Clinical trial NCT03075891
Conditions: Rosacea
Sponsor: Galderma R&D
Start date: 2017-07-05; Completion date: 2018-02-08
Enrollment: 273 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of this study is to evaluate the efficacy of Ivermectin 1% topical cream associated with Doxycycline 40 mg Modified release (MR) capsules versus Ivermectin 1% topical cream associated with Placebo in the treatment of severe Rosacea.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Ivermectin 1% cream intervention 2: Doxycycline 40 mg MR (30 mg Immediate Release & 10 mg Delayed Release beads) capsules intervention 3: Oral placebo capsules
Intervention descriptions: intervention 1: Topical to the face, approximately one small pea size amount per facial region (right and left cheeks, forehead, chin, and nose) once a day for 12 weeks intervention 2: 1 Capsule once-daily for 12 weeks intervention 3: 1 Capsule once-daily for 12 weeks

Protocol documents:
Prot_000.pdf: 
Efficacy Comparison of Ivermectin 1% Topical Cream Associated with Doxycycline 40 mg Modified Release 
(MR) Capsules Versus Ivermectin 1% Topical Cream Associated with Placebo in the Treatment of Severe 
Rosacea.
NCT Number:  NCT03075891 
Date: 10 Feb 2017


GALDERMA RESEARCH & DEVELOPMENT 
Protocol N° RD.03.SPR.113322  
version Final dated 10-FEB-2017 
Page 1 of 106 CONFIDENTIAL 
CLINICAL TRIAL PROTOCOL 
PROTOCOL NUMBER: RD.03.SPR.113322 
CONFIDENTIAL 
This document contains confidential, proprietary information 
All the information provided to the Investigator and his/her staff and all data obtained through 
this GALDERMA R&D clinical trial protocol are confidential.  The Sponsor reserves all 
proprietary rights. No information may be disclosed to any third party without prior written 
consent from GALDERMA R&D. 


GALDERMA RESEARCH & DEVELOPMENT 
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TITLE PAGE 
Title: Efficacy comparison of Ivermectin 1% topical cream associated with Doxycycline 
40 mg Modified release (MR) capsules versus Ivermectin 1% topical cream associated 
with Placebo in the treatment of  severe Rosacea. 
 
Project Name:  
Project Number: 
Clinical Trial Phase: 
Ivermectin 1% cream and  
Doxycycline 40 mg MR 
capsules 
838 
IV for US 
IIIb For Canada and Europe 
 
EUDRACT NUMBER: 2017-000157-40  
IND NUMBER: 076064 (Ivermectin 1% cream); 067833 (Doxycycline 40mg MR capsules) 
 
Version Number: Final - 10 Feb 2017 
 
Sponsor Contact details:  
Name 
GALDERMA R&D 
Address 
Les Templiers 
2400, Route des Colles 
06410 Biot - France 
Tel 
+33.4.93.95.47.68 
Fax 
+33.4.93.95.71.64 
 
For any urgent medical questions, including safety reasons, please use the contact 


GALDERMA RESEARCH & DEVELOPMENT 
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details provided in Section 8.2.2 
This clinical trial will be performed in compliance with applicable regulations, Good Clinical 
Practice (GCP) and the ethical principles that have their origin in the Declaration of Helsinki. 
This clinical trial Protocol follows guidelines outlined by the International Conference on 
Harmonization (ICH) and the GALDERMA R&D Phase IV department template. 


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CLINICAL TRIAL ADMINISTRATIVE STRUCTURE  
The following table contains the details of GALDERMA R&D employees involved in the conduct 
of the trial.  
SPONSOR PERSONNEL 
Name/Title 
Affiliation/Address/Tel./Fax 
Responsibilities 
 
 
GALDERMA R&D SNC, 
 
 
 
 
 
 
Responsible for clinical 
management and 
monitoring of clinical trial 
and for overall coordination 
of clinical project 
 
 
Galderma R&D, SNC 
Same as above 
 
 
 
Responsible for 
administrative follow-up and 
management of Trial Master 
File 
 
 
 
 
 
Galderma R&D, SNC 
Same as above 
  
 
  
Responsible for study  
medical management and 
safety surveillance 


GALDERMA RESEARCH & DEVELOPMENT 
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GALDERMA R&D SNC, 
Same as above 
 
 
 
Responsible for the Phase 
IV group 
 
 
GALDERMA R&D SNC, 
Same as above 
 
 
 
Responsible for the coordination 
of all data management activities 
 
 
GALDERMA R&D SNC, 
Same as above 
 
 
 
Responsible for the management 
of all statistical activities 
 
 
GALDERMA R&D SNC, 
Same as above 
 
 
 
Responsible for quality assurance 
and audits  


GALDERMA RESEARCH & DEVELOPMENT 
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GALDERMA R&D SNC, 
Same as above 
 
 
 
Responsible for the 
management of all clinical 
supplies activities 
 
 
GALDERMA R&D SNC, 
Same as above 
 
 
 
Responsible for safety 
surveillance 
 


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SIGNATURE PAGE 
Investigator’s Agreement 
I agree to: 
 Implement and conduct this clinical trial diligently and in strict compliance with the protocol, 
Good Clinical Practices and all applicable laws and regulations. 
 Accurately record all required data on each patient’s electronic Case Report Forms 
(eCRFs) in a timely manner on an ongoing basis. 
 Use the investigational product(s) for this clinical trial only. Maintain a complete and 
accurate inventory during and at the completion of the clinical trial. Maintain records of all 
investigational product units received, dispensed, returned by the subjects, and the 
number of product units returned to GALDERMA R&D. 
 Allow authorised representatives of GALDERMA R&D or regulatory authorities to conduct 
on-site visits to review, audit, and copy clinical trial documents. I will personally meet these 
representatives at mutually convenient times to answer any clinical trial-related questions. 
 Comply strictly with the agreement signed for the carrying out of my services within the 
scope of this protocol, especially with the provisions regarding confidentiality and 
intellectual property (results and publications). 
I have read this protocol in its entirety, including the above statement, and I agree to all aspects. 
PRINCIPAL INVESTIGATOR 
 
PRINTED NAME: 
 
SIGNATURE DATE 
 
 
SIGNATURE 
DATE 
GALDERMA R&D 
 
 
MEDICAL EXPERT 
PRINTED NAME: 
 
 
 


GALDERMA RESEARCH & DEVELOPMENT 
Protocol N° RD.03.SPR.113322  
version Final dated 10-FEB-2017 
Page 8 of 106 CONFIDENTIAL 
 
SPONSOR REPRESENTATIVE 
PRINTED NAME: 
 
 
 
RETURN THE ORIGINAL SIGNED COPY TO GALDERMA R&D AND KEEP A COPY AT YOUR SITE 


GALDERMA RESEARCH & DEVELOPMENT 
Protocol N° RD.03.SPR.113322  
version Final dated 10-FEB-2017 
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DISTRIBUTION 
Copy of the Protocol: 
All signatories and, 
 
, GALDERMA R&D   
 
, GALDERMA R&D 
  
, GALDERMA R&D 
  
, GALDERMA R&D 
   
, GALDERMA R&D 
  
, GALDERMA R&D 
  
, Galderma R&D 
  
, Galderma R&D 
 
 GALDERMA R&D  
 
 Product Development Coordination 
& Expertise Group GALDERMA R&D 
 
, Galderma R&D 
 
 GALDERMA International 
  
, GALDERMA R&D 
  
, GALDERMA International  
 
 Regulatory Affairs, Galderma Laboratories, L.P. 
USA 
 
 Prescription Business Unit, Galderma Laboratories, 


GALDERMA RESEARCH & DEVELOPMENT 
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L.P. USA 
 
, Galderma Laboratories, 
L.P. USA.  
 
 
, Regulatory, Medical & Technical Affairs, Galderma 
Canada 
 
, Galderma Germany 
 
Copy of the Synopsis: 
  
, GALDERMA International 
 
, GALDERMA 
International  
 
, GALDERMA International  
 
, GALDERMA Poland 
 
, GALDERMA Ceska & Slovenska 
Original Protocol: 
Archives (GALDERMA R&D Sophia Antipolis) 


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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................................................ 2 
CLINICAL TRIAL ADMINISTRATIVE STRUCTURE ............................................................................ 4 
SIGNATURE PAGE .................................................................................................................................... 7 
DISTRIBUTION ........................................................................................................................................... 9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS........................................................... 16 
1. 
SYNOPSIS ....................................................................................................................................... 20 
2. 
BACKGROUND AND RATIONALE ............................................................................................ 28 
2.1 
Medical background and rationale for the clinical trial ................................................. 28 
2.2 
Investigational product profile ............................................................................................. 31 
2.3 
Risk/Benefit assessment ....................................................................................................... 31 
3. 
CLINICAL TRIAL OBJECTIVES AND CLINICAL HYPOTHESIS ......................................... 31 
3.1 
Clinical trials objectives ......................................................................................................... 31 
3.2 
Clinical hypothesis .................................................................................................................. 31 
4. 
SELECTION AND DISPOSITION OF CLINICAL TRIAL POPULATION .............................. 32 
4.1 
Number of subjects ................................................................................................................. 32 
4.2 
Clinical trial population .......................................................................................................... 32 
 
Inclusion criteria ................................................................................................................. 32 
4.2.1
 
Exclusion criteria ................................................................................................................ 33 
4.2.2
4.3 
Prior and concomitant therapies ......................................................................................... 36 
 
Definition ............................................................................................................................... 36 
4.3.1
 
Categories ............................................................................................................................. 36 
4.3.2
 
Recording ............................................................................................................................. 36 
4.3.3
 
Authorised therapies during the clinical trial. ............................................................. 37 
4.3.4
 
Prohibited therapies during the clinical trial ............................................................... 37 
4.3.5


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4.4 
Procedures / reasons for discontinuation......................................................................... 38 
5. 
INVESTIGATIONAL PLAN ........................................................................................................... 40 
5.1 
Overall clinical trial design .................................................................................................... 40 
5.2 
Discussion of clinical trial design ....................................................................................... 40 
5.3 
Clinical trial duration and termination ................................................................................ 41 
5.4 
Clinical trial flow chart ............................................................................................................ 42 
5.5 
Clinical trial visit description and procedures ................................................................. 43 
 
Visit 1 – Screening/Baseline visit ................................................................................... 43 
5.5.1
 
Visit 2 and 3 – Week 4 and Week 8 ................................................................................. 45 
5.5.2
 
Visit 4- Week 12 / Last clinical trial visit ....................................................................... 46 
5.5.3
6. 
CLINICAL SUPPLIES .................................................................................................................... 48 
6.1 
Investigational product identification and use ................................................................ 48 
 
Product identity ................................................................................................................... 48 
6.1.1
 
Method of treatment assignment .................................................................................... 49 
6.1.2
 
Subject Identification Number (SIN) .............................................................................. 50 
6.1.3
 
Instructions for use and administration ....................................................................... 50 
6.1.4
6.2 
Other supplies .......................................................................................................................... 51 
6.3 
Investigational product packaging and labeling ............................................................. 52 
6.4 
Investigational product management ................................................................................. 52 
 
Accountability ...................................................................................................................... 53 
6.4.1
 
Dispensing ............................................................................................................................ 53 
6.4.2
 
Investigational product compliance management and record ............................... 54 
6.4.3
 
Storage of investigational product................................................................................. 54 
6.4.4
 
Return of investigational product................................................................................... 54 
6.4.5
6.5 
Blinding ...................................................................................................................................... 55 


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Verification of blinding ...................................................................................................... 55 
6.5.1
 
Unblinding during the clinical trial ................................................................................. 55 
6.5.2
7. 
EFFICACY AND SAFETY ASSESSMENT ................................................................................ 56 
7.1 
Efficacy assessments ............................................................................................................. 56 
 
Inflammatory Lesion Count .............................................................................................. 56 
7.1.1
 
Clinician’s Erythema Assessment (CEA) ..................................................................... 56 
7.1.2
 
Investigator’s Global Assessment (IGA) ...................................................................... 57 
7.1.3
 
Stinging/Burning sensation ............................................................................................. 57 
7.1.4
 
Ocular Signs and Symptoms ........................................................................................... 58 
7.1.5
 
Flushing ................................................................................................................................. 58 
7.1.6
 
Subject’s Global Improvement in Rosacea .................................................................. 60 
7.1.7
7.2 
Safety assessments ................................................................................................................ 61 
 
Adverse Events ................................................................................................................... 61 
7.2.1
7.3 
Patient related outcomes ....................................................................................................... 61 
 
Dermatology Life Quality Index (DLQI) questionnaire .............................................. 61 
7.3.1
 
EQ-5D-5L questionnaire .................................................................................................... 61 
7.3.2
 
Work Productivity and Activity Impairment Questionnaire: General 
7.3.3
Health Problem (WPAI:GH) modified for Rosacea. .................................................... 62 
 
Subject satisfaction questionnaire ................................................................................ 62 
7.3.4
7.4 
Other assessments ................................................................................................................. 62 
 
Photography ......................................................................................................................... 62 
7.4.1
 
Facial redness colorimetric measurements ................................................................ 62 
7.4.2
7.5 
Appropriateness of measurements .................................................................................... 63 
8. 
ADVERSE EVENT .......................................................................................................................... 64 
8.1 
Definitions .................................................................................................................................. 64 
 
Adverse Events (AE) .......................................................................................................... 64 
8.1.1


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Serious Adverse Events (SAE) ........................................................................................ 64 
8.1.2
 
Unexpected adverse drug reaction ................................................................................ 65 
8.1.3
 
Adverse event reporting period ...................................................................................... 65 
8.1.4
 
Severity .................................................................................................................................. 66 
8.1.5
 
Relationship to the study drug(s) and/or clinical trial procedure .......................... 66 
8.1.6
8.2 
Reporting procedures ............................................................................................................. 67 
 
Procedures for reporting adverse events .................................................................... 67 
8.2.1
 
Procedure for reporting a serious adverse event ...................................................... 68 
8.2.2
 
Procedure for suspected allergic contact reaction ................................................... 69 
8.2.3
8.3 
Procedures for reporting pregnancies ............................................................................... 72 
9. 
STATISTICAL METHODS PLANNED ........................................................................................ 74 
9.1 
Statistical and analytical plans ............................................................................................ 74 
 
Variables to be statistically analysed ............................................................................ 74 
9.1.1
 
Populations analysed, evaluability and limitations / evaluation of Bias .............. 75 
9.1.2
 
Data presentation and graphics ...................................................................................... 76 
9.1.3
 
Statistical analyses ............................................................................................................ 76 
9.1.4
9.2 
Sample size determination .................................................................................................... 77 
 
Historical data and assumptions .................................................................................... 77 
9.2.1
 
Sample size calculation .................................................................................................... 77 
9.2.2
10. 
TRAINING / MONITORING / DATA MANAGEMENT / QUALITY ASSURANCE ............... 78 
10.1 
Personnel training ................................................................................................................... 78 
10.2 
Clinical monitoring .................................................................................................................. 78 
10.3 
Data management .................................................................................................................... 78 
10.4 
Quality assurance / audit / inspection ................................................................................ 79 
11. 
ETHICS AND GENERAL CLINICAL TRIAL CONDUCT CONSIDERATIONS .................... 79 


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11.1 
Institutional review board (IRB) or ethics committee (EC) ........................................... 79 
11.2 
Ethical conduct of the clinical trial ...................................................................................... 80 
11.3 
Subject information sheet / informed consent ................................................................. 80 
11.4 
Contractual requirements ...................................................................................................... 80 
11.5 
Data collection and archiving ............................................................................................... 80 
 
Data Collection .................................................................................................................... 80 
11.5.1
 
Source documentation ...................................................................................................... 81 
11.5.2
 
Archives ................................................................................................................................ 81 
11.5.3
11.6 
Insurance ................................................................................................................................... 81 
12. 
REFERENCE LIST ......................................................................................................................... 82 
13. 
ATTACHMENTS ............................................................................................................................. 84 
13.1 
ATTACHMENT# 1 ..................................................................................................................... 84 
13.2 
ATTACHMENT# 2 ..................................................................................................................... 88 
13.3 
ATTACHMENT# 3 ..................................................................................................................... 92 
13.4 
ATTACHMENT# 4 ..................................................................................................................... 94 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
Adverse Event 
APT 
All Subjects Treated (Safety Population) 
CDMS 
Clinical Data Management System 
CEA 
Clinician’s Erythema Assessment 
CMH 
Cochran-Mantel-Haenszel 
CPM 
Clinical Project Manager 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
COPD  
Chronic Obstructive Pulmonary Disease 
CRO 
Contract Research Organization 
DLQI 
Dermatology Life Quality Index 
DMP 
Data Management Plan 
EC 
Ethics Committee 
EQ-5D 
EuroQol-5 Dimension-5 Level questionnaire 
FDA 
Food and Drug Administration 
FSI 
First Subject In (first subject who signs the Informed Consent Form) 
GCP 
Good Clinical Practice 


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Abbreviation 
Term 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
i.e. 
That is (Latin: id est) 
IGA 
Investigator’s Global Assessment 
IND 
Investigational New Drug 
IPL  
Intense Pulsed Light  
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intent-To-Treat 
IUD 
Intra Uterine Device 
IVM 
Ivermectin 
LOCF 
Last Observation Carried Forward 
LSI 
Last Subject In (Last subject randomized/assigned to treatment) 
LSO 
Last Subject Out (Last subject who completed last clinical trial visit) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Modified Release 


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Abbreviation 
Term 
NSAID 
Non-steroidal anti-inflammatory drug 
OTC 
Over-The-Counter 
PI 
Prescribing Information or Principal Investigator 
PIPEDA 
Personal Information Protection and Electronic Documents Act 
PRO 
Patient Reported Outctome 
PP 
Per Protocol 
QD 
Once Daily (Latin: quaque die) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis  System (SAS Institute Inc., Cary, NC) 
SD 
Standard Deviation 
SIN 
Subject Identification Number 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPF 
Sun Protection Factor 
SmPC 
Summary of Product Characteristics 
TOC 
Table of Contents 
UPT 
Urine Pregnancy Test 


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Abbreviation 
Term 
UV 
Ultraviolet 
WPAI:GH 
Work Productivity and Activity Impairment Questionnaire: General Health 


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1. 
SYNOPSIS 
Clinical trial title: 
Efficacy comparison of Ivermectin 1% topical cream associated with Doxycycline 40 mg Modified release (MR) capsules 
versus Ivermectin 1% topical cream associated with Placebo in the treatment of severe rosacea. 
 
Short title (± acronym): ANSWER study - oraceA soolaNtra aSsociation in patients With severE Rosacea 
 
Project number: 
838 
Clinical trial phase: 
IV for US 
IIIb For Canada and Europe 
Clinical trial period 
Planned  First Subject In: Q2 2017 
Planned Last Subject Out: Q1 2018 
 
 
 
 
Objective(s): 
The main objective of this study is to evaluate the efficacy of Ivermectin 1% 
topical cream associated with Doxycycline 40 mg Modified release (MR) capsules 
versus Ivermectin 1% topical cream associated with Placebo in the treatment of 
severe Rosacea. 
 
The Safety and Patient Reported Outcomes (PRO) will be also evaluated. 
 
Methodology: 
This is a multi-center, randomized, investigator-blind, controlled and 
parallel-group study in subjects with severe rosacea characterized by 
persistent diffuse facial erythema and inflammatory lesions (papules and 
pustules). 
Total number of planned subjects:  
A total of 270 subjects will be enrolled (i.e. 135 subjects in each group).  
Total number of planned sites: 
Approximately 50 sites  
Approximate number of 
subjects/site: 
Approximately 5 subject/site 
Country(ies) involved: 
USA, Canada and Europe (ie: Germany, Czech Republic, Hungary, and 
Poland). 


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Clinical trial title: 
Efficacy comparison of Ivermectin 1% topical cream associated with Doxycycline 40 mg Modified release (MR) capsules 
versus Ivermectin 1% topical cream associated with Placebo in the treatment of severe rosacea. 
 
Short title (± acronym): ANSWER study - oraceA soolaNtra aSsociation in patients With severE Rosacea 
 
Project number: 
838 
Clinical trial phase: 
IV for US 
IIIb For Canada and Europe 
Clinical trial period 
Planned  First Subject In: Q2 2017 
Planned Last Subject Out: Q1 2018 
 
 
 
 
Population and main inclusion 
criteria: 
Male or female subjects with severe rosacea, age of 18 years or older, with 
>20 to maximum 70 inflammatory lesions (papules and pustules) on the 
face & Investigator’s Global Assessment (IGA) score 4; meeting specific 
inclusion/exclusion criteria. 
Clinical trial duration per subject  
12 weeks 
Number of visits: 
Up to 5 visits for subjects at Screening/Baseline, Week 4, Week 8, and 
Week 12.   


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Clinical trial title: 
Efficacy comparison of Ivermectin 1% topical cream associated with Doxycycline 40 mg Modified release (MR) capsules 
versus Ivermectin 1% topical cream associated with Placebo in the treatment of severe rosacea. 
 
Short title (± acronym): ANSWER study - oraceA soolaNtra aSsociation in patients With severE Rosacea 
 
Project number: 
838 
Clinical trial phase: 
IV for US 
IIIb For Canada and Europe 
Clinical trial period 
Planned  First Subject In: Q2 2017 
Planned Last Subject Out: Q1 2018 
 
 
 
 
Investigational product: 
 
Ivermectin 1%  cream (Soolantra® 1% Cream  in the US, Soolantra® 10mg/g in 
Europe and Rosiver® 10mg/g in Canada) associated with Doxycycline 40 mg 
MR (30 mg Immediate Release & 10 mg Delayed Release beads) capsules 
(Oracea® in the US, Oraycea® /Efracea® in  Europe and Apprilon®in Canada) 
 
 
Ivermectin 1%  cream: Topical to the face, approximately one small pea 
size amount per facial region (right and left cheeks, forehead, chin, and 
nose) once a day 
 
Doxycycline 40 mg MR (30 mg Immediate Release & 10 mg Delayed 
Release beads): 1 Capsule once-daily 
 
 
12 weeks 
Name: 
 
 
 
 
Pharmaceutical form: 
Dose/concentration: 
Total daily dose: 
Mode and frequency of administration: 
Location of treated area: 
 
 
Duration of treatment: 


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Clinical trial title: 
Efficacy comparison of Ivermectin 1% topical cream associated with Doxycycline 40 mg Modified release (MR) capsules 
versus Ivermectin 1% topical cream associated with Placebo in the treatment of severe rosacea. 
 
Short title (± acronym): ANSWER study - oraceA soolaNtra aSsociation in patients With severE Rosacea 
 
Project number: 
838 
Clinical trial phase: 
IV for US 
IIIb For Canada and Europe 
Clinical trial period 
Planned  First Subject In: Q2 2017 
Planned Last Subject Out: Q1 2018 
 
 
 
 
Comparator product: 
Ivermectin 1%  cream (Soolantra® 1% Cream  in the US, Soolantra® 10mg/g in 
Europe and Rosiver® 10mg/g in Canada) associated with CD2475-101 
(Oracea®) oral placebo capsules. 
 
