Clinical trial NCT02556788
Conditions: Acne Vulgaris
Keywords: Efficacy Safety Acne vulgaris
Sponsor: Galderma R&D
Start date: 2015-11-01; Completion date: 2017-05-12
Enrollment: 1212 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:

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 during 12 weeks. intervention 2: Placebo cream applied once daily during 12 weeks.

Protocol documents:
SAP_002.pdf: 
A Multi-Center, Randomized, Double-Blind, Parallel-Group Vehicle Controlled Study To Compare The Efficacy 
And Safety Of CD5789 (Trifarotene) 50µg/g Cream Versus Vehicle Cream In Subjects With Acne Vulgaris.
NCT Number: NCT02556788
Date: 05 Oct 2015


Galderma R&D 
RD.06.SPR.18252 
Page 1 of 25 
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.18252 
Version Final 
05Oct2015 
This document is electronically approved and signed by:  Biometrics Manager 


Galderma R&D 
RD.06.SPR.18252 
Page 2 of 25 


Galderma R&D 
RD.06.SPR.18252 
Page 3 of 25 
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 .................................................................................................... 8 
4.1.2 
Secondary Efficacy Endpoint ................................................................................................. 9 
4.1.3 
Supportive Efficacy Endpoints .............................................................................................. 9 
4.2 
Safety Endpoints .......................................................................................................................... 9 
4.3 
Other Endpoints ........................................................................................................................... 9 
5 
POPULATIONS ANALYZED ......................................................................................................... 9 
5.1 
Intention to Treat (ITT) Population ......................................................................................... 10 
5.2 
Intention to Treat on the Trunk (ITTT) Population ............................................................... 10 
5.3 
Safety (SAF) Population ............................................................................................................ 10 
5.4 
Safety (SAFT) Population for Local Tolerability on the Trunk ............................................ 10 
5.5 
Per Protocol (PP) Population .................................................................................................... 10 
5.6 
Per Protocol (PPT) Population on the Trunk .......................................................................... 11 
6 
SAMPLE SIZE CONSIDERATION ............................................................................................. 11 
7 
STATISTICAL METHODS AND DATA CONSIDERATIONS ............................................... 12 
7.1 
Study subjects ............................................................................................................................. 12 
7.1.1 
Disposition of subjects .......................................................................................................... 12 


Galderma R&D 
RD.06.SPR.18252 
Page 4 of 25 
7.1.2 
Demographics and baseline characteristics ........................................................................ 12 
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 ............................................................................................ 17 
7.5 
Safety analysis ............................................................................................................................ 20 
7.5.1 
Extent of exposure ................................................................................................................. 20 
7.5.2 
Adverse events ....................................................................................................................... 21 
7.5.3 
Cutaneous safety .................................................................................................................... 21 
7.5.4 
Laboratory parameters ........................................................................................................ 22 
7.6 
Other analyses ............................................................................................................................ 22 
7.7 
Analysis visit definition .............................................................................................................. 23 
8 
CHANGES FROM THE PROTOCOL ANALYSIS PLAN ........................................................ 23 
9 
TABLE SHELLS AND REPORTING OUTPUT (GENERAL FEATURES) ........................... 23 
10 
REFERENCES ................................................................................................................................ 25 
 


Galderma R&D 
RD.06.SPR.18252 
Page 5 of 25 
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.18252 dated 21 July 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 USA (approximately 40%), EU and Russia (approximately 60%) will be 
randomized to the study stratified by center using a 1:1 ratio, to have 600 subjects per treatment 
arm randomized.  
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. 


Galderma R&D 
RD.06.SPR.18252 
Page 6 of 25 
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. 
 
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.  


Galderma R&D 
RD.06.SPR.18252 
Page 7 of 25 
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 by his/her own their facial acne improvement by comparing what they 
recall on their disease at the start of the study at the Week 12/ET visit according to the following 
scale: 
Subject’s Assessment of Acne Scale 
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. 
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.  


Galderma R&D 
RD.06.SPR.18252 
Page 8 of 25 
 
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 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. 
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. 
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 


Galderma R&D 
RD.06.SPR.18252 
Page 9 of 25 
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) 
4.3 
Other Endpoints 
Other endpoints are the following: 
1. Dermatology Life Quality Index (DLQI) / Children’s Dermatology Life Quality 
Index(CDLQI) 
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 


Galderma R&D 
RD.06.SPR.18252 
Page 10 of 25 
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 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 and therefore not planned to be treated on the trunk. 
Subjects in the ITTT population will be analyzed according to the treatment as randomized. 
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 (PP) 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. 


