................................... 47 
8.9.7.4 
Unblinding Treatment for a Subject During the Study .................................................. 47 
8.10 Criteria for Early Termination of the Study ......................................................................48 
9 
STATISTICAL METHODS ................................................................................................48 
9.1 
Statistical Analysis Plan ....................................................................................................48 
9.2 
Analysis Populations .........................................................................................................48 
9.3 
General Considerations .....................................................................................................48 
9.3.1 
Handling of Missing Data ..........................................................................................48 
9.4 
Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications .......................................................................................................................49 
9.5 
Exposure to Study Drug and Treatment Compliance .......................................................49 
9.6 
Efficacy Evaluations .........................................................................................................49 
9.6.1 
Co-Primary Endpoints ...............................................................................................49 
9.6.2 
Secondary Endpoints .................................................................................................50 
9.6.3 
Interim Analysis .........................................................................................................50 
9.7 
Safety Analyses .................................................................................................................50 
9.8 
Other Analyses ..................................................................................................................51 
9.8.1 
Exploratory Analyses .................................................................................................51 
9.9 
Sample Size Determination ...............................................................................................52 
10 ETHICS ..................................................................................................................................52 
10.1 Informed Consent ..............................................................................................................52 
10.2 Institutional Review Board (IRB) .....................................................................................53 
10.3 Subject Confidentiality .....................................................................................................53 
10.4 Study Registration .............................................................................................................53 
11 DATA HANDLING AND RECORDKEEPING ................................................................53 
11.1 Site Regulatory Documents Required for Initiation .........................................................53 
11.2 Maintenance and Retention of Records ............................................................................54 
11.2.1 Electronic Case Report Forms (eCRFs) .....................................................................54 
11.2.2 Primary Source Documents .......................................................................................55 
11.3 Study Monitoring ..............................................................................................................56 
11.4 Audits and Inspections ......................................................................................................56 
11.5 Modifications to the Protocol ............................................................................................56 
11.6 Completion of the Study ...................................................................................................56 
12 CONFIDENTIALITY, USE OF INFORMATION, AND PUBLICATION ....................57 
13 LIST OF REFERENCES .....................................................................................................57 
14 INVESTIGATOR AGREEMENT ......................................................................................60 
15 APPENDICES .......................................................................................................................61 
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15.1 IGA Scale ..........................................................................................................................61 
15.2 CEA Scale .........................................................................................................................61 
15.3 Diagram of the Face ..........................................................................................................62 
15.4 Example of the Rosacea Quality of Life Instrument ........................................................63 
15.5 Example of the Dermatology Life Quality Index .............................................................64 
 
4.1 
List of Tables 
Table 8.1 
Prohibited Topical Drugs, Systemic Drugs, and Other Treatments ......................21 
Table 8.2:  
Identity of Test .......................................................................................................25 
Table 8.3:  
Identity of Placebo .................................................................................................26 
Table 8.4:  
Identity of Doxycycline capsules 40 mg ................................................................26 
Table 8.5:  
Laboratory Tests ....................................................................................................32 
 
 
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5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Term 
Definition 
AE 
Adverse event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of variance 
CEA 
Clinician’s Erythema Assessment 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel test 
COVID-19 
Coronavirus disease 2019 
CRA 
Clinical Research Associate 
CRO 
Contract research organization 
CRP 
C-reactive Protein 
DFD-29 
Minocycline HCl (formulated as Extended Release capsules) 
DLQI 
Dermatology Life Quality Index 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End of study 
ET 
Early Termination 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
HCl 
Hydrochloride 
HDPE 
High-density polyethylene 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IGA 
Investigator’s Global Assessment modified scale without erythema 
ITT 
Intention to treat 
IRB 
Institutional review board 
IUD 
Intrauterine device 
IWRS 
Interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Affairs 
MI 
Multiple imputation 
MMRM 
Mixed model repeated measures 
MVOR-1 
Minocycline Versus Oracea in Rosacea – Study 1 
OTC 
Over the counter 
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Term 
Definition 
PI 
Principal Investigator 
PP 
Per protocol 
PT 
Preferred term 
QoL 
Quality of life 
RosaQoL 
Rosacea Quality of Life 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Suspected adverse reaction 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
US 
United States  
 