Ivermectin 1%  cream: Topical to the face, approximately one small pea 
size amount per facial region (right and left cheeks, forehead, chin, and 
nose) once a day 
 
 CD2475-101  (Oracea®)  placebo: 1 Capsule once-daily 
 
 
12 weeks 
Name: 
 
Pharmaceutical form: 
Strength/concentration: 
Total daily dose: 
Mode and frequency of administration: 
Location of treated area: 
 
Duration of treatment: 
Non-investigational product to be 
provided for the clinical trial: 
Gentle Skin Cleanser  
Facial Moisturizer SPF 30  
Urine Pregnancy Kits 


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Clinical trial title: 
Efficacy comparison of Ivermectin 1% topical cream associated with Doxycycline 40 mg Modified release (MR) capsules 
versus Ivermectin 1% topical cream associated with Placebo in the treatment of severe rosacea. 
 
Short title (± acronym): ANSWER study - oraceA soolaNtra aSsociation in patients With severE Rosacea 
 
Project number: 
838 
Clinical trial phase: 
IV for US 
IIIb For Canada and Europe 
Clinical trial period 
Planned  First Subject In: Q2 2017 
Planned Last Subject Out: Q1 2018 
 
 
 
 
Measurement criteria 
Efficacy 
 
Inflammatory lesion count by investigators at each visit 
 
Severity on the diffuse persistent facial erythema of rosacea based on 
Clinician’s Erythema Assessment (CEA) evaluated by investigators at 
each visit  
 
Severity of rosacea based on Investigator’s Global Assessment (IGA) 
evaluated by investigators at each visit 
 
Severity of stinging/burning sensation evaluated by subjects at each 
visit 
 
Global assessment of Ocular signs and symptoms, if present at 
baseline, evaluated by investigator at each visit  
 
Number of flushing per week evaluated by subject using diary 
throughout the study 
 
Severity of flushing evaluated by subject using diary throughout the 
study 
 
Global improvement in rosacea evaluated by subjects at the last visit 
 
Safety 
 
Adverse Events (AEs) throughout the study  
 
Others 
 
Dermatology Life Quality Index (DLQI) questionnaire at Baseline and 
the last visit  


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Clinical trial title: 
Efficacy comparison of Ivermectin 1% topical cream associated with Doxycycline 40 mg Modified release (MR) capsules 
versus Ivermectin 1% topical cream associated with Placebo in the treatment of severe rosacea. 
 
Short title (± acronym): ANSWER study - oraceA soolaNtra aSsociation in patients With severE Rosacea 
 
Project number: 
838 
Clinical trial phase: 
IV for US 
IIIb For Canada and Europe 
Clinical trial period 
Planned  First Subject In: Q2 2017 
Planned Last Subject Out: Q1 2018 
 
 
 
 
Analysed variables 
Primary efficacy variable  
 
Percent change from Baseline in Inflammatory Lesion count at Week 
12. 
 
Secondary efficacy variables 
 
Percent change from Baseline in Inflammatory Lesion count at each 
intermediate visit 
 
CEA at each post-Baseline visit: % of subjects across scores  
 
IGA at each post-Baseline visit: % of subjects across scores 
 
Stinging/burning at each post-Baseline visit: % of subjects across 
scores 
 
Percent change from Baseline (medical history) in terms of flushing 
count per week 
 
Change from Baseline (medical history) in mean score severity per 
week  
 
Global improvement in rosacea at the last visit: % of subjects across 
scores 
 
Exploratory efficacy variables 
 
Global assessment of Ocular signs and symptoms at each post-
Baseline visit: % of subjects across scores 
 
S f t
i bl


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Clinical trial title: 
Efficacy comparison of Ivermectin 1% topical cream associated with Doxycycline 40 mg Modified release (MR) capsules 
versus Ivermectin 1% topical cream associated with Placebo in the treatment of severe rosacea. 
 
Short title (± acronym): ANSWER study - oraceA soolaNtra aSsociation in patients With severE Rosacea 
 
Project number: 
838 
Clinical trial phase: 
IV for US 
IIIb For Canada and Europe 
Clinical trial period 
Planned  First Subject In: Q2 2017 
Planned Last Subject Out: Q1 2018 
 
 
 
 
Principal statistical methods and 
sample size calculation: 
Centers considered too small may be combined to create analysis-center. 
The Per Protocol (PP) population will consist of all enrolled and 
randomized subjects, except subjects who have major deviations from the 
protocol. The Intent-to-Treat (ITT) population will consist of the entire 
population enrolled and randomized. The last observation carried forward 
(LOCF) method will be used to impute missing values of lesion counts. 
Analysis population definitions and pooling of centers will be decided 
before the database lock and unblinding. 
 
The primary objective of this trial is to demonstrate the superiority of 
Ivermectin  associated with Doxycycline MR vs. Ivermectin associated with 
Placebo, in terms of % change from Baseline in Inflammatory Lesion count 
at Week 12. 
 
The primary efficacy criterion will be analyzed by using the Cochran-
Mantel-Haenszel (CMH) statistic, stratified by center (or analysis-center) 
after ridit transformation with the row mean difference statistics, testing the 
hypothesis of equality. The p-value will have to be inferior to 0.05 at Week 
12, on ITT/LOCF population.  PP analysis will be also performed to assess 
the robustness of the results obtained on ITT/LOCF population. 
 
The other variables will be analyzed similarly as primary analysis on 
appropriate population. Each test will be two-sided, at the 0.050 
significance level. 
 
The subject characteristics (previous medication, concomitant medication, 
demographics, baseline characteristics…), lesion counts and adverse 
events, will be summarized by descriptive statistics (usual statistics and 
frequency distribution)


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2. 
BACKGROUND AND RATIONALE 
2.1 
MEDICAL BACKGROUND AND RATIONALE FOR THE CLINICAL TRIAL 
Rosacea is a chronic inflammatory disease that affects around 10% of the population in 
Europe. Clinical characteristics include diagnostic features (persistent centrofacial erythema, 
phymatous changes); primary features (transient erythema or flushing, inflammatory 
papules/pustules, telangiectasia, ocular manifestations) and secondary features (burning 
sensation, stinging sensation, oedema, dry sensation) in various combinations1.1,1.2. Following 
the onset of the disease, patients with rosacea will experience cycles of relapse and 
remission of symptoms throughout their lives. Rosacea usually presents in the second or third 
decade of life, with prevalence of rosacea varying from less than 1% to more than 20%1.3,1.4. It 
is reported more frequently in fair-skinned people1.5,1.6,1.7.  Rosacea is known to have a 
negative impact on quality of life and is associated with depression and social isolation, 
hampering both social and professional lives. In a recent National Rosacea Society survey of 
1675 patients, 95% in patients with severe symptoms reported an adverse impact on their 
general outlook on life, highlighting that the emotional impact on patients appears to increase 
as symptoms become more severe1.8. 
 
Patients with inflammatory lesion of rosacea (papulo-pustular) show a chronic and recurrent 
course of their disease and it is usually accompanied by a persistent central facial erythema, 
potentially associated with telangiectasia. Eruptions usually occur on the center of the face 
with frequent involvement of the forehead and chin. The etiology of rosacea remains 
unknown, with both genetic and environmental factors potentially impacting pathogenesis. 
These etiological factors include enhanced vasomotor lability, immune system and 
sebaceous gland abnormalities, and greater susceptibility to heat and ultraviolet (UV) light 
exposure1.9. Patients with rosacea are reported to have an upregulated innate immune 
system, which can be triggered by various factors (including certain foods, UV exposure and 
temperature changes). This heightened immune response induces signaling cascades 
associated with inﬂammatory and vasoregulatory pathways. In addition, microorganisms such 
as the hair follicle mite Demodex folliculorum have been suggested to play a key role. 
Penetration of the mite into the dermis may stimulate a delayed hypersensitivity reaction and 
inflammation. Several published studies report abnormally high numbers of Demodex in 
subjects with papulo-pustular rosacea1.8.  
 


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In rosacea, the frequency of outbreaks varies with time, ranging from once or twice a year to 
continuous presence of symptoms. Management of the inflammatory lesions and the 
associated erythema warrants adherence with continued therapy1.10. Treatment options for 
rosacea with inflammatory lesions include various topical therapies such as ivermectin, 
metronidazole, azelaic acid, and sodium sulfacetamide-sulfur1.11,1.12. Systemic treatment with 
sub- antimicrobial dose formulation of doxycycline (referred to as doxycycline 40 mg modified 
release)  incorporating 30-mg immediate-release and 10-mg delayed-release beads 
administered once daily; first FDA-approved (2006) as oral treatment for rosacea with 
papulopustular lesions. Doxycycline 40 mg modified-release (Oracea®) has shown to 
decrease both gene expression and protein levels of MMPs, KLK, and cathelicidin, which 
resulted in a reduction in inflammatory lesion counts. By inhibiting the production and activity 
of MMPs, doxycycline 40 mg modified-release blocks multiple inflammatory pathways, which 
inhibits the production of proteins contributing to the pathophysiology of inflammation and 
thus exhibits anti-inflammatory properties while not exhibiting any antibiotic effect in rosacea 
patients1.10. 
 
Ivermectin is a macrocyclic lactone derivative with dual anti-inflammatory and anti-parasitic 
properties. Approved for the treatment of onchocerciasis, strongyloidiasis and scabies in 
humans by oral route, and in lotion foam for topical head lice treatment. Oral ivermectin has 
been demonstrated to be effective as an anti-parasitic agent in reducing the number of 
Demodex mites in demodicidosis and in blepharitis. Ivermectin (IVM) has also been shown to 
exert anti-inflammatory effects by inhibiting lipopolysaccharide-induced production of 
inflammatory cytokines, including tumor necrosis factor- alpha (TNF-α) and interleukin (IL)-1β, 
while increasing the anti-inflammatory cytokine IL-10. Ivermectin is able to suppress 
production of the inflammatory mediators and modulation of NO, iNOS, COX-2, and PGE-2 
release which are major contributing factors during the inflammatory process. It’s therapeutic 
effect as a topical cream in rosacea is assumed to be due to both, its anti-inflammatory and 
anti-demodex properties1.10. 
 


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The approval of Ivermectin 1% cream (FDA, 2015) for the treatment of the inflammatory 
lesions of rosacea was based upon two identically-designed large vehicle-controlled Phase 3 
randomized trials that demonstrated efficacy and safety in adults with moderate to severe 
papulopustular rosacea on a 12-week treatment period. In both studies, a greater proportion 
of subjects in the IVM 1% group achieved treatment success. Ivermectin was superior to 
vehicle in terms of reduction from baseline in inflammatory lesion counts (76% and 75% 
versus 50% for both vehicle groups, respectively)1.13. For Doxycycline the two placebo-
controlled pivotal phase 3 trials evaluated the efficacy and safety of doxycycline 40 mg 
modified release (MR) once daily versus placebo in participants with moderate to severe 
rosacea. These participants had 10 to 40 papules and pustules and moderate to severe 
erythema and telangiectasia. Both studies showed marked reductions in the number of 
inflammatory lesions compared with placebo. Treatment with doxycycline 40 mg MR 
significantly reduced the number of lesions from the first follow-up assessment at 3 weeks 
throughout the entire 16-week study compared with placebo (P≤ 0.005). Study by Sanchez et 
al.1.14 using doxycycline with metronidazole versus metronidazole alone did demonstrate in 
moderate to severe rosacea that adjunctive use of sub-antimicrobial dose doxycycline 
significantly reduced the clinical signs of rosacea compared with metronidazole alone1.6. 
Based on the complementary mechanism of action of doxycycline MR and ivermectin1.10, a 
scientific rationale to assess the combined therapy targeting inflammatory lesions in severe 
rosacea is planned. Topical ivermectin cream is a promising first-line treatment to target the 
inflammatory lesions of rosacea, which can be used in combination with systemic doxycycline 
modified-release as per the recent Canadian Rosacea guideline1.15 to provide an optimal 
treatment approach considering all inflammatory pathways involved in rosacea with 
inflammatory lesions. 
 
Unlike clinical studies evaluating monotherapy approaches, clinicians often use a combination 
of topical and oral therapy for patients with severe rosacea, as an increased or additive 
benefit has been suggested with combination regimens. Topical ivermectin cream 1% and 
oral anti-inflammatory doxycycline (40 mg MR, modified-release) are both approved for the 
treatment of rosacea with inflammatory papules and pustules. Associating those two 
products, each having demonstrated a good safety profile and efficacy on rosacea features, 
should lead to optimized clinical outcomes in a complex disease that has been proven difficult 
to manage comprehensively and would reflect a controlled study of that which is already 
prescribed in clinical practice1.15. In an attempt to further optimize comprehensive 
management of severe rosacea, this study aims to investigate the efficacy, patient 
satisfaction and safety of the association of topical Ivermectin 1% cream and oral Doxycycline 
MR 40mg once a day treatment. 
 
 


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2.2 
INVESTIGATIONAL PRODUCT PROFILE 
The products used in this clinical trial are Ivermectin 1% cream and Doxycycline MR 40 mg 
capsules. Both are approved for rosacea treatment and are well tolerated. See respective 
product information (PI-SmPC) for detailed efficacy and safety information. 
2.3 
RISK/BENEFIT ASSESSMENT 
Rosacea is a chronic, non-life-threatening skin disease characterized by two major features 
which are a persistent central facial erythema and recurrent eruptions of inflammatory lesions 
(i.e., papules, pustules, or both).  
The two investigational products are marketed individually for rosacea treatment and with proven 
efficacy and good safety profile including severe rosacea population. 
Whatever the randomization arm, all study subjects will benefit from an efficient and safe 
rosacea treatment. 
The association of investigational products is not expected to raise new tolerability issues and 
has the potential to reach to better and possibly faster efficacy outcome. 
 
3. 
CLINICAL TRIAL OBJECTIVES AND CLINICAL HYPOTHESIS 
3.1 
CLINICAL TRIALS OBJECTIVES 
The main objective of this study is to evaluate the efficacy of Ivermectin 1% topical cream 
associated with Doxycycline 40 mg capsules MR compared with Ivermectin 1% topical cream 
monotherapy in the treatment of severe rosacea with papulopustular lesions. 
The Safety and Patient Reported Outcomes (PRO) will be also evaluated. 
3.2 
CLINICAL HYPOTHESIS 
Associating IVM 1% cream and oral Doxycycline 40 mg MR in a comprehensive approach to 
address the severe inflammatory lesions of rosacea and should lead to an optimized clinical 
outcome.  Both drugs have only been evaluated individually so far, but never as an association.  
This study aims to assess both treatment evaluations on rosacea symptoms and will allow for 
the evaluation of the potential benefit of such treatment association on cumulative efficacy, time 
to onset of action with 2 products in rosacea, safety, and patient satisfaction needed in severe 
condition of rosacea. 


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4. 
SELECTION AND DISPOSITION OF CLINICAL TRIAL POPULATION 
4.1 
NUMBER OF SUBJECTS 
A total of 270 subjects will be enrolled (i.e. 135 subjects in each group) at approximately 50 sites 
located in the USA, Canada and Europe (Germany, Czech Republic, Hungary, and Poland). 
4.2 
CLINICAL TRIAL POPULATION  
Subjects who meet all of the following criteria will be eligible for the clinical trial. Some criteria 
are to be checked at screening visit and/or at baseline visit, as specified by the trial design. 
 
Inclusion criteria 
4.2.1
In order to be eligible for the clinical trial, the subject must meet all of the following inclusion 
criteria:  
1. 
Male or female subject age ≥ 18 years or older; 
2. 
Subject with a minimum of 20 but not more than 70 inflammatory lesions (papules and 
pustules) of rosacea on the face at Baseline visit; 
3. 
Subject with severe rosacea with papulopustular lesions (according to the Investigator’s 
Global Assessment, IGA score rated 4);  
4. 
Female Subject of childbearing potential must have a negative urinary pregnancy test 
(UPT) at baseline visit (UPT should have a sensitivity of 25 IU/L or less). They must agree 
to use/continue a highly effective and approved contraceptive method(s) for the duration of 
the study and at least 4 weeks after the last study drug(s) use. A highly effective method of 
contraception being defined as: 
 
bilateral tubal ligation; 
 
combined   oral   contraceptives   (estrogens   and   progesterone)   or implanted or 
injectable contraceptives with a stable dose for at least 1 month prior to Baseline 
visit; 
 
hormonal intra-uterine  device (IUD)  inserted at least 1 month prior to Baseline 
visit; 
 
vasectomized partner for at least 3 months prior to Baseline 
OR  


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5. 
Is of non-childbearing potential, defined as post-menopausal (absence of menstrual 
bleeding for one year prior to clinical trial entry without any other medical reasons), 
hysterectomy or bilateral oophorectomy prior to clinical trial entry. 
6. 
Willing and able to comply with all of the time commitments and procedural requirements 
of the clinical trial protocol. In particular, subject must adhere to the visit schedule, 
concomitant therapy prohibitions, and must be compliant with the treatment at study visits. 
7. 
Understand and sign an Informed Consent Form (ICF) and photo consent (when 
appropriate) at screening, prior to any investigational procedures being performed.  
8. 
Apprised of the Health Insurance Portability and Accountability Act (HIPAA), if in the US, or 
the Personal Information Protection and Electronic Documents Act (PIPEDA) if in Canada 
[or the equivalent in other regions] and is willing to share personal information and data, as 
verified by signing a written authorization at the screening/baseline. 
 
 
Exclusion criteria 
4.2.2
Any subject who meets one or more of the following exclusion criteria will not be included in this 
clinical trial.  
1. 
Subject with particular forms of rosacea (rosacea conglobata, rosacea fulminans, isolated 
pustulosis of the chin, isolated rhinophyma) or other facial dermatoses that may be 
confounded with papulopustular rosacea, such as perioral dermatitis, facial keratosis 
pilaris, acute lupus erythematosus, actinic telangiectasia or seborrheic dermatitis and acne 
vulgaris 
2. 
Subject with more than 2 nodules of rosacea (a circumscribed, elevated, solid lesion more 
than 1.0cm in diameter with palpable depth) on the face 
3. 
Subject with known allergies or sensitivities to any components of the formulation of the 
study drugs being tested (either Ivermectin 1% cream or Doxycycline, see package 
inserts) 
4. 
Female who is lactating. 
5. 
Female who intends to conceive a child during the clinical trial during the study period and 
for at least 4 weeks after the last study drug(s) use. 
6. 
Currently participating in any other clinical trial of a drug or device OR participated within 
30 days prior to baseline OR is in an exclusion period (if verifiable) from a previous clinical 
trial. 
7. 
The subject has received, applied or taken the following treatments within the specified 
time frame prior to the Screening/Baseline visit: 


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Topical facial treatments or procedures on the face: 
Astringents or abrasives (scrubs, exfoliating cleansers and products containing 
salicylic acid or alcohol) 
2 days 
Antibiotics (e.g. metronidazole or macrolides) 
4 weeks 
Benzoyl Peroxide 
4 weeks 
Anti-rosacea drugs (e.g. azelaic acid, brimonidine, oxymetazoline) 
4 weeks 
Immunomodulators 
4 weeks 
Corticosteroids 
4 weeks 
Retinoids 
4 weeks 
Any procedure on the face (e.g. laser, intense pulsed light-IPL, facial peel, 
dermabrasion, electrocoagulation, Thermage®) 
6 weeks 
Systemic treatments: 
Antibiotics (e.g. cyclines, macrolides, metronidazole) 
4 weeks 
Corticosteroids  
4 weeks 
Immunomodulators 
4 weeks 
Oral Ivermectin 
4 weeks 


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Other drugs used for the treatment of acne or rosacea (eg: spironolactone) 
4 weeks 
Oral retinoids 
12 weeks 
Anticoagulants of the dicoumarol type 
4 weeks 
Sulphonylurea oral antidiabetic agents 
1 week 
Other treatments: 
Inhaled Corticosteroids (for asthma or chronic obstructive pulmonary disease -
COPD) 
4 weeks 
Oxymetazoline (any route; e.g. eye drops, nasal sprays…) or vasodilators 
4 weeks 
8. 
The subject is unwilling to refrain from use of prohibited medication during the clinical trial 
(see section 4.3.5) 
9. 
Subject who is vulnerable as defined in Section 1.61 of the International Conference on 
Harmonisation (ICH) Guideline for Good Clinical Practice (GCP); eg: adult subject under 
guardianship, hospitalized subject in a public or private institution for a reason other than 
the research, and subject deprived of his/her freedom 
10. 
The subject has history of alcohol or drug abuse (positive urine drug screen and/or alcohol 
test) within the previous 12 months. 
11. 
The subject is a study site staff member (investigator, study nurse, etc.) or a relative of 
one. 
12. 
The initiation of a hormonal method of contraception within 1 month of baseline, or 
discontinuation during the course of study, or change in the actual product within 1 month 
of baseline or planned during the study 
13. 
Subject with clinically significant abnormal laboratory finding at the screening/baseline visit 
or an underlying known disease, a surgical or medical condition, which in the judgment of 
the Investigator, would put the subjects at risk (e.g., uncontrolled chronic or serious 
diseases which would normally prevent  participation in any clinical study, such as cancer, 
leukemia or hematologic dyscrasia), or might confound the study assessments (e.g. other 
dermatological diseases), or might interfere with the subject’s study participation (e.g. 
planned hospitalization during the study) 
14. 
Subject who is at risk in terms of precautions, warnings, and contra-indication (see 
package insert) 


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15. 
Subject with hairs on the treated area that might interfere with study assessments 
16. 
Subject exposed to excessive UV radiation within two weeks prior to the Baseline visit, or 
subjects planning exposure during the study (e.g. phototherapy, occupational exposure to 
the sun, planned holidays with excessive sun during the study period, tanning salon) 
 
4.3 
PRIOR AND CONCOMITANT THERAPIES 
 
Definition 
4.3.1
Previous therapies (drugs and/or procedures) are defined as therapies that have been stopped 
within 6 months prior to the first investigational product application/intake.  
An exception will be made on the last rosacea treatment taken, where no limit on period of time 
will be applied upon data collection. 
 
Concomitant therapies are defined as follows: 
 any existing therapies ongoing at the time of the screening/baseline visit , or 
 any changes to existing therapies (such as changes in dose or formulation) during the 
course of the clinical trial, or 
 any new therapies received by the subject since the screening/baseline visit 
 
Categories 
4.3.2
The following two categories will be considered for previous and concomitant therapies:  
 Drugs/therapies including, but not limited to, prescription, over-the-counter (OTC), birth 
control pills/patches/hormonal devices, vitamins, moisturizers, sunscreens, herbal 
medicines/supplements, and homeopathic preparations. 
 Medical and surgical procedures including, but not limited to, laser/radiation procedures, 
dermal fillers, X-rays, etc. 
 
 
Recording 
4.3.3
Previous and concomitant therapies will be recorded on the Drugs/Therapies Form (for 
drugs/therapies) and/or on the Medical and Surgical Procedures form (for medical/surgical 
procedures) in the case report form (CRF). 
Concomitant therapies will be recorded, reviewed, and updated at each trial visit. 