Galderma R&D 
RD.06.SPR.18252 
Page 11 of 25 
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. 
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 (SPR.18223) on the 
Non-Japanese population. 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.  
Based on the results from statum 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 95% at least for both lesion types. 


Galderma R&D 
RD.06.SPR.18252 
Page 12 of 25 
To compensate for drop-outs and non-evaluable subjects (estimated at 16%), a total of 1200 
subjects are to be randomized into each treatment group in a 1:1 ratio stratified by center, with 
600 subjects in each treatment group randomized. 
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 will be summarized by frequency and percentage for 
each response category (N, %); and the continuous 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.  
 
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 for each 
treatment group:  age, Ethnicity, Race, Skin phototype, gender, and country of origin (US, EU, 
Russia).  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.  


Galderma R&D 
RD.06.SPR.18252 
Page 13 of 25 
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 purpose, 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. 
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 from the overall 
population, who achieved the defined success criteria. 


Galderma R&D 
RD.06.SPR.18252 
Page 14 of 25 
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 from 
the overall population, 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 
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 


Galderma R&D 
RD.06.SPR.18252 
Page 15 of 25 
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-values 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 overall 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). The success rate for each treatment group will also be 
displayed for the overall ITT population. 
The treatment-by-analysis center interaction for success rate will be assessed for the overall ITT 
population by using the pair-wise Breslow-Day tests for homogeneity of the odds ratio across 
analysis centers 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.   
 Facial Lesion Counts: 
Changes from baseline in facial lesion counts at Week 12 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 overall 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 for the overall ITT population.   The consistency of the treatment effect across 


Galderma R&D 
RD.06.SPR.18252 
Page 16 of 25 
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 for the 
overall ITT population.   
 
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 counts data from subjects who are ‘failures’ of IGA success within the 
same treatment group. 
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 overall 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 for 
the overall ITTT population 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. 


Galderma R&D 
RD.06.SPR.18252 
Page 17 of 25 
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 in the overall 
ITTT population. 
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 overall 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 overall ITTT population.  
 Subjects’ assessment of facial acne improvement: 
The analysis of the subjects’ assessment of facial acne improvement will be based on the overall 
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. 
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.  


Galderma R&D 
RD.06.SPR.18252 
Page 18 of 25 
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 (18252) 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 final 95% confidence interval of the 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. 
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 


Galderma R&D 
RD.06.SPR.18252 
Page 19 of 25 
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). 
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, >=18 years) 
 Gender (female, male) 


Galderma R&D 
RD.06.SPR.18252 
Page 20 of 25 
 Race (white, non-white) 
 Country (US, EU, Russia) 
 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. 
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.  


Galderma R&D 
RD.06.SPR.18252 
Page 21 of 25 
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), Country (Russia, EU, US) and Skin Phototype (I-III, IV-VI) will be provided. 
 
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. 


Galderma R&D 
RD.06.SPR.18252 
Page 22 of 25 
Subgroup analyses by Age Group (<18 years, >=18 years), Race (white, non-white), Gender 
(female, male), Country (Russia, EU, US) 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. 
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 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. 
 
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.  
 


Galderma R&D 
RD.06.SPR.18252 
Page 23 of 25 
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 
 
 
7.7 
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.   


Galderma R&D 
RD.06.SPR.18252 
Page 24 of 25 
Details of analysis specifications including but not limited to the SAS code will be documented 
on the table shells. 


Galderma R&D 
RD.06.SPR.18252 
Page 25 of 25 
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. 
 
 


RD.06.SPR.18252 - FINAL
October 23,701'l
Galderma Statistician
Name:
Phastar Statistician


RD.06.SPR.18252 - FINAL 
October 23, 2017 
 
1. Purpose 
 
The purpose of this document is to give details and clarifications about the analysis as presented in the 
Statistical Analysis Plan dated October 5, 2015. Any changes from the planned analysis as described in 
that document are also detailed here, and any differences described here supersede the analysis as 
presented in the SAP. 
 
2. General Clarification and Considerations 
 
2.1. 
Decimal Precision 
 
Unless otherwise noted, means and medians will be presented to one more decimal place than the source 
data; standard deviations will be presented to two more decimal places than the source data; minimums 
and maximums will be presented to the same number of decimal places as the source data, percentages 
will be presented to one decimal place; confidence intervals will be presented to two decimal places; and 
p-values will be presented to three decimal places. 
 