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6 
INTRODUCTION 
6.1 
Background 
Rosacea is a chronic relapsing inflammatory cutaneous disorder, primarily of the convexities of 
the central face (cheeks, chin, nose, and central forehead). The main clinical forms of the disease 
are erythematotelangiectatic rosacea (subtype 1), papulopustular rosacea (subtype 2), phymatous 
rosacea (subtype 3), and ocular rosacea (subtype 4) [25]. In addition to the classification system, 
the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea 
devised a standard method for assessing gradations of the severity of rosacea [26]. This standard 
grading system is essential to perform research, analyze results, and compare data; provides a 
common reference for diagnosis, treatment, and assessment of results in clinical practice; and is 
the basis for the Investigator’s Global Assessment in rosacea. 
The accurate incidence of rosacea is not known but it is estimated by the National Rosacea Society 
of the US that 16 million Americans suffer from the signs and symptoms of rosacea, and millions 
more may be in temporary remission [17]. An earlier preliminary study conducted in the US in 
2993 women aged between 10 and 70 years found a prevalence rate for rosacea of 16% in 
Caucasian women and an overall rosacea incidence of nearly 10% in the total population including 
Hispanics, African-Americans, Asians, and Indians [23]. A recent epidemiological study estimated 
an overall incidence for diagnosed rosacea of 1.65 per 1000 person-years in the United Kingdom 
[18]. In 3052 and 3013 subjects aged between 18 and 65 years drawn from the general populations 
of Germany and Russia, respectively, the prevalence of rosacea was found to be 12.3% (95% 
confidence interval [CI], 10.2-14.4) in Germany and 5.0% (95% CI, 2.8-7.2) in Russia [21]. In a 
Swedish study in a non-selected population of 809 office employees (454 women and 309 men), 
81 people were diagnosed as having rosacea giving a prevalence of 10% (women 14%, men 5%) 
[2]. In a cross-sectional study of 348 subjects randomly selected from a working population ≥ 30 
years of age in Estonia, 78 (22%) had one or more primary features of rosacea [1]. Rosacea is a 
chronic skin condition that disproportionately affects fair-skinned persons of European and Celtic 
origin. 
The pathogenesis of rosacea is poorly understood. Contributing factors may include immune and 
inflammatory abnormalities, vascular alterations, neurogenic dysregulation, presence of cutaneous 
microorganisms, ultraviolet (UV) damage, and skin barrier dysfunction [10, 14, 20, 24, 27]. 
Clinical features and trigger factors of rosacea indicate a complex dysregulation of inflammatory, 
vascular, and neuronal systems at an early stage. Elevated levels of antimicrobial peptides 
(cathelicidins), processing enzymes (epidermal serine protease kallikrein 5), proinflammatory 
cytokines, and toll-like receptors (TLR) seem to play a role in maintaining chronic inflammation 
in rosacea, which may induce modification of dermal structures mediated by vascular changes and 
collagen degeneration. Complex vascular mechanisms contribute to local vasodilation, 
angiogenesis, and tissue fibrosis in rosacea. The involvement of the nervous system is supported 
by the fact that symptoms of rosacea are triggered when subjects are under emotional stress. 
Consistent with its immuno-inflammatory and neurovascular pathophysiology, rosacea was found 
to be associated with several autoimmune diseases [8], with cardiovascular disease risk factors and 
cardiovascular diseases [7, 15], with migraine [19], and with a 2- to 5-fold increased risk of 
depression and anxiety disorders [9, 13]. In addition, almost half of the rosacea subjects report a 
significant impairment in their quality of life [3, 21]. Taking into consideration these findings and 
that about 50% of the subjects receive no rosacea care, effective treatment might contribute not 
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only to symptomatic relief, but also to reduce cardiovascular risk and to improve the emotional 
health and the quality of life of subjects with rosacea. 
Oral tetracyclines, especially doxycycline and minocycline, have been a cornerstone of systemic 
treatment in rosacea. Independently of their antibacterial properties, tetracyclines at low doses 
exert anti-inflammatory effects, decrease matrix metalloproteinase activity involved in kallikrein 
activation, act as oxygen scavengers, and improve epidermal barrier function. All of these 
biological activities could contribute to the effectiveness of low-dose tetracyclines in rosacea 
treatment. The use of tetracyclines was also found to be associated with a decreased incidence of 
vascular disease in veterans with rosacea [6]. 
Details about specific benefits and risks for subjects participating in this study may be found in the 
accompanying consent documents for this study.  
The study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and 
all applicable regulatory requirements. 
6.2 
Rationale for the Study and Study Design 
6.2.1 
Study Rationale 
This is a Phase 3 multicenter, randomized, double-blind, parallel-group, active and placebo-
controlled study to assess the efficacy, safety and tolerability of oral DFD-29 (Minocycline 
Hydrochloride Extended Release Capsules), 40 mg (hereafter referred to as DFD-29) for the 
treatment of papulopustular rosacea over 16 weeks.  
Papulopustular rosacea is the second most common form of the disease and represents a more 
inflammatory subtype. Papulopustular rosacea is characterized by persistent central facial 
erythema with transient papules or pustules or both in a central facial distribution, but it can also 
present with telangiectasias (usually masked by its typical manifestations) and can occur 
concomitantly with acne vulgaris [25, 27]. Although multiple therapeutic options are available for 
the treatment of papulopustular rosacea, the most widely used systemic agents are oral tetracycline 
derivatives, particularly doxycycline and minocycline. 
The main concern with the long-term use of tetracyclines in rosacea has been antibacterial 
resistance. However, the recent findings that tetracyclines exert anti-inflammatory effects and 
seem to be effective in papulopustular rosacea at low sub-antimicrobial doses opens new options 
for its clinical use in this indication that warrant further investigation [10, 11, 12, 22]. Doxycycline 
and minocycline show a variety of biological actions independent of their antibiotic activity, 
including scavenging of oxygen radicals, anti-inflammatory and anti-apoptotic actions, and 
inhibition of proteolysis, angiogenesis, and tumor growth. Tetracyclines may reduce the 
inflammation associated with rosacea by downregulating proinflammatory cytokines and 
inhibiting matrix metalloproteinases involved in kallikrein activation [10, 11, 12]. 
Minocycline modulates glutamate-induced excitotoxicity and has anti-apoptotic, antioxidant, anti-
inflammatory, and neuroprotective effects that proved beneficial in experimental models of 
various diseases with an inflammatory basis, including dermatological, autoimmune, vascular, 
psychiatric, and neurological conditions, for which it has been postulated as an adjunctive therapy 
[4, 11, 12]. The lack of photosensitivity represents a potential advantage of minocycline for the 
treatment of papulopustular rosacea because doxycycline exhibits a dose-related phototoxicity [5]. 
Minocycline demonstrated benefit in the treatment of inflammatory lesions in subjects with 
rosacea [16, 22] and proved remarkably effective in decreasing serum C-reactive protein (CRP) 
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levels in other conditions [18]. However, the dose-related efficacy of minocycline at sub-
antimicrobial doses in improving the clinical symptoms and reducing serum CRP in 
papulopustular rosacea has not been investigated. 
Dr. Reddy’s completed a Phase 2 study in November 2018, which evaluated the efficacy, safety, 
and tolerability of DFD-29 for the treatment of papulopustular rosacea over 16 weeks, in Germany. 
This study demonstrated a significantly greater efficacy with DFD-29 (40 mg and 20 mg) 
compared to placebo, and with DFD 29 (40 mg) compared to Oraycea® (Doxycycline Capsules 
40 mg) (EU product). Based on the assessment of clinical and laboratory adverse events (AEs) as 
well as all other safety parameters, DFD-29 developed by Dr. Reddy´s Laboratories Ltd. was safe 
and well tolerated.  
This Phase 3 study is intended to provide efficacy data across a larger study population with 
approximately 29 study centers in the US. 
6.2.2 
Dose Selection 
The proposed dose strength of DFD-29 to be evaluated in this study is 40 mg. The safety, efficacy, 
and tolerability of DFD-29 at doses of 20 mg and 40 mg were evaluated in the Phase 2 study 
referenced above. Based on the assessment on the clinical and laboratory AEs as well as other 
safety parameters, DFD-29 (40 mg) demonstrated no significant safety or tolerability issues and 
therefore is considered to be safe and well tolerated when used in subjects with rosacea. 
Minocycline, along with doxycycline and tetracycline, has found a place in dermatologists’ 
therapeutic armamentarium for treatment of inflammatory lesions (papules and pustules) in 
subjects with moderate to severe rosacea; however, only a sub-antimicrobial dose of doxycycline 
has been approved in the US for this indication. 
The selection of DFD-29 doses lower than the approved minocycline dose is based on the lower 
protein binding and higher lipophilicity of minocycline compared to doxycycline, which is 
expected to lead to higher tissue penetration and exposures of minocycline than those achieved 
with the 40 mg oral dose of doxycycline used for rosacea. Assuming comparable 
anti-inflammatory effects, similar or higher exposure of minocycline achieved using the proposed 
DFD-29 doses is postulated to translate into efficacy that is better than that seen with doxycycline 
40 mg. 
7 
STUDY OBJECTIVES 
7.1 
Primary Objective 
To evaluate the safety, efficacy, and tolerability of oral DFD-29 compared to placebo in the 
treatment of papulopustular rosacea for 16 weeks 
7.2 
Secondary Objectives 
To evaluate the safety, efficacy, and tolerability of oral DFD-29 compared to Doxycycline capsules 
40 mg in the treatment of papulopustular rosacea for 16 weeks 
8 
INVESTIGATIONAL PLAN 
8.1 
Overall Study Design 
This is a 16-week, multicenter, randomized, parallel-group, double-blind, controlled study. After 
assessing eligibility during a screening period of up to 30 days, approximately 320 subjects at least 
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18 years old who are diagnosed with moderate to severe papulopustular rosacea will be 
randomized to one of the following treatment groups: 
x DFD-29 (Minocycline HCl Extended Release Capsules), 40 mg once daily for 16 weeks 
(DFD-29) 
x  Doxycycline capsules 40 mg once daily for 16 weeks * 
x Placebo capsules once daily for 16 weeks  
* An authorized generic of Oracea (Doxycycline capsules 40 mg) in the United States 
(marketed by – Prasco Laboratories , Mason OH 45040 USA) will be used as the active 
comparator product.  
Subject visits are scheduled at Screening, Baseline (Day 1), and Weeks 2, 4, 8, 12, and 16. Clinical 
assessments of efficacy will be conducted based on Investigator’s Global Assessment modified 
scale without erythema (IGA), Clinician’s Erythema Assessment (CEA), and total inflammatory 
lesion count at Weeks 2, 4, 8, 12, and 16 compared to Baseline.  
Laboratory assessments of blood (hematology and biochemistry) and urine (routine tests) will be 
conducted at Screening and Week 16 (end of study [EOS] or early termination) to assess for any 
changes in the safety parameters. Other safety assessments include vital signs, physical 
examination, urine pregnancy tests (for females of childbearing potential), and collection of AE 
data. 
The impact of the treatment on the quality of life (QoL) of the subjects will be assessed using the 
rosacea-specific tool RosaQoL in addition to the Dermatology Life Quality Index (DLQI) at 
Baseline and Weeks 2, 4, 8, 12, and 16. 
The study design is appropriate for the indication studied. Validated methods of data collection, 
analysis, and evaluation will be used for the study. 
8.2 
Beginning and End of Study 
A subject is considered to be enrolled in the study when he/she has provided written informed 
consent and has been randomized to study medication. 
A subject is considered to have completed the study after he/she has completed Visit 7 (Week 16). 
A subject is considered to have discontinued after he/she has withdrawn consent or has been 
discontinued under the conditions specified in Section 8.3.3. 
A subject is considered to have been lost to follow-up if he/she cannot be contacted by the 
investigator. The investigator will document efforts to attempt to reach the subject twice by 
telephone and will send a certified letter before considering the subject lost to follow-up. The end 
of participation for a subject lost to follow-up is documented as the delivery/return date of the 
certified letter. 
Each subject will be monitored for the occurrence of AEs, including serious adverse events 
(SAEs), starting immediately after the subject has signed the informed consent form (ICF). Each 
subject will be followed for safety monitoring until he/she is discharged from the study. Follow-up 
procedures related to pregnancy, AEs, or SAEs may continue beyond the end of the study. 
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Each subject will participate in the study for approximately 20 weeks from the time he/she signs 
the ICF through the final contact. After a screening phase of approximately 30 days, each subject 
will apply assigned treatment for 16 weeks.  
It is anticipated that the duration of this study will be 10 months. 
8.3 
Study Population 
Approximately 320 healthy males and females, at least 18 years of age and with a diagnosis of 
papulopustular rosacea (IGA grade 3[moderate] or grade 4 [severe]) will be selected to participate 
in the study. 
8.3.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1. Subjects must be able to understand the requirements of the study and be willing to give 
written informed consent. 
2. Male and female subjects aged 18 years and above. 
3. Subjects must be in good general health as determined by the investigator and supported 
by the medical history. 
4. Subjects must have a clinical diagnosis of papulopustular rosacea with IGA grade 3 
(moderate) or IGA grade 4 (severe) at Baseline. 
5. Subjects must have 15 to 60 (both inclusive) inflammatory lesions (papules and pustules) 
of rosacea over the face at Baseline.  
6. Subjects must have not more than 2 nodules or cysts at Baseline. 
7. Subjects must agree to only use the study medication and to not use any other treatment for 
rosacea (prescription or over-the-counter [OTC]) during the course of the study. 
8. Subjects must be willing to minimize or not significantly change external factors that might 
trigger rosacea flare-ups (such as spicy food, thermally hot foods, soups and drinks, hot 
environments, prolonged sun exposure, strong winds, alcoholic beverages, etc.) throughout 
the study. 
9. Subjects must be free of any systemic or dermatologic disorder that, in the opinion of the 
investigator, will interfere with the study results, and especially free of any skin diseases 
(for example peri-oral dermatitis, facial keratosis pilaris, seborrheic dermatitis, and acne 
vulgaris) that may confound the evaluation of rosacea. 
10. Females of childbearing potential must have a negative urine pregnancy test at the 
Screening and Baseline Visits. Sensitivity of such a test should at least be 25 mIU/mL or 
lower for human chorionic gonadotropin (hCG). 
11. Females must either be postmenopausal with no menses for at least 12 months or surgically 
sterile (hysterectomy or tubal ligation) or agree to use a highly effective method of 
contraception with a pearl index of <1% up to 1 month after last dose. Contraception 
methods with low user dependency should preferably be used, in particular when 
contraception is introduced as a result of participation in this clinical study.  
‘Highly effective’ methods of birth control include: 
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x combined (estrogen and progesterone containing) hormonal contraception 
associated with inhibition of ovulation*: 
o oral 
o intravaginal 
o transdermal 
x progesterone-only hormonal contraception associated with inhibition of 
ovulation*: 
o oral 
o injectable 
o implantable† 
x intra-uterine device (IUD) † 
x intra-uterine hormone releasing system (IUS) † 
x bilateral tubal occlusion† 
x vasectomy of sexual partner that was performed at least 90 days prior to Baseline, 
and has been medically assessed as successful† 
x total (as opposed to periodic or cyclic) sexual abstinence 
o Note: Sexually inactive female subjects may be enrolled at the 
investigator’s discretion provided that they are counseled to refrain from 
heterosexual intercourse for the duration of the study and for one month 
after the last dose, and understand the possible risks involved in getting 
pregnant during the study. 
* Hormonal methods: If on hormonal contraceptives, must have been on the 
same hormonal contraceptive product for 3 months (90 days) prior to 
Baseline and continued on the same method and dose throughout the 
duration of the study. If subject had used hormonal birth control and had 
stopped, this should have occurred more than 6 months prior to Baseline. 
Female subjects on low dose oral contraceptives (containing ≤35 μg of 
ethinyl estradiol or equivalent dose of other estrogens) must use a second 
form of contraceptive during the study. 
† Contraception methods that are considered to have low user dependency. 
8.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Female subjects who are pregnant or nursing or planning to become pregnant during the 
study. 
2. Male subjects whose female partner is planning to conceive a child. 
3. Clinically significant abnormal laboratory test results that, in the opinion of the 
investigator, would compromise the subject’s safety or ability to participate in the trial. 
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4. History of organ transplant requiring immunosuppression, HIV, or other immune 
compromised state. 
5. History of lupus-like syndrome, autoimmune hepatitis, vasculitis, or serum sickness. 
6. Use of any treatment listed in Table 8.1 more recently than the indicated washout period 
prior to Baseline (Visit 2/Day 1). 
Table 8.1 
Prohibited Topical Drugs, Systemic Drugs, and Other Treatments 
Product 
Washout period before Baseline 
Topical treatments on the face 
Corticosteroids 
30 days 
Retinoids (e.g., tretinoin, adapalene, retinol, tazarotene) and 
other cosmetic retinoids) 
30 days 
Immunomodulators (including topical calcineurin inhibitors 
[e.g. Protopic® (tacrolimus) ointment])  
30 days 
Anti-inflammatory agents or topical non-steroidal anti-
inflammatory drugs (NSAID) 
14 days  
Topical antimycotics 
14 days 
Benzoyl peroxide, Sodium Sulfacetamide 10%, Sulfur 5%  
14 days 
Topical antibiotics (e.g., Zilxi®  (minocycline) topical foam, 
macrolides, clindamycin) 
14 days 
Any anti-rosacea topical treatments (e.g., metronidazole, 
azelaic acid, brimonidine, ivermectin, oxymetazoline) 
14 days 
Medicated cleansers (e.g., benzoyl peroxide, salicylic acid, 
sulfur or triclosan) 
7 days 
Astringents or abrasives (OTC scrubs, exfoliating cleansers 
and products containing salicylic acid and alcohol) 
7 days 
Anti-microbial soaps and face wash 
Not applicable (use should be 
discontinued at baseline) 
Systemic Treatments 
Oral Retinoids [e.g., Accutane®] or therapeutic vitamin A 
supplements of >10,000 units per day 
180 days 
Radiation therapy and/or anti-neoplastic agents 
90 days 
Beta-blockers – use must remain constant during the study 
Initiation of therapy or change of 
dose within 90 days 
Hormonal treatment (oral, implant, topical contraceptives 
and androgens) – use must remain constant during the study 
Initiation of therapy or change of 
dose within 90 days 
Vitamin D supplements of > 4,000 units/day or >100 mcg 
(daily multivitamins with Vitamin D not exceeding more 
than 4,000 IU/day are allowed) 
A constant stable prescribed weekly dose is allowed and 
subjects should remain on this dose during the study 
30 days 
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Product 
Washout period before Baseline 
Oral antibiotics known to impact rosacea (e.g., tetracyclines, 
minocycline, doxycycline, metronidazole, or macrolides) 
Short-term treatment of all other antibiotics (not affecting 
rosacea) for ≤14 days is acceptable 
30 days 
Corticosteroids  – Intranasal and inhaled corticosteroids are 
allowed and may be used throughout the study if at a stable 
dose. 
30 days 
Immunosuppressive agents or Immunomodulators 
30 days 
Oral ivermectin 
30 days 
Spironolactone 
30 days 
Anticoagulants 
Subjects on anticoagulant therapy who are eligible will 
require consultation with their physician for review and 
downward adjustment of their dosage, if necessary.  
Documentation from their treating physician is required 
prior to randomization.  After any dose adjustment, use 
must remain on this dose for at least 30 days prior to 
randomization  
Initiation of therapy or change of 
dose within 30 days 
Other systemic drugs used for treatment of rosacea 
30 days 
Barbiturates 
30 days 
Rifampicin 
30 days 
Carbamazepine 
30 days 
Phenytoin (diphenylhydantoin) 
30 days 
Primidone 
30 days 
Cyclosporin 
30 days 
Methoxyflurane or other nephrotoxic drugs 
30 days 
Nonsteroidal anti-inflammatory drugs (NSAIDs) 
(except aspirin at subanalgesic doses < 325 mg once daily 
for subjects requiring platelet aggregation inhibition)  
Chronic use of NSAIDs  
(> 14 days) other than low-dose aspirin is prohibited. 
7 days 
Niacin at doses > 500 mg /day 
7 days 
Other Treatments 
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Product 
Washout period before Baseline 
Use on the face of the following: 
Cryodestruction or chemodestruction 
Dermabrasion 
Photodynamic therapy 
Acne Surgery 
Intralesional steroids 
Laser resurfacing or electrodessication 
X-ray therapy 
Laser: Non-ablative lasers, Vascular (Pulse dye lasers 585 
and 596 nm) lasers, multichromatic lasers, long-pulsed Nd-
YAG laser 
Intense pulse light (IPL) or pulse light laser 
Electrocautery or electrocoagulation 
CO2 laser, Fractioned lasers, or loop electrosurgery 
Facial peels or other facial cosmetic surgery (e.g. Thermage, 
etc.)  
30 days 
Use of tanning booths, sun lamps, or excessive UV radiation 
(e.g. phototherapy, daily extended exposure or occupational 
exposure to the sun), sunbathing or excessive exposure to sun  
7 days 
 
7. Need or intent to use any treatment listed in Table 8.1 during the current study. 
8. History of allergy or known sensitivity to minocycline, doxycycline, other tetracyclines, or 
any component of the study medication. 
9. Consumption of excessive alcohol, abuse of drugs, or a condition that could compromise 
the subject’s ability to comply with study requirements and/or have drug or alcohol 
addiction requiring treatment in the past 12 months. 
10. Any clinically significant condition or situation other than the condition being studied that, 
in the opinion of the investigator, would interfere with the study evaluations or optimal 
participation in the study. 
11. Use of any investigational drugs within 90 days prior to Baseline (Visit 2/Day 1). 
12. Participation in any other clinical study within 90 days prior to Baseline. 
13. Previous participation in this study. 
14. Subjects institutionalized due to legal or regulatory disorder 
15. Employees of the research center or Investigator. 
16. Family members of employees of the research center of Investigator 
8.3.3 
Subject Discontinuation Criteria 
A subject may discontinue from the study at any time for any reason. 
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A subject will be discontinued from the study if his/her safety or well-being is determined to be at 
risk. Discontinuation will be made at the discretion of the investigator or at the subject’s request. 
A subject must be discontinued from the study and study medication for any of the following 
reasons: 
x The subject or legal representative withdraws consent 
x The subject becomes pregnant 
x The subject’s medication code is unblinded 
x There is a significant protocol violation or non-compliance with the protocol 
A subject may be discontinued from the study for any of the following reasons: 
x AE, including intercurrent illness, for which the subject desires to discontinue treatment or 
the investigator determines that it is in the subject’s best interest to be discontinued  
x Condition worsens and requires alternative or supplemental therapy for treatment of 
rosacea during the study 
x Noncompliant use of the study medication 
x Lost to follow-up 
x Investigator discretion 
Discontinuation is permanent; after a subject has been discontinued, he/she will not be allowed to 
enroll again. 
If a subject is discontinued from the study for any reason, the Visit 7 (EOS or early termination) 
procedures should be completed and any outstanding data and study medication should be 
collected. Data, including the date and primary reason for discontinuation, must be documented 
on the EOS electronic case report form (eCRF) and source document.  
If a subject discontinues the study at any time due to an AE, the reason for discontinuation, the 
nature of the AE, and its clinical course must be fully documented. The investigator must strive to 
follow the subject until the AE has resolved, become clinically insignificant, is stabilized, or the 
subject is lost to follow-up. For any SAE, follow procedures provided in Section 8.9.6. 
Subjects with protocol deviations should not be withdrawn automatically unless there is a safety 
concern. The protocol deviation should be recorded in the subject’s case record form and included 
in the study report.  Any decision by the Investigator to discontinue a subject from the study for 
reasons of violation of inclusion/exclusion criteria or protocol deviations should be discussed with 
the CRO/Sponsor medical monitor, as far as possible, prior to discontinuing the subject. 
As far as possible, investigators must advise subjects to refrain from consuming the prohibited 
medication (as specified in Table 8.1). In case a subject consumes a prohibited concomitant 
medication or needs to take one, a joint decision will be taken by the CRO medical monitor and 
Sponsor medical monitor on whether or not the subject should continue in the study or be 
withdrawn, depending upon the potential for harmful drug-drug interaction and influence on study 
efficacy assessments. The investigator must communicate information about the drug 
taken/required by subject, including its generic name, dose and duration of treatment and reason 
for subject taking/being advised to take the drug, as soon as it comes to his/her knowledge, to CRO 
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Project Manager. The CRO Project Manager in turn should forward the information to CRO and 
Sponsor medical monitors for a decision on continuation of the subject to be taken. 
Subjects who experience an AE resulting in or requiring discontinuation of study product use 
should be encouraged to be followed up in the study until the AE is resolved or stabilized. 
Subjects whose treatment randomization is unblinded by the study site should stop the study 
treatment immediately and be withdrawn from the study after follow-up. 
If a female subject becomes pregnant during the study, the study product will be discontinued 
immediately, and she will be followed through the pregnancy and delivery. Details of the 
pregnancy, delivery and health of the infant should be recorded on the Pregnancy Report Form 
and the sponsor should be notified immediately. 
If the sponsor terminates or suspends the study, the investigator or his/her designee should 
promptly inform the IRB (and/or regulatory authorities where required) of a temporary halt 
including the reason for such an action. 
8.3.4 
Replacement of Subjects 
A subject who discontinues from the study after having received at least one dose of study 
medication will not be replaced. 
8.4 
Treatments 
The investigator will take responsibility for and will take all steps to maintain appropriate records 
and ensure appropriate supply, handling, storage, distribution, and use of study materials in 
accordance with the protocol and any applicable laws and regulations. 
8.4.1 
Dosage and Formulations 
The DFD-29, Placebo, and Doxycycline capsules 40 mg will be provided by Dr. Reddy’s 
Laboratories Ltd. To maintain the double-blind design, all 3 study medications will be over-
encapsulated with the original capsules enclosed within a second, larger (size 0) capsule shell. 
Table 8.2:  
Identity of Test  
 