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Any new concomitant therapy or modification of an existing therapy may be linked to an adverse 
event (AE). A corresponding Adverse Event Form must be completed to account for the change 
in therapy, except in some cases such as therapy used for prophylaxis, dose modification for a 
chronic condition, etc. 
 
Authorised therapies during the clinical trial. 
4.3.4
Unless listed in the exclusion criteria above or in the prohibited therapies (see sections 4.2.2 and 
4.3.5), all therapies are authorized. 
Subjects must use the study-provided cleanser, moisturizer/sunscreen for skin care as described 
in section 6.2. 
Subjects may use cosmetics and make-up if they are applied after study drug application. 
Subjects may not use foundation make-up or study provided moisturizer/sunscreen on the days 
of the visits. 
 
Prohibited therapies during the clinical trial  
4.3.5
The following therapies are prohibited because they may interfere with the efficacy and/or safety 
assessment of the investigational products, or because they may interact with the metabolism of 
the investigational products: 
 All topical or systemic therapies listed as exclusion criteria (section 4.2.2) 
 Chronic use (>14 days) of  sulpha drugs, erythromycin, cephalosporin, and quinolones 
 Use of systemic tetracycline antibiotics or tetracycline-like (doxycycline) antibiotics in 
conjunction with penicillin (drug interactions with bacteriostatic and bactericidal effects). 
 Use of Rifampicin, barbiturates, carbamazepine, diphenylhydantoin, primidone, phenytoin 
(hepatic enzyme inducers which will thereby decrease doxycycline’s half-life) and 
cyclosporine. 
 The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal 
renal toxicity   
 For ocular rosacea if new therapy required like topical ophthalmic treatments (including 
antibiotics eye drops or steroids); but can continue if stable over the past 2 weeks and 
planned to be maintained during the study (authorised to use lubricating ointments, artificial 
tears, eyelid care during the study). 
 Chronic use (>14 consecutive days) of NSAIDs, except chronic use of aspirin at sub-
analgesic dose (≤ 325mg QD) is permitted for patients requiring platelet aggregation inhibitors 
(dose modifications on PI discretion, refer SmPC) 


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 Use of protein pump inhibitors 
 Any other drugs/procedures which at the investigator’s judgement are liable to interfere or 
interact with the efficacy and the safety of investigational products. 
Antacids and vitamins containing aluminum, calcium, or magnesium are allowed only if are taken 
at least 1.5 hours before or 3 hours after the intake of study medication. A shorter interval is 
prohibited because these agents might impair drug absorption. 
If prohibited therapies become a necessary treatment for the safety or best interest of the 
subject, GALDERMA R&D will be notified to discuss possible alternatives prior to administration 
of a prohibited therapy and to discuss the pertinence and the modalities for the subject to 
continue in the clinical trial. 
4.4 
PROCEDURES / REASONS FOR DISCONTINUATION 
An Investigator may decide to discontinue a subject from the clinical trial for safety reasons. 
Although the importance of completing the entire clinical trial should be explained to the subject 
by the clinical trial personnel, any subject is free to discontinue his/her participation in this clinical 
trial at any time and for whatever reason, specified or unspecified, and without prejudice.  
Subjects who discontinue the clinical trial prematurely should be fully evaluated, whenever 
possible.  
The procedures designated for the early termination visit will be completed for all premature 
discontinuation subjects. The appropriate eCRF pages for the next scheduled visit should be 
completed. 
For all subjects who prematurely discontinue the clinical trial, the reason must be carefully 
documented by the investigator on the Exit Form, and, if applicable, on the Adverse Event Form 
for discontinuation due to an AE.  
A subject who has been randomized and assigned a kit number cannot be replaced by another 
subject if he/she discontinues the clinical trial for any reason. 
In the case of early termination, the investigator should ensure that the subject receives 
appropriate therapy for his/her condition. 
GALDERMA R&D may also decide to prematurely terminate or suspend the clinical trial or the 
participation of a subject in the clinical trial. 
All data gathered on the subject prior to termination will be made available to GALDERMA R&D. 


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Reasons for clinical trial completion/discontinuation, as listed on the Exit Form of the CRF are 
described below: 
Normal Study Completion 
Subject completes the clinical trial as planned in protocol. 
Pregnancy 
Withdraw the subject from the clinical trial following the procedure described in the 
protocol section 8.3 
Adverse Event 
Complete CRF Adverse Event Form. 
Withdrawal by subject  
Includes consent withdrawal, subject relocation, schedule conflicts, etc… Does not 
include AE. . Explain the reason for withdrawal in the comments section of the CRF 
Exit Form. 
Protocol Violation 
Explain the violation in the comments section of the CRF Exit Form 
Lost to Follow-up 
Confirm with 2 documented phone calls and a certified letter (delivery receipt 
requested) without response. Explain in the comments section of the CRF Exit Form. 
Other 
This category is to be used for a subject who discontinues for a reason other than 
those specified in the predefined categories above. Explain the reason for 
discontinuation in the comments section of CRF Exit Form. 
If reason for discontinuation is “subject request” or “other”, the subject must be questioned to 
rule out the possibility of an AE; this should be documented in the CRF. 
 
 


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5. 
INVESTIGATIONAL PLAN 
5.1 
OVERALL CLINICAL TRIAL DESIGN 
This clinical trial will be conducted as a multi-center, randomized, investigator-blind, controlled 
and parallel-group study in subjects with severe rosacea characterized by persistent diffuse 
facial erythema and inflammatory lesions (papules and pustules), and meeting other specific 
eligibility criteria. 
A total of 270 subjects will be enrolled (ie: 135 in each group) in approximately 50 sites in the 
USA, Canada and Europe. Approximately 5 subjects are planned from each site. 
Subjects will be enrolled at baseline and treated for 12 weeks with either Ivermectin 1% cream 
associated with Doxycycline 40 mg MR (CD2475-101)  capsules or Ivermectin 1% cream 
associated with CD2475-101 placebo capsules. 
There will be two parallel groups, randomized in a ratio of [1:1].  
There will be up to 5 trial visits: at baseline, Screening/Baseline, Week 4 (±3 days), Week 8 (±3 
days), and Week 12 (±5 days). 
5.2 
DISCUSSION OF CLINICAL TRIAL DESIGN 
IVM 1% cream and oral Doxycycline 40 mg MR have been individually approved for rosacea 
treatment in US, Canada and Europe, with demonstrated efficacy and good safety profile 
including in severe rosacea population. 
They will be used in this trial in their indication and approved dose and regimen. 
Unlike clinical studies evaluating monotherapy approaches, clinicians often use a combination of 
topical and oral therapy for patients with severe rosacea, as an increased or additive benefit has 
been suggested with combination regimens.  
Topical Ivermectin cream (10 mg/g) and systemic, oral Doxycycline 40 mg MR (modified-
release) have only been evaluated individually so far, but never as an association. The 
combined therapeutic approach of both drugs association may be more beneficial, but has never 
been assessed for rosacea treatment in a randomized clinical trial.  
To ensure an appropriate evaluation of this association benefit, it will be compared to Ivermectin 
1% topical cream alone associated to the placebo of Doxycycline 40 mg MR (CD2475-101).   
This clinical trial will compare the efficacy and safety of Ivermectin 1% topical cream associated 
with Doxycycline 40 mg Modified release (MR) capsules compared to Ivermectin 1% topical 
cream associated with Placebo in the treatment of severe Rosacea. 


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5.3 
CLINICAL TRIAL DURATION AND TERMINATION 
The average planned period for the clinical trial from First Subject In (FSI) to Last Subject Out 
(LSO)] is approximately 9 months. The end date of the clinical trial will be the date of the last 
visit of the last subject who participates in the clinical trial. 
The planned duration of recruitment (i.e. From FSI to Last Subject In (LSI)) is approximately 6 
months. 
The clinical trial may be terminated by the investigator at his/her clinical trial site at any time with 
appropriate notification to GALDERMA R&D. Likewise, GALDERMA R&D may terminate the 
clinical trial and/or the participation of the clinical trial site(s) with appropriate notification.  
The expected duration of subject participation is 12 weeks. 
 
 


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5.4 
CLINICAL TRIAL FLOW CHART 
PROCEDURES 
STUDY VISITS 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Screening/
Baseline 
Week 4 
(±3 d) 
Week 8 
(±3 d) 
Week 12 
 (±5 d) 
Informed Consent/Photography Consent 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
Demographics/Medical History (including 
flushing and co-morbidities) / Previous 
Therapies (including rosacea last treatment) 
X 
 
 
 
Concomitant Therapies 
X 
X 
X 
X 
Urine Pregnancy Test (UPT)a 
X 
 
 
X 
Inflammatory (Papules and Pustules) 
Lesion Counts 
X 
X 
X 
X 
Clinician Erythema Assessment (CEA) 
X 
X 
X 
X 
Investigator’s Global Assessment (IGA)  
X 
X 
X 
X 
Severity of Stinging/Burning sensation 
X 
X 
X 
X 
Global assessment of Ocular signs and 
symptoms 
X 
X 
X 
X 
Flushing via diary (frequency and 
severity) 
X 
X 
X 
X 
Subject’s Global Improvement in 
Rosacea 
 
 
 
Xd 
Standardized Facial photography / facial 
redness colorimetric measurements b   
X 
X 
X 
X 
Adverse Event (AE)c 
X 
X 
X 
X 
DLQI Questionnaire 
X 
 
 
Xd 


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EQ-5D-5L Questionnaire 
X 
 
 
Xd 
WPAI: GH questionnaire 
X 
 
 
Xd 
Subject Satisfaction Questionnaire 
 
 
 
Xd 
Dispensation of Investigational Products, 
Subject Diary and Other Supplies 
X 
X 
X 
 
Return of Investigational Products and 
Subject Diary 
 
X 
X 
X 
Exit form 
 
 
 
Xd 
a. For subjects of childbearing potential only. UPT is mandatory at Screening/Baseline and at last visit (Week 12 or before if early 
termination). 
b. Photography consent and standardized photography + facial redness colorimetric measurements at selected centers only. 
c. AEs are to be collected starting from the signing of the Informed Consent Form. 
d. Assessments to be performed in case of early termination visit. 
 
 
 
 
5.5 
CLINICAL TRIAL VISIT DESCRIPTION AND PROCEDURES 
 
Visit 1 – Screening/Baseline visit 
5.5.1
1. 
Explain the nature and the constraints of the clinical trial to the subject and to parent.  
2. 
Have the subject read, understand, date and sign an approved informed consent form 
(ICF). Give a dated and signed copy to each subject and parent/guardian if applicable.  
3. 
If subject female of childbearing potential agrees to participate to the clinical trial, make 
sure she is using the required method(s) of contraception (see inclusion criteria 4.2.1). 
Make sure that the urine pregnancy test is done and the result is negative before subject 
inclusion in the trial 
4. 
Log into the electronic case report form (eCRF) to get a Subject Identification Number. 
5. 
Question the subject about demography, medical history (including flushing and rosacea 
co-morbidities), prior and concomitant therapies (including rosacea last treatment). 


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6. 
Inform the subject about authorized and prohibited concomitant therapies. If the subject 
requires a medication washout period, the subject’s baseline evaluation must be 
conducted after the washout period has been completed. 
7. 
Check inclusion/exclusion criteria (see sections 4.2.1 and 4.2.2). 
8. 
Conduct facial inflammatory lesion count (see section 7.1.1). 
9. 
Assess and record the severity of the diffused facial erythema of rosacea using CEA (see 
section 7.1.2). 
10. 
Perform and record Investigator’s Global Assessment (IGA) (see section 7.1.3). 
11. 
Evaluate and record the severity of subject’s facial stinging/burning sensation (see section 
7.1.4). 
12. 
Assess and record the severity of the Ocular signs and symptoms (see section 7.1.5). 
13. 
Record in medical history the frequency of flushing (average per week) and the severity as 
reported by subject for the last week before baseline visit (see section 7.1.6). 
14. 
Ask subject to complete the Dermatology Life Quality Index (DLQI) questionnaire (see 
13.1) and review for completion; 
15. 
Ask subject to complete the EQ-5D-5L questionnaire (see 13.2) and review for completion; 
16. 
Ask subject to complete the WPAI:GH questionnaire (see 13.3) and review for completion; 
 
17. 
For selected sites only, take photographs of the face according to the provided 
photographic procedure, only if subject has agreed on the approved ICF. 
18. 
For selected sites only, perform facial redness colorimetric measurements. 
19. 
Record the occurrence of any new adverse events and/or any changes to adverse events. 
20. 
If subject is eligible according to the inclusion/exclusion criteria, the smallest subject kit 
number available must be assigned to the subject by the investigator; 
21. 
Fill in a prescription form, dispense the subject card, including the SIN, kit number and ask 
the subject to go see the person in charge of study medication, as relevant (hereafter 
referred to as investigational product dispenser). 
22. 
The person in charge of investigational product dispensation described here  as the 
investigational product dispenser will: 
a) 
Dispense to the subject the baseline investigational products from the subject kit 
according to the prescription form. 
b) 
Affix the tear-off portion of the label on the product dispensation log and report the 
required information on the labels if applicable. 


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c) 
Dispense to the subject associated non-investigational products  
d) 
Dispense the Subject diary. 
e) 
Provide appropriate verbal and written instructions on how to properly use the 
investigational products and how to keep a record of missed doses. The first dose of 
topical investigational products will be applied/taken by the subject under the 
direction of site personnel before leaving the investigational site. 
f) 
Emphasize the importance of complying with the given instructions and treatments; 
instruct the subject to bring back the dispensed investigational product(s) together 
with the subject diary at the next visit. 
23. 
For all female subjects, emphasize the guidelines about contraception and risks in case of 
pregnancy  
24. 
Schedule the next three visits [Week 4 (± 3 days), Week 8 (± 3 days) and Week 12 (± 5 
days)]. 
 
Visit 2 and 3 – Week 4 and Week 8 
5.5.2
1. 
Question the subject and record the occurrence of any new adverse events and/or any 
changes to adverse events that were ongoing at the previous clinical trial visit. Document 
all changes in the CRF. 
2. 
Enquire whether any concomitant therapies have been added, stopped, or changed since 
the subject’s last visit. Document all changes in the CRF. 
3. 
Conduct facial inflammatory lesion count (see section 7.1.1). 
4. 
Assess and record the severity of the diffused facial erythema of rosacea using CEA (see 
section 7.1.2). 
5. 
Perform and record Investigator’s Global Assessment (IGA) (see section 7.1.3). 
6. 
Evaluate and record the severity of subject’s facial stinging/burning sensation (see section 
7.1.4). 
7. 
Assess and record the severity of the Ocular signs and symptoms (see section 7.1.5). 
8. 
Check subject’s diary and record the frequency and severity of flushing for each week as 
reported by subject in the diary (see section 7.1.6). 
9. 
Take photographs of the face according to provided photographic procedure (for selected 
sites only).  
10. 
For selected sites only, perform facial redness colorimetric measurements. 
11. 
Fill in a prescription form and ask the subject to go see the Investigational product 
dispenser, as relevant. 


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12. 
Investigational product dispenser will: 
a) 
Check the investigational products; review the subject’s diary for completion and 
accuracy interview the subject about compliance. All missing tubes must be 
documented on the eCRF comments section and on other accountability forms. 
b) 
Record the investigational products and Facial Moisturizer compliance on the eCRF. 
c) 
Dispense to the subject the investigational products from the subject kit according to 
the prescription form. 
d) 
Affix the tear-off portion of the label on the product dispensation log and report the 
required information on the labels if applicable. 
e) Dispense to the subject associated non-investigational products (if necessary) and give back 
the subject diary. 
f) 
Provide appropriate verbal and written instructions on how to properly use the 
investigational products and how to keep a record of missed dose(s).  
g) 
Emphasize the importance of complying with the given instructions and treatments; 
instruct the subject to bring back the dispensed investigational product(s) together 
with the subject diary at the next visit. 
13. 
Check and confirm for next follow-up visit schedule until Final visit 4 - Week 12 (± 5 days). 
In case of early termination of the Clinical Trial for whatever reason: 
a) The subject will be fully evaluated 
b) The procedures designated for the last clinical trial visit should be performed 
 
 Visit 4- Week 12 / Last clinical trial visit  
5.5.3
1. 
Question the subject and record the occurrence of any new adverse events and/or any 
changes to adverse events that were ongoing at the previous clinical trial visit. Document 
all changes in the CRF. 
2. 
Enquire whether any concomitant therapies have been added, stopped, or changed since 
the subject’s last visit. Document all changes in the CRF. 
3. 
Conduct facial inflammatory lesion count (see section 7.1.1). 
4. 
Assess and record the severity of the diffused facial erythema of rosacea using CEA (see 
section 7.1.2). 
5. 
Perform and record Investigator’s Global Assessment (IGA) (see section 7.1.3). 


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6. 
Evaluate and record the severity of subject’s facial stinging/burning sensation (see section 
7.1.4). 
7. 
Assess and record the severity of the Ocular signs and symptoms (see section 7.1.5). 
8. 
Check subject’s diary and record the frequency of flushing for each week as reported by 
subject in the diary (see section 7.1.6). 
9. 
Ask the subject to assess her/his Global Improvement in Rosacea (see section 7.1.7) and 
record the outcome; 
10. 
Ask subject to complete the Dermatology Life Quality Index (DLQI) questionnaire (see 
13.1) and review for completion; 
11. 
Ask subject to complete the EQ-5D-5L questionnaire (see 13.2) and review for completion; 
12. 
Ask subject to complete the WPAI:GH questionnaire (see 13.3) and review for completion; 
13. 
Ask subject to complete the Subject Satisfaction questionnaire (see 13.4) and review for 
completion; 
14. 
Perform a urine pregnancy test (UPT) for female subjects of childbearing potential. 
15. 
For selected sites only, take photographs of the face according to the provided 
photographic procedure, only if subject has agreed on the approved ICF. 
16. 
For selected sites only, perform facial redness colorimetric measurements. 
17. 
Complete the Exit form in the CRF and give the reason for clinical trial discontinuation. 
18. 
 Investigational product dispenser will: 
a) 
Check the investigational products; review the subject’s diary for completion and 
accuracy interview the subject about compliance. All missing tubes must be 
documented on the eCRF comments section and on other accountability forms. 
b) 
Record the investigational products and Facial Moisturizer compliance on the eCRF. 
 
 


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6. 
CLINICAL SUPPLIES 
Investigational products and supplies will be provided by the sponsor and shipped by the clinical 
supply unit or local depot.  
6.1 
INVESTIGATIONAL PRODUCT IDENTIFICATION AND USE 
 
Product identity 
6.1.1
 
 
Galderma Product 
Galderma Product 
Comparator Product 
Trade Name 
Soolantra® cream 
Oracea®  capsules 
Not applicable 
Name of Active 
Ingredient 
Ivermectin 
(CD5024) 
Doxycycline 
monohydrate (CD2475-
101) 
CD2475-101 placebo 
capsule 
Form 
Cream 
Capsule 
Capsule 
Dose or 
Concentration 
1% 
 
40 mg MR (30 mg 
Immediate Release & 10 mg 
Delayed 
Release beads) 
 
Not applicable 
Manufacturer 
(Name and address) 
Galderma Production Inc, 
Montreal (Canada)  
 
 Catalent Pharma 
Solutions, LLC 
Winchester, Kentucky 
40391 USA 
Catalent Pharma 
Solutions, LLC 
Winchester, Kentucky 
40391 USA 
Packaging (primary) 
30g CRC tube 
Bottle of 30 capsules 
Bottle of 30 capsules 
Storage 
Requirements* 
Store at 20 to 25°C (68°F 
to 77°F), excursions 
permitted between 15°C 
and 30°C (for US supplies) 
 
Store at room 
temperature between 
59°F to 86°F (15°C to 
30°C) 
Store at room 
temperature between 
59°F to 86°F (15°C to 
30°C) 


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*the most restrictive storage conditions on the labels will be applied. 
 
 
 
 
 
 
 
 
 
Method of treatment assignment  
6.1.2
Prior to the start of the clinical trial a randomization list will be generated by GALDERMA R&D 
and transmitted to the assigned clinical packaging organization for labeling. The RANUNI routine 
of the SAS systems will be used for the kit number generation.  
A subject kit will be composed of: 
either Ivermectin 1% cream and Doxycycline 40 mg MR (CD2475-101) capsules, or Ivermectin 
1% cream and CD2475-101 placebo capsules. 
 
The kit number indicated on the randomization list will correspond to the kit number indicated on 
the label of subject kit. 
Treatments will be balanced in 1:1 ratio for each group. Complete blocks of treatment materials 
will be sent to the investigational sites.  
The randomization list will be secured in a locked cabinet and in an electronic file with restricted 
access to only the designated personnel directly responsible for labeling and handling the 
clinical trial treatments until the clinical trial database is locked and ready to be unblinded. 
At the baseline visit, all eligible and enrolled subjects will be dispensed treatment (ie: tube of 
Ivermectin and bottle of Doxycycline 40 mg MR or oral placebo  from the subject kit, which will 
be allocated in chronological order of inclusion into the clinical trial, without omitting or skipping 
any numbers.  


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If a number is omitted by mistake, the skipped kit number should be allocated to the next 
randomised subject. 
 
Subject Identification Number (SIN) 
6.1.3
Upon signature of the informed consent, a subject meeting all inclusion/exclusion criteria will be 
allocated a unique subject identification number automatically generated by the eCRF.  
During the whole clinical trial, the subject will only be identified using the SIN for all 
documentation and discussion. 
 
Instructions for use and administration 
6.1.4
The investigational product dispenser will give each subject verbal and written instructions on 
how to use the investigational and non-investigational products. A specific focus on risks in case 
of pregnancy will be made for female subjects.  
In addition, the investigational product dispenser will show the subject how to use/take the 
investigational products or how to perform the investigational product application at the baseline 
visit.  
Ivermectin 1% cream should be applied once daily in the evening. Subjects will be instructed to 
apply one small pea size of cream on the forehead, chin, nose, and each cheek (ie a total of 5 
pea-sized amounts). The product should be evened out to a thin film on the entire face. 
Application to the following areas must be avoided: eyes, eyelids, inner nose, mouth, and lips. 
Should this occur, areas will have to be washed with plenty of water. 
Subjects will be instructed to wash hands immediately after product application. 
Doxycycline 40 mg MR or its placebo should be taken once daily in the morning on an empty 
stomach, preferably at least one hour prior to or two hours after meals. 
The treatment administration is further described below. 


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Investigational  Product 
Ivermectin 
Investigational  Product 
Doxycycline monohydrate  
Comparator Product 
oral placebo 
Concentration 
1% 
40 mg MR 
(30 mg Immediate Release & 
10 mg Delayed 
Release beads) 
NA 
Dose regimen 
Once daily in the evening 
Once daily in the morning 
Once daily in the morning 
Period of administration 
12 weeks 
12 weeks 
12 weeks 
Route of administration 
Cutaneous to the entire 
face 
Oral 
Oral 
 
6.2 
OTHER SUPPLIES 
 
Gentle Skin Cleanser:  
Cetaphil Redness Relieving® Foaming Face Wash (or equivalent) 
 
 
Facial Moisturizer SPF 30:  
Cetaphil redness relieving® facial moisturizer1 (or equivalent) 
 
 
Urine Pregnancy Tests (UPT):  
Arrow™ (or equivalent)  
 
All the above supplies will be provided by the Sponsor.  
 