2.2. 
Missing Date Procedures 
 
Adverse events with completely missing dates will be considered treatment-emergent. Medications with 
completely missing end dates will be considered concomitant. Adverse events and medications with 
partially missing start or end dates will be considered treatment-emergent and concomitant respectively 
unless the non-missing portion of the dates definitively proves otherwise. 
 
For example, if a subject starts treatment on 10FEB2015, then adverse events with onset dates of 
FEB2015, 2015, or 05DEC would all be considered treatment-emergent, while onsets dates of 2014 or 
JAN2015 would not be considered treatment-emergent. Medications starting or ending in FEB2015 or 
2015 would be considered concomitant, medications ending in JAN2015 or 2014 would not. 
 
2.3. 
Coding Versions 
 
Adverse events, procedures, and non-drug therapies are coded using MedDRA 18.0. Medications and 
therapies are coded using WHO-DDE v2013 March. 
 
2.4. 
Subgroup Analysis 
 
Subgroup analyses for IGA and PGA success rate at Week 12, absolute change from baseline for 
inflammatory and non-inflammatory lesion counts at Week 12 on the face and trunk, treatment-emergent 
adverse events by SOC and PT, and local tolerability parameters worsened from baseline on the face and 
trunk will include an analysis by: 
• 
Age: 9-11 years, 12-17 years, and >=18 years of age 
• 
Gender: female and male 
• 
Age and gender: female <25 years, male <25 years, female >=25 years, and male >=25 years 
• 
Race: White, Black or African American, Asian, and Other 
• 
Ethnicity: Hispanic or Latino and Not Hispanic or Latino 
• 
Skin Phototype: I-III and IV-VI 
 


RD.06.SPR.18252 - FINAL 
October 23, 2017 
 
In addition, a subgroup analysis for IGA and PGA success rate at Week 12, treatment-emergent adverse 
events by SOC and PT, and local tolerability parameters worsened from baseline on the face and trunk 
will be provided for the additional age categories of: <14 Years, 14-17 Years, and >=18 Years. 
 
2.5. 
Subpopulations 
 
Three subpopulations of the ITT population will be studied using the primary and secondary efficacy 
analyses. Those populations are defined as: 
• 
Subjects with at least 75% non-inflammatory baseline lesions. A subject’s baseline total non-
inflammatory lesion count will be divided by their baseline total lesion count (inflammatory and 
non-inflammatory). If the result is greater than or equal to 0.75, they will be included in the 
subpopulation. Presence of nodules and/or cysts will not be included for the calculation of 
inflammatory lesion counts. 
• 
Subjects with no prior use of topical or oral retinoids. Use of topical and oral retinoids are 
identified using the ATC4 codes of D10AD and D10BA from the concomitant medication 
dataset. 
• 
Subjects with no prior use of medications for acne. Subjects with use of prior medication of acne 
are identified using the following indication terms from the concomitant medications dataset: 
o ACNE 
o ACNÉ 
o ACNE  ULGARIS 
o ACNE CONGLOBATA 
o ACNE FACE WASH 
o ACNE FACE/CHEST/BACK 
o ACNE ON FACE 
o ACNE VULARIS 
o ACNE VULGARIS 
o ACNE VULGARIS AND PITYROSPORUM FOLLICULITIS 
o ACNE VULGARIS OF FACE 
o ACNE VUOLGARIS 
o ACNE WASH 
o AKNE VULGARIS 
o FACIAL ACNE 
o FACIAL ACNE VULGARIS 
 
2.6. 
Site Pooling 
 
Analysis centers will be created by totaling the number of subjects at each site and pooling smaller sites 
together. 
 
Sites with fewer than 8 subjects will be pooled. Sites will be sorted by country, the number of subjects at 
that site in descending order, and then site number in ascending order. For each country separately, the 
site at the top of the list (the largest site with less than 8 subjects and, if tied, the smallest site number) 
will be pooled with the site at the bottom of the list (the smallest site with less than 8 subjects and, if tied, 
the largest site number). If the pooled site now has at least 8 subjects, it is removed from the list. 


RD.06.SPR.18252 - FINAL 
October 23, 2017 
 
Otherwise, it will continue to be combined with the smallest available site until it has at least 8 subjects or 
no sites remain. 
 