Test treatment 
Name: 
DFD-29 (Minocycline HCl Extended Release 
Capsules) 
Active ingredient: 
Minocycline HCl 
Formulation: 
Extended Release Capsules 
Dose strength: 
40 mg minocycline 
Dose: 
1 capsule 
Posology: 
Once daily, in the morning 
Mode of administration: 
Oral administration with approx. 240 mL water 
Administration condition: 
Fasting state preferred, but not mandatory 
Duration of administration: 
16 weeks 
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Test treatment 
Batch number & Expiry date: 
Will be given in the Trial Master File (TMF) ***. 
*** The documentation allowing traceability will be provided in the TMF. 
Table 8.3:  
Identity of Placebo  
 
Placebo treatment 
Name: 
Placebo for DFD-29 
Active ingredient: 
Not applicable 
Formulation: 
Capsules 
Dose strength: 
Not applicable 
Dose: 
1 capsule 
Posology: 
Once daily, in the morning 
Mode of administration: 
Oral administration with approx. 240 mL water 
Administration condition: 
Fasting state preferred, but not mandatory 
Duration of administration: 
16 weeks 
Batch number & Expiry date: 
Will be given in the TMF ***. 
*** The documentation allowing traceability will be provided in the TMF. 
Table 8.4:  
Identity of Doxycycline capsules 40 mg 
 
Doxycycline capsules 40 mg treatment 
Name: 
Doxycycline capsules 40 mg 
Active ingredient: 
Doxycycline anhydrous 
Formulation: 
Capsule with 30 mg immediate release and 10 mg 
delayed release beads 
Dose strength: 
40 mg doxycycline 
Dose: 
1 capsule 
Posology: 
Once daily, in the morning 
Mode of administration: 
Oral administration with approx. 240 mL water 
Administration condition: 
Fasting state preferred, but not mandatory 
Duration of administration: 
16 weeks 
Batch number & Expiry date: 
Will be given in the TMF ***. 
*** The documentation allowing traceability will be provided in the TMF. 
 
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8.4.2 
Method of Treatment Assignment, Randomization, and/or Stratification 
Upon screening, the subject will be assigned a unique 5-digit subject number preceded by the letter 
“S”, where the first 2 digits are the site number and the last 3 digits will be a subject number that 
increments sequentially at the site (i.e., S10-001, S10-002).   At the Baseline Visit (Visit 2/Day 1), 
subjects eligible for participation will retain the same subject number without the letter “S” 
preceding it (i.e., 10-001, 10-002).  All subjects will retain this subject number for the remainder 
of the study.  Each subject will be dispensed a total of 4 bottles and will be randomly assigned a 
unique bottle number at each visit study medication is dispensed (Visit 2/Day 1, Visit 4/Day 29, 
Visit 5/Day 57 and Visit 6/Day 85), using the Interactive Web Response System (IWRS). 
Subjects who satisfy all of the inclusion and none of the exclusion criteria will be randomized in a 
3:3:2 ratio to the DFD-29, Doxycycline capsules 40 mg, or Placebo group, respectively.  
Randomization will be stratified by site. Stratification will be managed via the IWRS. 
8.4.3 
Selection and Timing of Dose for Each Subject 
The study medication will be taken at a fixed time of the day once a day for 16 consecutive weeks. 
The preferred time of administration will be in the morning, after an overnight fast. One capsule 
of the assigned study medication will be swallowed with 240 mL (1 glass) of still water on an 
empty stomach.  
Substances that can potentially interfere with absorption of minocycline like antacids, 
multivitamins, or other products containing aluminum, magnesium and calcium, oral iron 
preparations, bismuth subsalicylate, and milk and other dairy products should be avoided from 1.5 
hours before to 3.0 hours after intake of study medication. 
The dosage regimen in this study is that approved for Doxycycline capsules 40 mg [28].  
8.4.4 
Blinding of Study Medication 
A double-blind technique will be used. DFD-29, its matching placebo, and Doxycycline capsules 
40 mg are indistinguishable after over-encapsulation. The investigator and study staff (including 
lab personnel), the subjects, the monitors, medical monitors, the CRO personnel involved in 
clinical operations, and the sponsor’s staff will remain blinded to the treatment until study closure.  
See Section 8.9.7.4 for a description of the method of unblinding a subject during the study if such 
action is warranted. 
8.4.5 
Method of Packaging, Labeling, Storage, and Dispensing 
Study medications will be supplied in high-density polyethylene (HDPE) bottles containing 
35 capsules each. Bottles will be individually labeled and packaged so that neither the subject nor 
the investigator can identify the treatment. 
Each subject will be dispensed a total of 4 bottles and will be randomly assigned a unique bottle 
number at each visit study medication is dispensed (Visit 2/Day 1, Visit 4/Day 29, Visit 5/Day 57 
and Visit 6/Day 85), using the IWRS. 
At the Visit 2/Day 1, each subject enrolled will receive 1 bottle of study medication. At Visits 
4/Day 29, 5/Day 57, and 6/Day 85, the study medication will be collected, and 1 new bottle of 
study medication will be dispensed. Study medication will be collected and re-dispensed at Visit 
3/Day 14. 
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A 2-part label will be attached to each bottle.  The tear-off section of the label will be attached to 
the Study Medication Dispensing Log when a new bottle is dispensed.  To nullify any remaining 
differences in product packaging and to maintain double-blinding, the investigator/sub-
investigator performing the study clinical assessments will not be involved with the dispensing or 
return of study medication.   
At the minimum, the following information will be stated on the labels: 
x Study number (DFD-29-CD-004) 
x Visit No. 
x Bottle number 
x Subject number and initials 
x Amount (35 capsules of either DFD-29 40 mg / Placebo / Doxycycline capsules 40 mg) 
x Sponsor’s Name and Address 
x CRO’s Name and Address 
x Route of administration (e.g., oral) 
x Directions for use 
x Storage conditions 
x “For clinical trial use only” or similar cautionary statement 
x “Keep out of reach of children” or similar cautionary statement 
All study medication will be stored at controlled room temperature 68° - 77°F (20° - 25°C) with 
excursions permitted between 59° - 86°F (15° - 30°C), in a climate-controlled, limited access area. 
The investigator agrees to store and dispense the study medication only at the site(s) listed on Form 
FDA 1572 (or investigator agreement/statement). The investigator, sub-investigator(s), or 
qualified designees also agree that the study medication will be dispensed only to subjects who 
have provided written informed consent and have met all entry criteria. Clinical supplies may not 
be used for any purpose other than as stated in the protocol. 
See the Study Flow Chart in Section 3.2 for a schedule of when clinical supplies are to be dispensed 
to the subjects. 
8.4.6 
Replacement of Study Medication 
If replacement bottles are needed for subjects for any reason, this will be done through IWRS.  The 
study site should contact the CRO to provide information regarding replacement bottles for 
documentation purposes. 
8.4.7 
Study Medication Accountability 
Subjects will be instructed to return all used and partially used study medication bottles at all 
protocol-specified visits for study medication inventory and assessment of subject compliance. 
All IP receipts at the site will be confirmed via IWRS and final IP reconciliation and returns will 
be conducted via IWRS, at study end. The dispensing and return of study medication for subjects 
will be recorded on the study medication dispensing log. The subject number/initials and the 
initials and date of the person dispensing and receiving the returned medication will be 
documented on this form. 
Inventory records must be readily available for inspection by the study monitor and/or auditor, and 
open to inspection by regulatory authorities at any time. 
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8.4.8 
Prior and Concomitant Medications 
All medications and other treatments taken by the subject within 30 days before signing the ICF 
and during the study are to be recorded on the eCRF using their generic name, if known, with the 
corresponding indication. The medications to be recorded include prescription and OTC 
medications and dietary supplements. All medications taken on a regular basis, including vitamins, 
aspirin, and acetaminophen, should be recorded prior to first use of the study medication. 
The use of any concomitant medication must relate to the subject’s documented medical history, 
prophylaxis, or an AE. 
8.4.8.1 
Medications, Supplements, and Other Substances Prohibited Before Study Entry and 
During the Study 
The medications prohibited prior to Baseline are listed in Table 8.1 in the exclusion criteria. 
The medications and therapies listed in Table 8.1 are the treatments that subjects must not take 
during the study, from Visit 2 through Visit 7 (EOS or early termination). 
Substances which can potentially interfere with absorption of minocycline like antacids, 
multivitamins or other products containing aluminum, magnesium and calcium, oral iron 
preparations, bismuth subsalicylate and milk and other dairy products should be avoided from 1.5 
hours before to 3.0 hours after intake of study drug. 
Anti-microbial soaps and face wash are not allowed during the study. 
In case a subject consumes a prohibited concomitant medication or needs to take one, a joint 
decision will be taken by the CRO medical monitor and Sponsor medical monitor on whether or 
not the subject should continue in the study or be withdrawn, depending upon the potential for 
harmful drug-drug interaction and influence on study efficacy assessments. 
8.4.8.2 
Other Restrictions 
8.4.8.2.1 Sun Exposure 
Excessive sun exposure and/or UV radiation should be avoided, and protective measures should 
be taken. 
8.4.8.2.2 Contraceptives 
Special attention has to be paid to female subjects taking low dose oral contraceptives 
(35 micrograms of ethinyl estradiol or equivalent dose of other estrogens) as their effectiveness 
may be affected by the use of DFD-29. To avoid contraceptive failure, female subjects who are 
taking low dose oral contraceptives have to use a second acceptable form of contraceptive from 
Screening up to 1 month after last dose. 
Note: ‘Acceptable’ methods of contraception include double barrier methods (e.g. a combination 
of male condom with either, cap, diaphragm or sponge with spermicide) in addition to the 
“highly effective birth control methods that are described in Section 8.3.1, inclusion criterion 10.  
Please refer to inclusion criterion 10 (Section 8.3.1) for further details on contraception for 
females. 
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8.4.8.3 
Concomitant Medications, Supplements, and Other Substances Allowed During the 
Study 
Medications necessary for the health and well-being of the subject are permitted. The use of any 
medication that could affect the course of rosacea is prohibited during the entire study period. 
Subjects should be instructed to refrain from making any significant change in the use of consumer 
products (including facial cleanser, make-up, bland non-medicated emollients or moisturizers, 
etc.) during the course of the study. 
Multivitamins and acetaminophen for pain relief may be used as needed throughout the study. 
8.4.9 
Assessment of Compliance 
At all protocol-specified visits, the investigator or qualified designee will record whether treatment 
had been taken per protocol in the preceding interval. If not, the date(s) and reason for each dosing 
noncompliance must be recorded. 
Compliance will be determined from the diary card, on which the subject will be instructed to 
record all doses taken or missed. The number of doses will be totaled by the study coordinator or 
designee and recorded on the diary card and on the compliance page of the eCRF. The total number 
of doses taken and/or missed will be determined based upon the first dose taken through and 
including the last dose taken. The first and last dates of treatment should be recorded in the eCRF. 
The total of taken and missed doses should also be recorded. By definition, there are no missed 
doses before the first date of treatment or after the last date of treatment. Subjects will be 
considered compliant if they administer at least 80% and no more than 120% of doses. Subjects 
who miss 7 or more consecutive doses of study medication will be considered noncompliant and 
must be withdrawn from the study by the investigator in agreement with the CRO/Sponsor medical 
monitor. 
8.5 
Study Schedule 
The visit-by-visit schedule of study activities is provided in the Study Flow Chart in Section 3.2. 
The timing of each visit is relative to Day 1. 
All visits should be performed within the windows specified on the Study Flow Chart. Every 
attempt should be made to have each subject attend each visit as scheduled. If a subject is unable 
to attend a visit within the specified window, however, the visit should be scheduled as closely as 
possible to the applicable window. 
8.6 
Study Procedures 
The Study Flow Chart in Section 3.2 summarizes the study procedures to be performed at each 
visit. Individual study procedures are described below. 
All clinical assessments (IGA, CEA, and total inflammatory lesion count) must be conducted by 
qualified investigators listed on the Form FDA 1572 who have been delegated these tasks by the 
principal investigator (PI). The PI may delegate this task to physicians, physician assistants, or 
nurse practitioners who have documented training and past experience conducting the assessment. 
To minimize variability of evaluations, the same investigator/sub-investigator should perform 
these assessments for any given subject and anticipate evaluating the subject at each visit, to the 
extent possible. 
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8.6.1 
Study Initiation 
The investigational staff may not enroll any subjects prior to completion of an initiation visit. This 
visit will include, but is not limited to, an inventory of study supplies (if present) and a detailed 
review of the protocol, eCRFs, investigator’s brochure, and the investigator’s responsibilities as 
outlined on Form FDA 1572. 
8.6.2 
Written Informed Consent 
The study personnel will review the ICF with each subject and give the subject an opportunity to 
have all questions answered before proceeding. A copy of the signed ICF will be given to every 
subject and the original will be maintained with the subject’s records. 
At selected study centers, consenting subjects will have lesions on the face photographed at 
Baseline and all subsequent visits. Neither the subject nor the investigator is permitted to refer to 
the photographs at any subsequent visit for the purposes of grading.  
8.6.3 
Significant Medical History/Demographic Information 
Significant medical history and demographic information will be obtained at Visit 1 (Screening). 
The medical history will include a complete review of all current diseases and their respective 
durations and treatments. Demographic information will include date of birth, sex, race, ethnicity, 
and Fitzpatrick skin type. 
For inclusion in the study subjects must have a clinical diagnosis of papulopustular rosacea, IGA 
grade 3 (moderate) or IGA grade 4 (severe). 
Medical history will be reviewed/updated at Visit 2 (Baseline). 
8.6.4 
Physical Examination (Including Vital Signs) 
A complete physical examination will be performed and height, weight, and vital signs recorded 
at Screening to determine that the subject is healthy enough to participate in the study. Weight will 
also be measured at Visit 2 (Baseline). Physical examination and weight will also be performed at 
Visit 7 (EOS or early termination).  
Blood pressure (measured after at least 5 minutes in a sitting position) and pulse rate will be 
measured at every study visit, as part of Vital Signs Assessment. 
8.6.5 
Prior Medication Review 
Prior medications (prescription, OTC, and dietary supplements), including the necessary washout 
times, will be reviewed with the subject. A record of prior medication taken or used by the subject 
within 30 days before signing the ICF will be obtained. Prior medication will be reviewed/updated 
at Visit 2 (Baseline). 
8.6.6 
Laboratory Assessments 
Laboratory tests for hematology, blood chemistry, and urinalysis are specified in Table 8.5. Blood 
samples for laboratory tests are to be taken prior to administration of study medication. Blood 
(hematology and chemistry) and urine samples will be collected at Visit 1 (Screening) and Visit 7 
(EOS or early termination).  Serology for anti-HIV I, anti-HIV 2, HBsAG, and anti-HCV 
antibodies will only be performed at screening. 
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The samples will be sent to the central laboratory for analysis. Details regarding overall blood 
volume collected, sample handling, processing and shipment will be provided in a separate 
laboratory manual.   
Any other investigation (including anti-nuclear antibody and hepatic transaminases for suspected 
drug-induced lupus or auto-immune hepatitis in symptomatic subjects) will have to be symptom-
driven or on investigator judgment on a case to case basis. 
Additional safety samples may be taken at investigator discretion in consultation with the Sponsor. 
Table 8.5:  
Laboratory Tests 
 
