Clinical trial NCT02566369
Conditions: Acne Vulgaris
Keywords: Efficacy Safety Acne vulgaris
Sponsor: Galderma R&D
Start date: 2015-11-30; Completion date: 2017-11-14
Enrollment: 1208 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Assessment of the efficacy and safety of CD5789 (trifarotene) 50μg/g cream applied once daily for 12 weeks in subjects with acne vulgaris.

Detailed description:
Clinical Trial for each subject is approximately 14 weeks and are randomized to one of the two treatments for 12 weeks. Subjects must be 9 years of age and older with acne vulgaris.

Arms: arm 1: CD5789 (trifarotene) 50μg/g Cream arm 2: Placebo cream
Interventions: intervention 1: CD5789 (trifarotene) 50μg/g cream intervention 2: Placebo cream
Intervention descriptions: intervention 1: CD5789 (trifarotene) 50µg/g cream applied once daily for 12 weeks. intervention 2: Placebo cream applied once daily for 12 weeks

Protocol documents:
SAP_002.pdf: 
A Multi-Center, Randomized, Double-blind, Parallel-group, Vehicle Controlled Study to Compare 
Efficacy and Safety of Cd5789 50μg/G Cream Versus Vehicle Cream in Subjects With Acne Vulgaris 
NCT number: NCT02566369
Date: 05 Oct 2015


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A MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, 
VEHICLE CONTROLLED STUDY TO COMPARE EFFICACY AND SAFETY OF 
CD5789 50µg/g CREAM VERSUS VEHICLE CREAM IN SUBJECTS WITH ACNE 
VULGARIS 
STATISTICAL ANALYSIS PLAN 
RD.06.SPR.18251 
Version Final 
05Oct2015 
This document is electronically approved and signed by:  Biometrics Manager 




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TABLE OF CONTENTS 
1 
OBJECTIVES ................................................................................................................................... 5 
2 
STUDY DESIGN ............................................................................................................................... 5 
3 
EFFICACY AND SAFETY ASSESSMENT .................................................................................. 6 
3.1 
Efficacy Assessment ..................................................................................................................... 6 
3.1.1 
IGA (Investigator’s global assessment) of facial acne ......................................................... 6 
3.1.2 
PGA (Physician Global Assessment) of truncal acne........................................................... 6 
3.1.3 
Lesions counts on the face and trunk .................................................................................... 7 
3.1.4 
Subject self-Assessment of facial acne improvement ........................................................... 7 
3.2 
Safety Assessment ........................................................................................................................ 7 
4 
EFFICACY AND SAFETY ENDPOINTS ..................................................................................... 8 
4.1 
Efficacy Endpoints ....................................................................................................................... 8 
4.1.1 
Primary Efficacy Endpoint .................................................................................................... 9 
4.1.2 
Secondary Efficacy Endpoint ................................................................................................. 9 
4.1.3 
Supportive Efficacy Endpoints .............................................................................................. 9 
4.2 
Safety Endpoints .......................................................................................................................... 9 
4.3 
Other Endpoints ......................................................................................................................... 10 
5 
POPULATIONS ANALYZED ....................................................................................................... 10 
5.1 
Intention to Treat (ITT) Population ......................................................................................... 10 
5.2 
Intention to Treat on the Trunk (ITTT) Population ............................................................... 10 
5.3 
Safety (SAF) Population ............................................................................................................ 11 
5.4 
Safety (SAFT) Population for Local Tolerability on the Trunk ............................................ 11 
5.5 
Per Protocol Population ............................................................................................................. 11 
5.6 
Per Protocol (PPT) Population on the Trunk .......................................................................... 11 
6 
SAMPLE SIZE CONSIDERATION ............................................................................................. 12 
7 
STATISTICAL METHODS AND DATA CONSIDERATIONS ............................................... 12 
7.1 
Study subjects ............................................................................................................................. 12 
7.1.1 
Disposition of subjects .......................................................................................................... 12 


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7.1.2 
Demographics and baseline characteristics ........................................................................ 13 
7.2 
Protocol deviations ..................................................................................................................... 13 
7.3 
Medical history, previous and concomitant therapies/procedures ........................................ 13 
7.4 
Efficacy analysis ......................................................................................................................... 13 
7.4.1 
Efficacy analysis methods ..................................................................................................... 13 
7.4.2 
Statistical and analytical issues ............................................................................................ 18 
7.5 
Safety analysis ............................................................................................................................ 20 
7.5.1 
Extent of exposure ................................................................................................................. 20 
7.5.2 
Adverse events ....................................................................................................................... 21 
7.5.3 
Cutaneous safety .................................................................................................................... 22 
7.5.4 
Laboratory parameters ........................................................................................................ 22 
7.6 
Other analyses ............................................................................................................................ 22 
7.7 
Analysis visit definition .............................................................................................................. 24 
8 
CHANGES FROM THE PROTOCOL ANALYSIS PLAN ........................................................ 24 
9 
TABLE SHELLS AND REPORTING OUTPUT (GENERAL FEATURES) ........................... 24 
10 
REFERENCES ................................................................................................................................ 25 


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1 
OBJECTIVES 
The purpose of this statistical analysis plan (SAP) is to describe the efficacy and safety of 
CD5789 50µg/g cream applied once daily for 12 weeks in subjects with moderate acne vulgaris 
to be included in the Clinical Study Report for Protocol RD.06.SPR.18251 dated 11Sept 2015. 
2 
STUDY DESIGN 
This is a Phase 3, multi-center, randomized, double blind, vehicle controlled study comparing 
CD5789 cream applied once daily in the evening versus its vehicle.  
Group 1: CD5789 50µg/g cream applied once daily 
Group 2: Vehicle Cream applied once daily 
This Phase 3 study is designed to evaluate the efficacy and safety of CD5789 50µg/g in subjects 
with moderate acne vulgaris on the face and moderate acne vulgaris on the trunk. Subjects with 
an IGA of 3 and a minimum of 20 inflammatory lesions and 25 non-inflammatory lesion counts 
on the face and a PGA of 3 and a minimum of 20 inflammatory lesions and 20 non-inflammatory 
lesion but no more than 100 non-inflammatory lesion counts on the trunk will be enrolled in the 
study. 
Subjects will be treated once daily for 12 weeks and evaluated at Baseline, Weeks 1, 2, 4, 8 and 
12/Early Termination.  
Specific requirements for children between 9 and 11 years old who do not have moderate acne 
on the trunk at Baseline (i.e. who do not have PGA of 3, at least 20 inflammatory lesions on the 
trunk and at least 20 non-inflammatory lesions on the trunk): 
In this case, it is up to the investigators to decide if these 9 to 11 years old subjects should be 
treated or not for truncal acne. In these subjects, treatment can be started (based on investigator’s 
decision) even if e.g. PGA=1, or the subject has less than 20 inflammatory lesions on the trunk 
and/or less than 20 non-inflammatory lesions on the trunk). These subjects will not be assessed 
for efficacy, but they will be assessed for safety and local tolerability.  
A total of approximately 1200 subjects from the USA and Canada will be randomized in this 
study stratified by center using a 1:1 ratio, to have 600 per treatment arm randomized. 
Approximately 70 sites will be selected with approximately 17 subjects enrolled per site. 
Prior to the start of the study, a kit list and randomization list will be generated by a statistician 
from GALDERMA R&D or designee and will be transmitted to the assigned Clinical Supplies 
Unit for packaging, labeling, and shipping. 


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Subjects will be randomized to study treatments in a 1:1 ratio within a block for CD5789 cream 
and Vehicle cream, respectively. Randomization will be stratified by clinical trial centers using 
the Interactive Response Technology (IRT) System.  
The kit number, a unique number corresponding to the number on the label of the study 
medication, will be assigned to each eligible subject at Baseline. 
3 
EFFICACY AND SAFETY ASSESSMENT 
3.1 
Efficacy Assessment 
IGA/PGA and Lesion Counts will be performed for face and trunk separately. The IGA/PGA 
assessments should be performed before the lesions counting. 
3.1.1 
IGA (Investigator’s global assessment) of facial acne 
The areas defined for IGA assessment are forehead, each cheek, chin and nose. The IGA will be 
assessed at Screening, Baseline, and Weeks 1, 2, 4, 8 and 12/ET visits according to the following 
scale: 
Investigator’s Global Assessment Scale (IGA) Face 
0 
Clear 
Clear skin with no inflammatory or non-inflammatory lesions. 
1 
Almost Clear 
A few scattered comedones and a few small papules. 
2 
Mild 
Easily recognizable; less than half the surface is involved. Some comedones and some papules 
and pustules. 
3 
Moderate 
 
More than half of the surface is involved. Many comedones, papules and pustules. One nodule 
may be present. 
4 
Severe 
 
Entire surface is involved. Covered with comedones, numerous papules and pustules. Few 
nodules may be present. 
3.1.2 
PGA (Physician Global Assessment) of truncal acne 
The PGA is a snapshot static assessment and is outlined in the following table and will be 
assessed at Screening, Baseline, and Weeks 1, 2, 4, 8 and 12/ET visits 
Physician Global Assessment Scale (PGA) Trunk 
0 
Clear 
Clear skin with no inflammatory or non-inflammatory lesions. 
1 
Almost Clear 
A few scattered comedones and a few small papules. 
2 
Mild 
Easily recognizable; less than half the surface is involved. Some comedones and some papules 
and pustules. 
3 
Moderate 
 
More than half of the surface is involved. Many comedones, papules and pustules. One nodule 
may be present. 
4 
Severe 
 
Entire surface is involved. Covered with comedones, numerous papules and pustules. Few 
nodules may or not be present. 
 