After all possible pooling is done, if all remaining small sites cannot be pooled together into an analysis 
center with at least 8 subjects, those sites will all be pooled into the analysis center created in the previous 
iteration of the pooling, even if that analysis center is not the smallest. If there was no other pooling done 
(because all small sites in the country total to less than 8 subjects), those sites will be pooled with the 
smallest site in the country. If no other sites are available in that country, the site will remain with fewer 
than 8 subjects. 
3. Protocol Deviations 
 
Protocol deviations will be provided in the DV SDTM dataset. Subjects with a deviation categorized as 
“Major” or “Major for face” will be excluded from the PP dataset. Subjects with a deviation categorized 
as “Major,” “Major for face,” or “Major for trunk” will be excluded from the PPT dataset. 
 
The number of subjects in each analysis population will be summarized, and specific protocol deviations 
will be summarized in a listing. 
 
4. Disposition 
 
For the purposes of disposition summaries, subjects are considered to be Screened if they have signed the 
Informed Consent form. Subjects will be considered randomized once they’ve been assigned a treatment. 
 
5. Prohibited Medications 
 
Prohibited medications will be flagged on the concomitant medications listing. A list of prohibited 
medications with ATC/Drug names will be identified prior to the database lock. 
 
6. Efficacy Analyses 
 
6.1. 
IGA/PGA Success Rate 
 
Success rate of IGA and PGA will be calculated for each visit. Success rate will be calculated as the 
number of subjects considered a success at that visit divided by the number of subjects with IGA/PGA 
data at that visit. 
 
The large-sample approximation for binary data will be used for the 95% confidence intervals around the 
difference in success rates. Continuity corrections will not be used for either the CMH test or the 
generation of 95% confidence intervals.  
 
The success rate of IGA and PGA using missing data procedures will be presented at Week 12. The 
success rate of IGA and PGA will be presented at each visit using the observed data; no missing data 
imputation will be used. 
 
In addition, overall success rate at Week 12 will be calculated using missing data procedures assuming 
that the data is missing at random. Overall success rate is defined as having an IGA score of “clear” or 


RD.06.SPR.18252 - FINAL 
October 23, 2017 
 
“almost clear” at Week 12 and a grade change of at least two from baseline and having a PGA score of 
“clear” or “almost clear” at Week 12 and a grade change of at least two from baseline. 
 
6.2. 
Multiple Imputation – Missing at Random 
 
A multiple imputation method will be used to account for missing data on efficacy analyses. The 
following steps will be followed: 
 
1) For lesion counts, the pattern of missingness in the data will be evaluated. If the data is not 
monotone missing, the MCMC method will be used to make it monotone missing. The single 
chain method will be used, with 200 burn-in iterations and 100 iterations between imputations. 
Fifty imputations will be created. The seed number will be 18252. Lesion counts generated as a 
result of the MCMC method will be re-imputed if they are below zero; they will not be rounded. 
2) The MI procedure in SAS will be used to create multiple imputations of the data that have no 
missing values. If the MCMC method was previously employed, one imputation will be made 
using each of the fifty MCMC-imputed datasets. If the MCMC method was not used, fifty 
imputations will be created using the MI procedure assuming the data is Missing at Random. The 
seed number will be 18252. These imputations will use the following models: 
a. For IGA and PGA scores, a logistic regression model will be used with covariates for 
treatment and non-missing data from earlier scheduled time points including baseline. 
Weeks will be imputed sequentially, with IGA/PGA data at prior non-baseline weeks 
treated as continuous data (baseline will be treated as categorical). 
b. For lesion counts, a linear regression model will be used with covariates for treatment 
and non-missing data from earlier scheduled time points including baseline. 
3) The imputed datasets will be analyzed as follows: 
a. For IGA and PGA scores, the number of successes at Week 12 will be analyzed using the 
CMH test stratified by analysis center. The sample difference in proportions and its 
standard error will also be calculated. No continuity corrections will be used. 
b. For lesion counts, change from baseline to Week 12 in lesion counts will be analyzed 
using an ANCOVA model with covariates for baseline count, analysis center, and 
treatment. 
4) The resulting analysis on the imputed datasets will then be combined to produce a single set of 
statistics. 
a. For IGA and PGA scores, the results from the CMH analysis will be combined using the 
procedure by Rubin (1987) and Li et al. (1991) to produce a pooled CMH statistic and p-
value. The differences in proportions and standard errors will be combined using the 
MIANALYZE procedure in SAS; the resulting pooled difference and standard errors will 
be used to produce 95% confidence intervals based on the large-sample approximation 
method for binary data without the use of a continuity correction. Both methods will be 
used as described in the Bohdana Ratitch et al. paper Combining Analysis Results from 
Multiply Imputed Categorical Data.  
b. For lesion counts, results from the ANCOVA analysis will be combined using 
MIANALYZE procedure in SAS. 
 