Hematology 
Chemistry 
Urinalysis 
Others 
Complete Blood Count 
(CBC) including 
differential count 
Glucose 
Uric acid 
Calcium 
Sodium 
Potassium 
Chloride 
Alkaline phosphatase 
Total bilirubin 
Direct bilirubin 
Creatinine 
BUN 
AST (SGOT) 
ALT(SGPT) 
LDH 
Total protein 
Albumin 
Urobilinogen 
Nitrites 
pH 
Glucose 
Protein 
Blood 
Ketones 
Pregnancya 
Serology (for anti-HIV I, 
anti-HIV 2, HBsAG, and 
anti-HCV antibodies)b 
 
ANA (Anti-nuclear-Ab)c 
AST/ALT/GGT (hepatic-
transaminases)c 
a Only required for women of childbearing potential 
b Will only be done at screening for eligibility  
c Will be done on a case to case basis based on Investigator judgement or symptom-
driven 
 
 
8.6.7 
Urine Pregnancy Test and Acceptable Contraceptive Methods 
Women of childbearing potential, in addition to having a negative urine pregnancy test at Visit 1 
(Screening) and Baseline, prior to randomization, must be willing to use an acceptable form of 
birth control during the study.  
‘Highly effective’ methods of birth control include 
x combined (estrogen and progesterone containing) hormonal contraception 
associated with inhibition of ovulation*: 
o oral 
o intravaginal 
o transdermal 
x progesterone-only hormonal contraception associated with inhibition of 
ovulation*: 
o oral 
o injectable 
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o implantable† 
x intra-uterine device (IUD) † 
x intra-uterine hormone releasing system (IUS) † 
x bilateral tubal occlusion† 
x vasectomy of sexual partner that was performed at least 90 days prior to Baseline, 
and has been medically assessed as successful† 
x total (as opposed to periodic or cyclic) sexual abstinence 
o Note: Sexually inactive female subjects may be enrolled at the investigator’s 
discretion provided that they are counseled to refrain from heterosexual 
intercourse for the duration of the study and for one month after the last dose, 
and understand the possible risks involved in getting pregnant during the study. 
*    Hormonal methods: If on hormonal contraceptives, must have been on the same 
hormonal contraceptive product for 3 months (90 days) prior to Baseline and 
continued on same method and dose throughout the duration of the study. If subject 
had used hormonal birth control and had stopped, this should have occurred more 
than 6 months prior to Baseline. Female subjects on low dose oral contraceptives 
(containing ≤35 μg of ethinyl estradiol or equivalent dose of other estrogens) must 
use a second form of contraceptive during the study. 
† Contraception methods that are considered to have low user dependency. 
A urine pregnancy test will be performed for women of child-bearing potential at every study visit 
from Screening up to Week 16 (or at early termination if previous pregnancy testing was performed 
more than 28 days prior). 
8.6.8 
Investigator’s Global Assessment (IGA) 
The IGA (Appendix 15.1) is carried out by visual inspection by the investigator or delegated sub-
investigator at every study visit from Screening through Week 16 (EOS or early termination). If 
possible, the same study staff member should perform the assessment on an individual subject at 
all visits. 
8.6.9 
Clinician’s Erythema Assessment (CEA) 
The CEA (Appendix 15.2) is carried out by visual inspection by the investigator or delegated sub-
investigator at every study visit from Screening through Week 16 (EOS or early termination). The 
erythema assessment will be carried out separately at 5 locations on the face: forehead, nose, chin, 
right cheek, and left cheek.    A 2-grade reduction from Baseline to Week 16 will be assessed on 
the most severe CEA score/s out of the 5 locations on the face. If more than one location have the 
most severe scores, then the 2-grade reduction has to be on the average scores for those locations 
at Week 16 (for e.g. if the baseline CEA scores for the right and left cheeks are 3, the nose is 1 and 
the forehead and chin are 0 each, the baseline average score is equal to 3 for the right and left 
cheeks, then the average of the scores for the two cheeks at Week 16 has to be ‘1’ or below, to be 
considered as at least a 2-grade reduction on the CEA).   
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8.6.10 
Total Inflammatory Lesion Count 
The total inflammatory lesion count is carried out by visual inspection by the investigator or 
delegated and trained study staff at every study visit from Screening through Week 16 (EOS or 
early termination). Inflammatory lesions will be recorded on a diagram of a human face 
(Appendix 15.3) divided in 4 quadrants. If possible, the same study staff member should perform 
the assessment on an individual subject at all visits. 
8.6.11 
Rosacea Quality of Life (RosaQoL) 
The RosaQoL assessment (Appendix 15.4) will be carried out by asking questions as per the 
validated RosaQoL questionnaire instrument at every study visit from Baseline through Week 16 
(EOS or early termination). Subjects will rate 21 questions on a 5-grade scale and their perception 
of the impact that rosacea has on various dimensions influencing their quality of life.  Calculation 
of the score will be described in the SAP. 
8.6.12 
Dermatology Life Quality Index (DLQI) 
The DLQI questionnaire (Appendix 15.5) will be carried out at every study visit from Baseline 
through Week 16 (EOS or early termination). 
The DLQI questionnaire consists of 10 questions covering the following topics: symptoms, 
embarrassment, shopping and home care, clothes, social and leisure, sport, work or study, close 
relationships, sexuality and treatment. Each question refers to the impact of the skin disease on the 
subject’s life. 
Each question is scored from 0 to 3 and totaled, giving a possible score range from 0 (meaning no 
impact of skin disease on quality of life) to 30 (meaning maximum impact on quality of life). 
8.6.13 
Photography 
Photography will be performed at 5 selected sites and subjects will have photographs taken at 
study visits (Baseline/Day 1, Visits 2, 3, 4, 5, 6, and 7).  Photographs will be taken of the subject’s 
face, to document all rosacea lesions that are present at Baseline/Day 1 and all subsequent visits. 
Neither the subject nor the investigator is permitted to refer to the photographs at any subsequent 
visit for the purposes of grading. 
Equipment, supplies, training and detailed instructions for obtaining and managing the 
photographs will be provided to the sites prior to the initiation of subject enrollment. 
8.6.14 
Review Inclusion/Exclusion Criteria 
The inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the study. 
8.6.15 
Study Medication Dispensing and Collection 
An independent drug dispenser, not involved in the clinical evaluations, will dispense study 
medication to qualified subjects and keep accurate accountability of all study medication. Study 
medication will be dispensed at Visits 2, 4, 5, and 6 and bottles will be collected at Visits 3, 4, 5, 
6, and 7 to assess compliance and drug accountability. Study medication will be collected and re-
dispensed at Visit 3.  
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8.6.16 
Subject Instruction, Diary Card, and Compliance  
Subjects will be instructed on the correct use of study medication at the study site during Visit 2 
(Baseline). Subjects will be instructed to take study medication at a fixed time of the day once a 
day for 16 consecutive weeks. The preferred time of administration will be in the morning, after 
an overnight fast. One capsule of the assigned study medication will be swallowed with 240 mL 
(1 glass) of still water on an empty stomach. Additional instructions will be reviewed with each 
subject. 
A diary card will be dispensed to each enrolled subject at Visit 2 (Baseline). The subject will be 
instructed to complete the diary card to record each dose or missed dose of study medication. At 
subsequent visits, study personnel will review and collect the diary card, and dispense a new diary 
card and re-review subject instructions.  
8.6.17 
Adverse Events and Serious Adverse Events Assessment 
See Section 8.9 for instructions on the assessment and reporting of AEs and SAEs and 
Section 8.9.6 for instructions on reporting SAEs to the sponsor or designee. 
8.6.18 
Concomitant Medication Review 
Medications, including prescription, OTC, and dietary supplements (other than study medication) 
taken and other treatments used by the subject during the study will be reviewed at each study 
visit. 
8.6.19 
Study Medication Accountability 
Adherence to study medications will be assessed by the study diary review, pill count and subject 
questioning at all visits during the treatment period. The investigator or other designated study 
personnel will note in the source documents and appropriate eCRF page whether the subject took 
study medication per protocol in the preceding interval. 
Subjects will be instructed to return all used and partially used bottles of study medication at Visits 
3, 4, 5, 6, and 7 for study medication inventory and assessment of subject compliance.  The site 
staff will count and record the number of remaining capsules in each returned bottle. 
All IP receipts at the site will be confirmed via IWRS and final IP reconciliation and returns will 
be conducted via IWRS, at study end. The dispensing and return of study medication for subjects 
will be recorded on the study medication dispensing log. The subject number/initials and the 
initials and date of the person dispensing and receiving the returned medication will be 
documented on this form. 
Inventory records must be readily available for inspection by the study monitor and/or auditor, and 
open to inspection by regulatory authorities at any time. 
8.7 
Visit-Specific Procedures 
The following sections outline the procedures required at each visit. 
8.7.1 
Visit 1/Day -30 to -3: Screening 
1. Obtain written informed consent (Section 8.6.2) 
2. Obtain medical history and demographic information (Section 8.6.3) 
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3. Perform physical examination, including height, weight, and vital signs (blood pressure 
and pulse rate) (Section 8.6.4) 
4. Obtain/record prior medications (Section 8.6.5) 
5. Collect blood and urine for laboratory assessments (Section 8.6.6) 
6. Perform urine pregnancy test for all women of childbearing potential (Section 8.6.7) 
7. Perform IGA (Section 8.6.8) 
8. Perform CEA (Section 8.6.9) 
9. Perform lesion count (Section 8.6.10) 
10. Evaluate inclusion/exclusion criteria (Section 8.6.14) 
11. Schedule next visit 
12. Complete eCRFs (Section 11.2.1) 
8.7.2 
Visit 2/Day -1: Baseline 
1. Update medical history (Section 8.6.3) 
2. Measure weight and vital signs (blood pressure and pulse rate) (Section 8.6.4) 
3. Update prior medications (Section 8.6.5) 
4. Perform urine pregnancy test for all women of childbearing potential (Section 8.6.7) 
5. Perform IGA (Section 8.6.8) 
6. Perform CEA (Section 8.6.9) 
7. Perform lesion count (Section 8.6.10) 
8. Perform RosaQoL (Section 8.6.11) 
9. Perform DLQI (Section 8.6.12) 
10. Evaluate inclusion/exclusion criteria (Section 8.6.14) 
11. Randomization (Section 8.4.2) 
12. Perform photography of the face on subjects at selected sites (Section 8.6.13)  
13. Dispense study medication and record study medication accountability (Sections 8.6.15 
and 8.6.19) 
14. Instruct subjects on proper study medication administration (Section 8.6.16) 
15. Assess AEs (Section 8.6.17) 
16. Dispense diary card and review instructions (Section 8.6.16) 
17. Schedule next visit 
18. Complete eCRFs (Section 11.2.1) 
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8.7.3 
Visit 3/Day 14 (± 3 days), Visit 4/Day 29 (± 3 days), Visit 5/Day 57 (± 5 days), and 
Visit 6, Day 85 (± 5 days) 
1. Measure vital signs (blood pressure and pulse rate) (Section 8.6.4) 
2. Concomitant medications (Section 8.6.18) 
3. Perform urine pregnancy test for all women of childbearing potential (Section 8.6.7) 
4. Perform IGA (Section 8.6.8) 
5. Perform CEA (Section 8.6.9) 
6. Perform lesion count (Section 8.6.10) 
7. Perform RosaQoL (Section 8.6.11) 
8. Perform DLQI (Section 8.6.12) 
9. Perform photography of the face on subjects at selected sites (Sections 8.6.15)  
10. Collect and dispense study medication, record study medication accountability, and assess 
compliance (Sections 8.6.15 and 8.6.19). Study medication will be collected and re-
dispensed at Visit 3/Day 14. 
11. Assess AEs (Section 8.6.17) 
12. Collect and dispense diary card and review instructions (Section 8.6.16) 
13. Schedule next visit 
14. Complete eCRFs (Section 11.2.1) 
8.7.4 Visit 7/Day 113 (± 5 days): End of Study or Early Termination 
1. Perform physical examination, including weight, and vital signs (blood pressure and pulse 
rate) (Section 8.6.4) 
2. Concomitant medications (Section 8.6.18) 
3. Collect blood and urine for laboratory assessments (Section 8.6.6) 
4. Perform urine pregnancy test for all women of childbearing potential (Section 8.6.7) 
5. Perform IGA (Section 8.6.8) 
6. Perform CEA (Section 8.6.9) 
7. Perform lesion count (Section 8.6.10) 
8. Perform RosaQoL (Section 8.6.11) 
9. Perform DLQI (Section 8.6.12) 
10. Perform photography of the face on subjects at selected sites (Sections 8.6.15) 
11. Collect study medication, record study medication accountability, and assess compliance 
(Sections 8.6.15 and 8.6.19) 
12. Assess AEs (Section 8.6.17) 
13. Collect diary card (Section 8.6.16) 
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14. Complete eCRFs (Section 11.2.1) 
8.7.5 
COVID-19 Considerations 
As a consequence to the COVID-19 pandemic that had a worldwide impact, including cases in 
North America and Europe, control measures in place in different regions may impact the ability 
to adhere to some of the study procedures described in this protocol. Due to challenges that include, 
but are not limited to, subject preferences, site closures, travel restrictions, and quarantines, some 
modifications to study conduct during the COVID-19 pandemic may be necessary to ensure study 
continuity. The following are allowable, as necessary, modifications to study conduct during the 
COVID-19 pandemic.  
x At Screening, if a potential subject is known to be infected with COVID-19, the subject 
should not be enrolled in the study.   
x Prior to a study visit at the site, the subject may be contacted and screened for potential 
exposure or infection to COVID-19 per site, local or federal requirements. If the subject is 
suspected to be exposed or infected with COVID-19, the on-site visit should either be re-
scheduled or a virtual visit may be performed instead, as applicable.  
x In the event that a subject cannot attend their regularly scheduled study visits in person due 
to COVID-19 due to quarantine, state COVID rules, etc. necessitating a limit on in-person 
contact, the Investigator may perform safety and certain efficacy assessments by phone or 
video (see below). The Investigator may use the technology platform that is currently 
available to them. Suggested platforms include Apple FaceTime, Zoom for Healthcare, 
Facebook Messenger video chat, Microsoft Team, Google Hangouts video, Skype, or any 
other platform, which is suitable from a technology and data protection perspective, as 
determined by the site.   
o Screening, Baseline and Week 16/ End of Study/ Early Termination visits must be 
conducted in-person. The efficacy assessments of Total Inflammatory Lesion 
count, IGA grading, and CEA grading as well as the Quality of Life assessment of 
DLQI scoring at Baseline and Weeks 16 visits must be performed in-person, as 
these serve as input data for the primary analysis of the primary and secondary 
endpoints of the study 
o Visits at Week 2, 4, 8 and 12 may be conducted in-person or as virtual (using 
suitable technology platform). QoL assessment of RosaQoL scoring at all visits 
(including Week 16) and the efficacy assessments of Total Inflammatory Lesion 
count, IGA grading, CEA grading, as well as the QoL assessment of DLQI scoring 
at weeks 2, 4, 8 and 12 may be performed in person or virtually. 
x Source documentation should note that the visit was performed virtually (not face-to-
face).  If certain study procedures or assessments cannot be completed per the schedule of 
events, the reason for the missed assessment must be noted in the source documentation 
(e.g., COVID-19), captured in the protocol deviations documentation, and reported to the 
IRB/Ethics Committee, as applicable. 
A detailed assessment of COVID-19 related risk and mitigation measures will be documented in 
the appropriate study plans. 
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8.8 
Efficacy Assessments 
8.8.1 
Co-Primary Efficacy Endpoints  
x Proportion of subjects with IGA (modified scale without erythema) “treatment success” – 
Grade 0 or 1 at Week 16 with at least a 2-grade reduction from Baseline to Week 16, in the 
DFD-29 group compared to placebo. 
x Total inflammatory lesion count (sum of papules, pustules, and nodules) reduction from 
Baseline to Week 16, in the DFD-29 group compared to placebo. 
8.8.2 
Secondary Efficacy Endpoints 
x Percentage Change in Total inflammatory lesion count (sum of papules, pustules, and 
nodules) from Baseline to Week 16, in the DFD-29 group compared to Placebo. 
x Proportion of subjects with IGA treatment success at Week 16 in the DFD-29 group 
compared to Doxycycline capsules 40 mg. 
x Total inflammatory lesion count reduction from Baseline to Week 16 in the DFD-29 group 
compared to Doxycycline capsules 40 mg. 
x Proportion of subjects with at least a 2-grade reduction in CEA score from Baseline to 
Week 16 in the DFD-29 group compared to placebo. 
x Change in DLQI score from Baseline to Week 16 in the DFD-29 group compared to 
placebo. 
8.8.3 
Exploratory Efficacy Endpoints 
All of the following endpoints for DFD-29 will be compared against Placebo and Doxycycline 
capsules 40 mg:  
x Proportion of subjects with IGA treatment success from Baseline to Weeks 2, 4, 8, and 12. 
x Total inflammatory lesion count (sum of papules, pustules, and nodules) reduction from 
Baseline to Weeks 2, 4, 8, and 12. 
x Percentage Change in Total inflammatory lesion count (sum of papules, pustules, and 
nodules) from Baseline to Weeks 2, 4, 8, 12 (and 16, in case of DFD-29 vs Doxycycline 
capsules 40 mg comparison).  
x Proportion of subjects with at least a 2-grade reduction in IGA score from Baseline to 
Weeks 2, 4, 8, 12 and 16. 
x Change in RosaQoL score from Baseline to Weeks 2, 4, 8, 12 and 16. 
x Change in DLQI score from Baseline to Weeks 2, 4, 8, 12 (and 16, in case of DFD-29 vs 
Doxycycline capsules 40 mg comparison). 
x Proportion of subjects with at least a 2-grade improvement in the CEA score at Weeks 2, 
4, 8, 12 (and 16, in case of DFD-29 vs Doxycycline capsules 40 mg comparison). 
8.9 
Assessment of Safety 
8.9.1 
Safety Endpoints 
The following parameters have been defined as parameters regarding safety and tolerability: 
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x Change from Baseline for vital signs and clinical laboratory tests. The clinical laboratory 
tests obtained at screening visit will be defined as baseline assessments.   
x Treatment-emergent AEs. 
x Treatment-emergent AEs leading to premature discontinuation of study medication. 
x Treatment-emergent SAEs. 
8.9.2 
Definitions of Terms 
8.9.2.1 
Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related (21 Code of Federal Regulations [CFR] 312.32 (a)). An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a drug, without 
any judgment about causality. 
A treatment-emergent AE (TEAE) is any AE temporally associated with the use of a study drug, 
whether or not considered related to the study drug. 
AEs will be collected by spontaneous reports from subjects, either verbal or recorded in the 
subject’s diary, by directed question of subjects, and by observation. All AEs from the time of 
signing of the ICF up to the EOS visit will be recorded. 
Adverse events include: 
x Exacerbation of a pre-existing disease. 
x Increase in frequency or intensity of a pre-existing episodic disease or medical condition. 
x Disease or medical condition detected or diagnosed after study drug administration even 
though it may have been present prior to the start of the study. 
x Continuous persistent disease or symptoms present at Baseline that worsen following the 
start of the study. 
x Events considered by the investigator to be related to study-mandated procedures. 
x Abnormal assessments, e.g., vital signs or physical examination findings, must be reported 
as AEs if they represent a clinically significant finding that was not present at Baseline or 
worsened during the course of the study. 
x Laboratory test abnormalities must be reported as AEs if they represent a clinically 
significant finding, symptomatic or not, which was not present at Baseline or worsened 
during the course of the study or led to dose reduction, interruption or permanent 
discontinuation of study drug. 
Adverse events do not include: 
x Medical or surgical procedure, e.g., surgery, endoscopy, tooth extraction, transfusion. 
However, the event leading to the procedure is an AE. If this event is serious, the procedure 
must be described in the SAE narrative. 
x Pre-existing disease or medical condition that does not worsen. 
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For the purpose of this study, worsening of rosacea is not to be recorded as an AE unless it results 
in discontinuation of the subject from the study or the use of further treatment for rosacea. 
8.9.2.2 
Suspected Adverse Reaction 
A suspected adverse reaction (SAR) is defined as any AE for which there is reasonable possibility 
that the drug caused the AE (21 CFR 312.32 (a)). 
8.9.2.3 
Unexpected Adverse Event 
An AE or SAR is considered unexpected if it is not listed in the Investigator Brochure or is not 
listed at the specificity or severity that has been observed or, if an Investigator Brochure is not 
required or available, is not consistent with the risk information described elsewhere (for example, 
approved prescribing information) (21 CFR 312.32 (a)). 
8.9.2.4 
Serious Adverse Event 
An SAE is defined as any AE or SAR that, in the view of the investigator or sponsor, results in 
any of the following outcomes (21 CFR 312.32 (a)): 
x Death 
x Life-threatening AE (Note: the term “life-threatening” as used here refers to an event that 
in the view of the investigator or sponsor places the subject at immediate risk of death at 
the time of the event; it does not include an AE or SAE that, had it occurred in a more 
severe form, might have caused death [21 CFR 312.32(a)]) 
x Inpatient hospitalization or prolongation of existing hospitalization 
x Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
x Congenital anomaly/birth defect 
x Any “other” important medical event. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
The following are not considered an SAE: 
x Treatment on an emergency or outpatient basis for an event not fulfilling the definition of 
seriousness given above and not resulting in hospitalization. 
x The following reasons for hospitalizations are not considered AEs, and therefore not SAEs:  
o Hospitalizations for cosmetic elective surgery, social and/or convenience reasons. 
o Standard monitoring of a pre-existing disease or medical condition that did not 
worsen, e.g., hospitalization for coronary angiography in a subject with stable 
angina pectoris. 
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o Elective treatment of a pre-existing disease or medical condition that did not 
worsen, e.g., hospitalization for chemotherapy for cancer, elective hip replacement 
for arthritis 
8.9.2.5 
Planned Hospitalization 
A hospitalization planned by the subject prior to signing the ICF is considered a therapeutic 
intervention and not the result of a new SAE and should be recorded as medical history. If the 
planned hospitalization or procedure occurs as planned, the record in the subject’s medical history 
is considered complete. However, if the event/condition worsens during the study, it must be 
reported as an AE. 
8.9.2.6 
Pregnancy 
Pregnancies occurring after the first dose of study medication require immediate reporting and 
discontinuation of the study medication. They must be reported within 24 hours after the 
investigator has become aware of the pregnancy. The subject should immediately be withdrawn 
from the study and early termination study procedures must be performed. 
A pregnancy report will be completed and sent by email to Dr. Reddy’s Laboratories Ltd, Clinical 
Pharmacovigilance, the Sponsor medical monitor, and the CRO medical monitor within 24 hours 
of becoming aware of the pregnancy. The expected date of delivery or expected date of the end of 
the pregnancy should be included in this information. The investigator is instructed to contact the 
subject every 3 months until the end of her pregnancy and report the outcome to the sponsor. The 
investigator is instructed to contact the subject for 8 weeks after delivery for follow up on infant. 
The investigator will collect follow-up information regarding the outcome of the pregnancy and 
any postnatal sequelae in the infant that must also be reported to the Dr. Reddy’s Laboratories Ltd, 
Clinical Pharmacovigilance, the Sponsor medical monitor, and the CRO medical monitor. Upon 
awareness of the outcome of the pregnancy, the PI or designee must forward a follow-up 
Pregnancy Report with any relevant information to Dr. Reddy’s Laboratories Ltd, Clinical 
Pharmacovigilance, the Sponsor medical monitor, and the CRO medical monitor.  
If the outcome of the pregnancy meets the criteria for immediate classification of an SAE (e.g., 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), the investigator will report 
the event by emailing a completed SAE report form to Dr. Reddy’s Laboratories Ltd, Clinical 
Pharmacovigilance, the Sponsor medical monitor, and the CRO medical monitor within 24 hours 
of being notified of the pregnancy report. 
Details of the pregnancy, delivery and health of the infant should be recorded on the Pregnancy 
Report Form. 
The following outcomes of pregnancy fall under the criteria for serious adverse events and should 
be reported as such: delivery complications prolonging hospitalization, spontaneous abortion, 
stillbirth, death of newborn baby, congenital anomaly, and anomaly in a miscarried/stillborn fetus 
8.9.3 
Monitoring Adverse Events and Laboratory Evaluations 
Each subject will be monitored for the occurrence of AEs, including SAEs, immediately after the 
subject has signed the ICF. Each subject will be followed for safety monitoring until discharged 
from the study. Follow-up procedures related to pregnancy or AEs or SAEs may continue beyond 
the end of the study. 
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Subjects will be questioned and/or examined by the investigator or a qualified designee for 
occurrence of AEs throughout the study. The presence or absence of specific AEs should not be 
elicited from subjects. Subjects having AEs will be monitored with relevant clinical assessments 
and laboratory tests, as determined by the investigator. 
AEs, actions taken as a result of AEs, and follow-up results must be recorded in the eCRF, as well 
as in the subject’s source documentation. Follow-up laboratory results should be filed with the 
subject’s source documentation. 
For all AEs that require the subject to be discontinued from the study and SAEs, relevant clinical 
assessments and laboratory tests will be repeated as clinically appropriate until final resolution or 
stabilization of the event(s). 
All laboratory assessments will be performed centrally at a certified laboratory selected by the 
sponsor. The clinical laboratory values will be reported to the investigator by the laboratory and 
the Investigator will review them for significance and consideration as an AE. 
8.9.4 
Assessment of Adverse Events 
8.9.4.1 
Assessment of Severity 
Severity of AEs will be graded according to the following definitions: 
Mild: Event may be noticeable to subject; does not influence daily activities; usually does not 
require intervention. 
Moderate: Event may make subject uncomfortable; performance of daily activities may be 
influenced; intervention may be needed. 
Severe: Event may cause noticeable discomfort; usually interferes with daily activities; subject 
may not be able to continue in the study; treatment or intervention is usually needed.   
8.9.4.2 
Assessment of Causality 
AEs should be assessed by the investigator as to whether or not there is a reasonable possibility of 
causal relationship to the study drug and reported as either definite, probable, possible, not related, 
as defined below: 
x Not Related: The event is clearly due to extraneous causes (e.g., diseases, environment, 
etc.) or the event is most probably produced by other factors such as the subject’s clinical 
state, therapeutic interventions, or concomitant therapy and does not follow a known 
response pattern to the study product. 
x Possibly Related: The event is temporally related to study product use but can be explained 
by another etiology. Information on the effect of study product withdrawal may be lacking. 
x Probably Related: The event is temporally related to study product use and is consistent 
with known effects of the study product and/or improves upon withdrawal of the study 
product.  
x Definitely Related: The event follows a reasonable temporal sequence from the time of 
study product administration and/or follows a known response pattern to the study product 
and could not have been produced by other factors such as the subject´s clinical state, 
therapeutic intervention, or concomitant therapy, and either occurs immediately following 
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study product administration or improves on stopping the product, or there is a positive 
reaction at the application site 
8.9.5 
Reference Safety Information for Assessing Expectedness of Adverse Events 
The reference safety information for assessing the expectedness of an AE for the study medication 
in this study is the most recent Investigator’s Brochure. 
8.9.5.1 
Known Potential Toxicities of Investigational Product 
Refer to the Investigator's Brochure OR package insert for additional information on AEs related 
to toxicities observed to date. 
8.9.6 
Reporting Safety Observations 
All SAEs must be reported by the investigator to Dr. Reddy’s Laboratories Ltd, Clinical 
Pharmacovigilance, the Sponsor medical monitor, and the CRO medical monitor within 24 hours 
of the investigator's knowledge of the event. 
All SAEs must be recorded on SAE forms, irrespective of the study drug received by the subject, 
whether or not this event is considered by the investigator to be related to study drug. 
These SAE forms must be sent via E-mail to Dr. Reddy’s Laboratories Ltd, Clinical 
Pharmacovigilance, the Sponsor medical monitor, and the CRO medical monitor. The investigator 
must assess the relationship to study drug. 
All AEs, regardless of the relationship to study drug, will be recorded in the subject source record 
and eCRF.  Standard medical terminology should be used when describing AEs. . The anatomical 
location of the AEs must be specified where applicable. 
Whenever possible a diagnosis should be made and recorded on the eCRF rather than listing signs 
and symptoms. Intermittent AEs can be recorded once 
The following information should be recorded on the eCRF: 
x Description 
x Onset date 
x Resolution date or date of death 
x Severity of the event (see Intensity for details) 
x Study drug use continued or not 
x Outcome of the event (resolved, unknown, death) 
x Relationship to study drug (see Relationship to Study drug (Causality) for details) 
x Indication of whether the event is serious (see Seriousness for details) 
x Actions taken including treatment with concomitant medication 
When reporting an SAE, the Investigator/designee must complete the SAE reporting form and 
mention Investigator’s name/designee’s name, email ID, the telephone number where they can be 
reached, and the protocol number and title as well as the information in the above paragraph. 
Contact details are provided below: 
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Dr. Reddy’s Laboratories Ltd, Pharmacovigilance: 
Pharmacovigilance GPVC 
Email:  pharmacovigilance@drreddys.com. 
 