 
Gentle Skin Cleanser: 
Subjects should use the Gentle Skin Cleanser to wash the face prior to applying the study 
treatment. 
                                                     
1 SPF= 30  (per ISO 24444:2010 SPF norm)  / SPF= 20 (per FDA Fed Register 2011:76 SPF norm)  
 


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No specific labels will be used. 
 
Facial Moisturizer SPF 30: 
Subjects will be recommended to use the provided moisturizer/sunscreen during the study, 
within 1 hour after study drug application, especially for outdoor activities and/or sun exposure.  
Subjects will be instructed not to apply the provided moisturizer/sunscreen on the days of study 
visits until the study assessments are performed. 
No specific labels will be used. 
 
6.3 
 INVESTIGATIONAL PRODUCT PACKAGING AND LABELING 
All investigational products will be supplied in the subject’s kit including visit boxes with an 
affixed and a tear-off portion.  
For treatment documentation, the affixed portion of the label will remain on the appropriate 
packaging. The tear-off portion of the label will be removed at the time of dispensation and 
attached to the corresponding product dispensation log. 
If more than one batch is used with different expiration dates, in order to maintain blinding, only 
one expiry date, the most conservative, will be listed on the container label. 
The same kit number will be printed on each investigational product container and subject kit 
labels. 
The Subject Identification Number and subject’s initials will be manually entered onto the subject 
kit/visit box and the dispensation date will be manually entered onto the visit label box. 
The labels (including tear-off part) will also contain information required by Good Manufacturing 
Practice (GMP), Good Clinical Practice (GCP) and local regulations and will be printed in local 
languages. 
 
 
 
 
 
6.4 
INVESTIGATIONAL PRODUCT MANAGEMENT 


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Accountability 
6.4.1
Upon receipt of the clinical supplies at the site, the investigational product dispenser will conduct 
a complete inventory of all investigational products and assume responsibility for their storage, 
accountability and dispensation. 
The Investigator or designee will sign the original “Receipt of Clinical Supplies” Form (or any 
acknowledgment of receipt) upon receipt and inspection of the supplies, send the signed copy 
and the temperature curve to GALDERMA R&D and retain the receipt in the Investigator Site 
File (ISF). 
All supplies sent to the investigator site will be accounted for and in no case used in any 
unauthorized situation.  
At the end of the trial, all used and unused investigational products will be returned to 
GALDERMA R&D or the designated contractor for further reconciliation, appropriate inventory 
and destruction. 
 
Dispensing 
6.4.2
Investigational products will be prescribed only to subjects enrolled into the clinical trial, at no 
cost and in accordance with the conditions specified in the protocol. 
Dispensation will be appropriately documented on the product dispensation log by the 
investigational product dispenser at each visit. 
It is important that no subject run out of clinical trial supplies between visits.  
The investigational product dispenser will follow the accurate prescription according to the 
allocated kit. 
Each Subject kit will contain 3 visit treatment boxes (each for 1 month of treatment) to be 
dispensed at Baseline, Week 4 and Week 8 visits, respectively.  
Each visit treatment box will contain 1 tube of Ivermectin 1% cream and 2 bottles of Doxycycline 
40 mg MR or its placebo.  
 
All efforts will be taken to keep the evaluator (investigator or designee) blinded by restricting 
his/her contact with the investigational products. 
The investigational product dispenser must be different from the clinical trial efficacy and safety 
evaluator in order to maintain the blind (see section 6.4).Treatment kits will be dispensed in 
ascending sequential order according to the chronological order of enrolment of subjects into the 
clinical trial. 


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Investigational product compliance management and record 
6.4.3
Each subject will be instructed by the investigational product dispenser about the importance of 
being compliant with clinical trial treatment(s) throughout the clinical trial as well as the 
importance of returning their investigational product (used and/or not used) at each follow-up 
visit. 
The investigational product(s) will be collected and counted at all visits by the investigational 
product dispenser. 
Subjects will also be questioned regarding the application technique, intake, frequency and 
missed doses of investigational products and the use of any other additional topical, systemic 
drug as well as OTC product. 
A subject’s diary will be given to each subject in order to record the use of investigational 
products and Facial Moisturizer. The investigational product dispenser will review the subject’s 
diary at every visit. 
The return of investigational products will be appropriately documented on the product 
dispensation log by the investigational product dispenser. 
During the data review meeting, investigational product compliance for all subjects will be 
determined and reviewed by the sponsor’s clinical team for possible exclusion from the Per 
Protocol (PP) population. 
 
Storage of investigational product 
6.4.4
The investigator has to agree to keep all investigational products in a safe, temperature 
controlled and secure area with restricted access, in accordance with applicable regulatory 
requirements (e.g., in the site pharmacy, if applicable). 
Investigational products should be stored at appropriate storage conditions specified by 
GALDERMA R&D (see section 6.1.1). 
 
Return of investigational product 
6.4.5
The investigational product dispenser will inform each subject about the importance of returning 
their investigational products (used and/or not used) at each trial visit. 
In the event of early termination/suspension of the clinical trial for safety reasons, a rapid recall 
of the trial products will be initiated.  The investigator or designee must immediately instruct all 
subjects to stop the clinical trial treatment regimen and return the investigational products to the 
clinical trial site. 


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As a general procedure, GALDERMA R&D will provide the investigator with a detailed list of 
units being recalled so that any of the units remaining on site can be put immediately into 
quarantine. 
6.5 
BLINDING 
 
Verification of blinding 
6.5.1
The clinical trial design is considered investigator-blind based on the following rationale: 
1. 
Oral placebo capsules will be free from marking unlike the Oracea capsules. Aside from 
this difference, both oral trial products will be filled in the same type of primary packaging 
materials (ie: bottle) and there will be no other sign that could indicate which one is the active 
product and which one is the placebo.  
2. 
The investigational products will be dispensed by someone other than the evaluator 
(investigator or designee) designated as the investigational product dispenser in order to 
maintain the blind. 
3. 
Additionally, both the investigational product dispenser and the subject will be instructed 
not to discuss the investigational products with the evaluator (investigator or designee) 
4. 
The investigational product dispenser and the investigator will not have access to the 
unblinded randomization list. 
The randomization list will be maintained secured in a locked cabinet and/or an electronic file 
with restricted access to only the designated personnel directly responsible for labeling and 
handling the study drugs at the Sponsor’s/designee’s location. The independent statistician 
providing analyses requested will be able to access the randomization list upon request. 
 
Unblinding during the clinical trial 
6.5.2
Emergency un-blinding during the clinical trial may be required for therapeutic or for regulatory 
reasons (e.g. for expedited safety reporting). 
A blind-break system will be available for Investigators.  At the clinical trial center, the blinded 
label containing the identification of the assigned study drug(s) will be revealed in emergency 
situations only.  In such an emergency, the Investigator will only break the blind for the subject 
involved. 
Treatment identification for emergency purposes will be possible with “unblinding envelopes”, 
stating the treatment number, investigational product identification, batch number and 
investigational product expiration date, as applicable.  


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The investigator must notify the sponsor immediately in the event of such an emergency (see 
contact details in Section 8.2.2).  If possible, the investigator should notify the sponsor before 
breaking the blind in order to discuss this decision with the sponsor.  The investigator is required 
to document each case of emergency un-blinding on the appropriate form (provided by the 
Sponsor) and send the completed form to the sponsor immediately.  
 
7. 
EFFICACY AND SAFETY ASSESSMENT 
Clinical evaluations should be performed by the same evaluator (investigator or designee) 
throughout the clinical trial.  
If it is not possible to use the same evaluator to follow a subject, then evaluations should overlap 
for at least one visit in order to examine the subject together and discuss findings. This should 
be documented in medical source documents. 
 
7.1 
EFFICACY ASSESSMENTS 
 
Inflammatory Lesion Count  
7.1.1
The evaluator will perform inflammatory lesion count on facial papules and pustules of rosacea 
at baseline and then at each visit.  
Inflammatory lesions are defined as follows: 
 
Papule – A small, solid elevation less than one centimeter in diameter 
 
Pustule – A small, circumscribed elevation of the skin, which contains yellow white 
exudates. 
Papules and pustules will be counted separately on each of the five facial regions (forehead, 
chin, nose, right cheek and left cheek). Nodules (defined as a circumscribed, elevated, solid 
lesion more than 1.0 cm in diameter with palpable depth) will not be included in the count of 
inflammatory lesions, and subjects are not eligible if they have more than 2 nodules on the 
face at screening/baseline visit.  
 
 
Clinician’s Erythema Assessment (CEA) 
7.1.2
The evaluator will assess the subject’s diffuse persistent facial erythema of rosacea by 
performing a static (“snap shot”) evaluation of erythema severity, at a social distance of 
approximately 50 cm, using CEA at each visit. The evaluator should make no reference to 
previous assessments when evaluating the subject’s erythema of rosacea and CEA must be 
evaluated after the inflammatory lesion count. 
 


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Grade 
Description 
0 
Clear skin with no signs of erythema 
1 
Almost clear; slight redness 
2 
Mild erythema; definite redness 
3 
Moderate erythema; marked redness 
4 
Severe erythema; fiery redness 
 
 
 
Investigator’s Global Assessment (IGA) 
7.1.3
The evaluator will assess the subject’s rosacea at each visit by performing a static (“snap-shot”) 
evaluation, at a social distance of approximately 50 cm, using IGA score. No reference to 
previous visits should be made by the evaluator. A subject must have an IGA of 4 (severe) to be 
eligible for the study.  
 
Grade 
Score Clinical Description 
Clear 
0 
No inflammatory lesions present, no erythema  
Almost Clear 
1 
Very few small papules/pustules, very mild erythema present 
Mild 
2 
Few small papules/pustules, mild erythema, 
Moderate 
3 
Several small or large papules/pustules, moderate erythema, 
Severe 
4 
Numerous small and/or large papules/pustules, severe erythema, 
 
 
Stinging/Burning sensation  
7.1.4
The evaluator will record the severity of subject’s facial stinging/burning sensation (a prickling 
pain sensation) during the last 24h at each visit.  


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Grade 
Score 
Clinical Description 
None 
0 
No stinging/burning 
Mild 
1 
Slight warm, tingling/stinging sensation; not really bothersome 
Moderate 
2 
Definite warm, tingling/stinging sensation that is somewhat 
bothersome 
Severe 
3 
Hot, tingling/stinging sensation that has caused definite discomfort 
 
 
Ocular Signs and Symptoms 
7.1.5
Ocular manifestations will be evaluated by the Evaluator after discussion with the subject.  The 
Evaluator may identify ocular manifestations by looking for tearing, redness of bulbar and/or 
palpebral conjunctivae, telangiectasia of conjunctiva and lid margin, lid or periocular erythema, 
or styes, and by inquiring about symptoms of foreign-body sensation, gritty feeling, burning, 
stinging, itching, dryness, light sensitivity, blurred vision, or decreased visual acuity.  
Grading of ophthalmological abnormalities in ocular rosacea will be based on clinical opinion of 
dermatologist and evaluated at each visit using the below scale. 
 
Grade 
 
Score Clinical Description 
None 
0 
No ocular sign/symptom 
Mild 
1 
Mild blepharitis with lid margin telangiectasia 
Mild-Moderate 
2 
Blepharoconjunctivitis 
Moderate-Severe 
3 
Blepharo-keratoconjunctivitis 
Severe 
4 
Sclerokeratitis, anterior uveitis 
 
 
Flushing 
7.1.6
At baseline, Investigator will record in medical history the frequency (number) of flushing as 
reported by subject for the previous week before baseline visit and the corresponding average 
severity by grading as mild, moderate or severe. 


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During the study, the number of weekly flushing and the average severity  will be recorded from 
Subject’s diary where subject will be asked to report each day the flushing episodes. Investigator 
or designee will have to check with subject for diary completeness at each visit and report 
flushing information in the eCRF.  
 
 


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Subject’s Global Improvement in Rosacea 
7.1.7
The subject will evaluate his/her improvement in rosacea at last visit, compared with his/her 
rosacea condition before the study.   
 
0 
Complete improvement 
All signs and symptoms of disease have resolved 
(100% improvement from Baseline) 
1 
Excellent Improvement 
Nearly all signs and symptoms cleared 
(90% improvement from Baseline). Only minimal 
residual signs and symptoms remain 
2 
Very good Improvement 
Majority of the signs and symptoms have resolved 
(about 75% improvement from Baseline) 
3 
Good Improvement 
Significant improvement, but many signs and 
symptoms remain (about 50% improvement from 
Baseline) 
4 
Minimal improvement 
Slight overall improvement, but not clinically 
significant(about 25% improvement from Baseline) 
5 
No Change 
Overall severity similar from Baseline 
6 
Worse 
Worse than Baseline 
 
 
 


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7.2 
SAFETY ASSESSMENTS 
A safety assessment will be conducted for all subjects at the screening/baseline visit (from the 
Informed consent signature) and every subsequent visit. The safety parameters and AEs are to 
be recorded as specified in section 7.2.1. 
 
Adverse Events 
7.2.1
Adverse events (AEs) are to be monitored throughout the course of the clinical trial. All AEs 
occurring after the subject signs the informed consent should be recorded on the AE form on the 
eCRF. 
All AEs are to be reported on an Adverse Event Form of the eCRF with complete information as 
required. If AEs occur, the main concern will be the safety of the subject. At the time of the ICF 
signature, each subject must be provided with the name and telephone number of clinical trial 
center personnel for reporting AEs and medical emergencies. 
All clinical medical events, whether observed by the investigator or reported by the subject and 
whether or not thought to be related to the study drug will be considered AEs. Assessment of 
seriousness, severity and causality will be based on specific definitions. If the subject 
discontinues due to an AE, both the AE Form and the Exit Form should be completed. 
Subjects reporting a worsening of rosacea (worsening of any signs and symptoms of rosacea 
including but not limited to inflammatory lesions, persistent erythema and flushing) will be 
evaluated in detail. This includes the onset, duration and outcomes of those events, as well as a 
complete history and potential triggers of the concerned signs and symptoms of rosacea. 
 
7.3 
PATIENT RELATED OUTCOMES 
 
Dermatology Life Quality Index (DLQI) questionnaire 
7.3.1
At Baseline and at last visit, subjects will answer the 10-item DLQI questionnaire (see section 
13.1), a validated quality-of-life questionnaire specific to dermatological conditions. The 
investigator or delegate will then check all questions of the questionnaire for completeness prior 
to the subject leaving the study visit.  
 
EQ-5D-5L questionnaire 
7.3.2
Subjects will answer the quality of life questionnaire EQ-5D-5L at Baseline visit and at last visit. 
EQ-5D-5L is a 5-level, 5-dimensional format standardized instrument for use as a measure of 
health outcome. Applicable to a wide range of health conditions and treatments, it provides a 
simple descriptive profile and a single index value for health status. EQ-5D was originally 


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designed to complement other instruments but is now increasingly used as a 'stand-alone' 
measure. EQ-5D-5L is designed for self-completion by respondents. It is cognitively simple; 
taking only a few minutes to complete (see section 13.2). The investigator or delegate will then 
check all questions of the questionnaire for completeness prior to the subject leaving the study 
visit. 
 
 
Work Productivity and Activity Impairment Questionnaire: General Health 
7.3.3
Problem (WPAI:GH) modified for Rosacea. 
Subjects will answer the quality of life questionnaire WPAI: GH at Baseline visit and at last visit. 
The WPAI: GH questionnaire consists of six questions (see section 13.3). It is an instrument to 
measure impairments in both paid work and unpaid work. It measures absenteeism, 
presenteeism as well as the impairments in unpaid activity because of health problem during the 
past seven days. It has been validated to quantify work impairments for numerous diseases 
including dermatological diseases such as psoriasis1.16. In addition, the WPAI: GH questionnaire 
has been used to compare work impairments between treatment groups in clinical studies or 
between subjects with different disease severity levels. As per WPAI questionnaire adaptation 
guidelines, the questionnaire has been adapted for rosacea by replacing the term ‘your health 
problems’ by ‘your rosacea’. 
The investigator or delegate will then check all questions of the questionnaire for completeness 
prior to the subject leaving the study visit. 
 
Subject satisfaction questionnaire 
7.3.4
At last visit, subjects will complete a questionnaire (see section 13.4). 
 
 
7.4 
OTHER ASSESSMENTS 
 
Photography 
7.4.1
Standardized photographs on the face (1 front view and 2 profile views) will be taken at selected 
investigational sites at each study visit. Pictures will be used for illustrative purpose and will not 
be subject to analysis. 
   Facial redness colorimetric measurements 
7.4.2
Complementary facial redness colorimetric measurements will be performed using a 
Chromameter at selected investigational sites, depending on material availability. 
 


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7.5 
APPROPRIATENESS OF MEASUREMENTS 
The clinical efficacy assessments will be based on inflammatory lesion counts, evaluation of 
facial erythema, stinging/burning sensation and flushing. The methods are established in the 
evaluation of rosacea products and used in previous studies with the study products. 
Safety is documented by recording adverse events on an ongoing basis as a well-established 
process in clinical trials. In case of reporting of a worsening of rosacea, specific complementary 
data will be collected. 
Impact of study treatments on subjects’ quality of life will be measured by using specific 
questionnaires. DLQI and EQ-5D-5L are two validated questionnaires for evaluating quality-of-
life: While EQ-5D-3L is more general and not disease-specific, the DLQI focuses on the impact 
of dermatological diseases on the quality-of-life.  
The WPAI:GH questionnaire is a validated instrument to quantify work impairments for 
numerous diseases including dermatological conditions.  
To collect specifically the patient satisfaction outcome, a subject satisfaction questionnaire will 
be used at the end of the study to collect the subjects’ feedback on the treatment regimen, the 
level of satisfaction and future usage. 
 
 


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8. 
ADVERSE EVENT 
8.1 
DEFINITIONS 
 
Adverse Events (AE) 
8.1.1
According to ICH E2A, an AE is any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory value), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product. 
Thus any new sign, symptom or disease, or clinically significant increase in the intensity of an 
existing sign, symptom or disease since the first visit (including the disease being treated), 
should be considered as an adverse event. Lack of efficacy should not be considered as an AE. 
Each new episode of a chronic disease (e.g., hay fever, allergy, etc.) from the screening visit 
should be reported as a new AE. 
Notes: 
 Any new sign or symptom reported by the subject that appears after accidental or intentional 
overdose or misuse should also be reported as an AE. 
 There should be an attempt to report a diagnosis rather than the signs, symptoms or 
abnormal laboratory values associated with the report of an AE.  However, a diagnosis should 
be reported only if, in the Investigator’s judgment, it is relatively certain.  Otherwise, 
symptoms, signs, or laboratory values should be used to describe the AE. 
 Pregnancy should not be considered as an adverse event but must be followed up as 
described in section 8.3 
 For an AE of irritation, the “date of onset” should be the date that the first symptom occurred. 
 
Serious Adverse Events (SAE) 
8.1.2


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A serious adverse event is any untoward medical occurrence that at any dose:  
 results in death, 
 is life-threatening, 
 requires hospitalization or prolongation of existing hospitalization, 
 results in persistent or significant disability/incapacity, or 
 is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the safety of the subject, and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasia, or 
convulsions that do not result in hospitalization. 
Note: 
 The term “life-threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death 
if it was more severe. 
 Inpatient hospitalization is considered to have occurred if the subject has had to stay in 
hospital overnight. The criterion for the prolongation of hospitalization is also defined as an 
extra night at the hospital. Hospitalization may not constitute sufficient grounds to be 
considered as an hospitalization if it is solely for the purpose of diagnostic tests, (even if 
related to an AE), elective hospitalization for an intervention which was already planned 
before subject enrolment in the clinical trial, admission to a day-care facility, social admission 
(e.g., if the subject has no place to sleep), or administrative admission (e.g., for a yearly 
examination). 
 
Unexpected adverse drug reaction 
8.1.3
According to ICH E6, an unexpected adverse drug reaction is defined as an adverse reaction, 
the nature or severity of which is not consistent with the applicable study drug information. 
 
Adverse event reporting period 
8.1.4
The clinical trial period during which AEs must be reported is the period from when the subject 
signs the Informed Consent Form to the end of the subject’s participation. 
The sponsor should be informed if the investigator becomes aware of any unusual safety 
information or any safety information that appears to be drug-related involving a subject who has 


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participated in a clinical trial, even after a subject has completed the clinical trial. The 
investigator should be diligent in looking for possible latent safety effects that do not appear until 
a medication has been discontinued. 
 
Severity 
8.1.5
Severity is a clinical determination of the intensity of an AE and not of a disease. 
The investigator will classify the intensity of AEs using the following definitions as a guideline for 
all AEs occurring during clinical trials conducted or sponsored by GALDERMA. For this 
classification, the investigator will take into account the possible range of the intensity of the 
event and report the grade of intensity which is the most appropriate according  his medical 
judgment. 
Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate 
Discomfort, enough to cause interference with usual activity 
Severe 
Incapacitating with inability to work or perform usual activity 
 
Relationship to the study drug(s) and/or clinical trial 
8.1.6
procedure 
The investigator is to determine whether there is a reasonable causal relationship between the 
occurrence of the AE and exposure to the study drug(s) and/or clinical trial procedure. Medical 
judgment should be used to determine the relationship, considering all relevant factors, including 
pattern of reaction, temporal relationship, positive de-challenge or re-challenge, relevant medical 
history, and confounding factors such as co-medication or concurrent diseases. 
The expression “reasonable causal relationship” is meant to convey in general that there are 
facts or arguments to suggest a causal relationship (International Conference on Harmonization 
(ICH) E2A, section IIIA 1). 
The relationship assessment for an AE is to be completed using the following definitions as a 
guideline for all adverse events occurring during clinical trials conducted or sponsored by 
GALDERMA: 
Reasonable possibility: 
According to the reporting investigator, there is a reasonable possibility (i.e. suggestive evidence 
or arguments) that there is a causal relationship irrespective of the dose administered between: 
 The study drug  (investigational product, active comparator, or vehicle, etc.) and the AE,  


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 The clinical trial protocol procedure (e.g., UV-induction, biopsy, xylocaine injection, blood 
test or intraocular pressure measurement, ancillary products provided by the sponsor, 
such as moisturizers, etc. and the AE. 
The Investigator has to complete these 2 causality assessments on the AE form. 
No Reasonable Possibility: 
No suggestive evidence or arguments can be identified regarding a causal relationship between 
the investigational product or the clinical trial protocol procedure and the AE. 
 