 
 
 
 
 
 


RD.06.SPR.18252 - FINAL 
October 23, 2017 
 
Below is an example of the SAS syntax for the MCMC and logistic MI procedures for IGA/PGA: 
 
 
 
Below is an example of the SAS syntax for the MCMC and linear MI procedures for lesion counts: 
 
 
 
 
 
 
 
 
 
 
 


RD.06.SPR.18252 - FINAL 
October 23, 2017 
 
6.3. 
Multiple Imputation – Missing Not at Random 
 
As a sensitivity analysis, the multiple imputation process will be repeated assuming that the data is 
missing not at random. This process will be the same as the one described for the Missing at Random 
analysis, but with the assumptions changed. The Missing Not at Random dataset will use data collected 
from vehicle subjects to impute missing observations. 
 
Below is an example of the SAS syntax for the logistic MI for IGA/PGA for the missing not at random 
assumption: 
 
 
 
Below is an example of the SAS syntax for the MCMC and linear MI procedures for lesion counts for the 
missing not at random assumption: 


RD.06.SPR.18252 - FINAL 
October 23, 2017 
 
 
 
 
6.4. 
Multiple Imputation – Categorical Sensitivity Analysis 
 
The primary multiple imputation method will treat IGA/PGA as continuous when used as covariates for 
the logistic regression model. As a sensitivity analysis, the multiple imputation process for IGA/PGA will 
be repeated treating those predictors as categorical. 
 
First, the pattern of missingness in the data will be evaluated. If the data is not monotone missing, the 
MCMC method will be used to make it monotone missing. The single chain method will be used, with 
200 burn-in iterations and 100 iterations between imputations. Fifty imputations will be created. If all 
subjects have the same baseline IGA/PGA value, the baseline visit will not be included in the model. The 
seed number will be 18252. IGA and PGA scores generated as a result of the MCMC method will be 
rounded prior to the next step; scores will be re-imputed if, after rounding, they are lower than 0 or higher 
than 4.  
 
Due to the categorical nature of the data, and the rarity of some values of IGA/PGA, there is the potential 
for convergence issues when using logistic regression with categorical covariates. If this is the case, each 
week will be imputed sequentially and predictor weeks that cause convergence issues (and thus can’t be 
used as valid predictors) will be dropped. 
 
The model will be chosen by first checking if the inclusion of any covariates causes convergence issues. 
If so, predictor weeks will be removed from the model and the model rerun until any convergence issues 
are solved. Earlier weeks will be dropped from the model before later weeks, and combinations of weeks 
will only be dropped if the removal of only one week does not cause the model to converge. Thus, weeks 
will be dropped in the following order: 
 
1. Week 1 
2. Week 2 
3. Week 4 
4. Week 8 
5. Weeks 1 and 2 
6. Weeks 1 and 4 
7. Weeks 2 and 4 
8. Weeks 1 and 8 
9. Weeks 2 and 8 
10. Weeks 4 and 8 


RD.06.SPR.18252 - FINAL 
October 23, 2017 
 
11. Weeks 1, 2, and 4 
12. Weeks 1, 2, and 8 
13. Weeks 2, 4, and 8 
 
After each removal, the model will be rerun. The first model that converges will be kept, and the process 
will restart with the next week until Week 12 is imputed. The final chosen models will be run with seed 
number 18252. Below is an example of the SAS syntax for the MCMC and logistic MI procedures 
treating predictor weeks as categorical, with no weeks removed: 
 
 
 
6.5. 
Analysis of Percent Change in Lesion Count 
 
The percent change in lesion count will be analyzed using a CMH test using ridit scoring. The resulting 
test statistics for the row-mean scores difference from the CMH analysis will be combined using the 
procedure by Rubin (1987) and Li et al. (1991) to produce a pooled CMH statistic and p-value. 
 