Dr. Reddy’s Laboratories Ltd, Medical Monitor: 
Srinivas Shenoy B., MD 
Director, Clinical Development 
Cell number: +91-9833974488 
E-mail:  srinivasshenoyb@drreddys.com 
 
Symbio (CRO) Medical Monitor: 
Evyan Cord-Cruz, MD 
 
Director, Medical Affairs 
Tel No: 516-982-0677 (cell)/ 631-403-5126 (direct) 
E-mail: ecruz@symbioresearch.com 
In addition, the Sponsor (or Sponsor’s designated agent) will evaluate the expectedness according 
to the reference document/the IB.  
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed in the 
SAE.  
Serious adverse event reporting will extend from signing of informed consent until End of Study 
Visit /Early Termination visit.  
An SAE which occurs before administration of study drug (e.g. during screening/as a result of 
screening) will not be considered for expedited reporting to the FDA but will be entered in the 
subject’s source records and the eCRF 
If the subject took one or more suspect medicinal product(s) other than the study drug, the relevant 
manufacturer(s) of this medicinal product(s), will be informed about the SAE by the sponsor. 
Preliminary reports will be followed by detailed descriptions that should include copies of hospital 
case reports, autopsy reports, hospital discharge summaries and other documents when requested 
and applicable. Follow-up information about a previously reported SAE must also be reported 
within 24 hours of receiving it. The Sponsor’s Pharmacovigilance department may contact the 
investigator to obtain further information.  
Suspected (considered related to the study drug) and Unexpected (not previously described in the 
reference safety document), Serious Adverse Reactions (SUSARs) will be expedited by the 
sponsor’s Pharmacovigilance department to Health Authorities. The CRO will report to the 
EC/IRBs as applicable. All SAEs judged to be SUSARs and reportable will be unblinded. SUSAR 
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related unblinding will be performed by the Sponsor’s Pharmacovigilance department as outlined 
within the Safety Management Plan.  
The Sponsor must notify FDA of any SAE observed during conduct of the study, which is serious 
and unexpected and for which there is a reasonable possibility that it has caused the SAE, for which 
there is basis to believe there is a causal relationship between the drug and the occurrence of the 
adverse event (21 CFR 312.32(c)(1)(i)), as soon as possible but in no case later than 15 calendar 
days after becoming aware of its occurrence as per regulatory guidelines. (21 CFR 320.31(d)(3)).  
If the AE is fatal or life-threatening, and with reasonable possibility of its being related to the study 
drug, the Sponsor must also notify the FDA as soon as possible but in no case later than 7 calendar 
days after becoming aware of its occurrence as per regulatory guidelines (21 CFR 320.31(d)(3)). 
Unblinding Instructions: 
Breaking the blind 
The blind should ordinarily be broken for all SAE IND safety report submitted to FDA. 
The unblinding procedures and follow-up will be performed in accordance with the protocol and 
the Sponsor’s SOPs. 
All SAEs observed in the investigational drug group, if considered drug related (Suspected 
Adverse Reaction) will be reported to the FDA as an unblinded IND Safety Report 
If the blind is broken and a subject with an adverse event was receiving placebo, the event should 
not be reported in an IND safety report because there is not a reasonable possibility that the drug 
caused the adverse event. 
The blind should not be broken at the study site level except in a medical emergency (where 
knowledge of the study drug received would affect the treatment of the emergency) or regulatory 
requirement (e.g., for SAEs or death).  
For medical emergency, the blind must only be broken following discussion on a case-by-case 
basis, at the discretion of the Investigator/treating physician/sponsor. 
If the blind is broken, the date, time, and reason must be recorded in the subject’s source record, 
eCRF, and any associated AE report.  
If an Investigator, site personnel performing assessments, or subject, is unblinded, the unblinding 
incident and unblinded subject must be listed as a major protocol deviation. 
A subject for whom the blind is broken will discontinue study product and be scheduled for a 
safety follow up visit and then discontinued from the study. The subject will be encouraged to stay 
in the study until the AE is resolved or stabilized. 
For regulatory requirement, reporting of SAEs not previously unblinded at the site level, the blind 
will be broken by Pharmacovigilance reporting team for all SAEs observed in any treatment arm.  
All other individuals, including primary investigators, will receive notification of the SAE in the 
form of a blinded report unless the SAE was previously unblinded at the site level due to a medical 
emergency. 
Laboratory and Vital Signs Variables 
Vital signs and laboratory abnormalities should be reported as an AE if they are considered to be 
clinically significant, as per Investigator’s judgment. If an abnormal laboratory value is associated 
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with clinical signs and symptoms, the sign/symptom should be reported as an AE and the 
associated abnormal laboratory result should be considered additional information. 
Subjects who have had an SAE must be followed clinically until the event has resolved, become 
clinically insignificant, has stabilized, or the subject is lost to follow-up. The investigator must 
provide a written follow-up report as soon as possible when any additional information is received. 
New SAEs occurring at any time after the 30-day follow-up period after study drug discontinuation 
(whichever comes first) may be reported to Dr. Reddy’s Laboratories Ltd, Clinical 
Pharmacovigilance within 24 hours of the investigator's knowledge of the event, if felt appropriate 
by the investigators. 
Such information will only be entered into the drug safety database and hence will not affect study 
closure. 
8.9.7 
Discontinuation, Treatment Interruption, and Unblinding of Blinded Treatment 
Due to Safety Observations 
8.9.7.1 
Discontinuation 
See Section 8.3.3 for the criteria for discontinuing a subject. If a subject is discontinued early from 
the study, the activities specified for Visit 7 on the Study Flow Chart (Section 3.2) should be 
completed if possible. 
8.9.7.2 
Treatment Interruption 
A subject may have the study medication temporarily interrupted for any of the following reasons: 
x 
An AE 
x 
A diagnostic or therapeutic procedure 
x 
An abnormal assessment (e.g., vital signs or laboratory abnormalities) 
x 
Administrative reasons, in particular withdrawal of the subject’s consent, or subject 
becomes uncooperative. 
The reason for study drug interruption or premature discontinuation must be documented in the 
eCRF and the Sponsor must be informed. If the reason for discontinuation from study drug is an 
abnormal result on a laboratory test or vital sign this information will be recorded as an AE in the 
eCRF. The subject will remain under the supervision of the investigator until satisfactory health 
has returned. 
8.9.7.3 
Modification of Dose of Study Medication 
The dose of study medication to any subject may not be modified. If necessary, a subject must be 
discontinued for the reasons described in Section 8.3.3.  
8.9.7.4 
Unblinding Treatment for a Subject During the Study 
IWRS will be used for emergency unblinding. The identity of the study drug may be revealed only 
if the subject experiences a medical emergency whose management would benefit by the 
knowledge of the treatment assignment. Subjects who have been unblinded by the study site must 
be discontinued from the study. 
The occurrence of any unblinding during the study must be clearly justified and explained by the 
investigator. Before unblinding, every attempt must be made by the investigator to discuss the 
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intended code break with the Sponsor Medical Monitor. In all cases, the Sponsor must be informed 
as soon as possible before or after the code break. 
8.10 
Criteria for Early Termination of the Study 
There are no prespecified criteria for terminating the study early.  
Further recruitment in the study or at (a) particular site(s) may be stopped due to insufficient 
compliance with the protocol, GCP, and/or other applicable regulatory requirements, procedure-
related problems, or the number of discontinuations for administrative reasons is too high.  
9 
STATISTICAL METHODS 
Prior to the database lock, a detailed, finalized Statistical Analysis Plan (SAP) will be completed 
and placed on file. The Statistical Analysis Plan will contain a more comprehensive explanation 
than that provided here of the methodology used in the statistical analyses, as well as the rules and 
data handling conventions used to perform the analyses and the procedure used to account for 
missing data. In case of any conflicting /discrepant information pertaining to statistical analysis 
between the methodology specified hereunder and in the final SAP, the information in the final 
SAP will supersede the protocol. 
9.1 
Statistical Analysis Plan 
A statistical analysis plan (SAP) will be written and finalized before the study closure, i.e., 
database closure and unblinding of the randomization code of the study. The SAP will provide full 
details of the analyses, level of significance to be used, the data displays and the algorithms to be 
used for data derivations.  
9.2 
Analysis Populations 
Three populations are defined for the analyses: 
x Intent-to-treat (ITT) population: This analysis population includes all randomized subjects 
(i.e., assigned to a treatment group). The ITT population will be the primary population for 
the efficacy analysis. 
x Safety population: This analysis population includes subjects who received at least one 
dose of study medication and had at least one safety assessment post-Baseline. The safety 
population will be used for analysis of tolerability and safety variables.  
x Per-protocol population (PP): This analysis population comprises all subjects who did not 
violate the protocol in a way that might affect the evaluation of the effect of the study 
medication on the primary endpoint (without major protocol violations or deviations). Key 
protocol deviation categories that would influence the decision to include a subject in the 
PP population at time of final review before study database lock will be pre-specified in 
the Statistical Analysis Plan (SAP).   
9.3 
General Considerations 
9.3.1 
Handling of Missing Data 
All safety analyses will be performed on data available at the time point considered. In summary 
tables, the number of subjects with missing data will be presented unless otherwise specified. In 
calculation of percentages, subjects with missing data will not be considered in the numerator or 
denominator unless otherwise specified. 
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For the ITT analysis of the total inflammatory lesion count, IGA, CEA, and DLQI efficacy data, 
in case of missing measurements at Week 16, multiple imputation (MI) will be used to impute the 
missing values. 
9.4 
Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications 
The statistical significance of any treatment group difference in the distribution of categorical 
variables such as gender will be tested using Cochran–Mantel–Haenszel (CMH) test for general 
association adjusted for site. Continuous variables, such as age, will be analyzed using a 2-way 
analysis of variance (ANOVA) model with site and treatment as a fixed effect. 
Summary statistics (mean, median, standard deviation, min, max, number of available 
observations) will be provided for continuous demographic variables (e.g., age, height, weight). 
Individual subject listings of demographic data will be provided. 
Qualitative demographic characteristics (gender, race) will be summarized by counts and 
percentages. Medical history will be summarized by system organ class (SOC) and preferred term 
(PT). Other Baseline subject characteristics (e.g., physical examination clinical findings, and 
inclusion/exclusion checklist) will only be listed.  
Distributions of these parameters will be compared between the treatment groups only 
descriptively. No statistical inference will be performed. 
9.5 
Exposure to Study Drug and Treatment Compliance 
A listing with information about the drug administration will be provided.  Summaries of study 
drug exposure and compliance will be provided. 
9.6 
Efficacy Evaluations 
For all endpoints, the comparison of DFD-29 versus placebo will be the primary objective of the 
study. Comparison between oral DFD-29 and Doxycycline capsules 40 mg will be treated as 
secondary. The ITT will be used to perform all efficacy analyses. The analyses of the co-primary 
endpoints will also be performed on the PP population. 
To maintain the study-wise Type I error rate of 0.05, the multiplicity issue of testing DFD-29 
against placebo and against Doxycycline capsules 40 mg for multiple primary and secondary 
endpoints will be addressed through a fixed-sequence method described in the SAP, according to 
a defined sequence for the primary and secondary endpoints.  
9.6.1 
Co-Primary Endpoints 
x The proportion of subjects with IGA treatment success (DFD-29 versus placebo) will be 
investigated with a CMH test for general association adjusted for site. Treatment success 
is defined as having at least a 2-grade reduction from Baseline with Grade 0 or 1 at Week 
16. 
x The difference between the treatments (DFD-29 versus placebo) in terms of the change 
from Baseline in the total inflammatory lesion count at Week 16 will be tested using an 
Analysis of Covariance (ANCOVA) model with treatment and site included in the model 
as fixed effects, and Baseline total inflammatory lesion count as a covariate. 
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9.6.2 
Secondary Endpoints 
x Percentage Change in Total inflammatory lesion count (sum of papules, pustules, and 
nodules) from Baseline to Week 16, in the DFD-29 group compared to Placebo will be 
tested using an ANCOVA model with treatment and site included as fixed effects, and 
Baseline total inflammatory lesion count as a covariate. 
x Proportion of subjects with IGA treatment success (DFD-29 versus Doxycycline capsules 
40 mg) at Week 16 will be investigated with a CMH test for general association adjusted 
for site.  
x The difference between treatments (DFD-29 versus Doxycycline capsules 40 mg) in 
change from Baseline in the total inflammatory lesion count at Week 16 will be tested 
using an ANCOVA model with treatment and site included in the model as fixed effects, 
and Baseline total inflammatory lesion count as a covariate. 
x Proportion of subjects with at least a 2-grade reduction in CEA score from Baseline to 
Week 16 will be investigated with a CMH test for general association adjusted for site 
(DFD-29 versus placebo).  
x Change in DLQI score from Baseline to Week 16 will be investigated using an ANCOVA 
model with treatment and site included in the model as fixed effects, and Baseline DLQI 
as a covariate (DFD-29 versus placebo). 
9.6.3 
Interim Analysis 
No formal interim analysis is planned. 
9.7 
Safety Analyses 
Definitions of the safety and tolerability parameters are described in Section 8.9.1. 
The safety population set is used to perform all safety analyses. 
The medical history is coded using the most recent Medical Dictionary for Regulatory Activities 
(MedDRA) version 24.1. 
All AEs and SAEs are coded using the most recent MedDRA version 24.1. 
The treatment-emergent AEs are tabulated by system organ class (SOC), and individual preferred 
terms within each SOC by treatment group. The number and percentage of subjects who 
experienced AEs coded with the same preferred term and SOC will be summarized by treatment 
group (in descending order according to the incidence in the investigational study drug group). 
AEs will also be tabulated by severity and by relationship to study drug. Summary tables will be 
accompanied by individual subject listings broken down by treatment group, including pre-dose 
events.  
SAEs, AEs leading to premature discontinuation of study drug, and AEs of special interest each 
will be listed and summarized similarly to AEs. 
Reasons for death will only be listed. 
Reasons for premature discontinuation of study drug will be listed and summarized by frequency 
tables. 
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Individual subject listings of vital signs data, physical examination, and laboratory measurements 
will be provided. 
Observed values and changes from Baseline in vital sign measurements and laboratory 
measurements will be summarized at each time point using mean, median, standard deviation, 
minimum, maximum, number of available observations. 
Standard numeric laboratory parameters are presented in the units supplied. If needed, a conversion 
will be made to standard units. 
Concomitant medications will be classified according to the World Health Organization (WHO) 
Drug Dictionary and will be presented in data listings. 
9.8 
Other Analyses 
9.8.1 
Exploratory Analyses 
Exploratory data-driven analyses may be performed with the caveat that any statistical inference 
will not have any confirmatory value. All of the following will be compared for DFD-29 versus 
placebo and Doxycycline capsules 40 mg. 
x Proportion of subjects with IGA treatment success from Baseline to Weeks 2, 4, 8, and 12 
will be investigated with a CMH test for general association adjusted for site. Treatment 
success is defined as having at least a 2-grade reduction from Baseline with Grade 0 or 1. 
x The difference between treatments in terms of the change from Baseline in the total 
inflammatory lesion count at Weeks 2, 4, 8, and 12 will be tested using mixed model 
repeated measures (MMRM) with treatment, site, visit, and treatment-by-visit interaction 
included in the model as fixed effects, Baseline total inflammatory lesion count as a 
covariate, and the subjects as a random factor. 
x Percentage Change in Total inflammatory lesion count from Baseline to Weeks 2, 4, 8, 12 
(and 16, in case of DFD-29 vs Doxycycline capsules 40 mg comparison) will be tested 
using MMRM with treatment, site, visit, and treatment-by-visit interaction included in the 
model as fixed effects, Baseline total inflammatory lesion count as a covariate, and the 
subjects as a random factor 
x The proportion of subjects with at least a 2-grade reduction in IGA score from Baseline to 
Weeks 2, 4, 8, 12, and 16 will be investigated with a CMH test for general association 
adjusted for site. 
x Change in total RosaQoL score from Baseline to Weeks 2, 4, 8, 12 and 16 will be 
investigated using MMRM with treatment, site, visit, and treatment-by-visit interaction 
included in the model as fixed effects, Baseline RosaQoL as a covariate, and the subjects 
as a random factor. 
x Change in DLQI score from Baseline to Weeks 2, 4, 8, 12 (and 16, in case of DFD-29 vs 
Doxycycline capsules 40 mg comparison) will be investigated using MMRM with 
treatment, site, visit, and treatment-by-visit interaction included in the model as fixed 
effects, Baseline DLQI as a covariate, and the subjects as a random factor. 
x Proportion of subjects with at least a 2-grade improvement in the CEA score at Weeks 2, 
4, 8, 12 (and 16, in case of DFD-29 vs Doxycycline capsules 40 mg comparison) will be 
investigated with a CMH test for general association adjusted for site. 
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Exploratory analyses for the following subgroups will be performed for the primary endpoints: 
x Males versus females 
x Baseline rosacea severity: moderate (IGA 3) versus severe (IGA 4) 
x Baseline total inflammatory lesion count below versus above the median count 
x Fitzpatrick skin types I-III versus IV-VI 
9.9 
Sample Size Determination 
The sample size for this study was calculated on the basis of the results obtained from the preceding 
Phase 2 study with orally administered DFD-29 (40 mg) in the treatment of inflammatory lesions 
of papulopustular rosacea. 
Assuming a difference in treatment means of 8.5 lesions between the DFD-29 and placebo groups, 
and a common standard deviation of 16.3 for the endpoint of inflammatory lesion count reduction, 
the sample size required is calculated to be 100 DFD-29 subjects and 65 placebo subjects to 
achieve 90% power, with a two-sided alpha of 0.05, for a 3:2 randomization ratio. 
Assuming the proportion of IGA treatment success will be 0.60 in the DFD-29 group and 0.15 in 
the placebo group, the sample size of 100 DFD-29 subjects and 65 placebo subjects will provide 
greater than 99% power to detect a statistically significant difference in these proportion at 
alpha=0.05 (two-sided), for a 3:2 randomization ratio. 
For the comparisons of DFD-29 to Doxycycline capsules 40 mg assuming a difference in treatment 
means of 7.5 lesions and the common standard deviation of 16.3 for the endpoint of inflammatory 
lesion count reduction, the sample size required is calculated to be 101 subjects in each treatment 