 
 
8.2 
REPORTING PROCEDURES  
 
Procedures for reporting adverse events 
8.2.1
The collection of AEs is from the time that a subject signs the ICF to their final trial visit. 
At each post-baseline visit, the investigator (or sub-investigator) will enquire about adverse 
events using an open question taking care not to influence the subject’s answer (e.g., “Have you 
noticed any change in your health since the last visit?”). Direct questioning and examination will 
then be performed as appropriate. 
Any AE occurring during the AE reporting period, whether it is related to the study drug  or not, 
will be recorded immediately in the source document, and described in the Adverse Event Form 
with the date of onset, severity, relationship to the study drug ), and outcome, without omitting 
any requested and known information.  Additional information will be requested under certain 
circumstances. Adverse Events (AEs) assessed as related to the treatment will be monitored 
until they are completely or satisfactorily resolved. Other AEs will be monitored until the last visit 
if they are not resolved or satisfactorily resolved. 
Adverse events assessed as related to the treatment or study procedure will be monitored until 
they have resolved or reached a stable condition. Other AEs will be monitored until the last visit 
if they have not resolved or reached a stable condition. The investigator will obtain and maintain 
in the subject’s files all pertinent medical records, information and medical judgment from 
colleagues who assisted in the treatment and follow-up of the subject. If necessary, the 
investigator will contact the subject’s personal physician or hospital staff to obtain further details. 
For SAEs (see section 8.2.2) and pregnancies (see section 8.3), the Sponsor is to be informed 


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immediately by e-mail/fax.  The event must be reported by fax or sent by e-mail to the Sponsor 
within 24 hours of receipt of the information (contact details in section 8.2.2). 
 
 
Procedure for reporting a serious adverse event 
8.2.2
 
For an SAE occurring during the period of the clinical trial, regardless of whether it is related to 
the treatment or not, and of whether it is expected or not, the investigator must do the following: 
1. 
Take prompt and appropriate medical action, if necessary. The safety of subject is 
the first priority. 
2. 
Ensure that the event is classified as an SAE. Immediately (no later than 24 hours) 
inform the Sponsor  of the event by email/ fax/, and discuss further actions  to be 
taken: 
 
 
GALDERMA R&D 
Name 
 
Title 
 
Address 
 
 
 
Tel. during office hours 
 
Tel. outside office hours 
 
Fax  
 
Email 
pharmacovigilance@galderma.com 
3. 
Print and complete the Serious Adverse Event form (available in the eCRF system as PDF 
document). Fax or send by email the completed form, accompanied any other relevant 
information or anonymized medical records (e.g., laboratory test results) within 24 hours of 


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receipt of this information to the sponsor (see contact details above). The demographics, 
medical history, drugs/therapies forms, and adverse event pages of the eCRF must be 
completed and available for review in the eCRF system at the time of the report. 
4. 
Monitor and record the progress of the event until it resolves or reaches a clinically 
stable outcome, with or without sequelae. For all additional follow-up evaluations, fax or 
send by e-mail all additional follow-up information on the SAE to the sponsor (see contact 
details above) within 24 hours of receipt of the updated information.  SAEs will be 
monitored until the Investigator and Sponsor agree that the event is satisfactorily resolved. 
5. 
Obtain and maintain in his/her files all pertinent medical records, information, and medical 
judgments from colleagues who assisted in the treatment and follow-up of the subject.  If 
necessary, contact the subject’s personal physician or hospital staff to obtain further 
details 
6. 
Inform the sponsor of the final outcome of the event. Send a revised or updated SAE 
form and AE form, if appropriate. 
7. 
Prompt notification of SAEs by the investigator to GALDERMA is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met. GALDERMA 
has a legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a product under clinical investigation. GALDERMA will comply 
with country specific regulatory requirements relating to safety reporting to regulatory 
authorities, IRBs/IECs and investigators. Investigator safety reports are prepared for 
Suspected Unexpected Serious Adverse Reactions (SUSARs) according to local 
regulatory requirements and GALDERMA policy and are forwarded to investigators as 
necessary. An investigator who receives an investigator safety report describing an SAE(s) 
or other specific safety information (e.g., summary or listing of SAEs) from GALDERMA 
will notify the IRB/IEC, if appropriate according to local requirements. 
8. 
Comply with the applicable regulatory requirements related to the reporting of SAEs to 
your IRB/EC. 
 
 
Procedure for suspected allergic contact reaction 
8.2.3
This is a general procedure and further details can be discussed with the sponsor. 
 Stop the trial product 
 Take a picture of the affected area and the non-affected surrounding skin  
 Document the event and report it immediately to the sponsor by email/fax, within 24 hours of 
receipt of the information as described in section 8.2.2. 
 


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In case of suspicion of allergic contact dermatitis  
1. 
After all signs and symptoms have resolved and after a minimum of two weeks from last 
dose application, a re-challenge test with the assigned trial product will be performed.  
2. 
Ensure the subject has not been under any treatment with corticosteroids or 
antihistamines, regardless of the route of administration, the week before testing. 
3. 
Ensure that the skin on the back has not been exposed to the sun or artificial ultraviolet 
sources the week before testing. 
4. 
Apply an appropriate quantity of the assigned trial product to fill the cupule of the test 
chamber on the skin of the upper back on either the right or left side of the center line (or 
the inner forearm if the back cannot be tested). If no test chamber is available on-site, 
patch test units will be provided. It may be preferable to perform the test under semi-
occlusive conditions depending on the irritant potential of the trial product and the intensity 
of the reaction that was observed. The method to be used will be discussed with the 
sponsor.  
5. 
Choose a skin site that was not previously involved in the inflammatory skin reaction. 
6. 
Cover it for 48 hours with a hypoallergenic tape. 
7. 
Subject should be informed about avoiding exercise, showers, application of toiletries 
products, etc. to keep the test system dry 
8. 
After 48 hours, remove the tests and evaluate the site: 
- At approximately 30 minutes after patch test removal (1st  reading) and, 
- 24 to 48 hours later (i.e. 72 or 96 hours after application) (2nd  reading). 
- A facultative 3rd  reading may be performed 96 to 120 hours later (i.e. 6 to 7 days after 
application of the patch) if the overall assessment so far equivocal or if asked by the 
sponsor. 
- Pictures of the tested areas will be taken systematically at each reading and properly 
documented. 
 
Duration of trial 
product application 
1st  Reading 
2nd   Reading 
3rd  reading  
(optional) 


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48 hours 
48 hours after trial 
product application (30 
minutes 
after patch test removal) 
 72 to 96 hours after trial 
product application (24 to 
48  hours after patch test 
removal) 
6 or 7 days after trial 
product application (96 to 
120 hours after patch 
removal) 
 
9. 
Refer to the scoring system (Spiewak, R. 20081.17) used by the International Contact 
Dermatitis Research Group (ICDRG) to assign a score at each reading:  
 
Score Morphology 
Interpretation 
- 
No skin changes in the tested area 
Negative 
? 
Faint, non-palpable erythema  
Doubtful reaction 
+ 
Palpable erythema (moderate edema or infiltrate), 
papules not present or scarce, vesicles not present  
Weak positive reaction 
++ 
Strong infiltrate, numerous papules, vesicles present 
Strong positive reaction 
+++ 
Erythema, infiltration, confluent vesicles, bullae or 
ulceration 
Extreme positive reaction 
ir 
Inflammation sharply limited to the exposed area, lack 
of infiltrate, small petechiae, pustules, and efflorescence 
other than papules and vesicles 
Irritant reaction 
Nt 
 
Not tested 
 
10. 
At last reading, the investigator will provide an assessment regarding a possible 
sensitization reaction using the following scale: 
Sensitization Reaction 
0 
Negative (absence of reaction or might be irritant reaction) 
1 
Equivocal 


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2 
Positive 
 
11. 
Report the results from the re-challenge test as directed by the sponsor and document with 
photographs. 
12. 
In case of absence of reaction, the subject may resume treatment if appropriate 
13. 
If the re-challenge is positive or equivocal, notify the sponsor immediately. Except specific 
situations, a new series of patch test will be initiated as directed by the sponsor (with 
individual ingredients at different concentrations if applicable, and possibly negative and 
positive controls) after a minimum of additional two weeks (but not later than 6 months) 
and after all signs and symptoms have resolved. The patch tests will be placed on the 
subject’s back (or the inner forearm if the back cannot be tested) distant from the site of 
the re-challenge test (e.g., the left upper back skin if the re-challenge test was done on the 
right side). Follow the same procedure for the patch test as for the re-challenge.  
14. 
In case of suspicion of immediate contact skin reaction (such as urticaria) 
A case by case approach will be applied and the procedure to follow will be discussed with the 
sponsor. 
 
8.3 
PROCEDURES FOR REPORTING PREGNANCIES 
Any pregnancy occurring during clinical trials, where the fetus could have been exposed to the 
investigational product(s), must be followed-up until outcome in order to ensure the complete 
collection of safety data on GALDERMA  product. 
If a subject becomes pregnant, the Investigator is to do the following: 
1. 
Withdraw the subject from the clinical trial  
2. 
Complete all appropriate visit evaluations and CRF pages. 
3. 
Immediately (no later than 24 hours) contact the Sponsor to inform them of the 
pregnancy occurrence and discuss further steps to be taken. 
4. 
Complete, as fully as possible, the pregnancy surveillance form – Part I: History and 
start of pregnancy - provided by the CRA at the beginning of the clinical trial, as fully as 
possible. Fax or send by email this pregnancy form along with the Exit form within 
24 hours of receipt of the information to the Sponsor. 


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GALDERMA R&D 
Name 
 
Title 
 
Address 
 
 
 
Tel. during office hours 
 
Tel. outside office hours 
 
Fax  
 
Email 
pharmacovigilance@galderma.com 
 
5. 
Monitor and record the progress of the pregnancy until its outcome.  Contact the subject’s 
regular physician (general practitioner or gynecologist) or hospital staff to obtain further 
details and ask regular follow-up information. 
6. 
Inform the Sponsor of the progress by tri-monthly updates up to the final outcome of 
the pregnancy. For all the additional follow-up evaluations, fax or send by e-mail the 
additional follow-up information to the sponsor within 24 hours of receipt of the information.  
If the subject can no longer be reached (lost to follow-up), documentation of the 
non-response/contact with two phone calls and a letter (certified with return receipt) is 
required. 
At outcome of pregnancy, complete as fully as possible the pregnancy surveillance 
form – Part II: Course and outcome of pregnancy, as full as possible. Inform the Sponsor 
by email/ fax, then fax or send by e-mail this pregnancy form to the Sponsor within 
24 hours of receipt of the information. 
7. 
If the pregnancy leads to an abortion (voluntary abortion, spontaneous abortion or 
therapeutic abortion), in utero death or congenital anomaly, follow the procedure for 
declaration of an SAE (see Section 8.2.2). 
 
 


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9. 
STATISTICAL METHODS PLANNED 
9.1 
STATISTICAL AND ANALYTICAL PLANS 
A Statistical Analysis Plan (SAP) will be developed as a separate document. The SAP will 
contain a more detailed and technical description of specific data conventions, calculations and 
of statistical procedures for executing the analyses that are specified in the sections of the 
clinical trial protocol below.  The SAP will be finalized prior to database lock and unblinding. 
Any change made to the finalized SAP will be documented in the clinical trial report. 
The purpose of the trial is to evaluate the efficacy of Ivermectin 1% topical cream associated 
with Doxycycline 40 mg Modified release (MR) capsules versus Ivermectin 1% topical cream 
associated with Placebo in the treatment of severe Rosacea. 
The Safety and Patient Reported Outcomes (PRO) will be also evaluated. 
 
Variables to be statistically analysed 
9.1.1
The following variables will be analysed: 
 
Primary efficacy variable 
9.1.1.1
The primary endpoint is the percent change from Baseline in Inflammatory Lesion count at Week 
12. 
 
Secondary efficacy variables 
9.1.1.2
The secondary efficacy endpoints are:  
 Percent change from Baseline in Inflammatory Lesion count at each intermediate visit 
 CEA at each post-Baseline visit: % of subjects across scores  
 IGA at each post-Baseline visit: % of subjects across scores 
 Stinging/burning at each post-Baseline visit: % of subjects across scores 
 Percent change from Baseline (medical history) in terms of flushing count per week over 12 
weeks 
 Change from Baseline (medical history) in terms of flushing severity score per week over 12 
weeks 
 Global improvement in rosacea at the last visit: % of subjects across scores 
 
Exploratory efficacy variable 
9.1.1.3
One exploratory endpoint is planned to be analyzed:  


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The global assessment of Ocular signs and symptoms at each post-Baseline visit: % of subjects 
across scores 
 
Safety variables  
9.1.1.4
 Incidence of adverse events 
 Incidence of serious adverse events 
 
Patient Reported Outcomes (PRO) 
9.1.1.5
 DLQI questionnaire at Baseline and the last visit  
 EQ-5D-5L questionnaire at Baseline and last visit  
 WPAI:GH questionnaire at Baseline and last visit  
 Subject Satisfaction Questionnaire at last visit  
 
    Populations analysed, evaluability and limitations / evaluation of Bias 
9.1.2
The statistical analyses will be performed based on the following subject populations: 
 
The Per Protocol efficacy population (PP) 
9.1.2.1
This population will consist of all enrolled and randomised subjects, except subjects who have 
major deviations from the protocol. Major deviations will be defined during a data review meeting 
after data entry and before unblinding the clinical trial treatment. Major protocol deviations will be 
considered as having a possible effect on the interpretation of primary efficacy results and may 
include: inclusion criteria not respected, non-available efficacy assessment, interfering therapy at 
inclusion, etc. The primary efficacy endpoint will be analysed based on this population. 
 
The Intent-to-Treat efficacy population (ITT) 
9.1.2.2
This population will consist of the entire population enrolled and randomised (i.e. assigned a kit 
number). The ITT population will be used for all variables except the safety variables. 
 
The Safety population (All subject treated [APT]) 
9.1.2.3
This population will consist of the Intent-to-Treat population, after exclusion of subjects who 
never used the treatment with certainty based on monitoring report. The APT population will be 
only used for the safety variables (AEs). 
 
Missing values 
9.1.2.4
The last observation carried forward (LOCF) method will be used to impute missing values of 
Inflammatory Lesion count, CEA, IGA and Stinging/burning sensation. If no post-baseline data 


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are available, baseline will be carried forward. Thus, the number of subjects will not vary at each 
visit. The other missing values will not be replaced (observed data). 
 
 
Data presentation and graphics 
9.1.3
All continuous data will be summarized using usual statistics: number of values, mean, median, 
standard deviation, minimum and maximum, and by frequency distribution (n, %) for qualitative 
data. For ordinal data, both frequency distribution and usual statistics will be presented. All 
tables will be presented by clinical trial treatment and by visit (when applicable).  
Therapies that have been stopped before the baseline visit will be presented as prior therapies. 
Those reported at screening or starting between screening and baseline visits and still 
continuing after baseline will be classified as concomitant therapies. 
The adverse events will be descriptively summarized (n, %) for the safety population (APT). The 
adverse events will be descriptively summarized (n, %) by relationship to clinical trial treatments 
within System Organ Class (SOC) and preferred term (MedDRA). Subjects will be descriptively 
summarized (n, %) by intensity (i.e. mild, moderate and severe) of adverse events, SOC and 
preferred terms. Deaths and serious adverse events will be reported as well as withdrawals due 
to adverse events. A subject will be counted only once per System Organ Class (SOC) and only 
once per preferred term even if more than one occurrence of an event was reported within a 
SOC or preferred term. In the summary by categories of intensity, the adverse event with the 
highest intensity will be used. The subject will be counted only once per SOC (highest intensity 
whatever the AE within the SOC) and once per preferred term (highest intensity whatever the AE 
within the preferred term).  
 
Statistical analyses 
9.1.4
Any changes of the statistical analyses decided after the database lock will be justified and 
documented. 
 The definition of the populations will be finalized after a blind data review meeting, during which 
the distribution of subjects per site will be reviewed. In case of too small sites or in case of 
severe unbalance between the size of sites, some sites may be combined, e.g. per geographical 
area, to form analysis-center for purpose of stratification of the statistical analyses. 
The primary objective of this study will be to demonstrate the superiority of the Ivermectin 1% 
topical cream associated with Doxycycline 40 mg MR capsules compared to versus Ivermectin 
1% topical cream associated with Placebo, in terms of Inflammatory Lesion count at week 12.  
The primary efficacy endpoint will be analyzed by using the Cochran-Mantel-Haenszel (CMH, 
FREQ procedure from SAS®) statistic, stratified by center (or analysis-center) after ridit 


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transformation with the row mean difference statistics, testing the hypothesis of equality on 
ITT/LOCF population. PP analysis will also be performed to assess the robustness of the results 
obtained on ITT/LOCF population. The p-values will have to be inferior to 0.05 at week 12.  
The secondary efficacy variables, questionnaires will be analyzed similarly as primary analyses 
on appropriate population. 
The subject characteristics (disposition, previous and concomitant therapies, study treatments 
duration/ compliance, demographics, baseline characteristics,…), lesion counts and adverse 
event(s) will only be summarized descriptively, on appropriate population. 
9.2 
SAMPLE SIZE DETERMINATION 
 
Historical data and assumptions 
9.2.1
No previous study exists associating Ivermectin 1% cream and Doxycycline MR. Therefore, this 
sample size was calculated using the results (% change from baseline in inflammatory lesion 
counts at Week 12) of previous studies on subjects treated with: 
 Ivermectin 1% cream alone, which showed a standard deviation (SD) between 25.4% to 
39.9% (with a mean around 35%).  
 Doxycycline MR alone, which showed a minimum difference of 26% at Week 12, vs. Placebo 
Using this historical data, we can assume that the difference between the association 
(Ivermectin + Doxycycline MR) and Ivermectin will be at least of 15% with a SD of 35%. 
 
     Sample size calculation 
9.2.2
With the assumptions mentioned above, a total of 114 evaluable subjects per group will be 
required to demonstrate at least 15% difference at Week 12, with 90% power. To allow a 15% 
rate of subjects excluded from analysis (drop out, lost to follow-up, etc.) at Week 12, 135 
subjects per group (270 in total) are to be enrolled. 
 
 


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10. 
TRAINING / MONITORING / DATA MANAGEMENT / QUALITY ASSURANCE 
A contract research organization (CRO) will be responsible for monitoring the clinical trial and 
the sponsor may perform co-monitoring visits at selected sites. 
10.1 
PERSONNEL TRAINING 
Clinical Research Associates (CRA) will be trained prior to clinical trial initiation. During this 
training, an overview of the disease of interest and treatment will be presented. Specific 
monitoring guidelines and procedures to be followed during monitoring visits will be discussed. 
Initiation visits will be conducted with all Principal Investigators and site teams. During these 
visits, an extensive review and discussion of the protocol, procedures and CRF will be 
conducted. Evaluation scales will also be reviewed. 
A trial reference monitoring manual will be provided to each CRA as an additional reference tool.  
An eCRF completion guideline will be provided to each CRA and site. These guidelines will 
contain instructions on how to fill-in the eCRF with some examples in order to standardize the 
eCRF completion as much as possible. 
A trial reference manual will be provided to each site as an additional reference tool. These 
guidelines will contain key CRO and Sponsor contacts and phone numbers and specific 
instructions for site in order to standardize as much as possible the assessments performed 
during the clinical trial.  
10.2 
CLINICAL MONITORING  
The conduct of the clinical trial will be closely monitored by representatives of CRO/GALDERMA 
R&D to verify the adherence to the clinical trial protocol, ICH-GCP regulations, applicable SOPs, 
guidelines, and all local regulations.  
The investigator will allow representatives of GALDERMA R&D/CRO to have direct access to all 
clinical trial records, CRFs, corresponding subject medical records, investigational product 
dispensing records and investigational product storage area, site facilities and any other 
documents considered as source documentation. 
The investigator also agrees to assist the GALDERMA R&D/ CRO representatives, if required. 
10.3 
DATA MANAGEMENT 
A CRO will be responsible for data management in connection with the sponsor’s data manager. 


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All data management procedures will be detailed in the Data Management Plan (DMP).  
The DMP will describe the Clinical Data Management System (CDMS) that will be used to 
collect and validate data. Computerized edit checks and review processes will be performed on 
an ongoing basis as outlined in the DMP until all data discrepancies are resolved. 
After all data discrepancies are resolved, coding is approved, and subject evaluability has been 
determined, the data will be exported to SAS datasets and will be locked. 
After unblinding, the locked SAS database will be used to generate subject listings, tabulations 
and analyses.  
The data may be audited by the sponsor and/or CRO Quality Assurance department before or 
after the first statistical analysis results on the primary criteria. 
10.4 
QUALITY ASSURANCE / AUDIT / INSPECTION 
The clinical trial will be conducted under the sponsorship of GALDERMA R&D in compliance 
with all appropriate local and local regulations as well as ICH guidelines and in accordance with 
the SOPs for clinical trial conduct and monitoring from GALDERMA R&D and/or the Contract 
Research Organization (CRO). 
Audits of clinical trial sites may be conducted by the Sponsor/CRO representatives, and 
inspection may be performed by Regulatory Authority inspectorates or IRBs/ECs before, during, 
or after the clinical trial.   
The investigator will allow and assist the CRO/Sponsor’s representatives, IRBs/ECs and any 
regulatory agency to have direct access to all requested clinical trial-related records. 
For the audits performed by, or on behalf of, GALDERMA R&D auditors, audit certificate(s) will 
be provided by Quality Assurance. 
 
11. 
ETHICS AND GENERAL CLINICAL TRIAL CONDUCT CONSIDERATIONS 
11.1 
INSTITUTIONAL REVIEW BOARD (IRB) OR ETHICS COMMITTEE (EC) 
This clinical trial protocol will be reviewed and approved by IRBs/ECs prior to clinical trial 
initiation. 
This protocol may be modified at any time for ethical, medical or scientific reasons. Such 
modifications will be documented by a clinical protocol amendment and, if deemed necessary, 
an amended protocol will be issued. 


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Before implementation, the amendment should be submitted and approved by applicable 
IRBs/ECs and, if required by the Regulatory Authority(ies). 
No amendment will be required for modification(s) due to a change in logistical or administrative 
aspects of the clinical trial (e.g., change in monitors, change of telephone numbers). In such a 
case, the appropriate institution(s) and/or person(s) will be directly notified of the changes. 
11.2 
ETHICAL CONDUCT OF THE CLINICAL TRIAL 
This clinical trial will be conducted in accordance with the ethical principles originating from the 
Declaration of HELSINKI declaration (1964) and subsequent amendments, the International 
Conference on Harmonization (ICH), Good Clinical Practice (GCP) and in compliance with local 
regulatory requirements. 
11.3 
SUBJECT INFORMATION SHEET / INFORMED CONSENT 
All subjects who participate in this trial will have to be fully informed about the clinical trial in 
accordance with the applicable regulations and GCP guidelines and in accordance with local 
legal requirements.  
Prior to any clinical trial procedures, the subject will sign and date the informed consent form(s) 
which is written in the local language. A copy of the signed and dated form(s) will be given to the 
subject. The investigator is responsible for maintaining each subject’s consent form(s) in the 
investigator’s site file (ISF) and providing each subject with a copy of the consent form. 
The informed consent form including photograph release form approved by an IRB/EC will be 
fully explained to the subject, when applicable.  
11.4 
CONTRACTUAL REQUIREMENTS  
A contractual agreement will be signed between the CRO/Sponsor and each 
Investigator/Institution.  This document will contain supplementary information, including 
financial terms, confidentiality, the clinical trial schedule, third party responsibility, and 
publication rights. 
11.5 
DATA COLLECTION AND ARCHIVING 
 
Data Collection 
11.5.1
The investigator must maintain required records on all clinical trial subjects.  
Data for this clinical trial will be recorded in the subject’s source documents and in the eCRF, the 
product dispensation logs, the subjects’ diaries and questionnaires provided by GALDERMA 
R&D.  


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All data recorded in the documents described above should be recorded completely, promptly, 
and legibly using black ink.  
The appropriate pages will be collected upon clinical trial completion or at any other time 
specified by CRO CRA/sponsor.  
A complete set of copies will remain at the investigational site. 
 
Source documentation 
11.5.2
Investigators must keep accurate separate records (other than the eCRF) of all subjects’ visits, 
and all procedures done, being sure to include all pertinent clinical trial related information from 
which CRF data will be recorded.  
A statement should be made on subject’s medical notes indicating that the subject has been 
enrolled in GALDERMA R&D protocol RD.03.SPR.113322 and has provided dated and 
signed informed consent.  
All adverse events with the associated concomitant therapies must be thoroughly documented. 
Results of any diagnostic tests conducted during the clinical trial will be included in the source 
documentation. 
Telephone conversations with the subjects and/or CRO/ GALDERMA R&D concerning the 
clinical trial may be recorded and kept on file. 
 
Archives 
11.5.3
All pertinent data, samples, photos, questionnaires, correspondence, original or amended 
protocol, all reports and all other material relating to the clinical trial will be maintained securely 
in GALDERMA R&D / Investigator/Institution archives for the legally-required duration of 
archiving. 
If the investigator retires, relocates, or for any other reason withdraws from the responsibility of 
keeping the clinical trial records, custody must be transferred to a person who will accept the 
responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. 
11.6 
INSURANCE 
A certificate attesting third party coverage of CRO/GALDERMA R&D will be provided upon 
request.  


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12. 
REFERENCE LIST 
1. 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 Jun; 50(6):907-12. 
2. Tan J et al. 2016 Updating the diagnosis, classification and assessment of rosacea: 
Recommendations from the global ROSacea COnsensus (ROSCO) panel. 
3. Chosidow O, Cribier B. Epidemiology of rosacea: updated data. Ann Dermatol Venereol. 
2011 Nov;138 Suppl 3:S179-83. 
4. Tan J, Berg M. Rosacea: current state of epidemiology. J Am Acad Dermatol. 2013;69(6 
Suppl 1):S27-35. 
5. Culp B, Scheinfeld N. Rosacea: a review. P T. 2009 Jan;34(1):38-45. 
6.  Korting HC, Schöllmann C. Current topical and systemic approaches to treatment of 
rosacea. J Eur Acad Dermatol Venereol. 2009 Aug;23(8):876-82. 
7. Powell FC. Clinical practice. Rosacea. N Engl J Med. 2005;352(8):793-803. 
8. A. Taieb, A. Khemis, T. Ruzicka, W. Baranska-Rybak, J. Berth-Jones, J. Schauber, P. 
Briantais, J. Jacovella, T. Passeron on behalf of the Ivermectin Phase III Study Group. 
Maintenance of remission following successful treatment of papulopustular rosacea with 
ivermectin 1% cream vs. metronid azole 0.75% cream: 36-week extension of the ATTRACT 
randomized study. JEADV 2016, 30, 829–836 
9. David A. Jones. Rosacea, Reactive Oxygen Species, and Azelaic Acid. J Clin Aesthet 
Dermatol. 2009 Jan; 2(1): 26–30. 
10. Martin Steinhoff, Marc Vocanson, Johannes J Voegel, Feriel Hacini-Rachinel and Gregor 
Schäfer Topical Ivermectin 10 mg/g and Oral Doxycycline 40 mg Modified-Release: Current 
Evidence on the Complementary Use of Anti-Inflammatory Rosacea Treatments. Adv Ther. 
2016; 33(9): 1481–1501. 
11. J Mark Jackson, Melissa Knuckles, John Paul Minni, Sandra Marchese Johnson, and Kevin 
Tate Belasco. The role of brimonidine tartrate gel in the treatment of rosacea. Clin Cosmet 
Investig Dermatol. 2015; 8: 529–538 
12. Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad Dermatol.2004 
Oct;51(4):499-512. 


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13. Martin Schaller, Thomas Dirschka, Lajos Kemény, Philippe Briantais, and Jean Jacovella. 
Superior Efficacy with Ivermectin 1% Cream Compared to Metronidazole 0.75% Cream 
Contributes to a Better Quality of Life in Patients with Severe Papulopustular Rosacea: A 
Subanalysis of the Randomized, Investigator-Blinded ATTRACT Study. Dermatol Ther 
(Heidelb). 2016 Sep; 6(3): 427–436. 
14. Sanchez J, Somolinos AL, Almodóvar PI, Webster G, Bradshaw M, Powala C. A 
randomized, double-blind, placebo-controlled trial of the combined effect of doxycycline 
hyclate 20-mg tablets and metronidazole 0.75% topical lotion in the treatment of rosacea. J 
Am Acad Dermatol. 2005 Nov;53(5):791-7.  
15. Asai Y, Tan J, Baibergenova A, Barankin B, Cochrane CL, Humphrey S, Lynde CW, 
Marcoux D, Poulin Y, Rivers JK, Sapijaszko M, Sibbald RG, Toole J, Ulmer M, Zip C. 
Canadian Clinical Practice Guidelines for Rosacea. J Cutan Med Surg. 2016 Sep;20(5):432-
45. 
16. Revicki DA, Willian MK, Menter A, Gordon KB, Kimball AB, Leonardi CL, Langley RG, Kimel 
M, Okun M: Impact of adalimumab treatment on patient-reported outcomes: results from a 
Phase III clinical trial in patients with moderate to severe plaque psoriasis. J Dermatolog 
Treat 2007, 18:341-350 
17. Spiewak R: Patch Testing for Contact Allergy and Allergic Contact Dermatitis. The Open 
Allergy Journal, 2008, 1, 42-51 


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13. 
ATTACHMENTS 
13.1 
ATTACHMENT# 1:  
DERMATOLOGY LIFE QUALITY INDEX QUESTIONNAIRE (DLQI)  
At the beginning and end of the trial, subjects will answer the 10-item DLQI questionnaire. 
 
The aim of this questionnaire is to measure how much your skin problem has affected your life 
OVER THE LAST WEEK. Please tick  one box for each question 
 
1. 
Over the last week, how itchy, sore,  
 
painful or stinging has your skin been? 
 Very much 
 
 
 
 
 
 
 
 
 
A lot 
 
 
 
 
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
 
2. 
Over the last week, how embarrassed or  
 
self-conscious have you been because of  
 
your skin? 
 Very much 
 
 
 
 
 
 
 
 
 
A lot 
 
 
 
 
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
3. 
Over the last week, how much has your  
 
skin interfered with you going shopping or  Very much 
 
 
looking after your home or garden?  
A lot 
 
 
 
 
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
Not relevant 
 


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4. 
Over the last week, how much has your  
 
skin influenced the clothes you wear? 
 
Very much 
 
 
 
 
 
 
 
 
 
A lot 
 
 
 
 
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
Not relevant 
 
5. 
Over the last week, how much has your  
 
skin affected any social or leisure activities? 
Very much 
 
 
 
 
 
 
 
 
 
A lot 
 
 
 
 
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
Not relevant 
 
 
 
6. 
Over the last week, how much has your  
 
skin made it difficult for you to do any sport? 
Very much 
 
 
 
 
 
 
 
 
 
A lot 
 
 
 
 
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
Not relevant 
 
 
7.  
Over the last week, has your skin prevented  
 
you from working or studying? 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
No 
 
 
Not relevant 
 
 
If "No", over the last week how much has  


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your skin been a problem at work  
or studying?  
 
 
 
 
A lot 
 
 
 
 
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
 
8. 
Over the last week, how much has your  
 
 
 
skin created problems with your partner or Very much 
 
  
any of your close friends or relatives? 
 
A lot 
 
 
 
 
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
Not relevant 
 
 
9. 
Over the last week, how much has your  
 
skin caused any sexual difficulties? 
 
Very much 
 
 
 
 
 
 
 
 
 
A lot 
 
 
 
 
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
Not relevant 
 
 
10. 
Over the last week, how much of a   
Very much 
 
 
problem has the treatment for your skin  
A lot 
 
 
 
been, for example by making your home  
A little  
 
 
messy, or by taking up time?  
 
Not at all 
 
 
 
 
 
 
 
 
 
Not relevant 
 
 
Please check you have answered EVERY question. Thank you. 


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®AY Finlay, GK Khan, April 1992 www.dermatology.org.uk, this must not be copied without the 
permission of the authors. 


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13.2 
ATTACHMENT# 2:   EQ-5D-5L QUESTIONNAIRE 
Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure 
activities) 
 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
 


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I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 
 
 
 
 


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10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
 
 
 
We would like to know how good or bad your health is TODAY. 
 
This scale is numbered from 0 to 100. 
 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
 
Mark an X on the scale to indicate how your health is TODAY. 
 
Now, please write the number you marked on the scale in the box below. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The best health you 
can imagine 


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The worst health 
you can imagine 
 
 
 
 
 
 
 
 
 
 
 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 
 
YOUR HEALTH TODAY = 


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13.3 
ATTACHMENT# 3:    
Work Productivity and Activity Impairment Questionnaire: 
General Health V2.0 (WPAI:GH)  
modified for Rosacea. 
 
 
 
The following questions ask about the effect of your rosacea on your ability to work and perform 
regular activities. Please fill in the blanks or circle a number, as indicated. 
 
1. 
Are you currently employed (working for pay)?  
____  NO 
____  YES 
 
If NO, check “NO” and skip to question 6. 
The next questions are about the past seven days, not including today. 
 
2. 
During the past seven days, how many hours did you miss from work because of your 
rosacea? Include hours you missed on sick days, times you went in late, left early, etc., 
because of your rosacea. Do not include time you missed to participate in this study. 
_____HOURS 
 
3. 
During the past seven days, how many hours did you miss from work because of any other 
reason, such as vacation, holidays, time off to participate in this study? 
_____HOURS 
 
4. 
During the past seven days, how many hours did you actually work? 
_____HOURS (If “0”, skip to question 6.) 


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5. 
During the past seven days, how much did your rosacea affect your productivity while you 
were working?  
 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as 
usual. If rosacea affected your work only a little, choose a low number. Choose a high 
number if rosacea affected your work a great deal.  
 
Consider only how much rosacea affected  
productivity while you were working. 
Rosacea had no 
effect on my 
work 
 
 
 
 
 
 
 
 
 
 
 
Rosacea 
completely 
prevented me 
from working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 
CIRCLE A NUMBER 
 
6. 
During the past seven days, how much did your rosacea affect your ability to do your 
regular daily activities, other than work at a job?  
 
By regular activities, we mean the usual activities you do, such as work around the house, 
shopping, childcare, exercising, studying, etc. Think about times you were limited in the 
amount or kind of activities you could do and times you accomplished less than you would 
like. If rosacea affected your activities only a little, choose a low number. Choose a high 
number if rosacea affected your activities a great deal.  
 
Consider only how much rosacea affected your ability  
to do your regular daily activities, other than work at a job. 
Rosacea had no 
 
 
 
 
 
 
 
 
 
 
 
Rosacea 


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effect on my daily 
activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
completely 
prevented me 
from doing my 
daily activities 
CIRCLE A NUMBER 
 
 
 
WPAI:GH  V2.0 (US English)   modified for Rosacea   
Reilly MC, Zbrozek AS, Dukes E: The validity and reproducibility of a work productivity and activity impairment measure.  PharmacoEconomics 
1993; 4(5):353-365. 
13.4 
ATTACHMENT# 4:   SUBJECT’S SATISFACTION QUESTIONNAIRE 
The Subject’s Satisfaction Survey will be completed at Week 12 / Early Termination by the 
Subject. 
A- 
Questions about study drugs (capsules and cream) 
1. 
How satisfied are you with the time the study regimen took to work? 
 
Very satisfied 
 
Satisfied 
 
Somewhat satisfied 
 
Not satisfied 
 
2. 
How satisfied are you with the improvement of your facial lesions since starting the study 
regimen? 
 
Very satisfied 
 
Satisfied 
 
Somewhat satisfied 
 
Not satisfied 
 
3. 
How satisfied are you with the improvement of your facial redness since starting the 
study regimen? 
 
Very satisfied 
 
Satisfied 


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 
Somewhat satisfied 
 
Not satisfied 
 
4. 
How satisfied are you with the improvement of your ocular symptoms since starting the 
study regimen? 
 
Very satisfied 
 
Satisfied 
 
Somewhat satisfied 
 
Not satisfied 
 
Not applicable 
 
 
5. 
How satisfied are you with the improvement of your flushing episodes since starting the 
study regimen? 
 
Very satisfied 
 
Satisfied 
 
Somewhat satisfied 
 
Not satisfied 
 
Not applicable 
6. 
How bothered are you by the side effects of the study regimen? 
 
Not bother at all 
 
Bothered a little 
 
Bothered somewhat 
 
Bothered a great deal 
 
7. 
How does your face look since starting the study regimen? 
 
A lot better 
 
A little better 
 
No change 
 
Worse 


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8. 
How do feel since starting the study regimen? 
 
A lot better 
 
A little better 
 
No change 
 
Worse 
 
9. 
The study  regimen was  easy to incorporate in your daily routine 
 
Strongly agree 
 
Agree  
 
Disagree 
 
Strongly disagree 
 
10. 
Would you consider using the study regimen again?  
 
Yes  
 
No 
 
11. 
How satisfied are you overall with the study regimen? 
 
Very satisfied 
 
Satisfied 
 
Somewhat satisfied 
 
Not satisfied 
  
12.     How did you find the study regimen compared to the last treatment(s) you received prior 
starting the study? 
 
 
A lot better 
       Better 
 
Similar 


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 
Worse 
 
Never treated with a previous treatment


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B- 
Questions about both provided skin care products Cleanser and Moisturizer 
  
1. 
Both skin care products were easy to incorporate into a daily routine: 
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 
2. 
I would recommend  both skin care products to my family or friends: 
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 
3. 
I felt - both skin care products helped my skin look healthier 
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 
4. 
Using both skin care products for rosacea, made me feel more confident  
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 


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5. 
I felt - both skin care products made me feel more confident with my skin appearance 
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 
6. 
I felt – both skin care products helped make a positive difference in the appearance of 
my skin 
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 
7. 
I would keep using both skin care products 
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
  
8. 
 Both skin care products make my skin more hydrated 
 
Strongly agree 


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 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 
 


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9. 
 Both skin care products improved the texture of my skin  
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 
10. 
Both skin care products are pleasant to use  
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 
 
  
 
 


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C - Questions about the cosmetic product cleanser 
1. 
The Cleanser left my skin with a clean healthy feeling:  
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 
2. 
The Cleanser provided deep cleansing without stripping the skin’s moisture:  
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 
3. 
The Cleanser rinsed off easily:  
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 
4. 
The Cleanser did not make my skin feel tight or dry:  
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
  


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D - Questions about the cosmetic product Moisturizer  
1. 
The Moisturizer made my skin feel soft and smooth:  
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 
2. 
The Moisturizer improved my skin’s texture:  
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 
3. 
The Moisturizer left my skin feeling hydrated and protected:  
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 
4. 
The Moisturizer provided a comforting sensation on the skin:  
 
Strongly agree 
 
Agree  
 
Neither agree or disagree  
 
Disagree 
 
Strongly disagree 
 


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SAP_001.pdf: 
Efficacy Comparison of Ivermectin 1% Topical Cream Associated with Doxycycline 40 mg Modified Release 
(MR) Capsules Versus Ivermectin 1% Topical Cream Associated with Placebo in the Treatment of Severe 
Rosacea.
NCT Number: NCT03075891 
Date: 12 Apr 2018


GALDERMA PHASE IV  
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN FOR RD.03.SPR.113322 
12 April 2018 
Page 1 of 39 – FINAL 
STATISTICAL ANALYSIS PLAN FOR RD.03.SPR.113322 
EFFICACY COMPARISON OF IVERMECTIN 1% TOPICAL CREAM ASSOCIATED 
WITH DOXYCYCLINE 40 MG MODIFIED RELEASE (MR) CAPSULES VERSUS 
IVERMECTIN 1% TOPICAL CREAM ASSOCIATED WITH PLACEBO IN THE 
TREATMENT OF SEVERE ROSACEA. 
APPROVALS 
_________________________/____/____/____/ 
GALDERMA PHASE IV 
_________________________/____/____/____/ 
______________________/____/____/____/ 
GALDERMA PHASE IV  
GALDERMA PHASE IV 
Distribution: 
Original: GALDERMA RESEARCH & DEVELOPMENT Archives, Sophia-Antipolis site 


GALDERMA PHASE IV  
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN FOR RD.03.SPR.113322 
12 April 2018 
Page 2 of 39 – FINAL      
TABLE OF CONTENTS    
1.
LIST OF ABBREVIATIONS
5 
2.
STUDY OBJECTIVES
5 
3.
INVESTIGATIONAL PLAN
5 
3.1 
OVERALL STUDY DESIGN
5 
3.2 
SAMPLE SIZE CONSIDERATION
6 
3.2.1 
Historical data and assumptions 
6 
3.2.2 
Sample size calculation 
6 
4.
ANALYZED VARIABLES
7 
4.1 
EFFICACY VARIABLES
7 
4.1.1 
Primary efficacy variable 
7 
4.1.2 
Secondary efficacy variables 
7 
4.1.3 
Exploratory efficacy variables 
8 
4.2 
PATIENT-REPORTED OUTCOMES VARIABLES 
9 
4.3 
SAFETY VARIABLES
10 
5.
POPULATIONS ANALYZED
10 
5.1 
INTENT TO TREAT POPULATION (ITT) 
10 
5.2 
PER PROTOCOL POPULATION (PP) 
10 
5.3 
SAFETY POPULATION (ALL SUBJECT TREATED (APT)) 
10 
5.4 
MISSING VALUES
10 
5.5 
POOLING OF CENTERS
10 
6.
STATISTICAL METHODS AND DATA CONSIDERATIONS
11 
6.1 
DATA PRESENTATION
11 
6.2 
STUDY SUBJECTS
11 
6.2.1 
Subject disposition 
11 
6.2.2 
Protocol deviation 
11 
6.2.3 
Data sets analyzed 
11 


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6.2.4 
Demographic data 
12 
6.2.5 
Rosacea co-morbidities and Medical history 
12 
6.2.6 
Medical history of acute rosacea (worsening) 
12 
6.2.7 
Previous and concomitant drug and procedure therapies 
12 
6.2.8 
Compliance 
12 
6.2.9 
Baseline disease characteristics 
12 
6.3 
EFFICACY ANALYSES
13 
6.3.1 
Primary efficacy analyses 
13 
6.3.2 
Secondary and other efficacy analyses 
13 
6.4 
PATIENT-REPORTED OUTCOMES ANALYSES 
13 
6.5 
SAFETY ANALYSES
13 
6.5.1 
Extent of exposure 
13 
6.5.1.1 
Treatment duration 
13 
6.5.2 
Adverse Events 
13 
7.
CHANGES FROM THE PROTOCOL ANALYSIS PLAN
14 
APPENDIX 1: LIST AND FORMAT OF TABLES 
15 
8.
TABLE SHELLS
16 
14.1. Study Subjects 
16 
14.1.1. Conduct of the study 
16 
14.1.2. Subject characteristics 
18 
14.2. Efficacy analyses 
21 
14.2.1. Primary efficacy analyses 
21 
14.2.2. Secondary efficacy analyses 
22 
14.2.2.1. Inflammatory lesions 
22 
14.2.2.2. Clinician's Erythema Assessment 
23 
14.2.2.3. Investigator’s Global Assessment 
23 
14.2.2.4. Stinging/Burning severity score 
24 
14.2.2.5. Flushing 
26 
14.2.2.6. Subject’s Global Improvement 
24 
14.2.3. Exploratory efficacy analyses 
25 
14.2.4. Patient reported outcomes 
28 
14.2.4.1. Dermatology Life Quality Index 
28 
14.2.4.2. EQ-5D-5L questionnaire 
29 
14.2.4.3. Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH)
30 


GALDERMA PHASE IV  
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14.2.4.4. Subject’s satisfaction questionnaire 
31 
14.2.5. Colorimetry 
27 
14.3 Safety analyses 
33 
14.3.1. Extent of Exposure 
33 
14.3.2. Adverse events 
35  


GALDERMA PHASE IV  
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN FOR RD.03.SPR.113322 
12 April 2018 
Page 5 of 39 – FINAL  
1. LIST OF ABBREVIATIONS
List all abbreviations used in the document e.g.:  
AE 
Adverse event 
APT 
All Patients Treated (Safety Population) 
ATC 
Anatomical-therapeutic-chemical classification of drugs 
CEA 
Clinician’s Erythema Assessment 
CMH 
Cochran-Mantel-Haenszel 
DLQI 
Dermatology Life Quality Index 
DOXY 
Doxycycline 
eCRF 
electronic Case Report Form 
EQ-5D-5L 
EuroQol-5 Dimensional-5 Level 
GH 
General Health 
IGA 
Investigator’s Global Assessment 
ITT 
Intention To Treat 
IVM 
Ivermectin 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Modified Release 
PP 
Per Protocol 
PRO 
Patient Reported Outcomes 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SOC 
System Organ Class 
WPAI 
Work Productivity and Activity Impairment    
2. STUDY OBJECTIVES
The main objective of this study was to evaluate the efficacy of Ivermectin 1% topical cream (IVM) 
associated with Doxycycline (Doxy) 40 mg Modified release (MR) capsules versus Ivermectine 
1% topical cream associated with Placebo  in the treatment of severe rosacea. The Safety and 
Patient Reported Outcomes (PRO) were also be evaluated.    
3. INVESTIGATIONAL PLAN
3.1 OVERALL STUDY DESIGN
This study was to be conducted as a multi-center, randomized, investigator-blind, 
vehicle-controlled and parallel-group comparison trial, involving subjects of any gender or race, 
aged 18 years or older, with severe rosacea characterized by persistent diffuse facial erythema and 
inflammatory lesions (papules and pustules), and meeting specific inclusion/exclusion criteria.  


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A total of 270 subjects (135 in each group) were to be enrolled at approximately 50 sites in the 
United States of America, Canada and Europe (Germany, Czech Republic, Hungary and Poland). 
Subjects were to be enrolled at baseline and, depending on randomization scheme, were to be 
treated for 12 weeks as follows: 
 
IVM/Doxy: 
• Ivermectin 1% cream: one small pea size amount per facial region (forehead, chin, nose, and 
each cheek) once a day in the evening for 12 weeks.  
• Doxycycline 40 mg MR (30 mg Immediate Release & 10 mg Delayed Release beads): 1 
capsule once-daily in the morning on an empty stomach for 12 weeks.  
 
IVM/Placebo: 
• Ivermectin 1% cream: one small pea size amount per facial region (forehead, chin, nose, and 
each cheek) once a day in the evening for 12 weeks.  
• CD2475-101 placebo: 1 capsule once-daily in the morning on an empty stomach for 12 
weeks.  
 
There were up to 5 study visits: screening/baseline, week 4, week 8 and week 12. 
 
 
3.2 SAMPLE SIZE CONSIDERATION 
3.2.1 Historical data and assumptions 
No previous study exists associating Ivermectin 1% cream and Doxycycline MR. Therefore, this 
sample size was calculated using the results of previous studies on subjects treated with Ivermectin 
1% cream alone and Doxycycline MR alone.  
With Ivermectin 1% cream alone, for % change from baseline in inflammatory lesion counts at 
week 12, results showed a standard deviation (SD) between 25.4% to 39.9% with a mean around 
35%. 
With Doxycycline MR alone, results showed a minimum difference of 26% at Week 12 versus 
Placebo. 
 
Using this historical data, we assumed that the difference between the association (Ivermectin + 
Doxy) and (Ivermectin + Placebo) was at least of 15% with a SD of 35%.  
 
3.2.2 Sample size calculation 
With the assumptions mentioned above, a total of 114 evaluable subjects per group were to be 
required to demonstrate at least 15% difference at Week 12, with 90% power.  
 
To allow a 15% rate of subjects excluded from analysis (drop out, lost to follow-up, etc.) at Week 
12, 135 subjects per group (270 in total) were to be enrolled. 
 
 


GALDERMA PHASE IV  
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4. ANALYZED VARIABLES 
4.1 EFFICACY VARIABLES 
4.1.1 Primary efficacy variable 
 Percent change from Baseline in inflammatory lesion (IL) count at Week 12: The evaluator 
performed inflammatory lesion count on facial papules and pustules of rosacea. 
 
4.1.2 Secondary efficacy variables 
 Percent change from Baseline in IL count at each intermediate visit: (week 4 and week 8). 
 
 Percent of subject clear inflammatory lesions at each post-baseline visit: % of subject with 
100% reduction of IL  
 
 Clinical Erythema Assessment (CEA) at each visit: % of subject across score. The evaluator 
assessed the subject’s diffuse persistent facial erythema of rosacea by performing a static 
(“snap shot”) evaluation of erythema severity at a social distance of approximately 50 cm using 
CEA, at each visit.  
 
Grade 
Score 
Description 
Clear 
0 
Clear skin with no signs of erythema 
Almost Clear 
1 
Almost clear; slight redness 
Mild 
2 
Mild erythema; definite redness 
Moderate 
3 
Moderate erythema; marked redness 
Severe 
4 
Severe erythema; fiery redness 
 
 Investigator’s Global Assessment (IGA) at each post-baseline visit: % of subject across score. 
The evaluator assessed the subject’s rosacea at each visit by performing a static (“snap-shot”) 
evaluation at a social distance of approximately 50 cm, using IGA score. No reference to 
previous visits was to be made. 
 
Grade 
Score 
Clinical Description 
Clear 
0 
No inflammatory lesions present, no erythema  
Almost Clear 
1 
Very few small papules/pustules, very mild erythema present 
Mild 
2 
Few small papules/pustules, mild erythema, 
Moderate 
3 
Several small or large papules/pustules, moderate erythema, 
Severe 
4 
Numerous small and/or large papules/pustules, severe erythema, 
 


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CONFIDENTIAL 
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 Stinging/Burning at each post-baseline visit: % of subject across score. The evaluator recorded 
the severity of subject’s facial stinging/burning sensation (a prickling pain sensation) during the 
last 24h at each visit. 
 
None 
0 
No stinging/burning 
Mild 
1 
Slight warm, tingling/stinging sensation; not really bothersome 
Moderate 
2 
Definite warm, tingling/stinging sensation that is somewhat bothersome 
Severe 
3 
Hot, tingling/stinging sensation that has caused definite discomfort 
 
 Subject’s Global Improvement in Rosacea at week 12/early termination visit: % of subject across 
score. The subject evaluated his/her improvement in rosacea at last visit compared with his/her 
rosacea condition before the study 
 
Complete Improvement 
0 
All signs and symptoms of disease have resolved  
(100% improvement from Baseline)  
Excellent Improvement 
1 
Nearly all signs and symptoms cleared  
(90% improvement from Baseline) 
Very good Improvement 
2 
Majority of the signs and symptoms have resolved  
(about 75% improvement from Baseline) 
Good Improvement 
3 
Significant improvement, but many signs and symptoms remain  
(about 50% improvement from Baseline) 
Minimal Improvement 
4 
Slight overall improvement, but many signs and symptoms remain  
(about 25% improvement from Baseline) 
No Change 
5 
Overall severity similar from Baseline 
Worse 
6 
Worse than Baseline 
 
4.1.3 Exploratory efficacy variables 
 Global assessment of ocular signs and symptoms at each post-baseline visit: % of subject across 
score. The evaluator recorded the severity of the ocular signs and symptoms after discussion 
with the subject. 
 
Grade 
Score Clinical Description 
None 
0 
No ocular sign/symptom  
Mild 
1 
Mild blepharitis with lid margin telangiectasia 
Mild-Moderate 
2 
Blepharoconjunctivitis 
Moderate-Severe 
3 
Blepharo-keratoconjunctivitis 
Severe 
4 
Sclerokeratitis, anterior uveitis 
 
 


GALDERMA PHASE IV  
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN FOR RD.03.SPR.113322 
12 April 2018 
 
 
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 Percent change from baseline (medical history) in terms of flushing count per week: At baseline 
the investigator recorded in medical history the frequency of flushing as reported by subject for 
the previous week before baseline visit. During the study, the number of weekly flushing was 
reported in the eCRF by the investigator or designee based on the flushing episodes recorded 
daily by the subject in the diary. 
 
 Change from baseline (medical history) in mean score severity per week: At baseline the 
investigator recorded in medical history the average severity of flushing by grading as mild, 
moderate or severe. (severity from the previous week before baseline visit). During the study, 
the average severity was reported in the eCRF by the investigator or designee based on the 
severity recorded daily by the subject in the diary. 
 
 Change from baseline in Facial redness colorimetric measurements (CEI) at each post-baseline 
visit: In selected investigational sites, the investigator assessed the colorimetry using a 
Chromameter that converts colors perceived by the human eye into a digital code composed of 
the following parameters: L*: for clarity (from dark to light), a*: for the green-to-red 
component, b*: for the blue-to-yellow component. 
 
When evaluating an erythema, the a* parameter is of highest importance. The decrease in 
luminance L* can also be considered useful because it reflects the darkest character of an 
erythema. The CEI (Colormetric Erythema Index) is the reflection of these two parameters. It 
is calculated on the zone treated with the tested product and the blank formulation zone 
according to the following formula: CEI = (ΔL*² + Δa*²)1/2 
 
ΔL*: variation in the skin luminosity under the effect of the erythema 
Δa*: variation in the skin color on the green-to-red axis under the effect of the erythema. 
 
4.2 PATIENT-REPORTED OUTCOMES VARIABLES 
 Dermatology Life Quality Index (DLQI) at week12/early termination: % of subject across Total 
score at baseline and last visit; and the % change from baseline. 
 
Grade 
Description 
0-1 
No effect at all on patient's life 
2-5 
Small effect on patient's life 
6-10 
Moderate effect on patient's life 
11-20 
Very large effect on patient's life 
21-30 
Extremely large effect on patient's life 
 
 EQ-5D questionnaire at week12/early termination: % of subjects across score of questions at 
baseline and last visit. 
 
 Work Productivity and Activity Impairment Questionnaire at week 12/early termination: General 
Health (WPAI: GH) modified for Rosacea. % of subjects across score of questions at baseline 
and last visit.  
 
 Subject’s satisfaction questionnaire at week12/early termination: % of subjects across score of 
questions at last visit.  


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4.3 SAFETY VARIABLES 
 Adverse events: Incidence of adverse events - All clinical medical events, whether observed by 
the investigator or reported by the subject and whether or not thought to be study product 
-related were to be considered adverse events. 
 
 
 
5. POPULATIONS ANALYZED 
The definition of the populations and the pooling center will be finalized after a blind data review 
meeting, during which the distribution of subjects per site will be reviewed. 
 
 
5.1 INTENT TO TREAT POPULATION (ITT) 
This population consists of the entire population enrolled and randomized (i.e., assigned a kit 
number). The ITT population will be used for all variables except the safety variables. 
 
 
5.2 PER PROTOCOL POPULATION (PP) 
The PP Population is defined as comprising the ITT subjects who have no major protocol 
deviations that will be refined during a blind review. The primary efficacy endpoint will be 
analysed based on this population.  
 
 
5.3 SAFETY POPULATION (ALL SUBJECT TREATED (APT)) 
This population consists of the ITT population, after exclusion of subjects who never used the 
treatment with certainty based on monitoring report. The APT population will be only used for the 
safety variables (AEs) 
 
 
5.4 MISSING VALUES 
In order to evaluate the effect of major deviations or of data exclusions, the last observation carried 
forward (LOCF) method will be used to impute missing values for inflammatory lesion count and 
IGA. If no post-baseline data are available, baseline will be carried forward. Thus, the number of 
subjects will not vary at each visit. The other missing values will not be replaced (observed data). 
 
 
5.5 POOLING OF CENTERS 
In case of too small sites or in case of severe unbalance between the size of sites, some sites may be 
combined, e.g. per geographical area, to form analysis-center for purpose of stratification of the 
statistical analyses. 


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6. STATISTICAL METHODS AND DATA CONSIDERATIONS 
SAS version 9.3 will be used for all analyses. All tests will be two-sided and significance will be 
declared at a 0.05 level. 
 
 
6.1 DATA PRESENTATION 
All continuous data will be summarized at each visit using usual statistics: number of values, mean, 
median, standard deviation, minimum and maximum, and by frequency distribution (n, %) for 
qualitative data. For ordinal data, both frequency distribution and usual statistics will be presented. 
All tables will be presented by parallel group and by visit (when applicable).  
 
The adverse events will be descriptively summarized (n, %). All summaries are based on the safety 
population (APT). The adverse events will be descriptively summarized (n, %) by relationship to 
study treatments within System Organ Class (SOC) and preferred term (MedDRA). Subjects will 
be descriptively summarized (n, %) by intensity (i.e. mild, moderate and severe) of adverse event, 
SOC and preferred term. Deaths and serious adverse events will be reported as well as withdrawals 
due to adverse events. A subject will be counted once per System Organ Class (SOC) and once per 
preferred term even if more than one occurrence of an event was reported within a SOC or 
preferred term. In the summary by categories of intensity, the adverse event with the highest 
intensity will be used. The subject will be counted once per SOC (highest intensity whatever the 
AE within the SOC) and once per preferred term (highest intensity whatever the AE within the 
preferred term).  
 
 
6.2 STUDY SUBJECTS 
6.2.1 Subject disposition 
Normal completion as well as early discontinuation will be described on the ITT population.  
Reasons for withdrawals and normal completions will be summarized using frequency distribution 
(n, %).  All withdrawals will be detailed in a subject-by-subject listing. 
6.2.2 Protocol deviation 
Major protocol deviations will be summarized using frequency distribution (n, %) detailed in a 
subject-by-subject listing. 
6.2.3 Data sets analyzed 
Number of subjects included in each efficacy analyses (PP, ITT) and number of patients included in 
the safety analysis (APT) will be presented by parallel group and overall. 
 


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6.2.4 Demographic data 
Demographic data collected at baseline will be descriptively summarized for ITT population by 
parallel group and overall. 
6.2.5 Rosacea co-morbidities and Medical history  
Rosacea co-mobordities and medical history defined as the relevant or major illnesses not 
previously reported as co-mobordities present before the baseline visit will be presented separately 
by System Organ Class and preferred term (MedDRA). 
6.2.6 Medical history of acute rosacea (worsening) 
Facial rosacea duration will be descriptively summarized on the ITT population, by duration 
classes, study group and overall. 
History of flushing or worsening of erythema will be descriptively summarized on the ITT 
population using frequency distribution (n, %), by type of stimuli triggers, study group and overall.  
6.2.7 Previous and concomitant drug and procedure therapies 
Previous drugs/procedures therapies are defined as drugs/procedures stopped on or before the 
baseline visit. Concomitant drugs/procedures are defined as drugs/procedures occurred between 
the baseline visit and the last visit. Previous and Concomitant drugs/procedures will be 
descriptively summarized on the ITT population, by Anatomical-therapeutic-chemical (ATC) text 
level 5 and drug name for drugs and by SOC and preferred term for procedures, by study group and 
overall. Frequency distribution of subjects with at least one previous drug/ procedure at baseline 
and/or with at least one concomitant drug/procedure will be tabulated (n, %). 
6.2.8 Compliance 
Compliance of investigational products (oral and topical) will be calculated from the data captured 
at every visit and will be summarized by group in terms of frequency counts and percentages by 
products and for the association of investigational products. The compliance will be calculated as 
follows: 
 
Compliance= ((Date of last visit - Date of baseline) - total number of missing applications)*100 
(Date of last visit - Date of baseline). 
 
Compliance of the moisturizer will be also calculated as follows: 
 
Moisturizer compliance = Total number of days where the moisturizer was used *100 
(Date of last visit – Date of baseline) 
6.2.9 Baseline disease characteristics 
The characteristics of the disease collected at baseline will be descriptively summarized on ITT 
population by parallel group and overall. 


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6.3 EFFICACY ANALYSES 
 
6.3.1 Primary efficacy analyses 
The primary objective of this study was to demonstrate the superiority of the IVM/Doxy compared 
to IVM/Placebo, in terms of percent change from baseline in inflammatory lesion count at week 12.  
 
The primary efficacy endpoint will be analyzed by using the Cochran-Mantel-Haenszel (CMH, 
FREQ procedure from SAS®) statistic, stratified by center (or analysis-center) after ridit 
transformation with the row mean difference statistics, testing the hypothesis of equality on 
ITT/LOCF population. PP analysis will also be performed to assess the robustness of the results 
obtained on ITT/LOCF population. The p-values will have to be inferior to 0.05 at week 12.  
6.3.2 Secondary and other efficacy analyses 
The variables will be analyzed similarly as primary analyses on ITT/LOCF population at each 
post-baseline evaluation time on appropriate population. 
 
 
6.4 PATIENT-REPORTED OUTCOMES ANALYSES 
DLQI, EQ-5D-5L, WPAI-GH and subject satisfaction questionnaires will be statistically analyzed 
similarly as primary analyses on ITT population at each post-baseline evaluation time. 
 
 
6.5 SAFETY ANALYSES 
6.5.1 Extent of exposure 
6.5.1.1 Treatment duration 
Treatment duration will be calculated as the number of days between the date of first use and the 
date of the last use of each study treatment (oral and topical). In case of missing data of last use, the 
last visit will be taken into account. 
 
6.5.2 Adverse Events 
The adverse events will be summarized (n, %) for APT population by parallel group. Deaths and 
serious adverse events will be reported as well as withdrawals due to adverse events. 
In case of worsening of rosacea, a specific questionnaire was filled on and the results will be listed. 


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7. CHANGES FROM THE PROTOCOL ANALYSIS PLAN 
 
The Percent of subject clear inflammatory lesions (100% reduction of IL) at each post-baseline 
visit will be analyzed. 
 
 


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APPENDIX 1: LIST AND FORMAT OF TABLES 
GENERAL FEATURES 
 
 Margins for portrait orientation 
 
• Top 
= 3.71 cm 
 
• Bottom 
= 3.17 cm 
 
• Left 
= 3 cm 
 
• Right 
= 1.4 cm 
 
• Heading 
= 2.41 cm 
 
• Footnote 
= 2.16 cm 
 
 Margins for landscape orientation 
 
• Top 
= 3 cm 
 
• Bottom 
= 1.4 cm 
 
• Left 
= 3.17 cm 
 
• Right 
= 3.71 cm 
 
• Heading 
= 2.16 cm 
 
• Footnote 
= 1.25 cm 


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8. TABLE SHELLS 
14.1. Study Subjects 
14.1.1. Conduct of the study 
Table 1. Enrolment by analysis center and investigational site (ITT) 
 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
Total  
(N=xxx) 
Analysis-Center 1 (n,%) 
 
 
Center 1 (n,%) 
 
 
….. 
 
 
Analysis-Center 2 (n,%) 
 
 
…. 
 
 
 
 
Table 2.1. Subjects who discontinued study and reason for discontinuation (ITT) 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
Total 
(N=xxx) 
Randomized 
 
 
 
Normal study completion n (%) 
 
 
 
Premature discontinuation n (%) 
 
 
 
Lack of efficacy n (%) 
 
 
 
Adverse event n (%) 
 
 
 
….. 
 
 
 
Table 2.2. Listing of subjects who discontinued treatment and reason for discontinuation (ITT) 
(Include : treatment, investigator number, subject number and reason for discontinuation) 
 
 
Table 3. Adherence to the visit schedule in days (ITT) 
IVM + Doxycycline 
IVM + Vehicle 
Total 
Nb of days between baseline visit and week 4 visit 
 
 
 
N 
 
 
 
Mean±SD 
 
 
 
Median 
 
 
 
(Min,Max) 
 
 
 
... 
 
 
 
Nb of days between baseline visit and week 12 visit 
 
 
 
N 
 
 
 
Mean±SD 
 
 
 
Median 
 
 
 
(Min,Max) 
 
 
 
Nb of days between baseline visit and last visit 
 
 
 
N 
 
 
 
Mean±SD 
 
 
 
Median 
 
 
 
(Min,Max) 
 
 
 
 


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Table 4.1. Major protocol deviations (ITT) 
 
IVM + Doxycycline 
IVM + Vehicle 
Total 
eg: 
N. 
% subj. 
N 
% subj. 
N 
% subj. 
AT LEAST ONE MAJOR DEVIATION 
 
 
 
 
 
 
No post-Baseline data 
 
 
 
 
 
 
No study medication dispensed 
 
 
 
 
 
 
… 
 
 
 
 
 
 
A subject may have several major protocol deviations  
Numbers in columns cannot be added because a given subject may have reported more than one deviation. 
 
Table 4.2. Listing of subjects with Major protocol deviations (ITT) 
(Include : treatment, investigator number, subject number, reason and detail of deviations) 
 
 
Table 5. Data sets analyzed 
IVM + Doxycycline 
IVM + Vehicle 
 Total 
Intent to treat population (ITT)  n(%) 
Per Protocol population (PP)  n(%)* 
Safety population (APT) n(%)* 
* Denominator is the number of subjects in the Intent to treat population 
 
 


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14.1.2. Subject characteristics 
Table 6. Demographic data (ITT) 
 
IVM + Doxycycline 
IVM + Vehicle 
Total 
Gender 
N 
Male n(%) 
Female n(%) 
 
 
 
Age 
N 
18-65 years 
>= 65 years 
Mean SD 
Median 
Min,Max 
 
 
 
Race 
N 
White n (%) 
Black n (%) 
… 
 
 
 
Ethnicity* 
N 
Hispanic or Latino n (%) 
Not hispanic or Latino n (%) 
… 
 
 
 
Phototype 
N 
I n (%) 
II n (%) 
…. 
 
 
 
* Ethnicity is optional for Canada and Europe 
 
 
Table 7. Rosacea co-morbidities (ITT) 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
Total 
(N=xxx) 
Subjects reporting at least one co-morbidity 
 
 
 
List all co-morbidities by SOC and preferred term 
 
 
 
The numbers in the columns cannot be added because a given subject could report more than one co-morbidity 
 
 
Table 8. Medical history other than co-morbidities (ITT) 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
Total 
(N=xxx) 
Subjects reporting at least one medical history 
 
 
 
List all medical histories by SOC and preferred 
term 
 
 
 
The numbers in the columns cannot be added because a given subject could report more than one medical history 
 
 


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Table 9. Medical history of rosacea (ITT) 
 
IVM + Doxycycline 
IVM + Vehicle 
Total 
For rosacea: duration in year  
N 
Less than 1 year  n(%) 
Between 1 and 5 year  n(%) 
More than 5 years  n(%) 
Mean ±SD 
Median 
Min,Max 
 
 
 
History of flushing or worsening of erythema 
N 
No  n(%) 
Yes n(%) 
 
 
 
Stimuli triggers 
Spicy food n(%) 
…. 
 
 
 
 
 
Table 10. Previous drug therapies within the previous 6 months, by ATC text and drug name (ITT) 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
Total 
(N=xxx) 
Subjects reporting at least one previous therapy 
 
 
 
List all previous drugs by ATC and drug name. 
 
 
 
The numbers in the columns cannot be added because a given subject could report more than one previous therapy 
 
 
Table 11. Previous procedure therapies within the previous 6 months, by System Organ class and Preferred 
Term (ITT) 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
Total 
(N=xxx) 
Subjects reporting at least one previous procedure 
 
 
 
List all previous procedures by SOC and preferred term 
 
 
 
The numbers in the columns cannot be added because a given subject could report more than one previous procedure. 
 
 
Table 12. Concomitant drug therapies by ATC text and drug name (ITT) 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
Total 
(N=xxx) 
Subjects with at least one concomitant medication 
 
 
 
List all concomitant drugs by ATC and drug name 
 
 
 
The numbers in the columns cannot be added because a given subject could report more than one concomitant therapy. 
 
 
Table 13. Concomitant procedure therapies by System Organ Class and Preferred Term (ITT) 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
Total 
(N=xxx) 
Subjects with at least one concomitant procedure 
 
 
 
List all concomitant procedures by SOC and preferred term 
 
 
 
The numbers in the columns cannot be added because a given subject could report more than one concomitant 
procedure. 


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Table 14. Baseline disease characteristics (ITT) 
 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
Total 
(N=xxx) 
Facial inflammatory lesion counts 
N 
Mean ±SD 
Median 
Min,Max 
 
 
 
Clinician's Erythema Assessment 
N 
3: Moderate n (%) 
4: Severe n (%) 
Mean ±SD 
Median 
Min,Max 
 
 
 
Investigator’s Global Assessment 
N 
4: Severe n (%) 
Mean ±SD 
Median 
Min,Max 
 
 
 
Severity Score of Stinging/Burning 
N 
0: None n (%) 
1: Mild n (%) 
2: Moderate n (%) 
3: Severe n (%) 
Mean ±SD 
Median 
Min,Max 
 
 
 
Ocular Signs and Symptoms 
N 
0: None n (%) 
1: Mild n (%) 
2: Mild-Moderate n (%) 
3: Moderate-Severe n (%) 
4: Severe n (%) 
Mean ±SD 
Median 
Min,Max 
 
 
 
Number of flushing during the last week before 
baseline  
N 
Mean ±SD 
Median 
Min,Max 
 
 
 
Average severity of flushing during the last week 
before baseline 
N 
Mild  n(%) 
Moderate n(%) 
Severe n(%) 
 
 
 


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14.2. Efficacy analyses 
14.2.1. Primary efficacy analyses 
 
Table 15. Inflammatory lesions: % change from baseline at week 12 (ITT/LOCF) 
 
IVM + Doxycycline 
IVM + Vehicle 
p-value (1) 
Week 12 (ITT/LOCF) 
N 
Mean ±SD 
Median 
Min,Max 
 
 
xxx 
Week 12 (PP) 
….. 
 
 
 
xxx 
(1) p-value of CMH test based on ridit scores stratified by analysis-center. 
 


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14.2.2. Secondary efficacy analyses 
14.2.2.1. Inflammatory lesions 
 
 
Table 16. Inflammatory lesions: % change from baseline at other post-baseline visit (ITT/LOCF) 
 
IVM + Doxycycline 
IVM + Vehicle 
p-value (1) 
Week 4 (ITT/LOCF) 
N 
Mean ±SD 
Median 
Min,Max 
 
 
xxx 
Week 8 (ITT/LOCF) 
….. 
 
 
 
xxx 
(1) p-value of CMH test based on ridit scores stratified by analysis-center.  
 
 
 
Table 17. Inflammatory lesions: 100% reduction from baseline at each post-baseline visit (ITT/LOCF) 
 
IVM + Doxycycline 
IVM + Vehicle 
p-value (1) 
Week 4 (ITT/LOCF) 
N 
No (n,%) 
Yes(n,%) 
 
 
xxx 
Week 8 (ITT/LOCF) 
… 
 
 
xxx 
Week 12 (ITT/LOCF) 
….. 
 
 
 
xxx 
(1) p-value of CMH test based on ridit scores stratified by analysis-center.  
 
 
 
Table 18. Inflammatory lesions: Count at each visit - Descriptive (ITT/LOCF) 
 
IVM + Doxycycline 
IVM + Vehicle 
Baseline 
N 
Mean ±SD 
Median 
Min,Max 
 
 
….. 
 
 
Week 12 (ITT/LOCF) 
….. 
 
 
 
 


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14.2.2.2. Clinician's Erythema Assessment 
 
 
Table 19. Clinician's Erythema Assessment: Raw value at each visit (ITT/LOCF) 
 
 
IVM + Doxycycline 
IVM + Vehicle 
p-value (1) 
Baseline 
….. 
 
 
 
NA 
Week 4 (ITT/LOCF) 
N 
0: Clear n (%) 
1: Almost clear n (%) 
2: Mild n (%) 
3: Moderate n (%) 
4: Severe n (%) 
Mean ±SD 
Median 
Min,Max 
 
 
 
xxx 
….. 
 
 
 
Week 12 (ITT/LOCF) 
….. 
 
 
 
xxx 
(1) p-value by CMH test based on ridit scores stratified by analysis-center. 
 
 
 
14.2.2.3. Investigator’s Global Assessment 
 
Table 20. Investigator’s Global Assessment full scale at each visit (ITT/LOCF) 
 
IVM + Doxycycline 
IVM + Vehicle 
p-value (1) 
Baseline 
N 
0: Clear n (%) 
1: Almost clear n (%) 
2: Mild n (%) 
3: Moderate n (%) 
4: Severe n (%) 
Mean ±SD 
Median 
Min,Max 
 
 
 
NA 
….. 
 
 
 
Week 12 (ITT/LOCF) 
…… 
 
 
 
xxx 
(1) p-value by CMH test based on ridit scores stratified by analysis-center. 


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14.2.2.4. Stinging/Burning severity score 
 
Table 21. Stinging/Burning at each visit (ITT/LOCF) 
 
 
IVM + Doxycycline 
IVM + Vehicle 
p-value (1) 
Baseline 
N 
0: None n (%) 
1: Mild n (%) 
2: Moderate n (%) 
3: Severe n (%) 
Mean ±SD 
Median 
Min,Max 
 
 
NA 
 … 
 
 
 
Week 12 (ITT/LOCF) 
... 
 
 
 
xxx 
(1) p-value by CMH test based on ridit scores stratified by analysis-center. 
 
 
 
14.2.2.5. Subject’s Global Improvement  
 
 
Table 22. Subject’s Global Improvement at last visit (ITT) 
 
 
IVM + Doxycycline 
IVM + Vehicle 
p-value (1) 
N 
0: Complete Improvement n (%) 
1: Excellent Improvement n (%) 
2: Very good Improvement n (%) 
3: Good Improvement n (%) 
4: Minimal Improvement n (%) 
5: No Change n(%) 
6: Worse n (%) 
Mean ±SD 
Median 
Min,Max 
 
 
 
xxx 
(1) p-value for between treatment difference, by CMH test based on ridit scores stratified by analysis-center. 
 
 


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14.2.3. Exploratory efficacy analyses 
 
14.2.3.1. Ocular signs 
 
Table 23. Ocular signs and symptoms at each visit (ITT) 
 
 
IVM + Doxycycline 
IVM + Vehicle 
p-value (1) 
Baseline 
N 
0: None n (%) 
1: Mild n (%) 
2: Mild-Moderate n (%) 
3: Moderate-Severe n (%) 
4: Severe n (%) 
Mean ±SD 
Median 
Min,Max 
 
 
NA 
 … 
 
 
 
Week 12 (ITT) 
... 
 
 
 
xxx 
(1) p-value by CMH test based on ridit scores stratified by analysis-center. 
 
 


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14.2.3.2. Flushing 
 
Table 24. Number of flushing per week: % change from baseline (ITT) 
 
IVM + Doxycycline 
IVM + Vehicle 
p-value (1) 
Week1 
N 
Mean ±SD 
Median 
Min,Max 
 
 
xxx 
 … 
 
 
 
Week 12 
….. 
 
 
 
xxx 
(1) p-value of CMH test based on ridit scores stratified by analysis-center. 
 
 
 
 
Table 25. Number of flushing per week: Count at each visit - Descriptive (ITT) 
 
IVM + Doxycycline 
IVM + Vehicle 
Baseline 
N 
Mean ±SD 
Median 
Min,Max 
 
 
….. 
 
 
Week 12 
….. 
 
 
 
 


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Table 26. Mean score severity of flushing per week: change from baseline (ITT) 
 
IVM + Doxycycline 
IVM + Vehicle 
p-value (1) 
Week1 
2 grades less n (%) 
1 grade less n (%) 
0: No change  n (%) 
1 grade more n (%) 
2 grades more n (%) 
 
 
 
xxx 
 … 
 
 
 
Week 12 
….. 
 
 
 
xxx 
(1) p-value of CMH test based on ridit scores stratified by analysis-center. 
 
 
Table 27. Mean score severity of flushing per week: Count at each visit - Descriptive (ITT) 
 
IVM + Doxycycline 
IVM + Vehicle 
Baseline 
N 
1-Mild 
2-Moderate 
3-Severe 
Mean ±SD 
Median 
Min,Max 
 
 
….. 
 
 
Week 12 
….. 
 
 
 
 
 
 
14.2.3.3. Colorimetry 
 
Table 28. Colorimetry CEI: % change from baseline (ITT) 
 
IVM + Doxycycline 
IVM + Vehicle 
p-value (1) 
Week4 
N 
Mean ±SD 
Median 
Min,Max  
 
 
xxx 
 … 
 
 
 
Week 12 
….. 
 
 
 
xxx 
(1) p-value of CMH test based on ridit scores stratified by analysis-center. 


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14.2.4. Patient reported outcomes 
 
14.2.4.1. Dermatology Life Quality Index 
Table 29. DLQI at baseline - Descriptive (ITT) 
 
IVM + Doxycycline 
IVM + Vehicle 
1. DLQI itch, sore, painful, stinging? 
 
 
N  
 
 
0: Not at all 
 
 
1: A little  
 
 
2: A lot 
 
 
3: Very much 
 
 
…… 
 
 
10. DLQI problem caused by treatment? 
 
 
N  
 
 
0: Not at all 
 
 
0: Not relevant 
 
 
1: A little  
 
 
2: A lot 
 
 
3: Very much 
 
 
 
 
Table 30. DLQI at last visit - Descriptive (ITT) 
 
 
Table 31. DLQI: Total score at each visit and percent change from baseline (ITT) 
 
IVM + Doxycycline 
IVM + Vehicle 
p-value 
Baseline (Total score) 
 
 
 
N  
 
 
NA 
0-1: No effect at all on patient's life 
 
 
 
2-5: Small effect on patient's life 
 
 
 
6-10: Moderate effect on patient's life 
 
 
 
Mean±SD 
 
 
 
Median 
 
 
 
(Min,Max) 
 
 
 
Last visit (Total score) 
 
 
xxx 
… 
 
 
 
Last visit (% change from Baseline) 
 
 
 
N  
 
 
xxx 
Mean±SD 
 
 
 
Median 
 
 
 
(Min,Max) 
(1) p-value by CMH test based on ridit scores stratified by analysis-center. 


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14.2.4.2. EQ-5D-5L questionnaire 
Table 32. EQ-5D-5L questionnaire at baseline - Descriptive (ITT) 
 
IVM + Doxycycline 
IVM + Vehicle 
Mobility 
 
 
N  
 
 
I have no problems walking 
 
 
I have slight problems walking 
 
 
I have moderate problems walking 
 
 
I have severe problems walking 
 
 
I have unable to walk 
 
 
Self-Care 
 
 
… 
 
 
Usual Activities 
 
 
… 
 
 
Pain/Discomfort 
 
 
… 
 
 
Anxiety/Depression 
 
 
… 
 
 
Health State Today 
N 
Mean SD 
Median 
Min,Max 
 
 
 
 
Table 33. EQ-5D-5L questionnaire at last visit (ITT) 
 
IVM + Doxycycline 
IVM + Vehicle 
p-value (1) 
Mobility 
 
 
 
N  
 
 
xxx 
I have no problems in walking about 
 
 
 
I have slight problems in walking about 
 
 
 
I have moderate problems in walking about 
 
 
 
I have severe problems in walking about 
 
 
 
I have unable to walk about 
 
 
 
Self-Care 
 
 
 
….  
 
 
xxx 
Usual Activities 
 
 
 
… 
 
 
xxx 
Pain/Discomfort 
 
 
 
… 
 
 
xxx 
Anxiety/Depression 
 
 
 
… 
 
 
xxx 
Health State Today 
N 
Mean SD 
Median 
Min,Max 
 
 
 
xxx 
(1) p-value by CMH test based on ridit scores stratified by analysis-center. 


GALDERMA PHASE IV  
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN FOR RD.03.SPR.113322 
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14.2.4.3. Work Productivity and Activity Impairment Questionnaire: General Health 
(WPAI:GH) 
 
Table 34. WPAI :GH questionnaire at baseline - Descriptive (ITT) 
 
IVM + Doxycycline 
IVM + Vehicle 
Currently employed 
 
 
N  
 
 
No 
 
 
Yes 
 
 
Missed hours from work because of rosacea? 
 
 
N 
Mean SD 
Median 
Min,Max 
 
 
Missed hours from work because of other reason? 
 
 
… 
 
 
Number of Working hours 
 
 
… 
 
 
How much rosacea affect productivity at work? 
 
 
… 
 
 
How much rosacea affect daily activity? 
N 
Mean SD 
Median 
Min,Max 
 
 
 
Table 35. WPAI :GH questionnaire at last visit (ITT) 
 
IVM + Doxycycline 
IVM + Vehicle 
p-value (1) 
Currently employed 
 
 
 
N  
 
 
xxx 
No 
 
 
 
Yes 
 
 
 
Missed hours from work because of rosacea? 
 
 
xxx 
N 
Mean SD 
Median 
Min,Max 
 
 
 
Missed hours from work because of other reason? 
 
 
xxx 
… 
 
 
 
Number of Working hours 
 
 
xxx 
… 
 
 
 
How much rosacea affect productivity at work? 
 
 
xxx 
… 
 
 
 
How much rosacea affect daily activity? 
N 
Mean SD 
Median 
Min,Max 
 
 
xxx 
(1) p-value by CMH test based on ridit scores stratified by analysis-center. 
 


GALDERMA PHASE IV  
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STATISTICAL ANALYSIS PLAN FOR RD.03.SPR.113322 
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14.2.4.4. Subject’s satisfaction questionnaire 
 
Table 36. Subject's satisfaction questionnaire – Part A at last visit (ITT) 
 
Questions about study drugs 
IVM + 
Doxycycline 
IVM +  
Vehicle 
p-value (1) 
1. How satisfied are you with the amount of time the study 
regimen took to work? 
 
 
 
N  
 
 
xxx 
Very satisfied 
 
 
 
Satisfied 
 
 
 
Somewhat satisfied 
 
 
 
Not satisfied 
 
 
 
….. 
 
 
 
12. How did you find the study regimen compared to your last 
treatment? 
 
 
 
N 
 
 
xxx 
A lot better 
 
 
 
Better 
 
 
 
Similar 
 
 
 
Worse 
 
 
 
Never treated with a previous treatment 
 
 
 
(1) p-value by CMH test based on ridit scores stratified by analysis-center. 
 
 
 
 
 
Table 37. Subject's satisfaction questionnaire – Part B at last visit (ITT) 
 
Questions about skin care products Cleanser and Moisturizer 
IVM + 
Doxycycline 
IVM +  
Vehicle 
p-value (1) 
1. Both skin care products easy to incorporate into a daily 
routine 
 
 
 
N  
 
 
xxx 
Strongly agree 
 
 
 
Agree 
 
 
 
Neither agree or disagree 
 
 
 
Disagree 
 
 
 
Strongly disagree 
 
 
 
….. 
 
 
 
10. Both skin care products are pleasant to use? 
 
 
 
N 
 
 
xxx 
Strongly agree 
 
 
 
Agree 
 
 
 
Neither agree or disagree 
 
 
 
Disagree 
 
 
 
Strongly disagree 
 
 
 
(1) p-value by CMH test based on ridit scores stratified by analysis-center. 


GALDERMA PHASE IV  
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STATISTICAL ANALYSIS PLAN FOR RD.03.SPR.113322 
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Table 38. Subject's satisfaction questionnaire – Part C at last visit (ITT) 
 
Questions about the cosmetic product cleanser 
IVM + 
Doxycycline 
IVM +  
Vehicle 
p-value (1) 
1. The Cleanser left my skin with a clean healthy feeling 
 
 
 
N  
 
 
xxx 
Strongly agree 
 
 
 
Agree 
 
 
 
Neither agree or disagree 
 
 
 
Disagree 
 
 
 
Strongly disagree 
 
 
 
….. 
 
 
 
4. The Cleanser did not make my skin feel tight or dry 
 
 
 
N 
 
 
xxx 
Strongly agree 
 
 
 
Agree 
 
 
 
Neither agree or disagree 
 
 
 
Disagree 
 
 
 
Strongly disagree 
 
 
 
(1) p-value by CMH test based on ridit scores stratified by analysis-center. 
 
 
 
 
 
Table 39. Subject's satisfaction questionnaire – Part D at last visit (ITT) 
 
Questions about the cosmetic product Moisturizer 
IVM + 
Doxycycline 
IVM +  
Vehicle 
p-value (1) 
1. The Moisturizer made my skin feel soft and smooth 
 
 
 
N  
 
 
xxx 
Strongly agree 
 
 
 
Agree 
 
 
 
Neither agree or disagree 
 
 
 
Disagree 
 
 
 
Strongly disagree 
 
 
 
….. 
 
 
 
4. The Moisturizer provided a conforting sensation on the 
skin 
 
 
 
N 
 
 
xxx 
Strongly agree 
 
 
 
Agree 
 
 
 
Neither agree or disagree 
 
 
 
Disagree 
 
 
 
Strongly disagree 
 
 
 
(1) p-value by CMH test based on ridit scores stratified by analysis-center. 


GALDERMA PHASE IV  
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN FOR RD.03.SPR.113322 
12 April 2018 
 
 
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14.3 Safety analyses 
14.3.1. Extent of Exposure  
Table 40. Quantity of topical treatment in gram (1) used during the study (APT) 
 
IVM + Doxycycline 
IVM + Vehicle 
N 
Mean±SD 
Median 
Min,Max 
 
 
(1) Assumes non-returned products were used in the same way as returned products. 
 
 
Table 41. Extent of exposure (days) (APT) 
 
IVM + Doxycycline 
IVM + Vehicle 
Oral treatment 
N 
Mean±SD 
Median 
Min,Max 
 
 
Topical treatment 
N 
Mean±SD 
Median 
Min,Max 
 
 
Treatment duration will be calculated as the number of days between the date of first use and the date of the last use of each study 
treatment (oral and topical). In case of missing data of last use, the last visit will be taken into account. 
 


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Table 42. Compliance for investigational products (APT) 
 
IVM + Doxycycline 
IVM + Vehicle 
Compliance for oral treatment 
N 
<25% of compliance 
[25%;50%[of compliance 
[50%;75%[of compliance 
>=75% of compliance 
Mean±SD 
Median 
Min,Max 
 
 
Compliance for topical treatment 
N 
<25% of compliance 
[25%;50%[of compliance 
[50%;75%[of compliance 
>=75% of compliance 
Mean±SD 
Median 
Min,Max 
 
 
Overall compliance of investigational product 
N 
<25% of compliance 
[25%;50%[of compliance 
[50%;75%[of compliance 
>=75% of compliance 
Mean±SD 
Median 
Min,Max 
 
 
Compliance= ((Date of last visit - Date of baseline) - total number of corresponding missing applications)*100/ (Date 
of last visit - Date of baseline). 
Overall compliance is the mean of each compliance. 
 
Table 43. Compliance for the Moisturizer (APT) 
 
IVM + Doxycycline 
IVM + Vehicle 
N 
<25% of compliance 
[25%;50%[of compliance 
[50%;75%[of compliance 
>=75% of compliance 
Mean±SD 
Median 
Min,Max 
 
 
Moisturizer compliance = total number of days where the moisturizer was used *100/ (Date of last visit – Date of 
baseline) 
 


GALDERMA PHASE IV  
CONFIDENTIAL 
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14.3.2. Adverse events  
Table 44. Overview of adverse events by group (APT) 
 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
Event 
Subject* n(%) 
Event 
Subject* n(%) 
All AEs 
 
 
 
 
All dermatologic AEs 
 
 
 
 
All worsening of rosacea AEs 
 
 
 
 
All severe AEs 
 
 
 
 
All serious AEs 
 
 
 
 
Deaths 
 
 
 
 
All AEs leading to discontinuation 
 
 
 
 
Related AEs 
 
 
 
 
Related dermatologic AEs 
 
 
 
 
Related worsening of rosacea AEs 
 
 
 
 
Related severe AEs 
 
 
 
 
Related serious AEs 
 
 
 
 
Related AEs leading to discontinuation 
 
 
 
 
* Subjects with at least one event. Numbers in columns cannot be added because a given subject may have reported 
more than one AE. 
 


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Table 45. Frequency of all adverse events by preferred term (APT) 
e.g. 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
Abdominal pain nos 
Event 
Subject* n(%) 
Event 
Subject* n(%) 
Diarrhoea nos 
 
 
 
 
Peptic ulcer 
 
 
 
 
…. 
 
 
 
 
* Subjects with at least one event.  
Numbers in columns cannot be added because a given subject may have reported more than one AE. 
 
 
Table 46. Frequency of all adverse events (except SAE) by preferred term (APT) 
 
 
Table 47. Frequency of related adverse events by preferred term (APT) 


GALDERMA PHASE IV  
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Table 48: Frequency of all adverse events by SOC and preferred term (APT) 
e.g. 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
ANY ADVERSE EVENT 
Event 
Subject* n(%) 
Event 
Subject* n(%) 
GASTROINTESTINAL DISORDERS 
 
 
 
 
Abdominal pain nos 
 
 
 
 
Diarrhoea nos 
 
 
 
 
Peptic ulcer 
 
 
 
 
Vomiting nos 
 
 
 
 
IMMUNE SYSTEM DISORDERS 
 
 
 
 
Allergic sinusitis 
 
 
 
 
Conjunctivitis allergic 
 
 
 
 
…. 
 
 
 
 
*Subjects with at least one event. Numbers in columns cannot be added because a given subject may have reported 
more than one AE. 
A subject was counted once per SOC and once per preferred term even if more than one occurrence of an event was 
reported within a SOC or preferred term. 
 
Table 49. Frequency of related adverse by SOC and preferred term (APT) 


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Table 50. Subject incidence by severity of all adverse events by SOC and preferred term (APT) 
 
e.g. 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
Mild  
n(%) 
Moderate  
n(%) 
Severe  
n(%) 
Mild  
n(%) 
Moderate  
n(%) 
Severe  
n(%) 
ANY ADVERSE EVENT 
 
 
 
 
 
 
GASTROINTESTINAL DISORDERS 
 
 
 
 
 
 
Abdominal pain nos 
 
 
 
 
 
 
Diarrhoea nos 
 
 
 
 
 
 
Peptic ulcer 
 
 
 
 
 
 
Vomiting nos 
….. 
 
 
 
 
 
 
IMMUNE SYSTEM DISORDERS 
 
 
 
 
 
 
Allergic sinusitis 
 
 
 
 
 
 
Conjunctivitis allergic 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
*Subjects with at least one event.  
Numbers in columns cannot be added because a given subject may have reported more than one AE. 
A subject was counted once per SOC (highest intensity whatever the AE within the SOC) and once per preferred term (highest 
intensity if more than one occurrence of an event is reported) 
 
 
 
Table 51. Subject incidence by severity of related adverse events by SOC and preferred term (APT) 


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Table 52. Incidence of subject with serious adverse events by SOC and preferred term (APT) 
e.g. 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
Event 
Subject* n(%) 
Event 
Subject* n(%) 
ANY SERIOUS ADVERSE EVENT 
 
 
 
 
GASTROINTESTINAL DISORDERS 
Abdominal pain nos 
…. 
 
 
 
 
*Subjects with at least one event. Numbers in columns cannot be added because a given subject may have reported more than one 
AE. 
A subject was counted once per SOC and once per preferred term even if more than one occurrence of an event was reported within 
a SOC or preferred term. 
 
(A listing can be provided with the information of the AE form if too few SAE) 
Table 52. Listing of subjects with serious adverse events (APT) 
(Include : subject number, treatment group, SOC, preferred term, date of onset, severity, subject discontinued, outcome, 
date of resolution and relationship 
 
 
Table 53. Incidence of subject with adverse events leading to discontinuation of treatment by SOC and 
preferred term (APT) 
e.g. 
IVM + Doxycycline 
(N=xxx) 
IVM + Vehicle 
(N=xxx) 
Event 
Subject* n(%) 
Event 
Subject* n(%) 
ANY SERIOUS ADVERSE EVENT 
 
 
 
 
GASTROINTESTINAL DISORDERS 
Abdominal pain nos 
…. 
 
 
 
 
*Subjects with at least one event. Numbers in columns cannot be added because a given subject may have reported more than one 
AE. 
A subject was counted once per SOC and once per preferred term even if more than one occurrence of an event was reported within 
a SOC or preferred term. 
 
(A listing can be provided with the information of the AE form if too few subjects with adverse events leading to 
discontinuation of treatment) 
Table 53. Listing of subjects with adverse events leading to discontinuation of treatment (APT) 
(Include : subject number, treatment group, SOC, preferred term, date of onset, severity, SAE, outcome, date of 
resolution and relationship) 
 
 
 
Table 54. List of worsening of rosacea AEs (APT)