6.6. 
Missing as Failure Analysis of Lesion Counts 
 
The missing-as-failure analysis will be used for lesion counts to impute missing lesion count change from 
baseline at week 12. 
 
For missing facial lesion count data, the median change from baseline in lesion counts from among all 
observed IGA failures at Week 12 will be substituted. For missing truncal lesion count data, the median 
change from baseline in lesion counts from among all observed PGA failures at Week 12 will be used.  
 
In both cases the median will be calculated separately for each treatment group, using actual treatment, 
and the imputation will use the median that corresponds to the treatment group of the subject being 
imputed. 
 
6.7. 
Efficacy Figures 
 
Figures will be presented for IGA and PGA success rate by visit using observed data. The week 12 
success rate using the same MAR multiple imputation method as used in the primary analysis will also be 
graphed. 
 
Figures will also be presented for the success rate at week 12 for each subgroup using MAR multiple 
imputation. 
 


RD.06.SPR.18252 - FINAL 
October 23, 2017 
 
6.8. 
Efficacy Subgroup Analysis 
 
The subgroup analyses will repeat the analysis of the three co-primary and co-secondary endpoints on all 
subgroups. The MAR multiple imputation method will be used to handle missing data. 
 
For lesion count subgroup analysis, the t-tests will be done assuming unequal variances using 
Satterthwaite’s formula for variance. 
 
6.9. 
Dermatology Life Quality Index 
 
Descriptive statistics treating the (C)DLQI totals scores as a continuous measure will be presented with 
observed and change from baseline summaries. Counts and percentages of subjects within categorized 
ranges (“No effect” to “Extremely large effect”) will also be presented. These summaries will be 
presented for the DLQI and CDLQI. 
 
Total score is calculated assigning a numerical equivalent to each answer, and summing them across the 
10 questions. Answers are scored as follows: 
• 
Very much: 3 
• 
A lot/Quite a lot: 2 
• 
A little/Only a little: 1 
• 
Not at all: 0 
 
For question 7, answering a “Yes” scores as 3 and a “No” scores as 0, however answering “No” requires 
answering question 7b where “A lot,” “A little,” and “Not at all” as scored as normal. 
 
Descriptive statistics treating the (C)DLQI dimensional scores as a continuous measure will also be 
presented with observed and change from baseline summaries. These will be presented for DLQI and 
CDLQI separately. 
 
For the DLQI, dimensional scores will be calculated using the following questions: 
• 
Symptoms and Feelings: questions 1 and 2 
• 
Daily Activities: questions 3 and 4 
• 
Leisure: questions 5 and 6 
• 
Work and School: question 7 
• 
Personal Relationships: questions 8 and 9 
• 
Treatment: question 10 
 
For the CDLQI, dimensions cores will be calculated using the following questions: 
• 
Symptoms and Feelings: questions 1 and 2 
• 
Sleep: question 9 
• 
Leisure: questions 4, 5, and 6 
• 
School or Holidays: question 7 
• 
Personal Relationships: questions 3 and 8 
• 
Treatment: question 10 
 


RD.06.SPR.18252 - FINAL 
October 23, 2017 
 
7. Safety Analyses 
 
7.1. 
Drug Exposure 
 
Study and Treatment Duration 
 
Study duration will count the number of days a subject is on the study, regardless of their treatment 
requirements. It is calculated as study end date minus study start date plus one. 
 
Subjects are expected to take one application per day on the study. Treatment duration for the face will be 
calculated as the subject’s treatment end date minus treatment start date plus one; treatment duration on 
the trunk will be calculated as the subject’s treatment end date minus treatment start date plus one. 
 
Total Applications 
 
Applications taken is not collected on the CRF, so to estimate the number of applications a subject took, 
the number of recorded missed doses will be subtracted from the number of doses the subject should have 
taken to arrive at the number of taken applications. 
 
Subjects who have visits after their treatment end date record the time between in one of two different 
ways: 
1. Some record a number of missed doses between treatment end and their current visit. These do 
not count as actual missed doses, as the subject was off treatment. 
2. Others record “NA” or leave it missing. 
 
Thus, the calculation of total applications on the face will be done in the following steps: 
1. Start with the subject’s treatment start date. 
2. Chose an end date to use to calculate the starting number of doses measured on the CRF. If the 
subject has a non-missing recorded number of missed doses at any date after their treatment end 
date, use the latest date available with missed doses recorded. Otherwise, use treatment end date. 
3. Calculate the starting number of doses as end date minus treatment start date plus 1. 
4. From that, the total number of all missed doses on the face will be subtracted.. 
 