group to achieve 90% power, with a two-sided alpha of 0.05. In addition, the sample size of 
100 subjects per group will yield greater than 90% power to detect a difference in the assumed 
proportion of IGA success of 0.60 in the DFD-29 group 0.35 in the Doxycycline capsules 40 mg 
group, using a two-sided alpha of 0.05.  
Based on these sample size calculations and an assumed dropout rate of 20%, the final sample size 
will be 120 subjects each in the DFD-29 and Doxycycline capsules 40 mg groups and 80 subjects 
in the placebo group for a total of 320 subjects. This sample size will provide adequate power to 
assess the superiority of DFD-29 against both placebo and Doxycycline capsules 40 mg in terms 
of efficacy on both co-primary endpoints. 
Efforts will be made to minimize the dropout rate and to ensure proper follow-up of subjects. 
10 
ETHICS 
10.1 
Informed Consent 
The principles of informed consent, according to FDA regulations and International Council for 
Harmonization (ICH) guidelines on GCP, will be followed. A copy of the proposed ICF must be 
submitted with the protocol to the IRB for approval. 
The informed consent process must be conducted and the ICF must be signed before each subject 
undergoes any Visit 1 procedures that are performed solely for the purpose of determining 
eligibility for the study, in compliance with 21 CFR Part 50. Each subject’s signed ICF must be 
kept on file by the investigator for inspection by regulatory authorities at any time. A copy of the 
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signed ICF will be given to the subject. A notation will be made in the subject’s medical record 
indicating the date informed consent was obtained. 
10.2 
Institutional Review Board (IRB) 
The study protocol and ICF must be approved in writing by an appropriate IRB as defined by FDA 
regulations prior to enrollment of any study subjects. 
Any changes to the protocol or a change of investigator approved by the sponsor must also be 
approved by the site’s IRB and documentation of that approval provided to the sponsor or designee. 
Records of the IRB review and approval of all documents pertaining to this study must be kept on 
file by the investigator and are subject to inspection by regulatory authorities during or after 
completion of the study. SAEs must also be reported to the IRB. 
Periodic status reports must be submitted to the IRB at least annually, as well as notification of 
completion of the study and a final report at study completion or termination.  
The investigator will ensure that an IRB that complies with the requirements set forth in 21 CFR 
Part 56 will be responsible for the initial and continuing review and approval of the study. 
10.3 
Subject Confidentiality 
All subject data will be identified only by a subject identification number and subject initials. 
However, in compliance with federal guidelines regarding the monitoring of clinical studies and 
in fulfillment of his/her obligations to the sponsor, the investigator must permit the study monitor, 
sponsor representative or auditor, and/or FDA representative or other regulatory authority to 
review the portion of the subject’s medical record that is directly related to the study. This shall 
include all study-relevant documentation including medical history to verify eligibility, 
admission/discharge summaries for hospital stays occurring while the subject is enrolled in the 
study, and autopsy reports if a death occurs during the study. 
As part of the required content of informed consent, each subject must be informed that his or her 
medical chart may be reviewed by the sponsor, the sponsor’s authorized representatives, FDA or 
other regulatory authority. If access to the medical record requires a separate waiver or 
authorization, it is the investigator’s responsibility to obtain such permission from the subject in 
writing before the subject is entered into the study. 
10.4 
Study Registration 
The study will be registered by the sponsor on an appropriate free public web site such as 
clinicaltrials.gov, which is a service of the United States National Institutes of Health. 
11 
DATA HANDLING AND RECORDKEEPING 
11.1 
Site Regulatory Documents Required for Initiation 
The sponsor or designee will receive the following documents prior to the initiation of the study: 
x Completed, signed Form FDA 1572 
x Current curricula vitae, signed and dated, for the principal investigator (PI) and 
co-investigators named on Form FDA 1572 
x Current license(s) of the PI and co-investigators named on Form FDA 1572 
x Documentation of IRB approval of the study protocol, investigator, and ICF 
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x Current IRB membership list 
x A copy of the protocol signature page signed by the PI 
x Original Non-disclosure Agreements for the PI and co-investigators named on Form FDA 
1572 
x Debarment Certification for the PI and co-investigators named on Form FDA 1572 
x Financial Disclosure Statement for all individuals named on Form FDA 1572 
11.2 
Maintenance and Retention of Records 
The study will be conducted according to GCP as outlined in ICH guidelines by the FDA. It is the 
responsibility of the investigator to maintain a comprehensive and centralized filing system of all 
relevant documentation. Investigators will be instructed to retain all study records required by the 
sponsor and the regulations in a secure and safe facility with limited access. Regulations require 
retention for a period of at least 2 years after marketing approval and notification from the sponsor. 
These regulatory documents should be retained for a longer period if required by local regulatory 
authorities.  
These records include documents pertaining to the receipt and return of drug supplies, IRB, 
informed consent, source documents, and final signed eCRFs. No documents shall be transferred 
from the site or destroyed without first notifying the sponsor. 
11.2.1 
Electronic Case Report Forms (eCRFs)  
Database set-up will be performed by Symbio (CRO) in collaboration with the electronic data 
capture (EDC) vendor, using an appropriate fully validated, 21 CFR Part 11 compliant EDC 
system. eCRFs will be provided to each site via a secured web link. All applicable study data 
collected on each subject will be recorded by approved site personnel into the eCRF. Only 
authorized site personnel will be able to enter/modify/correct data to the eCRF. 
Approved staff at CRO will verify all data entered into eCRFs for completeness and accuracy with 
reference to the source documents and records and will issue manual data queries to correct 
missing data or discrepancies found against the source within the EDC system. 
Data validation will consist of automated and manual edit checks that are created directly into 
EDC. Automated edit checks will be executed on all data points defined and documented by the 
study team and data management. Study metrics will be reported from the EDC system. 
After all data have been verified by approved staff at CRO, an Investigator or Sub-Investigator 
(listed on Form FDA 1572) is required to review and approve all eCRFs prior to database lock and 
breaking of the blind.  
After database lock, each site will be provided with a transportable media that will include the 
eCRF data from their site for local archival purposes. 
Quality assurance verification via a 10% database audit of eCRF data will be conducted before the 
treatment assignment codes are released. 
eCRF entry must be kept current to reflect the subject’s status during the study. Subjects are not 
to be identified on eCRFs by name; appropriately coded identification must be used. The 
investigator must keep a separate log of the subjects’ names and addresses. 
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Source documents such as the clinic chart are to be maintained separately from the eCRF to allow 
data verification. Because of the potential for errors, inaccuracies, and illegibility in transcribing 
data onto eCRFs, originals of laboratory and other test results must be kept on file with the 
subject’s eCRF. eCRFs, source documents, and copies of test results must be available at all times 
for inspection by the study monitor. The following should also be available for review: 
x Subject Screening Log, which should reflect the reason any subject screened for the study 
was found to be ineligible 
x Delegation of Authority Log, which will list all site personnel with their responsibilities as 
delegated by the PI and their signatures. This log will be maintained at the site throughout 
the study 
x Monitoring Log, which will list the date and purpose of all monitoring visits by the sponsor 
or designee 
x Enrollment Log, which will list subject initials and start and end dates for all enrolled 
subjects 
x Drug Inventory/Packing Slip, which will list the total amount of drug shipped to the site 
and received and signed for by the investigator 
x Study Medication Dispensing Log, which will list the total amount of study medication 
dispensed to and returned by each subject 
x ICF which must be available for each subject and be verified for proper documentation 
x All correspondence 
11.2.2 
Primary Source Documents 
The investigator must maintain primary source documents supporting significant data for each 
subject’s medical notes. These documents, which are considered “source data,” should include 
documentation of: 
x Demographic information 
x Evidence supporting the diagnosis/condition for which the subject is being studied 
x General information supporting the subject’s participation in the study 
x General history and physical findings 
x Hospitalization or Emergency Room records (if applicable) 
x Each study visit by date, including any relevant findings/notes by the investigator(s), 
occurrence (or lack) of AEs, and changes in medication usage, including the date the study 
medication was started and stopped 
x Any additional visits during the study 
x Any relevant telephone conversations with the subject regarding the study or possible AEs 
x An original, signed ICF for study participation 
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The investigator must also retain all subject-specific printouts/reports of tests and procedures 
performed as a requirement of the study. During monitoring visits the monitor will validate eCRF 
entries against these sources of data. 
11.3 
Study Monitoring 
Symbio (CRO) will be responsible for monitoring the study according to GCP and applicable 
regulations. The study will be monitored by a Clinical Research Associate (CRA) in compliance 
with GCP, ICH guidelines, and applicable regulations. The investigator will be visited by a CRA 
prior to the study and at regular intervals during the course of the study. These visits are to verify 
adherence to the protocol. The CRA will review the ICFs and verify eCRF entries by comparing 
them with the source documents (hospital/clinic/office records) that will be made available for this 
purpose. The CRA will review the maintenance of regulatory documentation and drug 
accountability (to the bottle level). The monitor will review the progress of the study with the 
investigator and other site personnel on a regular basis. At the end of the study, a closeout 
monitoring visit will be performed. Monitoring visits will be arranged with site personnel in 
advance at a mutually acceptable time. Sufficient time must be allowed by the site personnel for 
the monitoring of eCRFs and relevant source documents. The coordinator and/or investigator 
should be available to answer questions or resolve data clarifications. Adequate time and space for 
these visits should be made available by the investigator and study staff.  
11.4 
Audits and Inspections 
During the course of the study and/or after it has been completed, 1 or more sites may be audited 
by authorized representatives of the sponsor. The purpose of the audit is to determine whether or 
not the study is being conducted and monitored in compliance with recognized GCP/ICH 
guidelines and regulations. 
Additionally, the study may be inspected by regulatory authorities. These inspections may take 
place at any time during or after completion of the study and are based on local regulations. 
11.5 
Modifications to the Protocol 
The procedures defined in the protocol and eCRFs will be carefully reviewed to ensure that all 
parties involved with the study fully understand the protocol. To ensure the validity of the data, no 
deviations from the protocol (with minimal exceptions) may be made unless the issue is broad 
enough to warrant revision of the protocol. Such revisions must be submitted to and have 
documented approval from the sponsor and IRB prior to implementation. The only circumstance 
in which an amendment may be initiated without prior IRB approval is to eliminate an apparent 
immediate hazard to a subject or subjects. In such a case, however, the investigator must notify 
the sponsor immediately and the IRB within 5 working days after implementation. 
11.6 
Completion of the Study 
The investigator is required to forward eCRFs and all other relevant data and records to CRO. The 
investigator will complete and report (submission of eCRFs) his/her study in satisfactory 
compliance with the protocol as soon as possible after the completion of the study. 
The investigator must submit a final report to the IRB and the sponsor within 1 month of study 
completion or early termination. 
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12 
CONFIDENTIALITY, USE OF INFORMATION, AND PUBLICATION 
All information related to this study that is supplied by the sponsor and not previously published 
is considered confidential information. This information includes but is not limited to data, 
materials (protocol, eCRFs), equipment, experience (whether of a scientific, technical, 
engineering, operational, or commercial nature), designs, specifications, know-how, product uses, 
processes, formulae, costs, financial data, marketing plans and direct selling systems, customer 
lists, and technical and commercial information relating to customers or business projections used 
by the sponsor in its business. Any data, inventions, or discoveries collected or developed as a 
result of this study are considered confidential. This confidential information shall remain the sole 
property of the sponsor, shall not be disclosed to any unauthorized person or used in any 
unauthorized manner without written consent of the sponsor, and shall not be used except in the 
performance of the study. 
The information developed during the course of this study is also considered confidential and will 
be used by the sponsor in the development of the study medication. The information may be 
disclosed as deemed necessary by the sponsor. To allow the use of the information derived from 
this study, the investigator is obliged to provide the sponsor with complete test results and all data 
developed in the study. The information obtained during this study may be made available to other 
investigators who are conducting similar studies. 
The investigator shall not make any publication related to this study without the express written 
permission of the sponsor. If the investigator wants to publish or present the results of this study, 
he or she agrees to provide the sponsor with an abstract, manuscript, and/or presentation for review 
60 days prior to submission for publication or presentation. The sponsor retains the right to delete 
confidential information and to object to suggested publication/presentation and/or its timing (at 
the sponsor’s sole discretion). 
13 
LIST OF REFERENCES 
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classification. Acta Derm Venereol. 2010; 90:269–73. 
2. Berg M, Lidén S. An epidemiological study of rosacea. Acta Derm Venereol. 1989;69(5):419‐423. 
3. Bewley A, Fowler J, Schöfer H, Kerrouche N, Rives V. Erythema of Rosacea Impairs Health-Related 
Quality of Life: Results of a Meta-analysis. Dermatol Ther (Heidelb). 2016 Mar 16. [Epub ahead of print] 
4. Dean OM, Maes M, Ashton M, Berk L, Kanchanatawan B, Sughondhabirom A, Tangwongchai S, Ng C, 
Dowling N, Malhi GS, Berk M. Protocol and rationale-the efficacy of minocycline as an adjunctive 
treatment for major depressive disorder: a double blind, randomised, placebo controlled trial. Clin 
Psychopharmacol Neurosci. 2014;12(3):180-8. 
5. Del Rosso JQ. Oral Doxycycline in the Management of Acne Vulgaris: Current Perspectives on Clinical 
Use and Recent Findings with a New Double-scored Small Tablet Formulation. J Clin Aesthet Dermatol. 
2015;8(5):19-26. 
6. Dosal JR, Rodriguez GL, Pezon CF, Li H, Keri JE. Effect of tetracyclines on the development of vascular 
disease in veterans with acne or rosacea: a retrospective cohort study. J Invest Dermatol. 
2014;134(8):2267-9. 
7. Duman N, Ersoy Evans S, Atakan N. Rosacea and cardiovascular risk factors: a case control study. J Eur 
Acad Dermatol Venereol. 2014;28(9):1165-9. 
8. Egeberg A, Hansen PR, Gislason GH, Thyssen JP. Clustering of autoimmune diseases in patients with 
rosacea. J Am Acad Dermatol. 2016a;74(4):667-672.e1. 
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9. Egeberg A, Hansen PR, Gislason GH, Thyssen JP. Patients with Rosacea Have Increased Risk of 
Depression and Anxiety Disorders: A Danish Nationwide Cohort Study. Dermatology. 2016b;232(2):208-
13. 
10. Feldman SR, Huang WW, Huynh TT. Current drug therapies for rosacea: a chronic vascular and 
inflammatory skin disease. J Manag Care Spec Pharm. 2014;20(6):623-9. 
11. Garrido-Mesa N, Zarzuelo A, Gálvez J. Minocycline: far beyond an antibiotic. Br J Pharmacol. 
2013;169(2):337-52. 
12. Griffin MO, Fricovsky E, Ceballos G, Villarreal F. Tetracyclines: a pleitropic family of compounds with 
promising therapeutic properties. Review of the literature. Am J Physiol Cell Physiol. 2010;299(3):C539-
48. 
13. Gupta MA, Gupta AK, Chen SJ, Johnson AM. Comorbidity of rosacea and depression: an analysis of the 
National Ambulatory Medical Care Survey and National Hospital Ambulatory Care Survey--Outpatient 
Department data collected by the U.S. National Center for Health Statistics from 1995 to 2002. Br J 
Dermatol. 2005;153(6):1176-81.  
14. Holmes AD, Steinhoff M. Integrative concepts of rosacea pathophysiology, clinical presentation, and 
new therapeutics. Exp Dermatol. 2016 Jul 4. doi:10.1111/exd.13143. [Epub ahead of print] 
15. Hua TC, Chung PI, Chen YJ, Wu LC, Chen YD, Hwang CY, Chu SY, Chen CC, Lee DD, Chang YT, Liu 
HN. Cardiovascular comorbidities in patients with rosacea: A nationwide case-control study from Taiwan. 
J Am Acad Dermatol. 2015;73(2):249-54. 
16. Jackson JM, Kircik LH, Lorenz DJ. Efficacy of extended-release 45 mg oral minocycline and extended-
release 45 mg oral minocycline plus 15% azelaic acid in the treatment of acne rosacea. J Drugs Dermatol. 
2013;12(3):292-8. 
17. Scheinfeld N, Berk T. A review of the diagnosis and treatment of rosacea. Postgrad Med. 2010;122(1):139‐
143. doi:10.3810/pgm.2010.01.2107 
18. Spoendlin J, Voegel JJ, Jick SS, Meier CR. A study on the epidemiology of rosacea in the U.K. Br J 
Dermatol. 2012 Sep;167(3):598-605. 
19. Spoendlin J, Voegel JJ, Jick SS, Meier CR. Migraine, triptans, and the risk of developing rosacea: a 
population-based study within the United Kingdom. J Am Acad Dermatol. 2013;69(3):399-406. 
20. Steinhoff M, Buddenkotte J, Aubert J, Sulk M, Novak P, Schwab VD, Mess C, Cevikbas F, Rivier M, 
Carlavan I, Déret S, Rosignoli C, Metze D, Luger TA, Voegel JJ. Clinical, cellular, and molecular aspects 
in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011;15(1):2-11. 
21. Tan J, Schöfer H, Araviiskaia E, Audibert F, Kerrouche N, Berg M; RISE study group. Prevalence of 
rosacea in the general population of Germany and Russia -The RISE study. J Eur Acad Dermatol Venereol. 
2016 Mar;30(3):428-34.  
22. van Zuuren EJ, Fedorowicz Z, Carter B, van der Linden MM, Charland L. Interventions for rosacea. 
Cochrane Database Syst Rev. 2015;(4):CD003262. 
23. van Zuuren EJ, Gupta AK, Gover MD, Graber M, Hollis S. Systematic review of rosacea treatments. J Am 
Acad Dermatol. 2007;56(1):107‐115. doi:10.1016/j.jaad.2006.04.084 
24. Vemuri RC, Gundamaraju R, Sekaran SD, Manikam R. Major pathophysiological correlations of rosacea: a 
complete clinical appraisal. Int J Med Sci. 2015;12(5):387-96. 
25. Wilkin J, Dahl M, Detmar M, Drake L, Feinstein A, Odom R, Powell F. Standard classification of rosacea: 
Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J 
Am Acad Dermatol. 2002;46(4):584-7. 
26. Wilkin J, Dahl M, Detmar M, Drake L, Liang MH, Odom R, Powell F; National Rosacea Society Expert 
Committee. Standard grading system for rosacea: report of the National Rosacea Society Expert Committee 
on the classification and staging of rosacea. J Am Acad Dermatol. 2004;50(6):907-12. 
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27. Wollina U. Recent advances in the understanding and management of rosacea. F1000Prime Rep. 
2014;6:50. 
28. Oracea capsules [package insert]. Fort Worth, TX: Galderma Laboratories, L.P.; 2013.OR Doxycycline 40 
mg capsules [package insert].  DailyMed - DOXYCYCLINE capsule (nih.gov) 
 
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INVESTIGATOR AGREEMENT 
Protocol Number: 
DFD-29-CD-004 
Protocol Title: 
A Multicenter, Randomized, Double-Blind, Parallel-Group, Active and 
Placebo-Controlled Study to Assess the Safety, Efficacy, and 
Tolerability of Oral DFD-29 Extended Release Capsules for the 
Treatment of Inflammatory Lesions of Rosacea Over 16 Weeks 
 
I have carefully read and understand the foregoing protocol and agree that it contains all the 
necessary information for conducting this study safely. I will conduct this study in strict 
accordance with this protocol, ICH guidelines for Good Clinical Practice, the Code of Federal 
Regulations, the Health Insurance Portability and Accountability Act (HIPAA), and local 
regulatory guidelines. I will attempt to complete the study within the time designated. I will ensure 
that the rights, safety, and welfare of subjects under my care are protected. I will ensure control of 
the drugs under investigation in this study. I will provide copies of the protocol and all other study-
related information supplied by the sponsor to all personnel responsible to me who participate in 
the study. I will discuss this information with them to assure that they are adequately informed 
regarding the drug and conduct of the study. I agree to keep records on all subject information 
(case report forms, shipment and drug return forms, and all other information collected during the 
study) and drug disposition in accordance with FDA regulations. I will not enroll any subjects into 
this protocol until IRB approval and sponsor approval are obtained. 
 
 
 
 
 
 
 
 
 
 
 
Investigator Name (Print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator Signature  
 
 
 
 
Date 
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APPENDICES 
15.1 
IGA Scale 
 
 
 
15.2 
CEA Scale 
 
Score 
Definition 
0 = None 
No redness present 
1 = Mild 
Slight pinkness 
2 = Moderate 
Definite redness 
3 = Significant 
Marked erythema 
4 = Severe 
Fiery redness 
 
Tan J, Liu H, Leyden JJ, Leoni MJ. Reliability of clinician erythema assessment grading scale. J Am Acad Dermatol. 
2014;71(4):760-3. 
 
 
 
Score 
Definition  
0 = Clear 
No signs or symptoms present 
1 = Near clear 
Rare papules 
2 = Mild 
Some papules and pustules with no plaques 
3 = Moderate 
Several small/large papules and pustules, 
with no plaques 
4 = Severe 
Numerous small/large papules and pustules, 
with or without plaques and nodules 
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15.3 
Diagram of the Face 
 
 
Each pustule to be marked by “X” at its approximate location. 
Each papule to be marked by “□” at its approximate location. 
Each nodule/cyst to be marked by “O” at its approximate location 
 
 
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15.4 
Example of the Rosacea Quality of Life Instrument 
 
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15.5 
Example of the Dermatology Life Quality Index 
 
 
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