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Specific requirements for subjects between 9 and 11 years old who do not have moderate acne on 
the trunk at Baseline (i.e. who do not have PGA of 3, at least 20 inflammatory lesions on the 
trunk and at least 20 non-inflammatory lesions on the trunk): 
The PGA scale will be used by the investigators to decide if they want to start the treatment for 
truncal acne. However, the PGA data from these subjects will not be analyzed.  
3.1.3 
Lesions counts on the face and trunk 
Inflammatory Lesions will be defined as follows: 
Papule - A small, red, solid elevation less than 0.5 cm in diameter. 
Pustule - A small, circumscribed elevation of the skin that contains yellow-white exudates. 
Non-inflammatory Lesions will be defined as follows: 
Open Comedone - A pigmented dilated pilosebaceous orifice (blackhead). 
Closed Comedone - A tiny white papule (whitehead). 
Note: The truncal lesion counts will not be performed for subjects between 9 and 11 years old 
who do not have moderate acne on the trunk at Baseline (i.e. who do not have PGA of 3, at least 
20 inflammatory lesions on the trunk and at least 20 non-inflammatory lesions on the trunk).  
3.1.4 
Subject self-Assessment of facial acne improvement 
Subjects will evaluate their facial acne improvement at the Week 12/ET visit compared to the 
start of the study according to the following scale: 
Subject’s Assessment of Acne Improvement  
0 
Complete Improvement 
1 
Marked Improvement 
2 
Moderate Improvement 
3 
Minimal Improvement 
4 
No Change 
5 
Worse 
3.2 
Safety Assessment 
A safety assessment will be conducted for all subjects at the Screening visit (from the time of 
ICF signature) and every subsequent visit.  
The safety parameters are the recording of adverse events, laboratory safety tests, physical 
examination, vital signs and local tolerability scores (0 [none] to 3 [severe]) for erythema, 
scaling, dryness, and stinging/burning as specified in sections 7.2.1 to 7.2.5 of the protocol. 


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Specific requirements for children between 9 and 11 years old who do not have moderate acne 
on the trunk at Baseline (i.e. do not have PGA of 3, at least 20 inflammatory lesions on the trunk 
and at least 20 non-inflammatory lesions on the trunk): 
If the investigators decide to start the treatment for truncal acne in these subjects during the 
study, then the local tolerability scales (for trunk) will be completed and data will be evaluated in 
the safety analysis.  
 
Local tolerability (erythema, scaling, dryness, and stinging/burning) will be assessed on the face 
and trunk separately. 
3.3 
Other Assessment 
3.3.1 
Photographs (at selected sites) 
Facial and truncal photographs will be taken as per a standardized procedure and guideline at the 
Baseline, Week 2, 4, 8, and Week 12/ET Visits at selected sites to illustrate the observed effect.  
3.3.2 
Dermatology Life Quality Index (DLQI) / Children’s Dermatology Life Quality 
Index (C-DLQI) 
 
The Dermatology Life Quality Index (DLQI, designed for use in adults, i.e. subjects over the age 
16 years old) and Children’s Dermatology Life Quality Index (C-DLQI, designed for 16 years or 
younger at the date of Baseline visit) will be completed at Baseline and Week 12/ET visits.   
 
The DLQI/ C-DLQI will measure the dermatology-related limitations of functional ability and 
the frequency, severity and impact of acne symptoms on subjects’ lives and acne-related quality 
of life.  The six areas (domains) addressed in the questionnaire are: symptoms and feelings; daily 
activities; leisure; work/school; personal relationships; and treatment.  The score on the DLQI/ 
C-DLQI has a possible range of 0 to 30 and can also be presented as a percentage of the 
maximum possible score of 30. 
3.3.3 
Skin Oiliness Scale Questionnaire (SOS) 
A facial skin oiliness questionnaire will be completed by the subject and returned at the Baseline 
and Week 12/ET visits. SOS questionnaire  will measure if CD5789 50 μg/g cream has 
provided any beneficial effect in controlling skin oiliness. Subjects 18 years of age and older 
with moderate facial acne vulgaris are eligible to complete this questionnaire.  
4 
EFFICACY AND SAFETY ENDPOINTS 
4.1 
Efficacy Endpoints 
The imputation of missing data for the efficacy endpoints is described in Section 7.4.2.2. 


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4.1.1 
Primary Efficacy Endpoint 
 
The primary efficacy endpoint consists of the following 3 co-primary endpoints: 
1. Success Rate, defined as the percentage of subjects who achieve an IGA score of 1 
(almost clear) or 0 (Clear) and an at least a 2-grade improvement from Baseline at Week 
12. 
2. Absolute Change in facial non-inflammatory lesion count from Baseline to Week 12 
3. Absolute Change in facial inflammatory lesion count from Baseline to Week 12 
4.1.2 
Secondary Efficacy Endpoint 
 
The secondary efficacy endpoint consists of the following 3 co-secondary endpoints: 
1. Percentage of subjects who achieve a PGA score of 1 (almost clear) or 0 (Clear) and an at 
least 2 grade improvement from Baseline to Week 12. 
2. Absolute change in truncal non-inflammatory lesion count from Baseline to Week 12 
3. Absolute change in truncal inflammatory lesion count from Baseline to Week 12 
4.1.3 
Supportive Efficacy Endpoints 
 
1. Percent change in facial non-inflammatory lesion counts from Baseline to Week 12. 
2. Percent change in facial inflammatory lesion counts from Baseline to Week 12. 
3. Percent change in truncal non-inflammatory lesion counts from Baseline to Week 12. 
4. Percent change in truncal inflammatory lesion counts from Baseline to Week 12. 
5. Subjects’ assessment of facial acne improvement 
4.2 
Safety Endpoints 
The safety endpoints are the following: 
1. Treatment-emergent Adverse Events (TEAE): defined as an adverse event that occurred 
on or after the first study drug application.  
2. Change from baseline of Local tolerability (Face) 
3. Change from baseline of Local tolerability (Trunk) 
4. Change from baseline of Laboratory Safety Test (Hematology, Chemistry, UA) 


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4.3 
Other Endpoints 
Other endpoints are the following: 
1. Dermatology Life Quality Index (DLQI) / Children’s Dermatology Life Quality 
Index(CDLQI) 
2. Skin Oiliness Scale Questionnaire (SOS) 
5 
POPULATIONS ANALYZED 
The Intention to Treat (ITT) population will be used for all efficacy endpoints on the face. The 
Intention to Treat on the Trunk (ITTT) population will be used for all efficacy endpoints on the 
trunk. The Safety population (SAF) will be used for all safety analyses except for the local 
tolerability on the trunk; and the Safety Population on the Trunk (SAFT) will be used for the 
analysis of local tolerability on the trunk. The Per Protocol (PP) population will be used for 
supportive analyses of the primary efficacy endpoint on the face; and the Per Protocol 
Popoulation on the trunk (PPT) will be used for supportive analyses of the secondary efficacy 
endpoint on the trunk. 
In the case that the SAFT turns out to be identical to the SAF population, then all safety analysis 
will be based on the SAF population. 
In the case that the ITTT population turns out to be identical to the ITT population, then all 
efficacy analyses will be based on the ITT population. 
In the case that the PPT population turns out to be identical to the PP population, then the 
supportive analyses of the primary and secondary efficacy endpoints will be based on the PP 
population. 
5.1 
Intention to Treat (ITT) Population 
The ITT population is defined as any subjects who are randomized. Data from subjects included 
in the ITT population will be analyzed according to the treatment as randomized. 
5.2 
Intention to Treat on the Trunk (ITTT) Population 
The ITTT population is defined as any subjects in the ITT population with moderate truncal acne 
at the Baseline visit. In practice, this excludes from the ITT population the children between 9 
and 11 years old who did not meet inclusion criterion #4 (PGA) or #5 (Truncal lesion counts) at 
study entry (i.e. who do not have PGA of 3, at least 20 inflammatory lesions on the trunk and at 
least 20 non-inflammatory lesions on the trunk). 
Subjects in the ITTT population will be analyzed according to the treatment as randomized. 


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5.3 
Safety (SAF) Population 
The SAF population is defined as comprising the ITT population subjects who applied/were 
administered the study medication at least once.   
The SAF population is used for all safety analyses, except for the local tolerability on the trunk. 
5.4 
Safety (SAFT) Population for Local Tolerability on the Trunk 
The SAFT population is defined as the SAF subjects who also applied/were administered the 
study medication on the trunk at least once.   
5.5 
Per Protocol Population  
The PP population is defined as comprising the ITT subjects who have no major protocol 
deviations.  The primary efficacy analyses (on the face) will be repeated based on the PP 
Population to confirm the results. 
Potential major protocol deviations may include but are not limited to:  
 
1. Entrance Criterion Deviations:  
a. Out of range baseline lesion counts 
b. Out of range baseline IGA grade 
c. Inclusion/exclusion criterion violation  
2. Non-Compliance: 
a. Subjects who have dosing deviations more than 30% of the planned 84 doses 
b. Subjects who miss doses for 5 or more consecutive days just prior to the last visit 
3. Prohibited Medications: Subjects who have taken interfering concomitant therapies 
during treatment 
4. Administrative error:  
a. Accidental unblinding 
b. Medication dispensing errors 
c. Lesion counts and IGA/PGA performed by a non-approved evaluator  
 
The final list of major protocol deviation criteria and subjects who have any major protocol 
deviations will be documented in the blind review memo before database lock. 
5.6 
Per Protocol (PPT) Population on the Trunk 
The PPT population is defined as any subjects in the PP population with moderate truncal acne at 
the Baseline visit. In practice, this excludes from the PP population the children between 9 and 
11 years old who did not meet inclusion criterion #4 (PGA) or #5 (Truncal lesion counts) at 
study entry (i.e. who do not have PGA of 3, at least 20 inflammatory lesions on the trunk and at 
least 20 non-inflammatory lesions on the trunk); or subjects who will be deemed not evaluable 
for the analyses on the trunk. 


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The secondary efficacy analyses (on the trunk) will be repeated based on the PPT Population to 
confirm the results. 
6 
SAMPLE SIZE CONSIDERATION 
The assumptions used to power this study are based on the phase 2 study (SPR18223). Success 
rates based on IGA are assumed 23% (CD5789) and 15% (Vehicle). For a 90% power to detect a 
significant difference versus vehicle using a two-sided test at a type I error of 0.05, 504 subjects 
per arm are needed for analysis. To compensate for drop-outs and non-evaluable subjects 
(estimated at 16%), a total of 1200 subjects are to be randomized (600 per arm).  
Based on the results from stratum 1 in the phase 2 study (SPR18223), the mean difference  
between the active and vehicle is estimated at 3 inflammatory lesions and 6 non inflammatory 
lesions. Standard deviation of changes in lesion counts, based on phase 2 and on large phases 3 
trials from other projects are estimated at 12 for inflammatory lesions and 20 for non 
inflammatory lesions.  Using these as assumptions and a sample of 504 evaluable subjects per 
arm, power is above 95% for both lesion types. 
The assumptions for truncal acne being the same as for facial acne in terms of efficacy, therefore 
it is estimated that the power for truncal acne is adequate. 
7 
STATISTICAL METHODS AND DATA CONSIDERATIONS 
For statistical analyses purpose, baseline is defined as the last measurement prior to the first 
application of the study drug. 
A type I error of 0.05 (two-sided test) will be used to declare statistical significance. 
In general, no formal inferential analyses are planned for the baseline and safety data, and only 
summary statistics will be provided.  
For the summary statistics, the categorical variables will be summarized by frequency and 
percentage for each response category (N, %); and the continuous variables will be summarized 
using means, medians, minimum, maximum, and standard deviations.  
SAS version 9.3 or above will be used for all statistical analyses. 
7.1 
Study subjects 
7.1.1 
Disposition of subjects 
The number and percentage of subjects screened, randomized, completed, discontinued, and the 
primary reason for discontinuation based on the CRF exit form will be displayed.  
 


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In addition, the number and percentage of subjects in each study population (i.e., ITT, ITTT, 
SAF, SAFT, PP, and PPT) will be summarized by treatment group as well as by center. 
7.1.2 
Demographics and baseline characteristics 
The following demographics variables will be summarized for the ITT population by each 
treatment group :  Age, Ethnicity, Race, Skin phototype, and gender.  Age will be analyzed as a 
continuous variable and will be tabulated by age groups of “< 18years” (“9-11 years”,  “12-14 
years”, “15-17 years”), and “>= 18 years” (“18-64 years”,  “>=65 years”).  
 
Baseline IGA, PGA, facial lesion counts (inflammatory and non-inflammatory), and truncal 
lesion counts (inflammatory and non-inflammatory) will be summarized by treatment groups.  
7.2 
Protocol deviations 
Number and percentage of subjects with major protocol deviations will be summarized for each 
treatment group in the ITT population.  A listing of subjects with major protocol deviations will 
also be provided. 
7.3 
Medical history, previous and concomitant therapies/procedures 
For statistical analysis purposes, previous therapies/procedures are defined as those ending at 
Baseline visit or before; and concomitant therapies/procedures are defined as those ongoing at 
the Baseline visit or starting after the Baseline visit. 
Previous and concomitant therapies will be coded using WHODRUG dictionary.  Previous and 
concomitant procedures will be coded using MedDRA dictionary. 
A summary table will be provided for each of the following in the ITT population: 
1. number and percentage of subjects who had previous therapies/medications by ATC text 
and WHO drug name 
2. number and percentage of subjects who had concomitant therapies/medications by ATC 
text and WHO drug name 
3. number and percentage of subjects who had  previous procedures by System organ class 
and preferred term 
4. number and percentage of subjects who had concomitant procedures by System organ 
class and preferred term 
7.4 
Efficacy analysis 
7.4.1 
Efficacy analysis methods 
Table 1 summarizes the efficacy endpoints analyses. 


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7.4.1.1 
Analysis of the Primary Efficacy Endpoint 
Hypothesis testing 
Formally stated the hypotheses to be tested for the primary efficacy endpoint are: 
IGA Success Rate,   Ho: P• CD5789  = P•Vehicle   ,    
                     Ha: P• CD5789   P•Vehicle   
Where P• is the proportion of subjects in each treatment group, who achieved the 
defined success criteria. 
Change in facial Inflammatory and non-inflammatory lesions,    
                   Ho: • CD5789  = • Vehicle ,  
                   Ha: • CD5789   • Vehicle   
Where • is the difference from baseline to week 12 for each treatment group, in 
facial inflammatory and non-inflammatory lesion counts.  
 
Table 1   Analysis Strategy for Efficacy Endpoints 
Endpoint  
 
Primary vs. 
Supportive Approach† 
Statistical Method 
Analysis 
Population 
Missing Data 
 Approach 
Co-Primary 
 Success rate at week 12 (IGA) 
 Change from baseline of facial inflammatory 
lesion counts at week 12 
 Change from baseline of facial non-
inflammatory lesion counts at week 12 
 
P 
CMH, ANCOVA 
ITT 
MI 
S 
CMH, ANCOVA 
PP 
MI 
S 
CMH, ANCOVA 
ITT 
MI (MNAR) 
S 
CMH, ANCOVA 
ITT 
LOCF 
S 
CMH, ANCOVA 
ITT 
Missing as 
Failure 
Co-Secondary 
 Success rate at week 12 (PGA) 
 Change from baseline of truncal inflammatory 
lesion counts at week 12 
 Change from baseline of truncal non-
inflammatory lesion counts at week 12 
 
P 
CMH, ANCOVA 
ITTT 
MI 
S 
CMH, ANCOVA 
PPT 
MI 
S 
CMH, ANCOVA 
ITTT 
MI (MNAR) 
S 
CMH, ANCOVA 
ITTT 
LOCF 
S 
CMH, ANCOVA 
ITTT 
Missing as 
Failure 


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Supportive 
 Percent change from baseline in facial 
inflammatory lesion counts at week 12 
 Percent change from baseline in facial non-
inflammatory lesion counts at week 12)  
P 
CMHS 
ITT 
MI 
 Percent change from baseline in truncal 
inflammatory lesion counts at week 12 
 Percent change from baseline in truncal non-
inflammatory lesion counts at week 12)  
 
 
P 
 
CMHS 
 
ITTT 
 
MI 
 Subjects’ assessment of facial acne 
improvement at week 12 
P 
CMHS 
ITT 
as observed 
† P=Primary approach; S=Supportive approach  
ITT = Intention to Treat, ITTT = Intention to Treat for the truncal acne; PP = Per Protocol on the face;  PPT = Per Protocol on the trunk; MI = Multiple 
imputation using the missing at random assumption; MI (MNAR) = Multiple imputation using the missing not at random assumption; LOCF=Last 
Observation Carried Forward. 
CMH: Cochran-Mantel-Haenszel test stratified by analysis center. 
CMHS: Cochran-Mantel-Haenszel test stratified by analysis center using the RIDIT score.  
ANCOVA: Analysis of Covariance model including treatment, analysis center, and baseline lesion count as factors.  
                      
As the primary efficacy endpoint consists of 3 co-primary endpoints, all of which need statistical 
significance for the primary efficacy endpoint to be successful, there is no need for Type I error 
adjustment for the multiple comparisons of the 3 co-primary efficacy endpoints. 
 
The study will be declared positive if the two-sided p-value is statistically significant (< 0.05) for 
the difference between the 2 treatment groups in all 3 co-primary efficacy endpoints, and the 
superiority of CD5789 50 µg/g to Vehicle will be established. 
Statistical method 
 IGA Success Rate: 
Success rate at Week 12 based on the IGA will be analyzed using the Cochran Mantel Haenszel 
(CMH) test stratified by analysis center (see definition in Section 7.4.2.4). The primary analysis 
will be performed using the ITT population based on the Multiple Imputation methodology (MI) 
as the primary imputation method for missing values, see Section 7.4.2.2.  
The p-value for the treatment comparison will be generated from the general association statistic 
of the stratified CMH test. Difference in success rate between treatment groups (CD5789 50 µg/g 
– Vehicle) and the 95% confidence interval of the difference will be based on the large sample 
approximation method for binary data(1). In addition, the success rate for each treatment group 
will also be displayed. 
The treatment-by-analysis center interaction for success rate will be assessed by using the pair-
wise Breslow-Day tests for homogeneity of the odds ratio across analysis centers at Week 12 at 


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alpha level of 0.10.  The consistency of the treatment effect across analysis centers will be 
evaluated using descriptive statistics and using graphical methods.   
In addition, Success Rate will be summarized descriptively at each visit.   
 Facial Lesion Counts: 
 
Changes from baseline in facial lesion counts will be analyzed separately by type (inflammatory 
and non-inflammatory) using an ANCOVA (Analysis of Covariance) model including baseline 
count, analysis center, and treatment as factors. The primary analysis will be performed using the 
ITT population using the primary imputation method for missing values.  
The p-value for the treatment comparison, estimate of the LSMEANS treatment difference 
(CD5789 50 µg/g – Vehicle), and the 95% confidence interval of the LSMEANS difference will 
be generated from the ANCOVA model. 
The treatment-by-analysis centers and the treatment-by-baseline lesion counts interactions for 
Change in Lesions Counts will be assessed separately by the interaction term at Week 12 at alpha 
level of 0.10.   The consistency of the treatment effect across analysis centers will be evaluated 
using descriptive statistics and using graphical methods.  The consistency of the treatment effect 
by baseline lesion counts will be evaluated using graphical methods.  
In addition, change in Lesions Counts will be summarized descriptively at each visit.   
Sensitivity analyses 
The above primary efficacy analysis will be repeated using the PP population using the primary 
multiple imputation method for missing values. 
To assess the robustness of the primary efficacy result, the following sensitivity analyses will be 
conducted for each of the 3 co-primary efficacy endpoints (see Section 4.1) using the ITT 
population: 
a. 
The same imputation method above will be repeated based on the Pattern-Mixture 
Model(2) under the missing not at random (MNAR) assumption, by using the profiles from 
vehicle subjects with observed data to impute missing data. 
b. 
LOCF (Last observation carry forward) approach 
c. 
Subjects with missing IGA data at Week 12 will be considered as ‘failures’ for IGA 
success rate; and  subjects with missing lesion counts data at Week 12 will be assigned the 
median change of lesion count data from subjects who are ‘failures’ of IGA success within the 
same treatment group. 


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7.4.1.2 
Analysis of the Secondary Efficacy Endpoint 
The same statistical methods planned for the 3 co-primary efficacy endpoints will be used for the 
analyses of the 3 co-secondary efficacy endpoints using the ITTT population, with Multiple 
Imputation (MI) as primary imputation method for missing values (see Section 7.4.2.2). 
 
If the superiority of CD5789 50 µg/g to Vehicle is established for the primary efficacy endpoint, 
then CD5789 50 µg/g will be declared superior to Vehicle in the secondary efficacy endpoint if 
the two-sided p-value is statistically significant (< 0.05) for the difference between the 2 
treatment groups in all 3 co-secondary efficacy endpoints. 
As the testing of secondary efficacy endpoint is conditional on the success of primary efficacy 
endpoint,  and all of the 3 co-secondary efficacy endpoints need statistical significance for the 
secondary efficacy endpoint to be successful, no Type I error adjustment is needed for the 
multiple comparisons of the 3 co-secondary efficacy endpoints. 
 
The above secondary efficacy analysis will be repeated using the PPT population with the 
primary multiple imputation method for missing values. 
The same sensitivity analysis methods to handle missing data planned for the primary efficacy 
endpoint will also be applied for the analyses of the secondary efficacy endpoint. 
7.4.1.3 
Analysis of the Supportive Efficacy Endpoints 
No Type I error adjustment will be needed for the analyses of the supportive efficacy endpoints. 
 Facial Lesion Counts: 
The analyses of Percent Change in facial lesion counts by type (Inflammatory Lesion Count and 
non-inflammatory lesion count) will be performed by the Cochran-Mantel-Haenszel test (CMH) 
stratified by analysis center. The analyses will be carried out in the ITT population with the 
primary multiple imputation methodology for missing data (see Section 7.4.2.2).  
The p-value will be from the row mean difference statistic of the CMH test using RIDIT score. 
In addition, percent change in facial lesion counts by type will be summarized descriptively by 
visit. 
 Truncal Lesion Counts: 
The same analysis method planned for the facial lesion counts will be used for the analyses of 
Percent Change in truncal lesion counts using the ITTT population.  
 Subjects’ assessment of facial acne improvement: 
The analysis of the subjects’ assessment of facial acne improvement will be based on the ITT 
population using observed data at Week 12 (i.e., no missing data imputation).  
The p-value will be from the row mean difference statistic of the CMH test using RIDIT score. 


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In addition, the number and percent of subjects will be summarized for each treatment group by 
each scale of improvement. 
7.4.2 
Statistical and analytical issues 
This section is intended to be completed by actual results during CSR writing. 
7.4.2.1 
Adjustment for covariates 
The analysis of change from baseline in lesion counts will use an adjustment for the number of 
baseline lesions as described in Section 7.4.1.1. 
7.4.2.2 
Handling of dropouts or missing data 
The primary method of imputation for missing data will be MI (Multiple Imputation) using the 
Missing At Random (MAR) assumption.  
For the primary MAR based multiple imputation, the MI procedure of the SAS system will be 
used to generate sets of data with missing values imputed from observed data. It is expected that 
the pattern of missing data will be monotonic, with slight deviations being corrected by the 
Markov Chain Monte Carlo (MCMC) method of the MI procedure.   
Linear regression will be employed to model the missing lesion count data and a logistic 
regression model will be used for the ordinal IGA/PGA scores, with the following covariates 
included in the imputation model: treatment and non-missing data from earlier timepoints. 
IGA/PGA success will be calculated from the imputed IGA/PGA scores. The imputed datasets 
will be analyzed using the methodology described in Section 7.4.1.1 for changes in lesion counts, 
and IGA/PGA success. The results from the analysis of the multiple imputed datasets will be 
combined by the MIANALYZE procedure of the SAS system. The seed number to be used will 
be the protocol number (18251) and the number of imputation is planned to be 5. 
For success rate, the final p-value from the CMH test stratified by analysis center on each 
multiply imputed dataset will be generated using the Schafer, J. L.(3) Multiple Imputation 
Methodology. The final difference of success rate between treatment groups (CD5789 50 µg/g – 
Vehicle) and the 95% confidence interval of the final difference from each multiply imputed 
dataset will be generated using the method by Bohdana Ratitch ed. al.(4) . 
For changes in lesion counts, the final p-value, treatment difference (CD5789 50 µg/g – 
Vehicle), and the 95% confidence interval of the treatment difference from the ANCOVA model 
on each multiply imputed dataset will be generated from the MIANALYZE procedure of SAS. 
To assess the robustness of the primary efficacy results, the following sensitivity analyses will be 
also conducted: 
a. 
The same imputation method above will be repeated based on the Pattern-Mixture Model 
under the missing not at random (MNAR) assumption, by using the profiles from vehicle 
subjects with observed data to impute missing data. 


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b. 
LOCF (Last observation carry forward) approach 
c. 
Subjects with missing IGA/PGA data at Week 12 will be considered as ‘failures’ for 
IGA/PGA success rate; and  subjects with missing lesion counts data at Week 12 will be 
assigned the median change of lesion counts data from subjects who are ‘failures’ of IGA/PGA 
success within the same treatment group. 
7.4.2.3 
Interim analyses and data monitoring 
No interim analysis is planned for this study. 
7.4.2.4 
Multicenter studies 
 A small center is defined as the center which randomizes less than 8 subjects. Small centers will 
be pooled prior to analyses. First, centers will be sorted by country, number of randomized 
subjects (descending order) and center number (ascending order).  Pooling will start with 
combining the largest of the set of small centers with the smallest center within that country. If 
there is a further need to combine data (the size of the pooled centers includes less than 8 
subjects), the next smallest center will be combined with the next largest of the small centers, 
until the criterion of a minimum of 8 subjects is met. The process will continue until all pooled 
centers have a minimum of 8 subjects within the country.  Any remaining centers will be pooled 
with the last pooled center within the country. The pooled centers will be referred to as ‘analysis 
centers’ in the statistical analyses. 
7.4.2.5 
Multiple comparison/multiplicity 
Control of type 1 error, the experiment-wise error rate is controlled at alpha level of 0.05.  
No adjustment for multiplicity is required for the primary efficacy endpoint as the statistical 
significance needs to be met for all 3 co-primary endpoints.  
The statistical inferential testing for the secondary primary efficacy endpoint is conditional on 
the statistical significance of the primary efficacy endpoint, and all 3 co-secondary efficacy 
endpoints are required to reach statistical significance for the secondary efficacy endpoint to be 
statistically significant.  
Therefore, no adjustment for multiplicity is required in this study.   
7.4.2.6 
Use of an efficacy subset of patients 
The ITTT population is potentially a subset of the ITT population with moderate truncal acne at 
the Baseline visit. In practice, this excludes from the ITT population the children between 9 and 
11 years old who did not meet inclusion criterion #4 (PGA) or #5 (Truncal lesion counts) at 
study entry (i.e. who do not have PGA of 3, at least 20 inflammatory lesions on the trunk and at 
least 20 non-inflammatory lesions on the trunk). 


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The PP/PPT Population will be determined prior to breaking the study blind using the criteria 
described in Section 5.5.   
7.4.2.7 
Active-Control studies intended to show equivalence 
Not applicable. 
7.4.2.8 
Examination of Subgroups 
All subgroup analyses are exploratory in nature. 
To determine whether the treatment effect is consistent across various subgroups, the estimate of 
the between-treatment effect (with a nominal 95% CI) for the primary efficacy endpoint will be 
estimated and plotted within each category of the following classification variables: 
 Age Group [<18 years (“9-11 years”, “12-14 years”, “15-17 years”), >=18 years(“18-64 
years”, “>=65 years”)] 
 Gender (female, male) 
 Race (white, non-white) 
 Country (US, Canada) 
 Skin Phototype (I-III, IV-VI) 
 
Treatment effects and nominal 95% confidence intervals by category for the classification 
variables listed above will be reported as well as presented graphically. Formal statistical testing 
of these interactions will not be performed. 
For success rate on IGA, treatment effects and the nominal 95% confidence intervals will be 
summarized by category for the subgroup variable using the same method as the primary 
analysis.   
For the change in lesion counts by type, treatment effects and the nominal 95% confidence 
intervals will be summarized by category for the subgroup variable using two-sample t-test.  
7.5 
Safety analysis 
All safety analyses are descriptive, and no formal inferential testing will be performed. 
7.5.1 
Extent of exposure  
7.5.1.1 
Study Duration 
Study duration (day) is defined as the date of the last visit minus the date of the Baseline visit 
plus one. Study duration will be summarized by descriptive statistics using the ITT population. 


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7.5.1.2 
Treatment Duration  
Treatment duration (day) is defined as “the date of the last application on face or the trunk, 
whichever is later, minus the date of the first application on face or the trunk, whichever is 
earlier, plus one”.   
 
Treatment duration will be summarized by descriptive statistics using the SAF population.  
7.5.1.3 
Study Medication Usage (number of applications) 
The study medication usage will be based on data collected on the CRF in terms of the number 
of applications applied. 
 Number of applications applied is calculated as the expected number of applications minus the 
total number of missed doses/applications during the treatment. If the number of missed 
doses/applications is unknown, then 50% doses will be assumed to be missed between two 
adjacent visits.  
The expected number of applications is defined as the planned total number of applications  
during the exposed period.  
Number of applications applied and the daily average applications applied will be summarized 
by treatment group for the SAF population. 
In addition, study medication usage may also be summarized for the face using SAF population 
and for the trunk using the SAFT population separately. 
7.5.2 
Adverse events 
A treatment-emergent adverse event (TEAE) is defined as an adverse event that occurred on or 
after the first study drug application.  
The frequency (N %) of each adverse experience in the trial will be presented by system organ 
class and preferred term by treatment group using the SAF population. 
Adverse events will be coded using the MedDRA dictionary  
Overall summary of TEAEs [frequency (N, %) ] will be provide for each treatment group. 
Additional summaries by System Organ Class (SOC) and Preferred Term (PT) will also be 
provided, along with TEAEs of special interest, serious TEAEs (SAEs), TEAEs related to the 
study drug, and TEAEs leading to discontinuation and severe TEAEs.   
Subgroup analyses by Age Group (<18 years, >=18 years), Race (white, non-white), Gender 
(female, male) and Skin Phototype (I-III, IV-VI) will be provided. 
 


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All AE summary tables are based on the number and percentage of subjects who have 
experienced TEAE(s).  For a given TEAE, a subject will be counted once even if he or she has 
experienced multiple episodes for that particular TEAE.  
7.5.3 
Cutaneous safety 
Only local tolerability (erythema, scaling, dryness, stinging/burning) worsened from baseline 
will be analyzed.  
Analyses of the local tolerability on the face will be based on the SAF population; and the 
analyses of the local tolerability on the trunk will be based on the SAFT population. 
Number and percent of subjects with worsened local tolerability from baseline will be presented 
for each treatment group by the severity scale for each of the assessments (erythema, scaling, 
dryness, stinging/burning) by visit.  
Number and percent of subjects with worst local tolerability worsened from baseline during 
treatment period will also be presented for each treatment group by the severity scale for each of 
the assessments (erythema, scaling, dryness, stinging/burning). The same will be presented for 
the final local tolerability worsened from baseline during the treatment period. 
Summary statistics by treating the severity scale as continuous outcome will also be presented. 
Subgroup analyses by Age Group (<18 years, >=18 years), Race (white, non-white), Gender 
(female, male) and Skin Phototype (I-III, IV-VI) will be provided. 
7.5.4 
Laboratory parameters 
A summary table of the categorical grade shift changes using the normal ranges from baseline to 
Week 12/ET will be presented for each treatment group by each laboratory category parameter 
using the SAF population. 
Only subjects with both baseline and Week 12/ET assessments will be included in this analysis. 
7.6 
Other analyses 
For the other variables, only observed data will be summarized without imputation for missing 
data.  These data will be analyzed using the same methodology as described in Section 7.4.1.3. 
7.6.1.1 
Dermatology Life Quality Index (DLQI) / Children’s Dermatology Life Quality 
Index(CDLQI) 
DLQI(designed for use in adults, i.e. subjects over the age 16 years old) and C-DLQI (designed 
for use in children, i.e. subjects from age 5 to age 16) will be summarized descriptively.  
 
Only SAF subjects who have both baseline and Week 12/ET assessments using the same age-
appropriate questionnaire at both visits will be included in the analyses. 


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Total Scores and Change from Baseline at Week 12/ET for DLQI/C-DLQI, DLQI only, and 
C-DLQI only will be summarized.   
 
In addition, number and percent of subjects will be reported by treatment group for each of the 
following categories of the effect of disease on the quality of life as specified in Table 2: 
 
 
Table 2  DLQI/C-DLQI Categories 
DLQI 
C-DLQI 
DLQI Category 
Range of Total Score 
C-DLQI Category 
Score Maximum 
No effect 
0 - 1 
No effect 
0 - 1 
Small effect 
2 - 5 
Small effect 
2 - 6 
Moderate effect 
6 - 10 
Moderate effect 
7 – 12 
Very large effect 
11 – 20 
Very large effect 
13 – 18 
Extremely large effect 
21 - 30 
Extremely large effect 
19 - 30 
 
Summaries of DLQI only and C-DLQI only by each dimension as defined in Table 3 below will 
also be provided.  
 
Table 3  DLQI/C-DLQI Dimensions 
DLQI 
C-DLQI 
DLQI dimensions 
Score Maximum 
C-DLQI dimensions 
Score Maximum 
Total Score 
30 
Total Score 
30 
Symptoms and feelings 
6 
Symptoms and feelings 
6 
Daily Activities 
6 
Sleep 
3 
Leisure 
6 
Leisure 
9 
Work and School 
3 
School or holidays 
3 
Personal relationships 
6 
Personal relationships 
6 
Treatment 
3 
Treatment 
3 
 
 
7.6.1.2 
Skin Oiliness Scale Questionnaire (SOS) 
 
SOS questionnaire will be summarized at baseline and Week 12/ET for SAF subjects. Number 
and percent of subjects choosing each answer will be reported by treatment group for each of the 
questions. 


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7.7 
Analysis visit definition 
All efficacy variables and local tolerability variables will be summarized and analyzed by 
analysis visit. Analysis visit will be imputed according to the following algorithm to summarize 
the data by proper visit window interval. Study day is calculated as visit date minus the date of 
first application plus 1. 
 
Table 4  Analysis Visit and Visit Window 
Analysis Visit 
 
Analysis Visit Number in 
Derived Dataset 
Target Study Day 
Visit Window 
(Study Day) 
Baseline 
1 
1 
[ <= 1 ] 
Week 1 
2 
8 
[ 2 – 11 ] 
Week 2 
3 
15 
[ 12 – 21 ] 
Week 4 
4 
29 
[ 22 – 42 ] 
Week 8 
5 
57 
[ 43 – 70 ] 
Week 12 
6 
85 
    >70 or more] 
 
If multiple measurements are taken in the same interval, the one closest to the target study day 
will be used for the analysis. If two measurements are taken with equal differences in timing 
compared with the target date, the nominal visit number (recorded on the CRF page) will used. 
8 
CHANGES FROM THE PROTOCOL ANALYSIS PLAN 
Any change from the protocol will be justified and fully documented. 
9 
TABLE SHELLS AND REPORTING OUTPUT (GENERAL FEATURES) 
The final list of tables and figures and their shells for the reporting of this study will be available 
in a separate document to be developed and will be finalized before database lock.   
Details of analysis specifications including but not limited to the SAS code will be documented 
on the table shells. 


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10 
REFERENCES 
(1).  Fleiss, J. L.  “Statistical methods for rates and proportions”, 2nd ed. 1981, New York: John 
Wiley & Sons, Inc.   
(2). B. Ratitch, M. O’Kelly and R. Tosiello, “Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models”, January 2013, Pharmaceutical 
Statistics. 
(3). Schafer, J.L.  “Analysis of Incomplete Multivariate Data”,  page 115, 1st ed. 1997, Chapman 
& Hall/CRC Monographs on Statistics & Applied Probability. 
(4). Bohdana Ratitch, et al. “Combining Analysis Results from Multiply Imputed Categorical 
Data”, 2013,  PharmaSUG Proceedings, Paper SP-03. 
 
 



























Prot_000.pdf: 
RD.06.SPR.18251 Protocol summary  
Protocol V03-06Mar2017 
 
Page 1 of 10 
Final version dated 10 March 2017 
A Multi-Center, Randomized, Double-Blind, Parallel-Group Vehicle Controlled Study To Compare The 
Efficacy And Safety Of CD5789 50µg/g Cream Versus Vehicle Cream In Subjects With Acne Vulgaris 
RD.06.SPR.18251 
EUDRACT NUMBER : 2016-002860-15 
IND NUMBER : 111091 
1/ CLINICAL TRIAL OBJECTIVES  
The clinical trial objectives are to assess the efficacy and safety of CD5789 50 µg/g cream applied once 
daily for 12 weeks in subjects with moderate facial and truncal acne vulgaris. 
2/ STUDY DESIGN 
Phase 3, multi-center, randomized, double blind, vehicle controlled study comparing CD5789 cream 
applied once daily in the evening for 12 weeks versus its vehicle. 
Group 1: CD5789 50μg/g cream  
Group 2: Vehicle cream  
Subjects treated once daily for 12 weeks and evaluated at Baseline, Weeks 1, 2, 4, 8 and 12/Early 
Termination. 
3/ CLINICAL STUDY DURATION  
The planned clinical trial duration (from FSI to LSO) is approximately 26 months.  
The planned duration of recruitment (i.e. From FSI to LSI) is approximately 23 months. 
4/ DURATION OF SUBJECT PARTICIPATION & SUBJECTS’ VISITS 
Clinical trial participation for each subject is approximately 14 weeks (screening period of 14 days with a 
time window of + 3 days followed by 12 weeks of study treatment ±5 days). 
 
5/ TOTAL NUMBER OF SUBJECTS (PLANNED): 
Approximately 1500 subjects will be screened in order to obtain 1200 randomized subjects (600 per 
treatment arm).  
6/NUMBER OF CLINICAL TRIAL CENTERS (PLANNED):  
Approximately 160 sites 
7/ REGION(S) / COUNTRY(IES) INVOLVED (PLANNED): 
United States, Puerto Rico, Europe, Canada and Russia 
8/ INCLUSION/EXCLUSION CRITERIA 
8.1/ Inclusion criteria: 
1. 
The subject is a male or female, 9 years of age and older at the Screening visit. 
 
For Russia : The subject is a male or female, 9-17 years of age OR 18 years and older, at Screening 
visit 


RD.06.SPR.18251 Protocol summary  
Protocol V03-06Mar2017 
 
Page 2 of 10 
Final version dated 10 March 2017 
2. 
The subject has a facial acne severity grade of 3 (moderate) on the Investigator Global Assessment 
(IGA) scale at Screening and Baseline. 
3. 
The subject has a minimum of 20 inflammatory lesions and 25 non-inflammatory lesions on the 
face at Screening and Baseline. 
4. 
The subject has a truncal acne severity grade of 3 (moderate) on the Physician Global assessment 
(PGA) scale at Screening and Baseline visits on trunk (shoulders, upper back and upper anterior 
chest) reachable for self-application of study drug by the subject (optional criterion for subject 
between 9 and 11 years  of age). 
5. 
The subject has a minimum of 20 inflammatory lesions and 20 non-inflammatory lesions but no 
more than 100 non-inflammatory lesion counts on the trunk (shoulders, upper back and upper 
anterior chest) reachable to self-application of study drug by the subject at Screening and Baseline 
(optional criterion for subject between 9 and 11 years of age). 
6. 
The subject is a female of non-childbearing potential (pre-menarcheal or postmenopausal [absence 
of menstrual bleeding for 1 year prior to Screening, without any other medical reason], 
hysterectomy or bilateral oophorectomy). 


RD.06.SPR.18251 Protocol summary  
Protocol V03-06Mar2017 
 
Page 3 of 10 
Final version dated 10 March 2017 
7. 
The subject is a female of childbearing potential: 
7.1. With a negative urine pregnancy test (UPT) at Screening and Baseline visits, 
7.2. Who has been strictly abstinent for 1 month prior to Baseline and agrees to continue for the 
duration of the clinical trial and at least 1 month after the last study drug application, 
OR 
 
Who agrees to use an effective and approved contraceptive method(s) for the duration of the study 
and at least 1 month after the last study drug application. An effective method of contraception is 
defined as: 
7.2.a. bilateral tubal ligation;  
7.2.b. approved combined oral contraceptives (estrogens and progesterone), implanted or 
injectable contraceptives, or hormonal contraceptive vaginal rings with a stable dose for at 
least 1 month prior to the Baseline visit; 
7.2.c. hormonal intra uterine device (IUD) inserted at least 1 month prior to the Baseline visit; 
7.2.d. vasectomized partner for at least 3 months prior to the Baseline visit. 
8. 
If a female of childbearing potential uses combined oral contraceptives approved as acne treatments 
(e.g., Ortho Tri-Cyclen®, Yaz®, Diane-35®), the dose should be stable for at least 6 months prior to 
the Baseline visit. 
9. 
For a pre-menstrual female who begins menses during the study: 
9.1. Agrees to be strictly abstinent for the duration of the clinical trial and at least 1 month after the 
last study drug application,  
OR 
9.2. Agrees to use an effective and approved contraceptive method(s) for the duration of the study and 
at least 1 month after the last study drug application and agrees to undergo pregnancy tests. An 
effective method of contraception is defined as approved combined oral contraceptives 
(oestrogens and progesterone), implanted or injectable contraceptives, or hormonal intra-uterine 
device (IUD) or hormonal contraceptive vaginal rings.  
10. 
The subject is willing and is able to comply with all of the time commitments and procedural 
requirements of the protocol (for subjects who are minors, the parent(s)/legal representative must be 
also willing and able to comply with study requirements). 


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Protocol V03-06Mar2017 
 
Page 4 of 10 
Final version dated 10 March 2017 
11. 
The subject agrees to participate in the study, verified by dating and signing an approved written 
Informed Consent Form (ICF) or, for subjects under age of majority, an assent form signed by the 
subject (if required) in conjunction with an ICF signed by the parent(s)/legal representative at the 
Screening visit before any study procedures.   
 
At selected sites: If the subject agrees to participate to study photographs, verified by dating and 
signing a separate approved Informed Consent Form for photos and for subjects under the age of 
majority, an assent form signed by the subject in conjunction with a photo ICF signed by the 
parent(s)/legal representative at the Screening visit. Participation to photo procedures is not 
mandatory to participate in the Study. 
12. 
The subject is apprised of the Health Insurance Portability and Accountability Act (HIPAA), if in the US, 
Personal Information Protection and Electronic Documents Act (PIPEDA), if in Canada or local privacy 
act if in other countries, and is willing to share personal information and data, as verified by signing a 
written authorization at the Screening visit. 
8.2/ Exclusion criteria: 
1. 
The subject has severe forms of acne (e.g., acne conglobata, acne fulminans) or secondary acne 
form (e.g., chloracne, drug-induced acne, etc.). 
2. 
The subject has more than 1 nodule on the face at Screening and Baseline. 
3. 
The subject has more than 1 nodule on the trunk at Screening and Baseline. 
4. 
The subject has any acne cyst on the face at Screening and Baseline. 
5. 
The subject has any acne cysts on the trunk at Screening and Baseline. 
6. 
The subject has a beard or facial hair that may interfere with the study assessments. 
7. 
The subject has tattoos on the shoulders, upper back or upper anterior chest reachable to self-
application of study drug by the subject (evaluable area) that may interfere with the study 
assessments. 
8. 
The subject has any uncontrolled or serious disease or any medical or surgical condition that may 
either interfere with the interpretation of the trial results and/or put the subject at significant risk 
(according to the Investigator’s judgment) if the subject takes part to the trial. 
9. 
The subject has clinically significant abnormal laboratory values according to the Investigator at 
Screening (to be checked prior to Baseline). 
10. 
The subject has known or suspected allergies or sensitivities to any components of any of the study 
drugs (see Investigator’s Brochure). 
11. 
The subject is a female who is lactating. 
12. 
The subject is a female who intends to conceive a child during the trial or within 1 month after the 
last study drug application. 
13. 
The subject is currently participating in any other clinical trial of a drug or device OR past 
participation in any other clinical trial within the 30 days prior to the Baseline visit. 
14. 
The subject was previously or is currently enrolled in the long term safety study RD.03.SPR.18250 
conducted by Galderma.  
15. 
The subject has received, applied, or ingested the following treatments within the specified time 
frame prior to the Baseline visit as defined in below: 


RD.06.SPR.18251 Protocol summary  
Protocol V03-06Mar2017 
 
Page 5 of 10 
Final version dated 10 March 2017 
Treatment restrictions 
Topical treatment on the face and trunk: 
 
Antibiotics 
Benzoyl peroxide 
Azelaic acid 
Zinc 
Corticosteroids 
Other topical treatments (including laser) 
2 weeks 
Retinoids 
4 weeks 
Topical procedures on the face and trunk: 
Phototherapy devices for acne (e.g., ClearLight)  
Adhesive cleansing strips (e.g., Pond®, Biore®)  
Cosmetic procedures (i.e., facials, peeling, comedone extraction) 
1 week 
Systemic treatment: 
 
Non-steroidal anti-inflammatory drugs1 
2 weeks 
Corticosteroids (except inhaled corticosteroids or intrathecal corticosteroids) 
4 weeks 
Antibiotics (except plain penicillin) 
4 weeks 
Oral retinoids 
6 months 
Immunomodulators, including biologics 
6 months 
Note:  
1) During the study, the use of Non-steroidal Anti-Inflammatory Drugs (NSAIDs) is acceptable for up to 21 days (cumulative) of treatment; 
however, it should be avoided during the 1 week period prior to the final study assessment. 
No time frame period is specified for Alpha-hydroxy acid products, medicated shaving creams, after-shaves, colognes, astringents, or 
preparations with alcohol, but their application is prohibited during the study. 
16. 
The subject has been exposed to excessive ultraviolet (UV) radiation within one month prior to the 
Baseline visit or the subject is planning intense UV exposure during the study (i.e., occupational 
exposure to the sun, sunbathing, tanning salon use, phototherapy, etc.) 
17. 
The subject is unwilling to refrain from use of prohibited medication during the clinical trial (see 
Section 5.5.5 of the protocol v06 March 2017). 
18. 
The subject is vulnerable (such as deprived from freedom) as defined in Section 1.61 of the ICH 
GCP. 
9/ EFFICACY ASSESSMENT  
9.1 Efficacy Measurements  
9.1.1 Investigator’s Global Assessment (IGA)/ Physician Global Assessment (PGA): 
The IGA/PGA assessments will be performed before the lesion counting. 
The areas defined for IGA assessment are forehead, each cheek, chin and nose. 
The areas defined for PGA assessment are shoulders, upper back and anterior chest which are 
accessible to self-application by the subject, i.e., the regions that the subject can easily reach and apply 
the study drug without assistance. 


RD.06.SPR.18251 Protocol summary  
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Qualified Investigators who successfully complete IGA/PGA training will evaluate the facial and 
truncal acne at Screening, Baseline, Week 1, Week 2, Week 4, Week 8 and Week 12/Early 
Termination visit, according to the following scale: 
Global Assessment Scale (IGA/PGA)) 
0 
Clear 
Clear skin with no inflammatory or non-inflammatory lesions. 
1 
Almost Clear 
A few scattered comedones and a few small papules. 
2 
Mild 
Easily recognizable; less than half the surface is involved. Some comedones and some 
papules and pustules. 
3 
Moderate 
More than half of the surface is involved. Many comedones, papules and pustules. One nodule 
may be present. 
4 
Severe 
Entire surface is involved. Covered with comedones, numerous papules and pustules. Few 
nodules may be present. 
 
For PGA assessments there are specific requirements for subjects between 9 and 11 years old who do 
not have moderate acne on the trunk at Baseline (i.e., who do not have PGA of 3, at least 20 
inflammatory lesions and at least 20 non-inflammatory lesions on the trunk): The PGA scale will be 
used by the investigators to decide if they want to start the treatment for truncal acne. If the subjects 
are treated, the PGA data from these subjects will not be analyzed. 
 
9.1.2 Lesion counts on the face and on the trunk  
Lesions Count will be performed by Investigators or qualified Study personnel 
Lesion counting will be performed using both visual observations and palpation strictly, after 
assessing the IGA and the PGA at all visits. 
Specific requirements for subjects between 9 and 11 years old who do not have moderate acne on the 
trunk at Baseline (i.e. who do not have PGA of 3, at least 20 inflammatory lesions on the trunk and at 
least 20 non-inflammatory lesions on the trunk): the truncal lesion counts will not be performed. 
It will be performed separately on the face and on the trunk at Screening, Baseline, Week 1, Week 2, 
Week 4, Week 8 and Week 12/Early Termination visit. 
 
9.1.3 Subject self-assessment of facial acne improvement 
Subject self-assessment should occur prior to any Investigator assessment in order to not influence 
the subject. 
Subjects will evaluate their facial acne improvement at the Week 12/ET visit compared to the start of 
the study.  
 
9.2 Primary Efficacy Endpoint  
The primary efficacy endpoint consists of the following 3 co-primary endpoints: 
1. 
Success Rate, defined as the percentage of subjects who achieve an IGA score of 1 (Almost Clear) 
or 0 (Clear) and at least a 2-grade improvement from Baseline to Week 12. 
2. 
Absolute Change in facial non-inflammatory lesion count from Baseline to Week 12. 


RD.06.SPR.18251 Protocol summary  
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3. 
Absolute Change in facial inflammatory lesion count from Baseline to Week 12. 
10/ SAFETY ASSESSMENTS 
The safety parameters are Adverse Events, local tolerability assessments, laboratory safety tests, physical 
exams and vital signs. 
11/ OTHER ASSESSMENTS  
11.1 Photographs (at selected sites) 
Facial and truncal photographs will be taken according to a standardized procedure guideline at the 
Baseline, Week 2, 4, 8, and Week 12/Early Termination Visits at selected sites to illustrate the effect 
observed. 
11.2 Dermatology Life Quality Index (DLQI) / Children’s Dermatology Life Quality Index 
(C-DLQI) 
Dermatology Life Quality Index (DLQI) and Children’s Dermatology Life Quality Index (C-DLQI) will 
be completed by the subject at the Baseline and Week 12/ET visits prior to any Investigator assessments to 
not impact the subject’s answers to the quality of life questionnaire. 
11.3 Skin Oiliness Scale Questionnaire (SOS) 
A facial skin oiliness questionnaire will be completed by the subject 18 years of age and older with 
moderate facial acne vulgaris and returned at the Baseline and Week 12/ET visits. 
As the questionnaire is only validated in English, only subjects who are native English speakers will 
complete it. 
11.4 Nodules and cysts count 
Nodules and cysts, if present, will be recorded at each visit. 
12/ STUDY DRUG DESCRIPTION 
 
Investigational Product 
Comparator Product 
Trade Name or 
Equivalent 
N/A 
N/A 
Name of Drug 
Substance 
N/A 
Vehicle 
Internal Code 
CD5789 
N/A 
Pharmaceutical Form 
Cream 
Cream 
Strength/ Concentration 50µg/g  
N/A 
Formula number 
0219.0102 
0219.0082P 
 Packaging (type and 
size) 
50 mL bottle with pump and overcap 
50 mL bottle with pump and overcap 
 Storage conditions 
Store below 25°C (77°F), do not freeze or refrigerate 
 Location of Treated 
Area 
Face: forehead, nose, chin and right 
and left cheeks 
Face: forehead, nose, chin and right 
and left cheeks 


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Investigational Product 
Comparator Product 
 Truncal region: right and left 
shoulders, right and left upper anterior 
chest, and right and left upper back;  
reachable to self-application by the 
subject. 
 Truncal region: right and left 
shoulders, right and left upper anterior 
chest, and right and left upper back;  
reachable to self-application by the 
subject. 
 Route 
Topical 
Topical 
 Dose Regimen 
Once daily in the evening after 
washing the treated areas 
Once daily in the evening after 
washing the treated areas 
 Duration of 
administration 
12 Weeks 
12 Weeks 
 N/A = Not Applicable 
 


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Schedule of assessments 
 
Screening 
Visit 1  
(maximum 
14 days+3 day
s prior to 
Baseline) 
Baseline Visit Week 1 Visit 
(±3 days) 
Week 2 Visit 
(±3 days) 
Week 4 Visit 
(±3 days) 
Week 8 Visit 
(±3 days) 
Week 12 
Final/ET Visit2 
(±5 days)  
Informed Consent/ HIPAA (US only)/ PIPEDA (Canada 
only) and Assent Form/ Photo Consent (selected sites) 
X 
 
 
 
 
 
 
Demographics 
X 
X3 
 
 
 
 
 
Medical History 
X 
X3 
 
 
 
 
 
Previous Therapies/Procedures 
X 
 
 
 
 
 
 
Vital Signs/Physical Examination 
X 
X 
 
 
 
 
X 
Laboratory Safety Test (hematology, chemistry, Urine 
Analysis) 
X 
 
 
 
 
 
X 
Urine Pregnancy Test4 
X 
X3 
 
 
X 
X 
X 
IGA (face)  
X 
X3 
X 
X 
X 
X 
X 
PGA (trunk)5 
X 
X3 
X5 
X5 
X5 
X5 
X 
Acne Lesion Counting on the Face  
X 
X3 
X 
X 
X 
X 
X 
Acne Lesion Counting on the Trunk5 
X 
X3 
X5 
X5 
X5 
X5 
X 
Local tolerability on treated areas  
 
X 
X 
X 
X 
X 
X 
Photographs (Face and Trunk at selected centers)6 
 
X 
 
X 
X 
X 
X 
Inclusion/Exclusion Criteria3 
X 
X3  
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Adverse Event recording7 
X 
X 
X 
X 
X 
X 
X 
Concomitant Therapies/Procedures8 
 
X 
X 
X 
X 
X 
X 
DLQI or CDLQI9 
 
X 
 
 
 
 
X 


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Final version dated 10 March 2017 
 
Screening 
Visit 1  
(maximum 
14 days+3 day
s prior to 
Baseline) 
Baseline Visit Week 1 Visit 
(±3 days) 
Week 2 Visit 
(±3 days) 
Week 4 Visit 
(±3 days) 
Week 8 Visit 
(±3 days) 
Week 12 
Final/ET Visit2 
(±5 days)  
Skin Oiliness Scale (SOS) Questionnaire11 
 
X 
 
 
 
 
X 
Self-assessment of facial acne improvement  
 
 
 
 
 
 
X 
Study drug(s) Dispensing (D) and Accountability (A) 
 
D 
 
 
D/A 
D/A 
A 
Moisturizer/cleanser Dispensing (D) 
 
D10 
 
 
 
 
 
Dosing calendar Dispensed (D) returned and reviewed 
(RR) 
 
D 
RR 
RR 
RR 
RR 
RR 
Exit Form11 
 
 
 
 
 
 
X 
(1) 
Baseline visit must be performed maximum 14 days after Screening with a time window of +3 days. For women of childbearing potential, there must be at least 14 days between Screening 
and Baseline visits (for UPT reason). No re-screening will be allowed. 
(2) 
Week 12 procedures will be performed earlier in case of study discontinuation. 
(3) 
Confirm information at Baseline  
(4) 
For subject of childbearing potential only: Urine Pregnancy Tests will be performed at Screening, Baseline, Week 4, Week 8, Week 12. For pre-menstrual subjects re-confirm pre-menses 
status at every visit and in case of status change collect information on contraceptive method and perform a UPT. For the ones who begin menses after the Screening visit, urine 
pregnancy tests will be performed at the visit where there was a change in status and according to the schedule for females of childbearing potential (Baseline, Week 4, 8, 12/ET). 
Additional UPTs may be performed at the Investigator’s discretion. 
(5) 
Subjects 9 to 11 years of age who did not meet the criteria for moderate truncal acne at Baseline: PGA will be evaluated after baseline to allow the investigators to decide to start the 
treatment on the trunk if the subject develops truncal acne during the study whatever the PGA grade. Local tolerability will be assessed. The Lesion counts will not be evaluated.  
(6) 
Photos are not mandatory; subjects will be able to participate in the study even if they refuse to participate in photo procedures. 
(7) 
Collection of Adverse Events will begin after signing of the informed consent/assent form. 
(8) 
Medication that continues after Screening visit should be recorded on the Concomitant Medication page of the eCRF. Medical or surgical procedures occurring after Screening visit should 
be recorded on the Procedures page of the eCRF 
(9) 
Dermatology Life Quality Index (DLQI) (age 17 and older)/Children’s Dermatology Life Quality Index (C-DLQI) (for 16 years and younger). If the subject completed a CDLQI at the Baseline 
visit, a C-DLQI should be completed at the Week 12/ET Visit, regardless of the subject’s age at the Week 12/ET visit.  
(10) 
Subjects will be encouraged to use a provided or personally preferred non-comedogenic and hypoallergenic moisturizer liberally from the Baseline visit throughout the end of the study.   
(11) 
The Skin Oiliness Scale (SOS) Questionnaire is only to be completed by subjects who are native English speakers. The subject should be provided with the SOS questionnaire at 
Screening and Week 8, with instructions to complete and return it at the Baseline visit and Week 12 visit respectively. 
(12) 
Exit form should be completed after subject data collection including evaluation of the laboratory test results has been completed. 
HIPAA=Health Insurance Portability and Accountability Act of 1996; PIPEDA=Personal Information Protection and Electronic Documents Act