The calculation of total applications on the trunk will be done following the same steps, but using PGA 
scores and counts of missing doses on the trunk. 
 
Expected Applications 
 
A subject’s expected number of applications will assume that subjects take one application per day of 
treatment duration. Thus, a subject’s expected applications is equal to their treatment duration. 
 
Compliance 
 
Compliance percentage will be calculated as a subject’s total applications divided by their expected 
applications multiplied by 100. 
 


RD.06.SPR.18252 - FINAL 
October 23, 2017 
 
7.2. 
Medication Usage 
 
A subject’s average daily medication usage (g/day) will be calculated as their total medication usage 
divided by their overall treatment duration. Overall treatment duration is calculated as the subject’s 
treatment end date minus their treatment start date plus one. 
 
As per Galderma’s clinical supply process, the weight of each dispensed tube is assigned based on the 
average weight of a sample of kits from each batch. Hence, it is possible that some subjects are recorded 
as having returned more grams of drug than they were dispensed. If a subject’s total medication usage is 
negative, it will be set to zero. 
 
7.3. 
Adverse Events 
 
A treatment-emergent adverse event is defined as an adverse event that occurred, or increased in severity, 
on or after the date of the first does of study drug. Events with missing severity will be considered severe; 
events with missing relatedness data will be considered related to the study drug. 
 
Adverse events of special interest will be summarized, and are defined as follows: 
• 
Out-of-range laboratory results that are identified as clinically significant and related to the study 
drug, 
• 
Related cutaneous AEs which lead to permanent treatment discontinuation, and 
• 
Suspicion of allergic reaction suspected to be related to the study drug. 
 
Severe adverse events are defined as those with severity marked as “Severe” on the CRF. Adverse events 
related to study drug or protocol procedure are defined as those marked as having a “reasonable 
possibility” of being related to study drug or protocol procedure, respectively, on the CRF. 
 
A listing of pre-treatment adverse events will be included. Pre-treatment adverse events are those with an 
onset date prior to the date of the first application of study drug. 
 
7.4. 
Local Tolerability 
 
Local tolerability will be summarized by visit on the face and trunk separately. Summaries will present 
descriptive statistics of local tolerability scores when treated as a continuous measure, as well as counts 
and percentages of subjects with each score treated as categorical. Categorical summaries of scores that 
are worsened from baseline will also be presented.  
 
Worsened from baseline is defined as having a local tolerability assessment at the summarized time point 
that is greater than the local tolerability assessment at baseline. 
 
Subgroup analysis of local tolerability scores will be presented separately for the face and trunk. These 
summaries will treat the scores as categorical, and will present scores that have worsened from baseline 
for both the final and worst scores per subject. 
 
Local tolerability scores will also be presented treating the score as dichotomous. Subjects will be 
summarized into two categories based on their score: “None (0)” or “Mild/Moderate/Severe (1-3),” and 
presented at Baseline, Final visit, and their Worst score.  
 


RD.06.SPR.18252 - FINAL 
October 23, 2017 
 
Graphical assessment of local tolerability will be done on all subjects, not just those with a local 
tolerability assessment worsened from baseline. Subgroup analysis of local tolerability will not be 
graphed. 
 
7.5. 
Laboratory Values 
 
Laboratory values will be presented using the International System of Units (SI units). 
 
For summary purposes, laboratory values that are listed as above or below particular thresholds will be 
numerically listed as above or below that threshold, respectively, by the minimum measured amount for 
that parameter. For example, if a parameter is measured to two decimal places, and has a result of “> 5” 
then, for summary purposes, the value of 5.01 will be used. Values with “<” or “>” will be classified as 
Low or High, respectively, unless such classifications aren’t applicable for that parameter, in which case 
they will be classified as Normal. 
 
Shifts in laboratory assessments will be presented from the baseline visit to the last post-baseline visit; 
subjects missing baseline or post-baseline laboratory data will not be included. 
 
7.6. 
Vital Signs 
 
Pulse rate, systolic blood pressure, and diastolic blood pressure will be summarized by visit. Shifts in 
overall vital sign assessments will be presented from the baseline visit to the last post-baseline visit; 
subjects with no post-baseline vital sign data will not be included. Shifts in normality classification of 
vital sign parameters based on normal reference ranges will also be presented. 

Prot_001.pdf: