Clinical trial NCT04856904
Conditions: Acne Vulgaris
Keywords: Acne vulgaris Trifarotene AKLIEF® CD5789
Sponsor: Galderma R&D
Start date: 2021-05-28; Completion date: 2023-06-30
Enrollment: 121 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of trifarotene 50 microgram per gram (mcg/g) cream compared to its vehicle on the risk of formation of atrophic acne scars after 24 weeks of treatment in facial acne participants assessed by atrophic acne scars count.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Trifarotene Cream intervention 2: Trifarotene Vehicle Cream
Intervention descriptions: intervention 1: Participants will apply a thin a layer of trifarotene (CD5789) 50 mcg/g cream to the face once daily, in the evening for 24 weeks intervention 2: Participants will apply a thin a layer of trifarotene vehicle cream to the face once daily, in the evening for 24 weeks

Protocol documents:
Prot_000.pdf: 
Signature page 1 of 1
Version: 
28-Jul-2021 00:00:00
RD.06.SPR.202395 Amended Clinical Protocol 01-
Global 09Jul2021 eUS
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TABLE OF CONTENTS
TITLE PAGE...............................................................................................................................................1
PROTOCOL APPROVAL SIGNATURES..............................................................................................2
TABLE OF CONTENTS............................................................................................................................3
LIST OF TABLES.......................................................................................................................................7
LIST OF FIGURES.....................................................................................................................................7
1
SYNOPSIS .........................................................................................................................................8
2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..............................................18
3
BACKGROUND AND RATIONALE...........................................................................................20
3.1
Medical Background and Rationale.........................................................................................20
3.2
Risk/Benefit Assessment............................................................................................................22
3.3
Drug profile ................................................................................................................................23
3.4
Dose selection rationale .............................................................................................................23
4
STUDY OBJECTIVE and ENDPOINTS .....................................................................................24
4.1
Study objective ...........................................................................................................................24
4.2
Study endpoints..........................................................................................................................24
4.2.1
Primary Endpoint.................................................................................................................24
4.2.2
Secondary Endpoints............................................................................................................24
....................................................................25
4.2.4
Safety......................................................................................................................................25
5
INVESTIGATIONAL PLAN.........................................................................................................25
5.1
Overall Study Design .................................................................................................................25
5.1.1
Study Schema........................................................................................................................27
5.1.2
Schedule of Assessments.......................................................................................................28
5.2
Discussion of Study Design........................................................................................................31
5.3
Selection of Study Population ...................................................................................................33
5.3.1
Number of Planned Subjects................................................................................................33
5.3.2
Inclusion Criteria..................................................................................................................33
5.3.3
Exclusion Criteria.................................................................................................................35
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5.3.4
Removal of Subjects from Therapy or Assessments..........................................................37
5.4
Investigational Products............................................................................................................39
5.4.1
Study Drug Description........................................................................................................39
5.4.2
Instructions for Use – Study Drug and Non-Investigational Products ............................40
5.4.3
Study Drug Application with Video Collection..................................................................41
5.4.4
Other Subject Instructions...................................................................................................43
5.4.5
Packaging and Labelling......................................................................................................44
5.4.6
Study Drug Management .....................................................................................................44
5.4.7
Method of Subject ID and Treatment Assignment............................................................47
5.4.8
Dose Modification .................................................................................................................48
5.4.9
Allocation Concealment and Blinding.................................................................................48
5.4.10
Unblinding During the Clinical Study ................................................................................48
5.4.11
Non-Investigational Study Supplies ....................................................................................49
5.4.12
Prior and Concomitant Therapy.........................................................................................49
5.5
Duration of Subject Participation ............................................................................................52
5.5.1
Early Termination Visit .......................................................................................................52
5.5.2
Unscheduled Visit .................................................................................................................53
6
STUDY ASSESSMENTS................................................................................................................53
6.1
Efficacy Assessments..................................................................................................................53
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6.11
Safety Assessments.....................................................................................................................60
6.11.1
Local Tolerability Assessment .............................................................................................60
6.11.2
Adverse Events......................................................................................................................62
7
PLANNED STATISTICAL ANALYSES .....................................................................................72
7.1
Statistical Analysis Plan.............................................................................................................72
7.2
Sample Size Determination .......................................................................................................73
7.3
Populations Analyzed, Evaluability and Limitation / Evaluation of Bias.............................74
7.3.1
Intent-to-treat (ITT) population..........................................................................................74
7.3.2
Per Protocol (PP) population...............................................................................................74
7.3.3
Safety (SAF) Population.......................................................................................................75
7.4
Statistical Analysis .....................................................................................................................75
7.4.1
General Methods...................................................................................................................75
7.4.2
Demographics and Subject Disposition...............................................................................75
7.4.3
Efficacy Analysis...................................................................................................................75
7.4.4
Subject-Reported Outcomes ................................................................................................78
7.4.5
Safety Analysis ......................................................................................................................78
8
TRAINING / MONITORING / DATA MANAGEMENT / QUALITY ASSURANCE ...........79
8.1
Personnel Training.....................................................................................................................79
8.2
Monitoring..................................................................................................................................79
8.3
Data Management......................................................................................................................80
8.4
Clinical Study Conduct..............................................................................................................80
8.5
Protocol Amendments................................................................................................................80
8.6
Quality Management and Risk Evaluation..............................................................................81
8.7
Quality Assurance / Audit / Inspection ....................................................................................81
9
ETHICS AND GENERAL CLINICAL STUDY CONSIDERATIONS.....................................81
9.1
Institutional Review Board or Independent Ethics Committee.............................................81
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9.2
Regulatory Authorities ..............................................................................................................82
9.3
Ethical Conduct of the Clinical Study......................................................................................82
9.4
Subject Information and Consent ............................................................................................82
9.5
Subject Confidentiality..............................................................................................................83
9.6
Contractual Requirements........................................................................................................83
9.7
Data Collection and Source Documentation............................................................................83
9.8
Insurance ....................................................................................................................................84
10
PUBLIC DISCLOSURE OF CLINICAL STUDY.......................................................................84
11
REPORT AND PUBLICATION, INCLUDING ARCHIVING .................................................85
12
SUSPENSION OR PREMATURE TERMINATION..................................................................85
13
REFERENCES................................................................................................................................86
14
APPENDICES .................................................................................................................................89
14.6
Investigator Notification of Ingredient Patch Test Results....................................................99
INVESTIGATOR SIGNATURE PAGE ...............................................................................................101
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LIST OF TABLES
Table 1:
Possible Reasons for Study Discontinuation ..........................................................................37
Table 2:
Description of the Study Drugs...............................................................................................40
Table 3:
Guidelines for Using Study Drug and Non-Investigational Products.....................................41
Table 4:
List of Prohibited Medications/Therapies During Study........................................................51
Table 5:       Investigator Scar Global Assessment......................................................................................56
Table 6:
....................................................................................57
Table 7:
Local Tolerability Assessment................................................................................................61
Table 8:
Patch Testing Readout Schedule.............................................................................................70
Table 9:
Grading System for Suspected Allergic Contact Reaction .....................................................70
Table 10:
Investigator Overall Conclusion of Suspected Sensitization..................................................71
LIST OF FIGURES
Figure 1:  Study Drug Application on Each Half-Face ...............................................................................42
Figure 2: Anatomic Regions for Efficacy Assessments..............................................................................55
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Title: Evaluation of the risk of atrophic acne scar formation during treatment of acne vulgaris subjects with 
trifarotene 50 µg/g cream versus vehicle cream over 24 weeks
study (i.e. after ~33% of the initial planned subjects complete/discontinue the study) 
in order to evaluate the need for additional subjects to be randomized.
Site enrollment strategies should include outreach plans with a goal for approximate 
even distribution of male to female subjects, to the extent possible.
Number of clinical centers: Approximately 25 sites
Region(s) / country(ies) 
involved:
France, Canada, United States
Duration of subject 
participation: 
The expected duration for each subject’s participation in the study is 28 weeks
(including a 4-week screening period and a 24-week treatment period).
Inclusion criteria
Subjects must fulfill inclusion criteria to participate in the study.
1.
Male or female subject aged 17 to 35 years inclusive, at Screening visit.
2.
Subject with clinical diagnosis of acne vulgaris on the face as defined by
(excluding the nose and middle zone of approximatey 2 cm):
a.
Investigator’s Global Assessment (IGA) score of 3 (Moderate) or 4 
(Severe), with the same score on both sides of the face; and
b.
A minimum of 20 inflammatory lesions (papules and pustules) in total, 
with at least 10 on each side; and 
c.
No more than 2 nodules (1cm in diameter) on the face; and
d.
A minimum of 10 atrophic acne scars in total (≥2 mm),
3.
Subject with a symmetrical number of the following lesions/scars on the whole 
face (i.e., there are no more than twice as many lesions/scars of each type on 
one half of the face than on the other half):
a.
Inflammatory and non-inflammatory lesions; and
b.
Atrophic acne scars (minimum of 4 scars per half-face)
4.
The subject is a female of non-childbearing potential (premenarchal or 
postmenopausal [absence of menstrual bleeding for 1 year prior to Screening, 
without any other medical reason], hysterectomy or bilateral oophorectomy).
5.
The subject is a female of childbearing potential:
5.1. Who is willing to undergo UPTs throughout the course of the study, as 
required.
5.2. Who has been strictly abstinent for 1 month prior to Screening and agrees 
to continue for the duration of the clinical study and at least 1 month after 
the last study drug application,
OR
Who agrees to use highly effective and approved contraceptive method(s) 
for the duration of the study and at least 1 month after the last study drug
application. 


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Title: Evaluation of the risk of atrophic acne scar formation during treatment of acne vulgaris subjects with 
trifarotene 50 µg/g cream versus vehicle cream over 24 weeks
Highly effective methods of contraception include:
a.
bilateral tubal ligation; 
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 
Screening visit;
c.
intrauterine device or intrauterine hormonal-releasing system inserted 
at least 1 month prior to the Screening visit;
d.
vasectomized partner for at least 3 months prior to the Screening visit
Note: This criterion applies to a prepubertal female subject who begins
menses during the study.
6.
If a female of childbearing potential uses oral contraceptives that are also 
approved for treating acne vulgaris (such as cyproterone acetate and ethinyl 
estradiol; drospirenone and ethinyl estradiol; norgestimate and ethinyl 
estradiol; norenthindrone acetate and  ethinyl estradiol; etc) the dose should be 
stable for at least 6 months prior to the Screening visit.
7.
Subject having read, understood and signed the approved Informed Consent 
Form (ICF) prior to any participation in the clinical study. Subject under the 
age of 18 having signed an assent form to participate in the clinical study and 
their parent(s) or legal representative having read and signed the informed 
consent form prior to any clinical study related procedure.
8.
Subject (and legal guardian, if applicable) agrees and is able to comply with all 
time commitments and procedural requirements of the protocol, including daily 
recording of dosing compliance by the subject using an electronic tablet
provided for this study, as well as taking daily videos of study medication use.
Consent to taking daily videos is mandatory for study participation at all sites.
9.
Subject agrees to having photographs taken (mandatory for study participation, 
at designated imaging centers), and verified by the subject signing and dating
an approved ICF (includes willingness to remove all makeup prior to study 
visits, remove jewelry in the areas to be photographed, keep facial hair well-
groomed prior to study visits).
10. Subject is informed of terms pertaining to personal information protection and 
privacy and is willing to share personal information and data, as verified by 
signing a written authorization at the Screening visit.
Exclusion criteria
Subjects meeting any of the exclusion criteria are not eligible to participate in the 
study.
1.
Subject with acne conglobata, acne fulminans, secondary acne [chloracne, 
drug-induced acne, polycystic ovary syndrome (PCOS), pyogenic arthritis-
pyoderma gangrenosum-acne (PAPA), synovitis-acne-pustulosis-hyperostosis-
osteitis (SAPHO), seborrhoea-acne-hirsutism-androgenetic alopecia (SAHA), 
Hidradenitis suppurativa (HS), congenital adrenal hyperplasia (CAH) etc.], 
nodulocystic acne, acne requiring systemic treatment.
2.
Subject with any acne cyst on the face or with more than 3 excoriated acne 
lesions. 


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Title: Evaluation of the risk of atrophic acne scar formation during treatment of acne vulgaris subjects with 
trifarotene 50 µg/g cream versus vehicle cream over 24 weeks
3.
Subject with known active or chronic allergies or suspected allergy to 
trifarotene or excipients of the formulation.
4.
Prior failure of trifarotene treatment including intolerance that resulted in 
stopping treatment; lack of clinical improvement, etc.  
5.
Subject with facial dermal conditions (e.g. tattoo, skin abrasion, eczema, 
sunburned skin, scars, nevi, etc.) that may interfere with study assessments in 
the opinion of the investigator.
6.
Subject with excessive facial hair that would interfere with study assessments, 
as judged by the investigator, or unwilling to keep facial hair well-groomed 
prior to study visits, as judged appropriate by the investigator to perform study 
assessments.
7.
Pregnant women (positive urine pregnancy test at the Screening or Baseline 
visits), breastfeeding women, or women planning a pregnancy during the study
or within 1 month after the last study drug application
8.
Subject with known impaired hepatic or renal functions, based on medical 
history.
9.
Subjects taking Vitamin A supplements in excess of the recommended daily 
allowance (4000 – 5000 IU; no washout period is required)
10. Subjects with a washout period for topical treatment or procedures on the face 
less than:
Topical treatments: Corticosteroids, antibiotics, benzoyl 
peroxide, azelaic acid, alpha hydroxy acids, salicylic acid, zinc 
containing treatments, hydroquinones, and other anti-acne 
treatments
2 weeks
Topical retinoids
2 weeks
Clascoterone cream 1% (Winlevi)
2 weeks
Cosmetic/aesthetic procedures (e.g., comedo extraction, 
desquamating, or abrasive agents, adhesive”pore” cleansing 
strips)
1 week
Wax epilation 
2 weeks
Photodynamic therapy
4 weeks
Laser therapy, microdermabrasion, deep chemical peel, and 
other plastic surgical treatments for acne
12 weeks
11. Subject with a washout period for systemic treatment less than:
Corticosteroids, (except locally acting corticosteroids such as 
inhaled or intrathecal), antibiotics and spironolactone
4 weeks 


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Title: Evaluation of the risk of atrophic acne scar formation during treatment of acne vulgaris subjects with 
trifarotene 50 µg/g cream versus vehicle cream over 24 weeks
Oral retinoids/isotretinoin
12 weeks
Cyproterone acetate / Chlormadinone acetate
12 weeks
Immunomodulators
12 weeks
12. Currently receiving any prescription testosterone therapy (e.g., testosterone 
cypionate, testosterone enanthate, testosterone pellet, testosterone undecanoate) 
or on a testosterone booster or prescription testosterone (e.g., DHEA, 
Omnadren®, Sustanon®, testosterone cypionate, testosterone enanthate, 
testosterone propionate, testosterone phenylpropionate) or testosterone 
supplements (e.g., Tribulus).
13. The subject is unwilling to or unable to refrain from use of prohibited 
medication or procedures during the clinical study (see Section 5.4.12.5)
14. Subject who foresees intensive ultraviolet exposure during the study (mountain 
sports, sailing, sunbathing, tanning beds, etc.).
15. Subject who is at risk in terms of precautions, warnings, and contraindications 
for trifarotene based on approved labeling.
16. Subject with an acute / chronic disease or a history of major medical or surgical 
or psychiatric condition or surgical interventions that may either interfere with
the interpretation of the study results and/or might put the subject at risk in the 
opinion of the investigator.
17. Subject under guardianship (for reason other than minor status), hospitalized 
subject in a public or private institution for a reason other than the research, 
and subject deprived of his/her freedom.
18. More than one subject sharing the same household.
19. Study site personnel, close relatives of the study site personnel (e.g., parents, 
children,siblings, or spouse), employees, or close relatives of employees at the 
Sponsor company.
20. Subject who has participated in another investigational drug or device research 
study within 30 days prior to Screening OR is in an exclusion period from a 
previous clinical study.
21. Subject who is unable to communicate or cooperate with the investigator due to
history of alcohol/drug abuse, language problems, poor mental development, or 
impaired cognitive or verbal function.
Investigational Products:
Drug substance:
Trade name:
Dose form:
Strength/Concentration:
Administration:
trifarotene (CD5789) cream
trifarotene vehicle
AKLIEF®
-
cream
cream
50 µg/g 
-
topical
topical












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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation Term
°C
Degrees Celsius
°F
Degrees Fahrenheit
AE
Adverse Event
AESI
Adverse Event of Special Interest
BPO
Benzoyl Peroxide
CDMS
Clinical Data Management System
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
CSR
Clinical Study Report
DMP
Data Management Plan 
EDC
Electronic Data Capture
e.g.
For Example (Latin: exempli gratia)
ET
Early Termination 
etc.
Et cetera
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
i.e.
That is (Latin: id est)
IEC
Independent Ethics Committee 
IL
Inflammatory Lesions
IND
Investigational New Drug
IRB
Institutional Review Board
ITT
Intention-to-treat
IUD
Intrauterine Device
J2R
Jump-to-Reference
LOAEL
Lowest-observed-adverse-effect level
LOCF
Last Observation Carried Forward
LSI
Last Subject In (Last subject enrolled/randomized)
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Abbreviation Term
MD
Medical Doctor
MedDRA
Medical Dictionary for Regulatory Activities
mL
milliliter
MNAR
Missing Not At Random
NIL
Non-Inflammatory Lesions
NOAEL
No Observed Adverse Effect Level
OTC
Over-the-Counter
PK
Pharmacokinetics
PP
Per-Protocol
PT
Preferred term
RAR
Retinoic Acid Receptor
RXR
Retinoid X Receptor
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan 
SAF
Safety
SCARS
Self-assessment of Clinical Acne-Related Scars
SGA
Scar Global Assessment
SIN
Subject Identification Number 
SOC
System Organ Class
SOP
Standard Operating Procedure
SPF
Sun Protection Factor
TEAE
Treatment-Emergent Adverse Event
TL
Total lesions
UPT
Urine Pregnancy Test 
USA
United States of America
UV
Ultraviolet
WOCBP
Women of child-bearing potential
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3
BACKGROUND AND RATIONALE
3.1
Medical Background and Rationale 
Acne vulgaris (AV) is a common, chronic, inflammatory disorder estimated to affect 9.4% of the 
global population that usually starts in early adolescence (ultimately affecting approximately 
85% of adolescents); however, AV can occur at any age and persist well into adulthood (Heidel 
B, 2016; Tan J, 2015). Acne is a multifactorial inflammatory disease affecting pilosebaceous 
follicles (Dreno 2005, Gollnick 2003, Tsatsou, 2014). In European populations over 70–80 % of 
all males will experience acne in some point of their lifetime. In the USA, acne has been reported 
to affect an estimated number of over 25 (17–45) million Americans (Tsatsou, 2014). As acne is 
a chronic and relapsing disease, normalizing follicular desquamation is then the key to achieve 
and maintain control of acne. This is a polymorphic disease in which several types of lesions are 
usually present at the same time: primary lesions, found in active acne defined by the non-
inflammatory and the inflammatory lesions; secondary lesions which came from the first ones 
and which are defined by scarring and postinflammatory hyperpigmentation (PIH). It can persist 
for years and result in disfigurement and permanent scarring (Koo et al., 1991). The 
consequences of AV and its sequelae may include physical (e.g., skin discomfort/pain, erythema, 
hyperpigmentation, scarring), psychological (e.g., anxiety, poor self-esteem, depression, suicidal 
ideation), and social repercussions (e.g., avoidance of interpersonal interactions). Teenagers with 
even mild acne feel stigmatized and frustrated (Osterweil N, 1993). The incidence of AV 
typically increases throughout adolescence, and the severity of both physical and psychosocial 
sequelae tend to increase as AV severity worsens (Silverberg JI, 2014; Tan J 2017). 
Secondary acne lesions, including atrophic scars, are an unfortunate clinical outcome of acne
(Layton, et al., 1994). Acne scars are not uniform and there are several subtypes.  Some are more 
hypertrophic and keloidal in appearance, while others could be more atrophic (Goodman, et al., 
2000; Goodman, et al., 2006(a); Goodman, et al., 2006(b)).  The severity of the acne scars is 
correlated with the acne grade and with the delay between the start of the disease and the start of 
an adapted treatment.  In her clinical evaluation of acne scarring, Layton indicated that facial 
scarring occurs to some degree in most acne sufferers (95% of the population) even in the mild 
to moderate population. Although not universal, acne scars generally occur more with 
inflammatory acne lesions that were not properly treated (Layton, et al., 1994). 
Loss of dermal matrix is a contributing factor in atrophic acne scars (Kang, et al., 2005).  This 
loss of dermal matrix consists in degradation of collagen produced by intracellular pathway 
activated by inflammation during the acne lesion formation (Kang, et al., 2005) (Trivedi, 2006).  
This leads to the transcription factor activation coding for matrix-degrading metalloproteinases 
(MMPs). MMPs degrade extracellular matrix molecules during physiological and pathological 
tissue remodeling. Three MMPs (MMP-1 [collagenase], MMP-3 [stromelysin] that can initiate 
collagen degradation and MMP-9 [gelatinase] that can further degrade collagen fragments) have 
been shown to be increased in inflammatory acne lesion in vivo (Kang, et al., 2005) (Trivedi, 
2006) (Fisher, et al., 2000) (Papakonstantinou, et al., 2005). The same enzymes are involved in 
the remodeling of the dermal matrix in the photoaging process (Kang, et al., 1997) (Kang, et al., 
1998) (Fisher, et al., 2000).


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Over the past decades, significant evidence has demonstrated that topical retinoids can stimulate 
dermal fibroblasts to produce more procollagen in photoaged skin (Kang, et al., 1997) (Kang, et
al., 1998) (Fisher, et al., 2000).  Type I and type III procollagen are reduced in photodamaged 
skin but it has been demonstrated that isotretinoin, either oral or topical, protects against UV-
induced loss of procollagen, leading to MMP-1, 3 and MMP-9 decrease in relation to the 
duration of the treatment (Kang, et al., 1997) (Kang, et al., 1998) (Fisher, et al., 2000).  This 
increase in collagen production is clinically appreciated as effacement of wrinkles. After 24 
weeks of treatment with topical retinoid, an increase of the epidermal thickness has been 
observed (Kang, et al., 2001) (Philips, et al., 2002). 
As photodamage lesions and atrophic acne scars are partially linked to a dermal matrix loss, a 
potential effect of trifarotene to prevent secondary acne lesions (scars) of occurring and/or to 
improve the pre-existing ones might exist. 
Today it is established including in the guidelines that retinoids acts in the pathology of acne 
vulgaris: a potent modulator of cellular differentiation and keratinisation. Topical retinoids have 
been the first-line treatment for most forms of acne vulgaris (Bayramgurler D et al, 2017). 
Trifarotene, a new generation topical retinoid with its unique mechanism of action, binds to 
specific retinoic acid nuclear receptor (RAR-ɤ) (Thoreau E, 2018). Current evidence suggests 
that topical trifarotene normalizes the differentiation of follicular epithelial cells resulting in 
decreased microcomedo formation. It may be an ideal topical agent with high selectivity towards 
gamma receptors, skin metabolism and with very low systemic absorption for management of 
acne treatment (Del Rosso 2011, Gollnick H, 2003, Eichenfield LF, 2013, Strauss JS, 2007). 
Proper skin care is considered an important component of the total management for patients with 
AV. There are several ways to mitigate adverse effect and prevent further worsening of skin 
tolerability. These include initiating patients on lower concentrations of topical retinoids, 
choosing cream or lotion (than gel) and trifarotene being a highly selective RAR-ɤ with low 
concentration and in cream formulation with adequate recommendations for its use would be 
appropriate in acne subjects. Skin irritation can lead to poor compliance and subsequently lack of 
efficacy. Hence, the addition of a topical gentle moisturizer for these subjects (Del Rosso, 2013; 
Davis and Callender, 2010) and recommendation for avoiding sun exposure is a part of the skin 
care regimen for these acne subjects. Minimizing skin irritation and photoprotection can be 
achieved by the use of non-comedogenic moisturizers with appropriate SPF that hydrate and 
protect the skin from UV irradiation (Schorr E.S., 2012; Whitney P., 2014; Del Rosso, 2013). 
Also, using an appropriate cleanser should reduce oil on the face and therefore should not affect 
skin hydration or the skin barrier function. 
Currently, trifarotene 50 µg/g cream is commercially approved in countries including France, 
Canada and the United States for the treatment of acne vulgaris. Registration studies included two 
12-week pivotal trials to confirm safety and efficacy (Tan J, et al, 2019). A long-term safety study 
was also conducted involving once daily treatment for 1 year that showed trifarotene 50 µg/g cream
was well-tolerated, without undue safety risks (Blume-Peytavi U, et al, 2019).    
A small, single-arm, open-label, Phase 3b study (Galderma protocol RD.06.SPR.118295) 
showed that over a 24 week treatment period, trifarotene reduced inflammatory and non-










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application frequency for the topical study drug, up to a maximum of 2 weeks, within the first 
four (4) weeks of the treatment period (Section 5.4.8 – Dose Modification).
Subjects will receive an electronic tablet at baseline for daily recording of study medication use 
(electronic dosing calendar), as well as for capturing daily videos of applying study medication 
to each side of the face. Study medication dosing data will be uploaded for remote assessment by 
the clinical site, and will serve as the primary means for recording dosing compliance (Section 
5.4.6.4 – Treatment Compliance – Primary Source Data). All videos will remain on the local 
drive of the study electronic tablet, and reviewed by site staff at scheduled office visits for 
supportive evidence of treatment compliance (Section 5.4.6.5 – Treatment Compliance –
Supportive Video Evidence). 
Subjects who do not require a washout period may complete the Screening and Baseline 
assessments on the same day. Subjects who initially fail screening may be re-screened once,
provided the reason for screen failure is not due to atrophic scar counts, acne severity (IGA) or 
lesion counts.  
Subjects will return to the clinic for safety and efficacy assessment at Weeks 1, 2, 4, 8, 12, 16, 20
and 24. Study procedures and assessments are performed according to the schedule of 
assessments (Section 5.1.2).




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5.1.2
Schedule of Assessments
5.1.2.1
Study Assessment Considerations Pertaining to the COVID-19 Pandemic
Subjects who are wearing a face mask should continue to do so until seated in an exam room, in 
accordance with your local guidelines. The general sequence of examinations should begin with 
a wellness assessment, review of dosing calendar/compliance and completion of subject 
questionnaires prior to performing scar and acne assessments, local tolerability assessment and 
imaging (for designated imaging centers).
The following study procedures are permitted, within the protocol defined visit windows, to 
ensure safety of enrolled subjects and continuity of the follow-up visit schedule, due to 
circumstances when a subject is unable to return to the clinic due to the COVID-19 pandemic. 
These circumstances include, but are not limited to:  shelter in place guidelines, quarantines, 
travel restrictions, clinical site closures, etc.  As with all study procedures, clear and complete 
documentation in source records is required in these circumstances.   

Remote Visits (phone, etc) in lieu of scheduled office visits 
o
for safety and wellness assessment (concomitant medications, AEs, etc)

Subject questionnaire completion 
o
sent to subject by email or mail
o
subject signs, dates and returns, by email of mail.

Collection of previously dispensed study drugs, from an adult family member, along with 
the study electronic tablet
o
Weighing of returned topical study drug is required
o
A follow-up phone call with the subject is required to review the dosing compliance
and returned study drug, for appropriate clarification in study medication use.  

Dispensing of new study drug, non-investigational supplies (non-IP supplies, electronic 
tablet after video reviews, etc) to an adult family member
o
Weighing of topical study drug is required, before dispensing
o
A follow-up phone call with the subject is required to convey reminders on proper 
instructions for study medication and other supply use, and to use the newly 
dispensed study drug beginning that evening (and to stop using previously 
dispensed medication, if not returned). 

FDA COVID-19 guidance allows for secure delivery for self-administered study 
medication. In cases where a family member is not available for dispensing study 
medication and other supplies, delivery using an express courier with appropriate 
temperature control capability is permitted. A follow-up phone call is required in these 
circumstances to confirm receipt and provide the subject with appropriate reminders and 
proper instructions for study medication and other supply use.
Note:  The decision to dispense additional study drug should be based on the 
investigator’s clinical judgment that ongoing dosing does not pose undue safety risks to 
the subject, and that the subject is willing to continue using the study drug. In all cases 










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A 24-week treatment period is utilized knowing acne is a chronic skin condition, which should 
be sufficient to assess clinical effect on the basis of the following points:

Scarring appears secondarily to acne lesions and may correspond to a resolution of these
lesions

It is generally agreed in acne clinical studies that a 12-week treatment p e r i o d  is
sufficient to evaluate the efficacy on the acne lesions. An additional 12 weeks is included 
to further evalute the clinical outcomes associated with treatment of acne lesions

24 weeks is considered adequate to allow for potential underlying tissue remodeling by 
dermal fibroblasts and collagen production associated with trifarotene 50 µg/g cream
treatment, and any effects thereof that may translate to clinical improvement of scars 
Overall, the study design is considered to be scientifically robust and clinically relevant for 
evaluating trifarotene (CD5789) cream for the treatment of acne lesions to assess the risk of 
atrophic scar formation.
5.3
Selection of Study Population
5.3.1
Number of Planned Subjects
An initial number of 
 subjects is planned to be randomised. A blinded sample size re-estimation 
will be performed after 
 subjects complete/discontinue the study (i.e. after ~33% of the initial 
planned subjects complete/discontinue the study) in order to evaluate the need for additional 
subjects to be randomized.
Site enrollment strategies should include outreach plans with a goal for approximate even 
distribution of male to female subjects, to the extent possible. Refer to Section 7.2 for the statistical 
considerations on which the sample size is based.
5.3.2
Inclusion Criteria
Subjects must fulfill inclusion criteria to participate in the study:
1. Male or female subject aged 17 to 35 years inclusive, at Screening visit.
2. Subject with clinical diagnosis of acne vulgaris on the face as defined by (excluding the nose 
and middle zone of approximatey 2 cm):
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3. Subject with a symmetrical number of the following lesions/scars on the whole face (i.e., 
there are no more than twice as many lesions/scars of each type on one half of the face than 
on the other half): 
a.
Inflammatory and non-inflammatory lesions; and
b. Atrophic acne scars (minimum of 4 scars per half-face)
4. The subject is a female of non-childbearing potential (premenarchal or postmenopausal 
[absence of menstrual bleeding for 1 year prior to Screening, without any other medical 
reason], hysterectomy or bilateral oophorectomy).
5. The subject is a female of childbearing potential:
5.1  Who is willing to undergo UPTs throughout the course of the study, as required.
5.2  Who has been strictly abstinent for 1 month prior to Screening and agrees to continue for 
the duration of the clinical study and at least 1 month after the last study drug application,
OR
Who agrees to use highly effective and approved contraceptive method(s) for the duration 
of the study and at least 1 month after the last study drug application. 
Highly effective methods of contraception include:
a.
bilateral tubal ligation; 
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 Screening visit;
c.
intrauterine device or intrauterine hormonal-releasing system inserted at least 1 month 
prior to the Screening visit;
d.
vasectomized partner for at least 3 months prior to the Screening visit
Note: This criterion applies to a prepubertal female subject who begins menses during the
study.
6. If a female of childbearing potential uses oral contraceptives that are also approved for 
treating acne vulgaris (such as cyproterone acetate and ethinyl estradiol; drospirenone and 
ethinyl estradiol; norgestimate and ethinyl estradiol; norenthindrone acetate and  ethinyl 
estradiol; etc) the dose should be stable for at least 6 months prior to the Screening visit.
7. Subject having read, understood and signed the approved Informed Consent Form (ICF) prior 
to any participation in the clinical study. Subject under the age of 18 having signed an assent 
form to participate in the clinical study and their parent(s) or legal representative having read 
and signed the informed consent form prior to any clinical study related procedure.
8. Subject (and legal guardian, if applicable) agrees and is able to comply with all time 
commitments and procedural requirements of the protocol, including daily recording of 
dosing compliance by the subject using an electronic tablet provided for this study, as well as 
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taking daily videos of study medication use. Consent to taking daily videos is mandatory for 
study participation at all sites.
9. Subject agrees to having photographs taken (mandatory for study participation, at designated 
imaging centers), and verified by the subject signing and dating an approved ICF (includes 
willingness to remove all makeup prior to study visits, remove jewelry in the areas to be 
photographed, keep facial hair well-groomed prior to study visits).
10. Subject is informed of terms pertaining to personal information protection and privacy and is 
willing to share personal information and data, as verified by signing a written authorization 
at the Screening visit.
5.3.3
Exclusion Criteria
Subjects meeting any of the exclusion criteria are not eligible to participate in the study:
1. Subject with acne conglobata, acne fulminans, secondary acne [chloracne, drug-induced 
acne, polycystic ovary syndrome (PCOS), pyogenic arthritis-pyoderma gangrenosum-acne 
(PAPA), synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO), seborrhoea-acne-
hirsutism-androgenetic alopecia (SAHA), Hidradenitis suppurativa (HS), congenital adrenal 
hyperplasia (CAH) etc.], nodulocystic acne, acne requiring systemic treatment.
2. Subject with any acne cyst on the face or with more than 3 excoriated acne lesions. 
3. Subject with known active or chronic allergies or suspected allergy to trifarotene or 
excipients of the formulation.
4. Prior failure of trifarotene treatment including intolerance that resulted in stopping treatment; 
lack of clinical improvement, etc.  
5. Subject with facial dermal conditions (e.g. tattoo, skin abrasion, eczema, sunburned skin, 
scars, nevi, etc.) that may interfere with study assessments in the opinion of the investigator.
6. Subject with excessive facial hair that would interfere with study assessments, as judged by 
the investigator, or unwilling to keep facial hair well-groomed prior to study visits, as judged 
appropriate by the investigator to perform study assessments.
7. Pregnant women (positive urine pregnancy test at the Screening or Baseline visits), 
breastfeeding women, or women planning a pregnancy during the study or within 1 month 
after the last study drug application
8. Subject with known impaired hepatic or renal functions, based on medical history.
9. Subjects taking Vitamin A supplements in excess of the recommended daily allowance (4000 
– 5000 IU; no washout period is required)
10. Subjects with a washout period for topical treatment or procedures on the face less than:


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Topical treatments: Corticosteroids, antibiotics, benzoyl peroxide, azelaic 
acid, alpha hydroxy acids, salicylic acid, zinc containing treatments, 
hydroquinones, and other anti-acne treatments  
2 weeks
Topical retinoids
2 weeks
Clascoterone cream 1% (Winlevi)
2 weeks
Cosmetic/aesthetic procedures (e.g., comedo extraction, desquamating, or 
abrasive agents, adhesive”pore” cleansing strips)
1 week
Wax epilation 
2 weeks
Photodynamic therapy
4 weeks
Laser therapy, microdermabrasion, deep chemical peel, and other plastic 
surgical treatments for acne
12 weeks
11. Subject with a washout period for systemic treatment less than:
Corticosteroids, (except locally acting corticosteroids such as inhaled or 
intrathecal), antibiotics and spironolactone 
4 weeks 
Oral retinoids/isotretinoin
12 weeks
Cyproterone acetate / Chlormadinone acetate
12 weeks
Immunomodulators
12 weeks
12. Currently receiving any prescription testosterone therapy (e.g., testosterone cypionate, 
testosterone enanthate, testosterone pellet, testosterone undecanoate) or on a testosterone 
booster or prescription testosterone (e.g., DHEA, Omnadren®, Sustanon®, testosterone 
cypionate, testosterone enanthate, testosterone propionate, testosterone phenylpropionate) or 
testosterone supplements (e.g., Tribulus).
13. The subject is unwilling to or unable to refrain from use of prohibited medication or 
procedures during the clinical study (see Section 5.4.12.5)
14. Subject who foresees intensive ultraviolet exposure during the study (mountain sports, 
sailing, sunbathing, tanning beds, etc.).
15. Subject who is at risk in terms of precautions, warnings, and contraindications for trifarotene 
based on approved labeling.
16. Subject with an acute / chronic disease or a history of major medical or surgical or 
psychiatric condition or surgical interventions that may either interfere with the interpretation 
of the study results and/or might put the subject at risk in the opinion of the investigator.






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5.3.4.1
Pregnancy
Subjects will be instructed that known or suspected pregnancy occurring during the study should 
be confirmed and reported to the investigator. If a subject becomes pregnant, the investigator 
must withdraw the subject from the study without delay. The subject must not continue
further use of the study drug.
The investigator must:

Follow the procedures for reporting/follow-up of a pregnancy within 24 hours (see Section 
6.11.2.2.2) of receipt of the information.

Complete as fully as possible the applicable Pregnancy Surveillance Form(s) (see Section 
6.11.2.2.5).

Monitor and record the progress of the pregnancy until its outcome. Contact the subject’s 
regular physician (general practitioner or gynecologist) or hospital staff to obtain further 
details and ask for regular follow-up information.

Provide trimonthly updates until the final outcome of the pregnancy. If the subject can no 
longer be reached (lost to follow-up), documentation of the non-response/contact with 2
phone calls and a letter (certified with return receipt) is required.

If the pregnancy leads to an abortion (i.e., voluntary abortion, spontaneous abortion, or 
therapeutic abortion), in utero death, or congenital anomaly, follow the procedure for 
declaration of/reporting an SAE (Section 6.11.2.2.2). 
In the event that a subject is subsequently found to be pregnant after inclusion in the study, any 
pregnancy will be followed to term, and the status of mother and child will be reported to the 
Sponsor after delivery.
Full details will be recorded on the withdrawal page (exit form), or an SAE report will be 
completed if the subject has completed the study. Pregnancy is not to be considered as an AE; 
however, it must be monitored and reported as described in Section 6.11.2.2.5.
5.4
Investigational Products
Investigational products include trifarotene (CD5789) cream and trifarotene vehicle. 
5.4.1
Study Drug Description
Table 2 summarizes the investigational medication.






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Figure 1:  Study Drug Application 
The objective is to cover each 
 with a thin layer of the proper study drug, even on areas 
on the face with no clinically evident acne (no spot or localized treatment). One pump actuation 
should be enough to cover the forehead, cheek, nose, and chin. Avoid application in/close to 
eyes, or angles of the mouth, lips and mucous membrane.
The study drug should not be applied to cuts, abrasions, eczematous, or sunburned skin.
Each evening, subjects will collect a video of applying the study drug, as follows:
1. Have the study drug available and the electronic tablet ready for use
2. Wash hands
3. Wash the entire face with Cetaphil Gentle Skin Cleanser or approved cleanser 
4. Pat dry the face
5. Begin recording with the study electronic tablet
6. Follow instructions for applying the proper study drug to the RIGHT side of the face  
a. Briefly video the study drug container and label, to document which product was 
applied
b. Apply a thin layer of study drug to the entire RIGHT face (forehead, nose, cheek, chin).  
DO NOT SPOT APPLY
c. One pump actuation should be adequate
d. Avoid eyes, lips and mucous membranes
7. Wash hands
8. Follow instructions for applying the proper study drug to the LEFT side of the face.    
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a. Briefly video the study drug container and label, to document which product was 
applied. 
b. Apply a thin layer of study drug to the entire LEFT face (forehead, nose, cheek, chin).  
DO NOT SPOT APPLY
c. One pump actuation should be adequate
d. Avoid eyes, lips and mucous membranes
9. Stop video recording (and follow further instructions associated with the electronic tablet)  
The video capture of study drug use will be used as supportive evidence of treatment compliance 
(Section 5.4.6.5 - Treatment Compliance – Supportive Video Evidence).
5.4.4
Other Subject Instructions
The subject should maintain a consistent lifestyle throughout the study regarding exposure to 
external factors that may produce an exacerbation of their acne. These factors include, but are 
not limited to, excessive exposure to UV radiation (occupational exposure to the sun, sunbathing, 
tanning salon use, phototherapy, etc.). Subjects should avoid excessive sun exposure, wind and 
cold, as much as possible during the study. The subject will be instructed to apply the Cetaphil 
PRO Moisturizer with SPF30 (or permitted alternative sunscreen with SPF equivalent) on the 
face every morning, and re-apply to the face when sun exposure is expected. Subject should use 
protective apparel (e.g, hat) when sun exposure cannot be avoided. Avoid sunless tanning 
products for the duration of the study. Extra care should be taken to wear protective clothing and 
sunglasses and avoid sun exposure from 10 AM to 3 PM. 
Cosmetics may generally be used during the study, but not on study visit days (or must be 
removed at least 30 minutes prior to study visit). Non-comedogenic cosmetics (cosmetics that do 
not cause acne) may be used as well as eye and lip makeup. Cosmetics can be applied after the 
study drug has dried. Foundation make-up is allowed on the days of study visits as long as 
subjects wash their face at least 30 minutes prior to the study visit. Use of moisturizing 
foundation will be acceptable during the study if subject has a history of safe usage of the 
foundation. 
Study drug application should not occur on the first evening if first dose occurred at the clinic. 
Study drug should be applied approximately 1 hour before or 1 hour after application of any 
other permitted skin care products (e.g. non-comedogenic moisturizers, cosmetic products, etc). 
Subjects will video the application of study drug to both sides of the face each evening using the 
study assigned electronic tablet.  
Products containing alcohol, alpha hydroxy or glycolic acids and astringents should not be used 
during the study.
Face shaving is allowed during the study. Male subjects with excessive facial hair that would 
interfere with acne assessments, as judged by the investigator, are not eligible to participate in 
the study. Male subjects with facial hair will be expected to keep areas well-groomed prior to 
study visits, as judged appropriate by the investigator, to perform the acne assessments. 


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Subjects should wash their face and remove all makeup at least 30 minutes prior to each 
scheduled clinic visit and should not apply any other topical products to the face or eye area until 
the study visit has been completed. If a subject arrives having not removed all makeup, subject 
will be required to remove the residual makeup at the clinic and wait at least 30 minutes prior to 
procedures.
Subjects who are wearing a face mask should continue to do so until seated in an exam room, in 
accordance with your local guidelines. Mask removal is required for the investigator to perform 
the study assessments. 
Subjects enrolled at designated imaging centers will also be asked to remove all jewelry, 
eyewear and pull hair back from their face, prior to study imaging.
5.4.5
Packaging and Labelling
Study medication will be individually labeled and assembled into kits, for subject assignment. 
Product appearance, packaging and labeling will ensure subject and clinical site blinding. Study 
drug labeling (e.g., instructions and/or label color, etc) will make it clear which product is 
applied to each half of the face.  
Each subject kit will include a total of 7 dispensers: 6 dispensers for each scheduled dispensing 
visit (Baseline and Weeks 4, 8, 12, 16, 20), with 1 extra dispenser, if needed (eg, lost pump, etc).  
Each dispenser will contain the following quantities of study drug:

Two (2) pumps (1 trifarotene cream; 1 trifarotene cream vehicle)
Each kit will include a total of 14 pumps (7 trifarotene cream; 7 trifarotene cream vehicle). 
Individual pumps will be uniquely labeled (e.g., pump 1, 2, 3, etc), within each kit, to assess 
product usage over a specific visit interval and overall.
5.4.6
Study Drug Management
5.4.6.1
Storage of Study Drug
Study drug must be stored in a safe and secure area with restricted access, upon receipt and 
throughout the study. Refer to storage conditions as specified in Section 5.4.1 – Study Drug 
Description.  
Storage should be temperature monitored daily, and if a temperature excursion occurs, the 
designated personnel should promptly inform the study monitor, as specified in the current 
version of the pharmacy manual.


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5.4.6.2
Study Drug Shipment and Accountability
The drug depot will ship appropriate quantities of study drug kits to each site, based upon 
individual site needs and within whole block sizes, as specified per the randomization list.  
Upon receipt, the site must conduct a complete inventory of all study drug kits. If a damaged 
shipment is received and/or a temperature excursion has been experienced, the site will notify the 
Sponsor/CRO and follow the guidelines according to the current version of the pharmacy 
manual.
All study drug sent to the Investigator/Institution will be accounted for and no unauthorized use 
is permitted. Subjects will be instructed to return all study drug and the study electronic tablet 
per the Schedule of Assessments (Section 5.1.2).
The investigator or designee will maintain accurate records of supplies received, inventoried at 
the clinical study site and used per subject. Used and unused study drug will be appropriately 
reconciled by the monitor and returned to the Sponsor or designee for destruction as instructed 
by the Sponsor (Section 5.4.6.3 – Dispensing and Return of Study Drug).
5.4.6.3
Dispensing and Return of Study Drug
Designated study personnel at each investigational site will be responsible for dispensing the 
study drug at the appropriate visits and will record the dispensing information for each subject
(see Section 5.1.2 – Schedule of Assessments).
Each subject will receive a study drug dispenser at each designated dispensing visit. The visit 
designation will be captured on the study drug dispenser. Study drugs within each kit will be 
uniquely identified with the corresponding kit number and a pump identifier to assess usage for 
each 
, per dosing interval. Upon dispensing, the affixed portion of the label will remain 
on the dispensing box. The tear-off portion of the label is to be removed from the dispenser and 
attached to the appropriate drug accounting record.
Each subject will be instructed on the importance of returning study drug (used and/or unused) as 
specified in the schedule of assessments (Section 5.1.2). Drug accountability and dosing 
compliance will be assessed by the designated clinical study center personnel. Subjects will be 
instructed to return the electronic tablet and all study medication at each study visit, for review 
by study personnel in the presence of the subject. At study visits Week 1 and Week 2, study drug 
dispensed at Baseline will be re-dispensed after compliance checks are completed (see Section 
5.4.6.4 – Treatment Compliance – Primary Source Data).
In the event of early termination/suspension of the clinical study, a rapid recall of study drug will 
be initiated. The Investigator or designee must immediately instruct the subjects to stop the study 
drug and return all study drug to the clinical study center.
For subjects who do not complete the entire clinical study, all used and unused study drug should 
be returned by the subjects to the clinical study center.
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At each visit, the subject will return the electronic tablet. Site staff will review videos and 
provide subject counseling and reminders on the importance of following study drug dosing 
instructions, throughout the study.  At least two videos since the prior visit should be 
reviewed.  Subjects who display repeated non-compliance based on video evidence, despite 
repeated counseling and re-training, should be discontinued from the study, based on investigator 
discretion.  
Note:   Subjects will be informed that videos will be reviewed to ensure proper use of study 
drug throughout the study; however, they will not be told how many videos will be 
reviewed. This non-disclosure allows subjects to be appropriately informed with sufficient 
detail of what study procedures will be performed and does not create any added risks to 
the subjects by withholding this level of detail. Preserving the notion that someone is 
watching is considered critical to maintaining the integrity of the split-face study design, as 
it provides motivation to remain compliant, while attempting to balance the administrative 
burden of daily video review by site staff, over a total treatment period of approximately 
170 days, for each subject.  The subject-reported dosing compliance data recorded on the 
electronic dosing calendar will be used to derive compliance, which is a common 
procedure used in clinical studies to reliably assess daily product use.  Repeated non-
compliance observed by video evidence should result in subject termination, based on 
investigator discretion.    
At the end of the study, the electronic tablet will be collected, and all collected information fully 
removed by the clinical site and confirmed by the equipment vendor.
5.4.7
Method of Subject ID and Treatment Assignment
Upon signature of the ICF, each subject will be assigned a Subject Identification Number (SIN) 
to be used throughout the study. Once a SIN has been assigned, that number must not be used 
again for any other subject. Subjects may be re-screened once provided the reason for re-
screening is not related to atrophic scar counts, acne severity (IGA) or lesion counts. 
Prior to the start of the clinical study, a randomization list will be generated and transmitted
to the clinical packaging organization for study drug labeling. The randomization will assign
the trifarotene (CD5789) cream or trifarotene vehicle cream to the right or left side of the face, 
for each study drug kit, and study drug instructions will include which study drug should be 
applied on which side of the face.
NOTE:   For the purposes of this protocol, the “left” or “right” side of the face is always 
defined as the subject’s left or right.
Upon chronological order of confirming subject eligibility, subjects are assigned a study drug kit 
in ascending numerical order of kit ID.
Refer to Section 5.1.1 for an illustration of the study design and split-face treatment allocation.


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5.4.8
Dose Modification
If a subject experiences persistent skin dryness or irritation, the Investigator may consider a 
reduced application frequency for the study drug in the first 4 weeks of the study, for a maximum 
duration of 2 weeks. In such cases, the treatment on each 
 should be reduced in a similar 
fashion, even if the irritation is only on one 
Subjects should be instructed to capture all missed applications in the dosing calendar. Sites will 
record the timing and details of a prescribed dose reduction for topical medication in source 
records.
Signs and symptoms of local cutaneous irritation will be considered as Adverse Events if they 
are severe enough to lead to permanent discontinuation of study drug or if they require the use of 
concomitant treatment including OTC products (other than moisturizers). Refer to Section 6.11.1
for further details on local tolerability assessment.
5.4.9
Allocation Concealment and Blinding
Allocation concealment is ensured as the kits will be assigned in chronological order on the basis 
of the confirmed subject eligibility. Randomization will occur individually, each kit will be 
assigned to a unique randomized subject and the simultaneous randomization of groups of 
subjects will be prevented.
All attempts will be made to keep the study team, site staff and subjects blinded to study 
treatment throughout the study, including:

Members of the study team or site staff will not have access to the randomized treatment 
assignment. 

Study drug will have similar appearance, packaging and use instructions as the 
corresponding vehicle.
5.4.10
Unblinding During the Clinical Study 
At the initiation of the study, site staff will be instructed on the method to follow for emergency 
breaking of the blind. The randomization information for any particular subject may be made 
available to the investigator in the event of a medical emergency or an AE that necessitates 
identification of the study drugs for the welfare of that participant. Whenever possible, the 
investigator should consult with the medical monitor and the Sponsor before breaking the blind, 
to discuss the decision. Emergency un-blinding during the clinical study may be required for 
regulatory reasons (for expedited safety reporting).
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When the blinding code is broken, the reason must be fully documented. If the code is broken by 
the investigator, the subject must be withdrawn from the study after completing early termination 
procedures.
Advanced Clinical Pharmacovigilance should be contacted to report any unblinding (refer to 
Section 6.11.2.2.2 for Advanced Clinical Pharmacovigilance contact information). To avoid bias
and to ensure the integrity of the blind, personnel directly involved with the ongoing conduct of
the study from the Sponsor, CRO, or other investigational study centers will not have access to 
any information that may lead to unblinding.
The randomization code will remain blinded to all study sites and study team members until 
completion of the study, and after the study database has been locked.
5.4.11
Non-Investigational Study Supplies
The Sponsor or designee will supply the following non-investigational supplies or equivalent 
available skincare product per country including:

Cetaphil® Gentle Skin Cleanser

Cetaphil® PRO Oil Absorbing Moisturizer with SPF 30

Cetaphil® Moisturizing Lotion
Refer to guidelines for using the cleanser and moisturizer (Section 5.4.2 – Instructions for Use). 
Upon receipt of non-investigational supplies, the site must conduct an inventory of all non-
investigational supplies. If a damaged shipment is received and/or a temperature excursion has 
been experienced, the site will notify the Sponsor/CRO and follow the guidelines according to 
the current version of the pharmacy manual.
The investigator or designee will maintain accurate records of non-investigational supplies 
received and dispensed. The monitor will confirm global accountability of non-investigational 
supplies (total received = total dispensed + total unused non-dispensed). All unused non-
investigational supplies will be returned to the Sponsor or designee.
5.4.12
Prior and Concomitant Therapy
5.4.12.1
Definition
Information on previous and concomitant therapies will be collected and recorded in the CRF.
Previous therapies are defined as medications or procedures that have been stopped before the 
Screening visit, and includes all acne therapies (within 6 months) and all other therapies (within 
1 month).  


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Concomitant therapies are defined as:
any existing therapies ongoing at the Screening visit; 
any changes to existing therapies (such as changes in dose or formulation) during the course 
of the clinical study, or
any new therapies received by the subject since the Screening visit
Any new concomitant therapy or modification of an existing therapy may be linked to an adverse 
event (AE). A corresponding AE form must be completed to account for the change in therapy, 
except in some cases such as therapy used for prophylaxis, dose modification for a chronic 
condition, etc. In these cases, the medication will be linked to an item in the medical history.
5.4.12.2
Categories
The following two categories are to be considered for previous and concomitant therapies: 
Drugs/therapies including, but not limited to, prescription, over-the-counter (OTC), birth 
control pills/patches/hormonal devices, vitamins, cleansers, moisturizers, sunscreens, herbal 
medicines/supplements, and homeopathic preparations.
Medical and surgical procedures including, but not limited to, laser/radiation procedures, 
dermal fillers, X-rays (excluding dental X-rays), etc.
5.4.12.3
Recording
Previous and concomitant therapies are to be recorded on the Drugs/Therapies form 
(for drugs/therapies) and/or on the Medical and Surgical Procedures form (for medical/surgical 
procedures) in the case report form (CRF).
Concomitant therapies are to be recorded, reviewed, and updated at each visit. Every attempt 
should be made to keep concomitant therapy dosing and regimen constant during the study.
5.4.12.4
Authorized Medication/Therapy
Unless specified as prohibited medication/therapy (see Section 5.4.12.5), all therapies are 
authorized, including the following as long as they are not indicated for the treatment of acne 
vulgaris.
Topical products: 
The following topical products are authorized on the treated areas:
mild or soapless cleanser
A non-comedogenic sunscreen (SPF 30 or equivalent), non-comedogenic moisturizer (as 
needed but respecting an interval of approximately 1 hour before or 1 hour after the topical 
study drug application)


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Systemic treatments: 
The following systemic medications are permitted if they are not indicated for the treatment of 
acne vulgaris:
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 (Week 24).
Topical antibiotics prescribed for localized dermal infections 
Penicillin G or V
5.4.12.5
Prohibited Medication/Therapy
Medications/therapies listed in Table 4 are prohibited during the study as they may interfere with 
efficacy and/or safety assessments.  
Table 4:
List of Prohibited Medications/Therapies During Study
Topical treatments on the face: 
Corticosteroids, antibiotics , benzoyl peroxide, azelaic acid, alpha hydroxyl acids, salicylic acid, zinc containing 
treatments, other anti-acne treatments or other acne treatments (e.g., salicylic acid treatments)
Retinoids
Cosmetic/aesthetic procedures on the face (e.g., comedone extraction, desquamating or abrasive agents, adhesive pore 
cleansing strips)
Wax epilation
Photodynamic therapy
Laser therapy, microdermabrasion, deep chemical peel, and other plastic surgical treatments for acne
Agents with potential drying effects on the skin:  i.e. antibacterial soaps, astringents, other alcohol-containing topical 
preparations
Use of tanning booths or lamps, as well as sunless tanning products 
Intensive ultraviolet (UV) radiation exposure (mountain sports, sailing, sunbathing, etc.)


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Table 4:
List of Prohibited Medications/Therapies During Study
Systemic treatments:
Initiate use of combined oral contraceptives (estrogens and progesterone), implantable/injectable contraceptives, 
hormonal contraceptive vaginal rings or change of dose (of existing medication)
Initiate use of combined oral contraceptives approved as acne treatments (e.g., Ortho Tri-Cyclen®, Yaz®, Diane-35®),
or change of dose (of existing medication)
Corticosteroids (except locally acting corticosteroids such as inhaled or intrathecal), antibiotics (except penicillin G 
and V)
Oral retinoids / isotretinoin
Cyproterone acetate / chlormadinone acetate
Spironolactone
Immunomodulators
Vitamin A supplements exceeding the recommended daily allowance (4000 – 5000 IU)
Prescription testosterone therapy (e.g., testosterone cypionate, testosterone enanthate, testosterone pellet, testosterone 
undecanoate) or on a testosterone booster or prescription testosterone (e.g., DHEA, Omnadren®, Sustanon®, 
testosterone cypionate, testosterone enanthate, testosterone propionate, testosterone phenylpropionate) or testosterone 
supplements (e.g., Tribulus)
Other:
Any drug (topical or systemic) or procedures that are used off label for the treatment of acne vulgaris
If a prohibited therapy becomes necessary for the safety of the subject, the investigator should 
notify the medical monitor and discuss possible alternatives. If a subject receives a prohibited 
therapy during the clinical study (e.g., inadvertent short-term use), the investigator should also 
notify the medical monitor and discuss whether or not it is appropriate for the subject to continue 
receiving study drugs.
5.5
Duration of Subject Participation
The expected duration for each subject’s participation in the study is approximately 28 weeks 
(including a 4-week screening period and a 24-week treatment period). 
5.5.1
Early Termination Visit
When a subject does not complete the clinical study, he/she will be fully assessed, if such 
assessment is possible. The procedures designated for the Week 24/Early Termination visit 
should be completed for all subjects discontinuing the study and the appropriate CRF page 
should be completed.


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Refer to Section 5.3.4 for reasons for early study discontinuation.  
5.5.2
Unscheduled Visit
The subject should be reminded to adhere to the study visit schedule. Unscheduled visits are 
unplanned and may include examinations for safety or repeat study assessments.  Visits 
occurring outside of the visit window are not considered unscheduled visits.
Assessments to be conducted at the unscheduled visit will depend on the reason for the visit: Any 
of the procedures/assessments listed in Section 5.1.2 – Schedule of Assessments may be 
conducted, as appropriate.  
6
STUDY ASSESSMENTS 
The protocol specifies the planned efficacy and safety assessments.
Subjects who are wearing a face mask should continue to do so until seated in an exam room, in 
accordance with your local guidelines. The general sequence of examinations should begin with 
a wellness assessment, review of dosing calendar/compliance and completion of subject 
questionnaires prior to performing scar and acne assessments local tolerability assessment and 
imaging (for designated imaging centers).  
Any facial observations clearly judged by the investigator to be related to the mask (e.g. erythema 
or dermatitic effects) will be noted in source records and included in the CRF comments, 
attributable to the mask (e.g., increased erythema along mask edge, etc). An AE form can be 
submitted at the discretion of the investigator. If mask effects remain detectable at the time of the
acne assessments and local tolerability assessments, they should be considered and reported as part 
of these assessments.
Refer to Section 5.1.2 – Schedule of Assessments for guidelines to ensure safety of enrolled 
subjects and continuity of scheduled follow-up visits.
6.1
Efficacy Assessments
Efficacy measurements should be conducted by the investigators (or designees) or by subjects 
(for subject-reported assessments) according to Section 5.1.2 - Schedule of Assessments. 
Evaluators must complete standardized training prior to performing the following assessments: 
atrophic scar severity (SGA), atrophic scar counts, acne severity (IGA), inflammatory lesion 
counts (papules and pustules), non-inflammatory lesion counts (open and closed comedones), 
and other lesion counts (nodules and cysts). Refer to Section 8.1 – Personnel Training for further 
details on site personnel training. 
Notes: 






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CCI
CCI


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CCI


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CCI


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CCI


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6.11
Safety Assessments
Safety assessments include the recording of adverse events and local tolerability scores.
6.11.1
Local Tolerability Assessment 
Local tolerability assessment(s) on each 
 will include erythema, scaling, dryness and 
burning/stinging at visits specified in the schedule of assessments (Section 5.1.2). Table 7
summarizes the local tolerability assessment. Burning/stinging will be recorded by the 
investigator after discussion with the subject.
Local tolerability assessments for each 
 are reported as a global rating for each 
tolerability parameter, based on clinical judgment of the investigator.  
CCI
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Any new sign or symptom, which is not included in the scheduled evaluation of tolerability, 
should be recorded as an Adverse Event, including those of mild intensity.
6.11.2
Adverse Events
Adverse events (AEs) are to be monitored throughout the course of the clinical study. All AEs 
are to be reported on the Adverse Event Form with complete information as required. If AEs 
occur, the main concern will be the safety of the subjects. At the time of the ICF signature, 
each subject must be provided with the name and phone number of clinical study center 
personnel for reporting AEs and medical emergencies.
6.11.2.1
Definitions
6.11.2.1.1
Adverse Events
According to ICH E2A, an AE is any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory value), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.
Thus, any new sign, symptom or disease, or any clinically significant worsening of an existing 
sign, symptom or disease compared to the condition at the first visit (including disease treated), 
should be considered as an AE. Lack of efficacy is not considered as an AE.
Each new episode of a chronic disease (e.g., hay fever, allergy, etc.) should be reported as 
a new AE.
Notes:
Any new sign or symptom reported by the subject that appears after accidental or intentional 
overdose or misuse should also be reported as an AE.
Whenever possible, a diagnosis should be reported on the AE form rather than the signs, 
symptoms or abnormal laboratory values associated with the report of an AE. However, a 
diagnosis should be reported only if, in the Investigator’s judgment, it is relatively certain. 
Otherwise, symptoms, signs, or laboratory values should be used to describe the AE.
Pregnancy is not to be considered as an AE; however, is an important medical event that must 
be monitored as described in Section 6.11.2.2.5.


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6.11.2.1.2
Serious Adverse Events
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:
Results in death,
Is life-threatening,
Requires inpatient hospitalization or prolongation of existing hospitalization,
Results in persistent or significant disability/incapacity, or
Is a congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the safety of the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasia, or 
convulsions that do not result in hospitalization.
Note:
The term “life-threatening” refers to an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event that hypothetically might have caused death if it was 
more severe.
Inpatient hospitalization is considered to have occurred if the subject has had to stay for a night 
at the hospital. The criterion for prolongation of hospitalization is also defined as an extra night 
at the hospital. Hospitalization may not constitute sufficient grounds to be considered as an SAE 
if it is solely for the purpose of a diagnostic tests (even if related to an AE), elective 
hospitalization for an intervention that was already planned before subject enrollment in the 
clinical study, admission to a day-care facility, social admission (e.g., if the subject has no place 
to sleep), or administrative admission (e.g., for a yearly examination).
6.11.2.1.3
Adverse Events of Special Interest
An AESI is a noteworthy event for the particular study drug that can be appropriate for the 
Sponsor to monitor closely. It could be serious or non-serious and AESIs could include events 
that might be potential precursors or prodromal symptoms for more serious medical conditions in 
susceptible individuals.
The AEs of Special Interest for this protocol are pre-defined as follows: 
Related cutaneous AEs which lead to permanent treatment discontinuation
Suspicion of allergic contact reaction related to the study drug (see Section 6.11.2.2.4)


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For AESIs, the Investigator is required to complete the AESI Form and follow the AESI 
reporting procedures in Section 6.11.2.2.3 even if the event is considered non-serious according 
to the usual regulatory criteria. For suspected sensitizations associated with study medication 
use, follow the re-challenge with the study drug patch test procedures in Section 6.11.2.2.4 (and 
subsequent ingredient patch testing, if the re-challenge with the study drug is positive or 
equivocal).  
6.11.2.1.4
Unexpected Adverse Drug Reaction
According to ICH E6, an unexpected adverse drug reaction is defined as an adverse reaction, the 
nature or severity of which is not consistent with the applicable study drug information 
(e.g., reference safety information in Investigator Brochure, package insert/summary of product 
characteristics, etc).
6.11.2.1.5
Adverse Event Reporting Period
The clinical study period during which AEs must be reported is the period from when the subject 
signed the ICF to the end of the subject’s participation.
The Sponsor should be informed if the Investigator becomes aware of any unusual safety 
information or any safety information that appears to be drug-related involving a subject who has 
participated in a clinical study, even after a subject has completed the clinical study. 
The Investigator should be diligent in looking for possible latent safety effects that may not 
appear until a medication has been discontinued.
6.11.2.1.6
Adverse Event Severity
Severity is a clinical determination of the intensity of an AE and not of a disease.
The Investigator is to classify the intensity of AEs using the following definitions as a guideline 
for all AEs. For this classification, the Investigator will take into account the possible range of 
the intensity of the event and report the grade of intensity which is the most appropriate 
according his medical judgment.
Mild
Awareness of signs or symptom, but easily tolerated.
Moderate
Discomfort, enough to cause interference with usual activity
Severe
Incapacitating with inability to work or perform usual activity


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6.11.2.1.7
Relationship to the Study Drug
The investigator is to determine whether there is a reasonable causal relationship between the 
study drug and the AE. Medical judgment should be used to determine the relationship, 
considering all relevant factors including the pattern of reaction, temporal relationships, positive 
challenge or rechallenge, relevant medical history, and confounding factors such as 
co-medication or concurrent diseases.
The expression “reasonable causal relationship” is meant to convey in general that there are facts 
or arguments to suggest a causal relationship (ICH E2A, Section IIIA 1).
The relationship assessment for an AE is to be completed using the following definitions as a 
guideline for all AEs occurring during clinical studies conducted or sponsored by 
GALDERMA R&D:
Reasonable possibility:
According to the Investigator, there is a reasonable possibility (i.e., suggestive evidence or 
arguments) that there is a causal relationship irrespective of the dose administered between:

The study drug and the AE, or

The study procedure and the AE (e.g, procedure include use of cleanser, moisturizer, etc.)
No reasonable possibility:

No suggestive evidence or arguments can be identified regarding a causal relationship 
between the study drug or study procedure and the AE.
6.11.2.2
Reporting Procedures
6.11.2.2.1
Procedures for Reporting Adverse Events
The collection of AEs is from the time that a subject signs the ICF to their final visit.
At each post-enrollment visit, the Investigator (or sub-Investigator) will question the subject 
about AEs using an open non-persuasive question to elicit reporting of AEs, for example: 
“Have you noticed any change in your health since the last visit?” Directed questioning and 
examination will then be performed, as appropriate. 
Any AE occurring during the AE reporting period, whether it is related to the study drug or not, 
will be recorded immediately in the source document, and described on the Adverse Event Form
along with the date of onset, severity, relationship to the study drug, and outcome, without 
omitting any requested and known information. Additional information may be requested under 
certain circumstances. Adverse Events assessed as related to the treatment will be monitored 


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until they are completely or satisfactorily resolved. Other AEs will be monitored until the last 
visit if they are not resolved or satisfactorily resolved.
The Investigator will obtain and maintain in the subject’s files all pertinent medical records, 
information and medical judgment from colleagues who assisted in the treatment and follow-up 
of the subject. If necessary, the Investigator will contact the subject’s personal physician or 
hospital staff to obtain further details.
For SAEs (see Section 6.11.2.2.2), AESIs (see Section 6.11.2.2.3), and pregnancies 
(see Section 6.11.2.2.5), Advanced Clinical Pharmacovigilance is to be informed immediately by 
fax or email (preferred method). The event must be reported by fax or sent by e-mail within 24 
hours of receipt of the information (contact details provided in Section 6.11.2.2.2). 
6.11.2.2.2
Procedure for Reporting a Serious Adverse Event
For an SAE occurring during the period of the clinical study, regardless of whether it is related to 
the treatment or not, and of whether it is expected or not, the Investigator must do the following:
1. Take prompt and appropriate medical action, if necessary. The safety of the subject is the 
first priority.
2. Ensure that the event is classified as an SAE. Immediately inform Advanced Clinical 
Pharmacovigilance of the event (within 24 hours of knowledge of the event) by fax or email 
and discuss further actions to be taken.  Email is the preferred method.
Advanced Clinical Pharmacovigilance:
DrugSafetyPV@advancedclinical.com  (preferred method)
or 
E-Fax: 1-847-589-5211     
3. Complete the Adverse Event Form provided in the CRF as fully as possible.
4. Ensure that the event is classified as an SAE in the CRF.
5. Print and complete the Serious Adverse Event Form available in the electronic data capture 
(EDC) system as PDF document.  Fax or scan and send by e mail the completed form, 
accompanied by any other relevant information or medical records (e.g., laboratory test 
results) within 24 hours to Advanced Clinical Pharmacovigilance. The demographics, 
medical history, previous and concomitant therapies, and adverse event pages of the CRF 
must be completed and available for review in the EDC system at the time of the report.
6. Monitor and record the progress of the event until it resolves or reaches a clinically stable 
outcome, with or without sequelae. For follow-up evaluations, notify Advanced Clinical 
Pharmacovigilance of updates within 24 hours. Serious Adverse Events will be monitored 
until the Investigator and Sponsor agree that the event is satisfactorily resolved.


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7. Obtain and maintain in his/her files all pertinent medical records, information, and medical 
judgments from colleagues who assisted in the treatment and follow-up of the subject. 
If necessary, contact the subject’s personal physician or hospital staff to obtain further 
details.
8. Inform Advanced Clinical Pharmacovigilance of the final outcome of the event. Send a 
revised or updated Serious Adverse Event Form and Adverse Event Form, if appropriate.
9. Comply with the applicable regulatory requirement(s) related to the reporting of SAEs to the 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC).
If there are serious, unexpected adverse drug reactions associated with the use of the study drug, 
the Sponsor or designee will notify the appropriate regulatory agency(ies), Ethics Committees 
(EC), and all participating Investigators on an expedited basis. 
6.11.2.2.3
Procedure for Reporting an Adverse Event of Special Interest
For any AESI (see Section 6.11.2.1.3) occurring during the period of the clinical study, whether 
related to the treatment or not, and whether expected or not, the Investigator is to do the following:
1. Take prompt and appropriate medical action, if necessary. The safety of subjects is the first 
priority.
2. Immediately inform Advanced Clinical Pharmacovigilance of the event by fax or email and 
discuss further actions to be taken (Section 6.11.2.2.2).
3. Complete the Adverse Event Form provided in the CRF as fully as possible.
4. Ensure that the event is classified as an AESI in the CRF.
5. Print the Adverse Event form. Fax or scan and send by e mail the completed form, 
accompanied by any other relevant information or medical records (e.g. laboratory test 
results) within 24 hours to Advanced Clinical Pharmacovigilance. The demographics, 
medical history, previous and concomitant therapies, and adverse event pages of the CRF 
must be completed and available for review in the EDC system at the time of the report.
6. Monitor and record the progress of the event until it resolves or reaches a clinically stable 
outcome, with or without sequelae. For follow-up evaluations, notify Advanced Clinical 
Pharmacovigilance within 24 hours. AESIs will be monitored until the Investigator and 
Sponsor agree that the event is satisfactorily resolved. 
7. Obtain and maintain in his/her files all pertinent medical records, information, and medical 
judgments from colleagues who assisted in the treatment and follow-up of the subject. 
If necessary, contact the subject’s personal physician or hospital staff to obtain further 
details.
8. Inform Advanced Clinical Pharmacovigilance of the final outcome of the event. Send a 
revised or updated Adverse Event Form, if appropriate.


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6.11.2.2.4
Procedures for Suspected Allergic Contact Reaction to Topical Study 
Medication (Re-Challenge Patch Test and Ingredient Patch Testing)
If a subject experience a suspected allergic contact reaction associated with study medication
use, the following actions should be taken to characterize the event:
Stop all study medication.
Take a picture of the affected area and the non-affected surrounding skin
Document the event as an Adverse Event of Special Interest, contact immediately Advanced 
Clinical Pharmacovigilance and report the event within 24hrs (see Section 6.11.2.2.2).
The subject continues to be followed for scheduled study visits while awaiting the re-
challenge test results. 
a) Re-Challenge with Assigned Topical Study Medication 
1) After all signs and symptoms of AESI have resolved and after a minimum of two weeks from 
last dose application, perform a re-challenge test with the study drug. Scheduling on a 
Monday or Tuesday is ideal, as it ensures the 48-hour and 72-96 hour follow-up assessments 
occur on weekdays (Table 8).
2) Ensure the subject has not been under any treatment with corticosteroids or antihistamines of 
any route of administration the week before testing. 
3) Ensure that the skin on the back has not been exposed to the sun or artificial UV sources the 
week before testing.
4) Apply an appropriate quantity of the topical study drug to fill in the cupule of the test 
chamber to a naïve zone on the back either the right or left side of the center line (or the inner 
forearm if the back cannot be tested). If no test chamber is available on site, patch test units 
will be provided by the Sponsor or designee. Apply an empty test chamber as a control for 
the re-challenge test with topical study drug (note: an empty test chamber will not be needed 
for ingredient testing, if such test is warranted, as the Sponsor/designee will provide one or 
more controls for testing). The use of semi-occlusive conditions depends on the irritant
potential of the study product and the intensity of the reaction that was observed. The method 
to be used should be discussed with the Medical Monitor.
Choose a skin site that was not previously involved in the inflammatory skin reaction. Cover 
the test chamber for 48 hours with a hypoallergenic tape.
5) Subject should be informed about avoiding exercise, showers, application of toiletries 
products, etc. to keep the test system dry
6) After 48 hours, remove the test chamber and evaluate the site and take photos after each 
reading (Table 9):
at approximately 30 minutes after patch test removal (1st reading) and,
24 to 48 hours later (i.e., 72 or 96 hours after application) (2nd reading).  


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If the result of the second reading is equivocal, the Investigator or at the Sponsors request, 
may perform an optional 3rd reading at 96 to 120 hours later (i.e., 6 to 7 days after 
application of the patch).
Pictures of each reading and the reading results should be sent to Advanced Clinical 
Pharmacovigilance and medical monitor. 






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1.
Immediately inform Advanced Clinical Pharmacovigilance of the event by fax or email 
(Section 6.11.2.2.2).
2. Withdraw the subject from the clinical study.
3. Complete the Pregnancy Surveillance Form – Part I: History and Start of Pregnancy, 
provided by the Clinical Research Associate (CRA) at the beginning of the clinical study, as 
fully as possible. Inform Advanced Clinical Pharmacovigilance of the pregnancy by sending 
this pregnancy form along with the Exit Form within 24 hours to Advanced Clinical 
Pharmacovigilance (see Section 6.11.2.2.2).
4. Monitor and record the progress of the pregnancy until its outcome. Contact the subject’s 
regular physician (general practitioner or gynecologist) or hospital staff to obtain further 
details and ask for regular follow-up information.
5. Inform Advanced Clinical Pharmacovigilance of the progress by tri-monthly updates until 
the final outcome of the pregnancy, within 24 hours of receiving updates. If the subject can 
no longer be reached (lost to follow-up), documentation of the non-response/contact with two 
telephone calls and a letter (certified with return receipt) is required.
6. At the outcome of the pregnancy, complete the Pregnancy Surveillance Form – Part II: 
Course and Outcome of Pregnancy, as fully as possible. Send this pregnancy form to 
Advanced Clinical Pharmacovigilance within 24 hours (see Section 6.11.2.2.2).
7. If the pregnancy leads to an abortion (voluntary, spontaneous or therapeutic), in-utero death, 
or congenital anomaly, follow the procedure for reporting an SAE (see Section 6.11.2.2.2).
7
PLANNED STATISTICAL ANALYSES
7.1
Statistical Analysis Plan
A statistical analysis plan (SAP) will be developed and issued as a separate document. The SAP 
will contain a more detailed and technical description of specific data conventions, calculations 
and of statistical procedures for executing the analysis strategies. The SAP will be finalized prior 
to the database lock.
Any change from the protocol will be justified and fully documented.
If the blind review suggests changes to the principal features stated in the protocol, these have to 
be documented in a protocol amendment. Otherwise, it will suffice to update the statistical 
analysis plan with the considerations suggested from the blind review. 
Post hoc exploratory analyses will also be clearly identified in the Clinical Study Report (CSR).




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the sample size for a Student's t-test for paired samples can be calculated according to the 
following formula:
. ≥
. . 	
,
	
 + 	
,
	



 − !"

where tν,p is the Student's t distribution quantile with ν degrees of freedom and probability p (n is 
rounded up to the closest integer).
α
(2-sided)
β
Power
(%)
µTrifarotene
- µVehicle σDiff n
Drop-out 
and
Non-
evaluable
Proportion
(%)
Subjects to be Randomized
0.05
0.2
80
-1.7
6.0 100
15
118
An initial number of 118 subjects is planned to be randomised. Due to the uncertainty of the 
estimation of the variability, a blinded sample size re-estimation will be performed after 40 
subjects complete/discontinue the study (i.e. after 33% of the initial planned subjects 
complete/discontinue the study) in order to evaluate the need for additional subjects to be 
randomized.
7.3
Populations Analyzed, Evaluability and Limitation / Evaluation of Bias
The Intention-to-Treat (ITT) population will be used for the analyses of efficacy endpoints on the 
face. The Per Protocol (PP) population will be used for a sensitivity analysis of the primary 
endpoint. The Safety population (SAF) will be used for all safety analyses. 
7.3.1
Intent-to-treat (ITT) population
The ITT population is defined as all randomized subjects and will be used for the analyses of 
efficacy endpoints on the face.  
7.3.2
Per Protocol (PP) population
The Per Protocol (PP) population is defined as comprising the ITT population subjects who are 
compliant to the treatment application (i.e. with an overall compliance between 80% - 120% 
inclusive), whose Baseline and Week 24 total atrophic acne scar counts are performed and who 






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7.4.3.3
Missing Data
Missing values of atrophic acne scar counts will be imputed using MI (Multiple Imputation) 
under the Missing At Random (MAR) assumption. 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.
Missing values of acne lesion counts, SGA scores and IGA scores will be imputed using Last 
Observation Carried Forward (LOCF). Moreover, for binary endpoints Missing as Failure 
(MAF) method will be used as additional analysis.
For the sensitivity analyses of the primary endpoint, missing data will be imputed using a Jump-
to-Reference (J2R) approach under the Missing Not At Random (MNAR) assumption and Last 
Observation Carried Forward (LOCF).
7.4.3.4
Sensitivity Analyses
To assess the robustness of the primary efficacy results, the following sensitivity analyses will be 
conducted:
1. Jump-to-Reference (J2R) approach under Missing Not At Random (MNAR) assumption, by 
imputing missing differences between treatments as zero (0).
2. Missing data of primary endpoint will be imputed using Last Observation Carried Forward 
(LOCF).
3. Observed Case (OC) analysis.
4. Per Protocol (PP) analysis.
7.4.5
Safety Analysis
Analysis of safety results include:

Local tolerability scores (erythema, scaling, dryness and stinging/burning) for face will be 
summarized using frequency tables for worst post-baseline score, the final score during 
treatment, as well as scores for each visit.
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The investigator must permit the monitor, the IEC/IRB, the Sponsor’s internal auditors, and 
representatives from regulatory authorities direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the CRFs.
8.3
Data Management
The Sponsor or designee will be responsible for activities associated with the data management 
of this study. This will include, but not limited to, setting up a relevant database and data transfer 
mechanisms, along with appropriate validation of data and resolution of queries. All data 
management activities will be detailed in a Data Management Plan (DMP).
Study sites will enter data into an electronic data capture (EDC) system by completing the CRF 
via a secure internet connection. Data entered into the CRF must be verifiable against source 
documents at the study center. Data to be recorded directly on the CRF will be considered the 
source document. Any changes to the data entered into the EDC system will be recorded in the 
audit trail.
8.4
Clinical Study Conduct
With the exception of avoiding an immediate risk to a subject, the investigator should not 
deviate from the clinical study protocol or implement any changes without written approval 
from the Sponsor and prior review and documented approval/favorable opinion from the 
IRB/IEC of a protocol amendment.
Changes that involve only logistical or administrative changes to the clinical study protocol are 
authorized. The investigator should document and explain any deviation from the clinical study 
protocol.
8.5
Protocol Amendments
The Sponsor may modify the clinical study protocol at any time for ethical, medical, or 
scientific reasons. Any amendments will be handled according to applicable local regulations.
Non-substantial protocol amendments (such as those pertaining to typographical errors, 
changes in study personnel, etc.) will not be submitted to the regulatory authorities but will be 
submitted to IRB/IEC for information only.  The Sponsor will ensure an acknowledgement is 
received and filed.  All non-substantial amendments will be included in subsequent 
submissions to regulatory authorities in cases of a substantial amendment.  


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8.6
Quality Management and Risk Evaluation
The quality of the study will be monitored for potential risks, with mitigating strategies 
identified, as defined in a separate risk management plan. The Sponsor will document a plan to 
ensure appropriate oversight and quality of the study.   
8.7
Quality Assurance / Audit / Inspection
At the completion of the study, digital images will be forwarded to the Sponsor according to 
agreed upon format.
Audits of clinical study centers may be conducted by the Sponsor/designee or regulatory 
authorities before, during, or after the clinical study. 
The Investigator will allow and assist the Sponsor/designee and any regulatory agency to have 
direct access to all requested clinical study-related records.
For the audits performed by, or on behalf of the Sponsor, audit certificate(s) will be provided by 
Quality Assurance.
9
ETHICS AND GENERAL CLINICAL STUDY CONSIDERATIONS
9.1
Institutional Review Board or Independent Ethics Committee 
Before initiation of the study at each study center, the protocol, the ICF, other written material 
given to the subjects, and any other relevant study documentation will be submitted to the 
appropriate IEC/IRB. Written approval of the study and all relevant study information must be 
obtained before the study center can be initiated or the study drug is released to the 
investigator. Any necessary extensions or renewals of IEC/IRB approval must be obtained for 
changes to the study such as amendments to the protocol, the ICF or other study
documentation. The written approval of the IEC/IRB together with the approved ICF must be 
filed in the study files.
The investigator will report promptly to the IEC/IRB any new information that may adversely 
affect the safety of the subjects or the conduct of the study. The investigator will submit written 
summaries of the study status to the IEC/IRB as required. On completion of the study, the 
IEC/IRB will be notified that the study has ended. 


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9.2
Regulatory Authorities
Relevant study documentation will be submitted to the regulatory authorities of the participating 
countries, according to local/national requirements, for review and approval before the beginning 
of the study. On completion of the study, the regulatory authorities will be notified that the study 
has ended.
9.3
Ethical Conduct of the Clinical Study
This clinical study will be conducted in accordance with the protocol, the Declaration of 
Helsinki, and the ICH GCP, and in compliance with other applicable regulatory requirements. 
9.4
Subject Information and Consent
All subjects who participate in this clinical study are required to be fully informed about the 
clinical study in accordance with GCPs guidelines, country regulations and guidelines (e.g., 
HIPAA, in the US), in accordance with local requirements.
All minor subjects who participate in this clinical study must be accompanied by a 
parent/guardian. Subjects and parent/guardians are required to be fully informed about 
the clinical study in accordance with GCP guidelines and relevant country regulations 
(e.g., for the US, HIPAA), in accordance with local requirements.
The investigator or designated personnel will inform the subject of the objectives, methods, 
anticipated benefits and potential risks and inconveniences of the study. The subject should be 
given every opportunity to ask for clarification of any points she/he does not understand and, if 
necessary, ask for more information. At the end of the interview, the subject will be given 
ample time to consider the study. Subjects will be required to sign and date the ICF. After 
signatures are obtained, the ICF will be kept and archived by the investigator in the 
investigator’s study file. A signed and dated copy of the subject ICF will be provided to the 
subject or his/her authorized representative.
It should be emphasized that the subject may refuse to enter the study or to withdraw from
the study at any time, without consequences for their further care or penalty or loss of 
benefits to which the subject is otherwise entitled. Subjects who refuse to give or who 
withdraw written informed consent should not be included or continue in the study.
If new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the study, a new ICF will be approved by the IEC(s)/IRB(s) (and 
regulatory authorities, if required). The study subjects will be informed about this new 
information and reconsent will be obtained.


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9.5
Subject Confidentiality
Monitors, auditors, and other authorized agents of the sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, and the US Food and Drug Administration, as well as 
that of any other applicable agency(ies), will be granted direct access to the study subjects’ 
original medical records for verification of clinical study procedures and/or data, without 
violating the confidentiality of the subjects to the extent permitted by the law and regulations.
In any presentations of the results of this study or in publications, the subjects’ identities will 
remain confidential.
All personal data collected and processed for the purposes of this study should be managed
by the investigator and his/her staff with adequate precautions to ensure confidentiality of 
those data, and in accordance with the applicable national and/or local laws and regulations 
(HIPAA for the US) on personal data protection.
9.6
Contractual Requirements
A contractual agreement will be signed between the Sponsor or CRO designee and each 
Investigator/Institution. This document will contain supplementary information, including 
financial terms, confidentiality, the clinical study schedule, third party responsibility, and 
publication rights.
9.7
Data Collection and Source Documentation
The Investigator must maintain all required records for all subjects. Data for this clinical study
will be recorded in the subject’s source documents, subject photographs and on the CRFs 
provided by the Sponsor. All data should be recorded on the CRFs completely and promptly.
The Investigator must keep accurate study records, other than the CRFs, of all subject visits, 
being sure to include all pertinent clinical study-related information (unless the CRF will serve as 
the source, such as subjects recording data directly to the electronic CRF). A statement should be 
made indicating that the subjects have been included in this clinical study and have provided 
signed written Informed Consent and Assent as applicable. All AEs must be thoroughly 
documented.
Results of any diagnostic tests conducted during the clinical study should also be included in the 
source documentation. 


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9.8
Insurance
The Sponsor will ensure appropriate insurance exists for the conduct of this study. 
10
PUBLIC DISCLOSURE OF CLINICAL STUDY
This clinical study will be recorded to a freely accessible public registry.


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11
REPORT AND PUBLICATION, INCLUDING ARCHIVING
Essential documents are those documents that individually and collectively permit evaluation of 
the study and quality of the data produced. After completion of the study (end of study defined 
as the date of the last visit of the last subject), all documents and data relating to the study will 
be kept in an orderly manner by the investigator in a secure study file. This file will be available 
for inspection by the Sponsor or its representatives. Essential documents should be retained for 
2 years after the final marketing approval in an ICH region or for at least 2 years since the 
discontinuation of clinical development of the investigational product. It is the responsibility of 
the Sponsor to inform the study center when these documents no longer need to be retained. 
The investigator must contact the Sponsor before destroying any study-related documentation.
In addition, all subject medical records and other source documentation will be kept for the 
maximum time permitted by the hospital, institution, or medical practice.
If the investigator retires, relocates, or withdraws from the responsibility of keeping the clinical 
study records for any other reasons, custody must be transferred to a person who will accept the 
responsibility. The Sponsor/CRO must be notified in writing of the name and address of the new 
custodian.
The Sponsor must review and approve any results of the study or abstracts for professional 
meetings prepared by the investigator(s). Published data must not compromise the objectives of 
the study. Data from individual study centers in multicenter studies must not be published 
separately.
12
SUSPENSION OR PREMATURE TERMINATION
The Sponsor will suspend or terminate the study if so instructed by the IRB/IEC or regulatory 
authority, or if it is judged that the subjects are subjected to unreasonable risks, or for valid 
scientific or administrative reasons. 
The Sponsor may also decide to close a single study site due to unsatisfactory subject enrollment
or non-compliance with the protocol, GCP, or applicable regulatory requirements.
In the event of premature termination, the Sponsor will provide information on the handling of 
currently enrolled subjects who have not completed the study.


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13
REFERENCES
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Acneiform Eruptions, March 2017; pp 118-127.
BlumePeytavi U et al. Longterm safety and efficacy of trifarotene 50 μg/g cream, a firstinclass RAR. γ selective topical retinoid, in patients with moderate facial and truncal acne. J Eur 
Acad Dermatol Venereol. 2020 Jan; 34(1): 166–173.
Davis, E.C. and Callender, V.D. (2010) A Review of Acne in Ethnic Skin. Pathogenesis, Clinical 
Manifestations, and Management Strategies. Journal of Clinical and Aesthetic Dermatology, 3, 4.
Del Rosso JQ. Oral antibiotics. in: Shalita Ar, Del rosso JQ, webster GF, eds. Acne Vulgaris. 
London, United Kingdom: informa Healthcare; 2011:113–124. 
Del Rosso JQ. The role of skin care as an integral component in the management of acne vulgaris: 
Part 1: The importance of cleanser and moisturizer ingredients, design, and product selection. J 
Clin Aesthet Dermatol.2013;6(12):19-27.
Del Rosso JQ, Brandt S. The role of skin care as an integral component in the management of acne 
vulgaris. Part 2: Tolerability and performance of a designated skin care regimen using a foam wash 
and moisturizer SPF 30 in patients with acne vulgaris undergoing active treatment. J Clin Aesthet 
Dermatol. 2013;6(12):28-36.
Dreno B. [Pathophysiology of acne] Presse Med. 2005 Apr 9; 34(7):537 539. French.
Eichenfield LF, Krakowski AC, Piggott C, et al. evidencebased recommendations for the diagnosis 
and treatment of pediatric acne. Pediatrics. 2013;131 Suppl 3:S163–186. 
Fisher, et al.Immunological identification and functional quantitation of retinoic acid and 
retinoid X receptor proteins in human skin J. Biol. Chem., 269 (1994), pp. 20629-20635.
Fisher GJ, Datta S, Wang Z, et al. c-Jun-dependent inhibition of cutaneous procollagen 
transcription following ultraviolet irradiation is reversed by all-trans retinoic acid. J Clin Invest. 
2000;106:663–70.
Galderma Protocol RD.06.SPR.118295, data on file.  
Galderma Protocol RD.03.SPR.105061, data on file.Gollnick H, Cunliffe w, Berson D, et al. 
Management of acne: a report from the global alliance to improve outcomes in acne. J Am Acad 
Dermatol. 2003;49(Suppl 1):S1–S38. 
Gollnick H. Current concepts of the pathogenesis of acne: implications for drug treatment. Drugs 
2003; 63 (15): 1579 1596.
Goodman G. Postacne scarring: a review of its pathophysiology and treatment. Dermatol 
Surg. 2000;26:857–871.
Goodman GJ and Baron JA. Postacne scarring: a qualitative global scarring grading system. 
Dermatol Surg 2006; 32: 1458–1466. 
Goodman GJ and Baron JA. Postacne scarring—a quantitative global scarring grading system. J 
Cosmet Dermatol 2006; 5: 48–52.


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Heidel B; Theresa N. Canavan. Edward Chen. Boni E. Eleski. Optimizing Non-Antibiotic 
Treatments for Patients with Acne: A Review. Dermatol Ther. Aug 2016: 1-24. 
Kang S, Cho S, Chung JH, Hammerberg C, Fisher GJ, Voorhees JJ. Inflammation and extracellular 
matrix degradation mediated by activated transcription factors nuclear factor-kappaB and activator 
protein-1 in inflammatory acne lesions in vivo. Am J Pathol. 2005;166:1691–9.
Kang S, Fisher GJ, Voorhees JJ. Photoaging and topical tretinoin: therapy, pathogenesis, and 
prevention. Arch Dermatol. 1997;133:1280–4.
Kang S, Leyden JJ, Lowe NJ, et al. Tazarotene cream for the treatment of facial photodamage. 
Arch Dermatol. 2001;137:1597–604.
Kang S, Voorhees JJ. Photoaging therapy with topical tretinoin: an evidence-based analysis. J Am 
Acad Dermatol. 1998;39:S55–61.
Koo JY, et al. Psychologic aspects of acne. Pediatr Dermatol. 1991. Vol. 8 (3): 185-188.
Layton AM, Henderson CA, Cunliffe WJ. A clinical evaluation of acne scarring and its 
incidence. Clin Exp Dermatol. 1994;19:303–308.
Leyden JJ. Topical treatment of acne vulgaris: retinoids and cutaneous irritation. J Am Acad 
Dermatol. 1998;38:S1-S4.
Osterweil N, ed. Frustrated adults told acne was adolescent disease, survey says. Dermatology 
Times (Suppl), 14, 1993:S5-S6.
Papakonstantinou E, Aletras AJ, Glass E, et al. Matrix metalloproteinases of epithelial origin in 
facial sebum of patients with acne and their regulation by isotretinoin. J Invest Dermatol. 
2005;125:673–84.
Pawin H, Beylot C, Chivot M, Faure M, Poli F, Revuz J, et al. Physiopathology of acne vulgaris: 
recent data, new understanding of the treatments. Eur J Dermatol. 2004;14:4–12.
Phillips TJ, Gottlieb AB, Leyden JJ, et al. Efficacy of 0.1% tazarotene cream for the treatment of 
photodamage. A 12-month multicenter, randomized trial. Arch Dermatol. 2002;138:1486–93.
Schorr ES, Sidou F, Kerrouche N. Adjunctive use of a facial moisturizer SPF 30 containing 
ceramide precursor improves tolerability of topical tretinoin 0.05%: a randomized, investigator-
blinded, split-face study. J Drugs Dermatol. 2012;11(9):1104-1107.
Silverberg JI, Silverberg NB. Epidemiology and extracutaneous comorbidities of severe acne in 
adolescence: a U.S. population-based study. Br J Dermatol. 2014;170(5):1136-1142. 
Spiewak R. Patch testing for contact allergy and allergic contact dermatitis. Open Allergy J 2008; 
1: 42-51.
Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care for acne vulgaris management. 
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Tan J, Bhate K. A global perspective on the epidemiology of acne. Br J Dermatol. 2015;172 Suppl 
1:3-12.
Tan J, Kang S, Leyden J. Prevalence and risk factors of acne scarring among patients consulting 
dermatologists in the Unites States. J Drugs Dermatol. 2017;16 (2):97-102. 
Tan J, Thiboutot D, Popp G, et al. Randomized phase 3 evaluation of trifarotene 50 µg/g cream 
treatment of moderate facial and truncal acne. J Am Acad Dermatol. 2019;80(6):1691-1699.
Thoreau E, Arlabosse JM, Bouix-Peter C, Chambon S, Chantalat L, Daver S, et al. Structure-based 
design of trifarotene (CD5789), a potent and selective RARgamma agonist for the treatment of 
acne. Bioorg Med Chem Lett. 2018;28 (10):1736-41.
Trivedi NR, Gilliland KL, Zhao W, Liu W, Thiboutot DM. Gene array expression profiling in acne 
lesions reveals marked upregulation of genes involved in inflammation and matrix remodeling. J 
Invest Dermatol. 2006;126:1071–9.
Tsatsou F, Zouboulis CC. Anatomy of the Sebaceous Gland. In: Christos C. Zouboulis, Andreas 
Katsambas, Albert Kligman, editors. Pathogenesis and Treatment of Acne and Rosacea. London: 
Springer, 2014. 27-31.
Whitney P. Bowe and Leon H. Kircik. The Importance of Photoprotection and Moisturization in 
Treating Acne Vulgaris . JDD August 2014; Vol 13 (8); s89.


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14
APPENDICES


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14.5
Acne Lesion Count
Lesions within the middle zone (2 cm) including the nose, under the jawline or along the hairline 
(including eyebrows) will not be included in the counts.


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14.6
Investigator Notification of Ingredient Patch Test Results
Dear Investigator, 
The accompanying form provides results of the ingredient patch testing for the topical study drug 
in Galderma clinical protocol: 202395.
If results for any of tested ingredients are positive or equivocal, please advise the subject to contact 
his/her primary care physician for further information (this should be a physician different than 
the study investigator(s), to maintain the study blind). 
This contact should be made no later than 5 business days after the date of receiving the ingredient 
test results. 
The subject should provide the primary care physician with the form appended to this letter 
containing blinded test results, and discuss whether it is relevant to unblind the results. If the 
decision is to unblind, the physician should contact the Clinical Safety Officer (contact details 
provided on the form). 
Sincerely,




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INVESTIGATOR SIGNATURE PAGE
Protocol Title:
Evaluation of the risk of atrophic acne scar formation during treatment of acne vulgaris 
subjects with trifarotene 50 µg/g cream versus vehicle cream over 24 weeks
Protocol Number:
RD.06.SPR.202395
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement 

I, the undersigned, have reviewed this protocol, including appendices, and I will conduct the study as 
described in compliance with this protocol (and amendments), GCP, and relevant International Council for 
Harmonisation guidelines.

I am thoroughly familiar with the appropriate use of the study drug as described in this protocol and any 
other available information (e.g., approved product labeling, investigator’s brochure, etc)

Once the protocol has been approved by the independent ethics committee (IEC)/institutional review board 
(IRB), I will not modify this protocol without obtaining prior approval of Galderma R&D and of the 
IEC/IRB. I will submit the protocol amendments and/or any informed consent form modifications to 
Galderma R&D and the IEC/IRB, and approval will be obtained before any amendments are implemented.

I ensure that all persons or party assisting me with the study are adequately qualified and informed about 
the Galderma R&D study drug and of their delegated study-related duties and functions as described in the 
protocol.

I ensure that source documents and study records that include all pertinent observations on each of the 
site’s study subjects will be attributable, legible, contemporaneous, original, accurate, and complete. 

I understand that all information obtained during the conduct of the study with regard to the subject’s state 
of health will be regarded as confidential. No subject’s name will be disclosed. All subjects will be 
identified by assigned numbers on all case report forms, laboratory samples, or source documents 
forwarded to the Sponsor. Clinical information may be reviewed by the Sponsor or its agents or regulatory 
agencies. Agreement must be obtained from the subject before disclosure of subject information to a third 
party.

Information developed in this clinical study may be disclosed by Galderma R&D to other clinical 
investigators, regulatory agencies, or other health authority or government agencies as required.
Investigator Name (print)
Investigator Signature
Investigator Title
Date (DD-Mmm-YYYY)
Institution

SAP_001.pdf: 
Study Number 202395
CONFIDENTIAL
Page 1 of 59
Statistical Analysis Plan
Final version 2.0, 27FEB2023
STATISTICAL ANALYSIS PLAN
Study Number:
202395
Study Title:
Evaluation of the risk of atrophic acne scar formation 
during treatment of acne vulgaris subjects with 
weeks
Study Short Name:
START
CD Number:
CD5789 
IND Number:
Not Applicable 
EudraCT Number:
Not Applicable 
Study Phase:
IV
Protocol Version and Date of Issue:
9Jul2021 
Sponsor:
1006 Lausanne 
Switzerland
Contract Research Organization:
Advanced Clinical 
6 Parkway North, Suite 100 
Deerfield, IL 60015 
United States
CRO Study Number:
Author:
Version and Date of Issue:
Final version 
, 27FEB2023 
This study is conducted in compliance with the clinical study protocol (and amendments), 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) guidelines for current Good Clinical Practice (GCP) and applicable regulatory 
requirements.
 
10-Jul-2023 00:00:00
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1.0
Approved
PPD








Study Number 202395
CONFIDENTIAL
Page 5 of 59
Statistical Analysis Plan
Final version 2.0, 27FEB2023
TABLE OF CONTENTS
DOCUMENT HISTORY
2 
3 
 
TABLE OF CONTENTS
5 
TABLE OF TABLES
8 
9 
LIST OF ABBREVIATIONS
10 
1 
INTRODUCTION
11 
2 
STUDY OBJECTIVES AND ENDPOINTS
11 
 
Study Objectives 
11 
 
Study Endpoints 
11 
 
Primary Endpoint 
11 
 
Secondary Endpoints 
11 
 
12 
 
Safety
12 
3 
13 
 
Overall Study Design and Plan
13 
 
Study Schema 
 
 
Schedule of Assessments
 
 
Study Assessments Considerations Pertaining to the COVID-19 Pandemic 
 
 
Study Assessments Schedule
16 
 
Selection of Study Population 
17 
 
Number of Planned Subjects 
17 
 
Inclusion Criteria
18 
 
Exclusion Criteria
18 
 
Removal of Subjects from Therapy or Assessments
18 
 
Investigational Products
19 
 
Treatments Administered
19 
 
Method of Assigning Subjects to Treatment Sides 
19 
 
Allocation Concealment and Blinding 
20 
 
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CD5789.SPR202395.SAP.V02 - Final Version 27F
1.0
Approved
CCI


Study Number 202395
CONFIDENTIAL
Page 6 of 59
Statistical Analysis Plan
Final version 2.0, 27FEB2023
 
Prior and Concomitant Therapy 
20 
 
Definition
20 
 
Categories
21 
 
Treatment Compliance - Primary Source Data
21 
 
Treatment Compliance - Supportive Video Evidence
21 
 
Duration of Subject Participation
22 
 
Early Termination Visit
22 
 
Unscheduled Visit 
23 
 
Efficacy and Safety Assessments
23 
 
Efficacy Assessments
23 
 
 
 
Atrophic Acne Scar Count 
25 
 
Investigator 
25 
 
Acne Lesion Counts on the Face 
26 
 
26 
 
Self-Assessment of Clinical Acne-Related Scars (SCARS) Questionnaire 
27 
 
Subject Satisfaction Questionnaire
27 
 
Other Assessments
27 
 
Safety Assessments
28 
 
Adverse Events 
29 
 
Local Tolerability
29 
 
SAMPLE SIZE CONSIDERATION
30 
 
Blinded Sample Size Re-estimation
31 
5 
POPULATIONS ANALYZED
 
 
Intent-to-Treat Population 
 
 
Per Protocol Population
 
 
Safety Population 
 
6 
STATISTICAL METHODS AND DATA CONSIDERATIONS
35 
 
35 
 
Baseline
35 
 
Missing and Partial Dates Management
35 
 
Reference Start Date and Analysis Day
37 
 
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Descriptive Statistics
37 
 
Statistical Tests and Confidence Intervals
37 
6 
Decimal Precision
37 
 
Software Version
38 
 
Study Subjects 
38 
 
Disposition of Subjects
38 
 
Accounting of Subjects
39 
 
Protocol Deviations 
39 
 
Data Sets Analyzed
39 
 
Demographic and Other Baseline Characteristics
 
 
Medical History, Prior and Concomitant Therapies and Procedures 
 
 
Measurements of Treatment Compliance
 
 
Study Duration and Treatment Duration 
 
 
Compliance and Drug Accountability 
 
 
Prescribed Dose Reductions
 
 
Non-Investigational Products 
 
 
Efficacy Analysis 
 
 
Missing Data Pattern
 
 
Efficacy Data Summary
 
 
Atrophic Acne Scar Counts 
 
 
 
 
Acne Lesion Counts on the Face 
 
 
 
 
Self-Assessment of Clinical Acne-Related Scars (SCARS) Questionnaire
 
 
Subject Satisfaction Questionnaire
 
 
Analysis of Primary Endpoint 
 
 
Sensitivity Analysis of Primary Endpoint
 
 
Analysis of Secondary Endpoints 
 
 
 
 
Other Secondary Endpoints 
 
 
50 
 
Adjustments for Covariates
50 
 
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Handling of Dropouts or Missing Data 
50 
 
Interim Analyses and Data Monitoring 
51 
 
Multicenter Study
51 
 
51 
 
Use of an Efficacy Subset of Subjects 
52 
 
Active-Control Studies Intended to Show Equivalence 
52 
 
Examination of Subgroups 
52 
 
Analysis Visits Definition
52 
 
Safety Analysis
53 
 
Extent of Exposure 
53 
 
Adverse Events 
 
 
Deaths, Other Serious Adverse Events and Other Significant Adverse Events 
56 
 
Clinical Laboratory Evaluation
56 
 
Vital Signs
56 
 
Physical Findings 
56 
 
Local Tolerability
57 
 
Photographs 
57 
 
Premenses Status
57 
 
Re-Challenge Patch Test and Ingredient Patch Test
57 
7 
57 
8 
57 
9 
REFERENCES
59 
TABLE OF TABLES
Table 1 Study Assessments Schedule
16 
Table 2 Possible Reasons for Study Discontinuation 
18 
 
25 
29 
 
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30 
31 
Table 8 Sample Size Calculation
31 
TABLE OF FIGURES
Figure 1 Study Schema 
 
Figure 2 Anatomic Regions for Efficacy Assessments
 
 
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LIST OF ABBREVIATIONS
AE
Adverse Event 
AESI
Adverse Event of Special Interest 
CI
Confidence Interval
CRO
Contract Research Organization 
CSR
Clinical Study Report
Electrocardiogram
ET
Early Termination
ICF
Informed consent form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
IRT
Interactive Response Technology
ITT
Intent-To-Treat
LOCF
Last Observation Carried Forward 
MAR
Missing At Random
MCMC 
Markov Chain Monte Carlo 
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple Imputations
MNAR 
Missing Not At Random  
OC
Observed Case
PP
Per Protocol
PTAE
Pre-treatment Adverse Event 
SAE
Serious Adverse Event
SAF
Safety Population 
SAP
Statistical Analysis Plan
TEAE
Treatment-emergent Adverse Event 
TLF
Tables, Listings and Figures 
 
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1
INTRODUCTION
This Statistical Analysis Plan (SAP) of the study 202395 is based on the global amendment of the 
study protocol dated 09JUL2021
2
STUDY OBJECTIVES AND ENDPOINTS
2.1
Study Objectives
The purpose of this 
2.2
Study Endpoints
2.2.1
Primary Endpoint
Absolute change from Baseline in total atrophic acne scar count per half-
2.2.2
Secondary Endpoints
Absolute change in total atrophic acne scar count per half-
Total atrophic acne scar count per half-
 
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2.2.4
Safety
Local 
evaluated per half-
-
Local tolerability scores will be summarized using frequency tables for worst post-baseline 
Incidence of all TEAEs including any dermatologic AEs per half-face, AESIs, SAEs and 
 
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3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
This is a multi-center, randomized, double-blind, vehicle-controlled study using intra-individual 
comparison (right half-face versus left half-face) to evaluate the safety and efficacy of trifarotene 
(CD5789) cream for preventing t
treatment variability associated with trifarotene vehicle, a blinded sample size re-estimation will 
ate the need for additional subjects to be 
Subject eligibility is evaluated over a 28-da
baseline assessments and be randomized (left face versus right face) to apply trifarotene (CD5789) 
-week treatment period, for an intra-individual, split face 
Subjects will apply study medication under site supervision, at the Baseline visit, and 
Cetaphil® PRO Oil Absorbing Moisturizer with SPF 30 for daily use on the face (morning) and to 
be re-
of an equivalent available skincare product per 
country is permitted as well as the subject’s preferred or investigator’s recommended non-
persistent dryness or irritation, the investigator may consider a reduced application frequency for 
the 
Subjects will receive an electronic tablet at baseline for daily recording of study medication use 
(electronic dosing calendar), as well as for capturing daily videos of applying study medication to 
clinical site and will serve as
remain on the local drive of the study electronic tablet and reviewed by site staff at scheduled office 
Subjects who do not require a washout period may complete the Screening and Baseline 
-screened once, 
Subjects will
(see Section
 
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Collection of previously dispensed study drugs, from an adult family member along with the 
study electronic tablet:
A follow-up phone call with the subject is required to review the dosing calendar and 
Dispensing of new study drugs and non-investigational supplies (a new dosing calendar, non-
IP supplies, etc) to an adult family member:
A follow-up phone call with the subject is required to convey reminders on proper 
instructions for study medication and other supplies use, and to use the newly dispensed 
study drugs beginning that evening (and to stop using previously dispensed medication, if 
FDA COVID-19 guidance allows for secure delivery for self-administered study
In cases where a family member is not available for dispensing study medication and other 
supplies, delivery using an express courier with appropriate temperature control capability is 
-up phone call is required in these circumstances to confirm receipt and 
provide the subject with appropriate reminders and proper instructions for study medication 
Note: The decision to dispense additional study drug should be based on the investigator’s
clinical judgement that ongoing dosing does not pose undue safety risks to the subject, and that 
availability to subjects, existing requirements for maintaining study supply accountability 
The following procedures require an in-office examination to perform:
 
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Prior to the start of the clinical study, a randomization list will be generated and transmitted to the 
trifarotene (CD5789) cream or trifarotene vehicle cream to the right or left side of the face, for each 
study drug kit, and study drug instructions will include which study drug should be applied on 
NOTE: For the purposes of this protocol, the “left” or “right” side of the face is always defined as 
the subje
Upon chronological order of confirming subject eligibility, subjects are assigned a study drug kit 
Refer to section 
for an illustration of the study d
3.3.3
Allocation Concealment and Blinding
Allocation concealment is ensured as the kits will be assigned in chronological order on the basis 
will be 
assigned to a unique randomized subject and the simultaneous randomization of groups of subjects 
All attempts will be made to keep the study team, site staff and subjects blinded to study treatment 
throughout the study, including: 
Members of the study team or site staff will not have access to the randomized treatment 
Study drug will have similar appearance, packaging and use instructions as the corresponding 
3.3.4
Prior and Concomitant Therapy
3.3.4.1
Definition
Informa
Previous therapies are defined as medications or procedures that have been stopped before the 
Screening visit and includes all acne therapies (within 6 months) and all other therapies (within 1 
Concomitant therapies are defined as:
any changes to existing therapies (such as changes in dose or formulation) during the course of 
the clinical study, or 
 
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any new therapies received by the subject since the Screening visit
Any new concomitant therapy or modification of an existing therapy may be linked to an adverse 
except in some cases such as therapy used for prophylaxis, dose modification for a chronic 
3.3.4.2
Categories 
The following two categories are to be considered for previous and concomitant therapies: 
including, but not limited to, prescription, over-the-counter (OTC), birth 
Medical and surgical procedures
dermal fillers, X-rays (excluding dental X-
3.3.5
Treatment Compliance - Primary Source Data
Subjects will be instructed by study personnel on the importance of being compliant with the use 
of the study drug and non-
Subjects will receive an electronic tablet at baseline for recording study medication use on each 
half-face (electronic dosing calendar) with clear instructions for daily use throughout the study (see 
Section
-reported data in the dosing calendar will be used as the primary source 
data for calculating treatment compliance, per each half-
Results are uploaded to a secure portal for remote monitoring, with subject counseling, as needed, 
Subjects will be instructed to return the study electronic tablet and all study medication at each 
eview dosing compliance data since the last visit, derive treatment 
compliance for each half-
-
compliance will 
be derived from the total expected doses and number of actual doses recorded, over a given visit 
Any missed dose will be considered a protocol deviation, based on recordings in the dosing 
dosing instructions and daily recordings in the dosi
encouraged to follow guidelines for non-
3.3.6
Treatment Compliance - Supportive Video Evidence
The assigned electronic tablet will also be used by subjects to capture videos of study drug 
application, for each half-
- Study Drug Application 
 
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ectronic 
Even though no videos will be uploaded to a central portal for remote viewing, the electronic dosing 
calendar will include a question whether the subject is collecting daily videos, which site staff can 
reference for remote monitoring and
videos are used for site staff to spot-check for proper use of study medication, and appropriately 
counsel and re-train subjects on the import
subject counseling and reminders on the importance of following study drug dosing instructions, 
throu
display repeated non-compliance based on video evidence, despite repeated counselling and re-
training, should be discontinued from the study, based on investigator 
Note: Subjects will be informed that videos will be reviewed to ensure proper use of study drug 
-
disclosure allows subjects to be appropriately informed with sufficient detail of what study 
procedures will be performed and does not create any added risks to the subjects by withholding 
maintaining the integrity of the split-face study design, as it provides motivation to remain 
compliant, while attempting to balance the administrative burden of daily video review by site staff, 
ect-reported 
dosing compliance data recorded on the electronic dosing calendar will be used to derive 
compliance, which is a common procedure used in clinical studies to reliably assess daily product 
- compliance observed by video evidence should result in subject termination, 
At the end of the study, the electronic tablet will be collected, and all collected information fully 
3.4
Duration of Subject Participation
The expected duration for each subject’s participation in the study is approximately 28 weeks 
-
-
3.4.1
Early Termination Visit
be completed for all subjects discontinuing the study and the appropriate CRF page should be 
 
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Refer to section 
3.4.2
Unscheduled Visit
unplanned and may include examinations for
 in section 
3.5
Efficacy and Safety Assessments
3.5.1
Efficacy Assessments
Efficacy measurements should be conducted by the investigators (or designees) or by subjects (for 
subject-reported assessments) according to section 
Evaluators must complete standardized training prior to performing the following assessments: 
(papules and pustules), non-inflammatory lesion counts (open and closed comedones), and other 
Notes:
1)
2)
a change in the assigned evaluator for 
evaluator to follow a given subject, evaluations between the primary and subsequent evaluator 
should overlap (both evaluators should examine the subject together and discuss findings) for at 
least one prior visit
made for the rater to be the same as baseline for the following assessments, to the extent possible:
For all efficacy assessments, the zone in the middle of the face (approximately 2 cm wide and 
inclusive of the nose) should be excluded for clinical efficacy evaluation because subjects may 
apply a mix of investigational products in this area (Figure 2
 
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3.5.2
Safety Assessments
 
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3.5.2.1
Adverse Events
to be reported on the Adverse Event F
must be provided with the name and phone number of clinical study center personnel for reporting 
AE
 
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4
SAMPLE SIZE CONSIDERATION
-Center 
of moderate facial and truncal acne vulgari
- 
ned for the absolute change from 
These results refer to a whole face treatment whilst in the current study a split-
Moreover, due to the lack of a Vehicle arm, it is not possible to estimate the mean value and the 
variability of the difference in mean absolute change from baseline in total atrophic acne scar 
It is possible to hypothesize that the mean reduction
half-face is treated is -
-face design was used and the following results were obtained 
 
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= 1
half face,
we can calculate the Left-Right difference as follows:
=
Since
=
the mean of squared differences can be re-calculated as follows:
= 1
= 1
=
and the following conditions hold for the mean of differences and the squared mean of differences
|
|
|
|
and 
0
|
|
where
|
| = 1
is the average of the absolute values of the Left-
According to the previous formulas, the following boundaries can be calculated for observed 
variance after n1 subjects:
1
|
|
1
The observed variance after n1 subjects can be estimated as follows:
=
1
Missing squared differences of atrophic acne scar counts between the left and right sides of the face 
at 
will be imputed using multiple imputation methodology (as specified in section 
) A linear regression model will be used with covariates for non-missing squared differences 
of atrophic acne scar counts between the left and right sides of the face from earlier scheduled time 
points including baseline
 
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5
POPULATIONS ANALYZED
For the purposes of this study, randomization (i e , treatment assignment to left or right side of the 
face) is achieved by assigning available treatment kit IDs, in increasing sequential order, at the time 
 This study will not use IRT technology to 
generate a randomization record
5.1
Intent-to-Treat Population
The Intent-to-Treat (ITT) population is defined as all randomized subjects and will be used for the 
be summarized and 
5.2
Per Protocol Population
The Per Protocol (PP) population is defined as comprising the ITT population subjects who are 
- 
have no major deviations from the protocol that could have a significant effect on the efficacy of 
5.3
Safety Population 
The Safety (SAF) population is defined as comprising the ITT population subjects who 
f the 
 
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6
STATISTICAL METHODS AND DATA CONSIDERATIONS
6.1
General Considerations
6.1.1
Baseline
For statistical analyses purpose, baseline is defined as the last non-missing measurement prior to 
the first treatment for subjects treated and as the last non-missing measurement prior to 
Absolute change from baseline and percent change from baseline will be calculated as follows:
Absolute Change from Baseline = PostBaseline
Baseline
Percent Change from Baseline = Baseline
0
100 PostBaseline
Baseline
Baseline
Baseline = 0
Missing                                          
6.1.2
Missing and Partial Dates Management
Start Date Imputation of Adverse Events: 
randomized but not treated, impute to th
Missing day and month: For subjects treated, impute to January 1st, unless year is the same 
For subject randomized 
but not treated, impute to January 1st, unless year is the same as year of randomization then 
st, unless 
year is the same as year of informed consent then impute to the informed consent date 
Missing day: For subjects treated, impute to the 1st of the month, unless month and year are 
For subject randomized but not treated, impute to the 1st of the month, unless month and 
year are the same as month and year of randomization then impute to the randomization 
st of the month, unless month and year 
are the same as month and year of informed consent then impute to the informed consent 
If imputed event start date is after event end date (imputed or not), set the event start date 
 
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randomized but not treated, imput
Missing day and month: For subjects treated, impute to January 1st, unless year is the same 
as year of first treatment dose then impute to the first treatment
but not treated, impute to January 1st, unless year is the same as year of randomization then 
st, unless 
year is the same as year of informed consent then impute to the informed consent date 
Missing day: For subjects treated, impute to the 1st of the month, unless month and year are 
For subject randomized but not treated, impute to the 1st of the month, unless month and 
year are the same as month and year of randomization then impute to the randomization 
st of the month, unless month and year 
are the same as month and year of informed consent then impute to the informed consent 
Start Date Imputation of Medical History Diseases:
Missing day and month: Impute to January 1st
Missing day: Impute to the 1st of the m
If imputed disease start date is after disease end date (imputed or not), set the disease start 
Procedures, Medical History Diseases:
Missing day and month: Impute to December 31st, unless year is the same as last contact 
Missing day: Impute to the last day of the month, unless year and month are the same as 
 
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6.1.3
Reference Start Date and Analysis Day
subject randomized 
Analysis day will be calculated from the reference start date and will be used to sh
ed' or 
'Unknown' and when a disease, therapy or procedure is reported as being ongoing), analysis day 
6.1.4
Descriptive Statistics
For the descriptive statistics, unless otherwise noted, the categorical variables will be summarized 
by frequencie
category and the continuous variables will be summarized using standard descriptive statistics (n, 
mean, standard deviation, median, first and third quartile, min and max
6.1.5
Statistical Tests and Confidence Intervals
A two-
-
coverage for the p
conventions will be applied for the p-values of all statistical testing:
-
-
-
p-
6.1.6
Decimal Precision
Unless otherwise noted, the following rounding conventions will be applied: 
means, medians, first and third quartiles will be rounded and presented to one more decimal 
confidence intervals of means and medians will be rounded and presented to one more decimal 
digit than 
standard deviations and standard errors will be rounded and presented to two more decimal 
 
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proportions will be reporte
0 will not be presented
p-
will be rounded and 
p-
p-
6.1.7
Software Version
6.2
Study Subjects
6.2.1
Disposition of Subjects
Subjects screened
-19 
-19 
Subjects randomized
Subjects randomized who discontinued before treatment 
Reasons for study discontinuation before treatment 
Subjects randomized who discontinued before treatment due to COVID-19
Reasons for study discontinuation before treatment due to COVID-19 
Subjects randomized who underwent the treatment 
Subjects randomized who completed the treatment
Subjects randomized who discontinued the treatment 
Reasons for treatment discontinuation
Subjects randomized who discontinued the treatment due to COVID-19 
 
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Reasons for treatment discontinuation due to COVID-19 
Subjects randomized who completed the study 
Subjects randomized who discontinued the study 
Reasons for study discontinuation 
Subjects randomized who discontinued the study due to COVID-19 
Reasons for study discontinuation due to COVID-19 
Subjects randomized affected by COVID-19 related study disruptions 
Subjects randomized affected by COVID-19 related study disruptions impacting efficacy
Subjects randomized affected by COVID-19 related study disruptions impacting safety
Listing for subjects' disposition, screen failures, discontinued subjects, treatment completion status, 
discontinued treatment and subjects affected by COVID-19 related study disruptions will be 
6.2.2
Accounting of Subjects
Listi
6.2.3
Protocol Deviations 
Major protocol deviations, major protocol deviations leading to the exclusion from the PP 
population, major protocol deviations due to COVID-19 and minor protocol deviations will be 
deviation coded term by 
 and 
Local protocol deviations (localized to right or left side) will be presented by treatment side 
will 
be presented overall
A listing of all prot
6.2.4
Data Sets Analyzed 
on
 
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6.2.5
Demographic and Other Baseline Characteristics
Descriptive statistics (n, mean, standard deviation, median, first and third quartile, min and max) 
will be presented using the ITT population for the following demographic data and baseline 
characteristics:
Age (years)
Age roups 
<18 years old
18 years old
Sex
Male
Female
Ethnicity
Hispanic or Latino
Not Hispanic or Latino 
Not Reported 
Race
Black or African American
Asian
American Indian or Alaska Native
Native Hawaiian or Other Pacific Islander
Other
Multiple
Body weight at Screening (kg) 
Fitzpatrick Skin Type
Type I 
Type II 
Type III 
Type IV 
Type V 
Type VI 
 
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 by treatment side (
versus vehicle) 
0 - Clear
1 - Almost Clear
2 - Mild
3 - Moderate 
- Severe
Baseline Total Atrophic Acne Scar Counts by treatment side (
) 
Baseline 2-
Atrophic Acne Scar Counts by treatment side (
vehicle) 
Baseline 
Atrophic Acne Scar Counts by treatment side (
vehicle) 
Baseline Investigator 
Assessment
 by treatment side (
vehicle) 
0 - Clear
1 - Almost Clear
2 - Mild
3 - Moderate 
- Severe
Baseline Total Lesion Counts by treatment side (
) 
Baseline Inflammatory Lesion Counts by treatment side (
) 
Baseline Non-Inflammatory Lesion Counts by treatment side (
vehicle) 
If ITT population and Safety population do not include the same subjects, the summary will be 
using the ITT population 
(females only) for the following classification category:
Childbearing Potential 
Strict Abstinence
Cap, Diaphragm or Sponge with Spermicide 
Combined (estrogen and progestogen containing) Oral, Intra-vaginal or Transdermal 
Hormonal Contraception 
 
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Injectable or Implanted Hormonal Contraception 
Intra-Uterine Devices
Vasectomized partner for at least 3 months prior to the Screening visit
Other
Non-childbearing Potential 
Post-Menopausal
Hysterectomy or Bilateral Oophorectomy
Pre-Menses
Listings for demographic data, baseline characteristics and childbearing potential status (inclusive 
6.2.6
Medical History, Prior and Concomitant Therapies and Procedures
ined as those ending before the 
treatment day and ongoing on the first treatment day and as those starting on the first treatment day 
(March 2021
procedures will be coded using MedDRA dictionary (version 2
Summaries will be presented overall using the ITT population for the following: 
stem 
l
procedures by System Organ Class and Preferred Term
 
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6.2.7
Measurements of Treatment Compliance
6.2.7.1
Study Duration and Treatment Duration
For randomized subjects who discontinued before treatment, study duration will be calculated as 
For randomized subjects who underwent treatment, study duration will be calculated as date of end 
Study duration will be summarized for all patients in the ITT population using descriptive statistics 
(n, mean, standard deviation, median, first and third quartile, 
Treatment duration will be calculated as date of last treatment minus date of first treatment plus 
one (1) and will be summarized using descriptive statistics (n, mean, standard deviation, median, 
first and third quartile, min and max) by t
 and 
overall 
6.2.7.2
Compliance and Drug Accountability
and vehicle, treatment compliance will be calculated as follows:
Treatment Compliance = 100
Actual Applications
Planned Applications
Missed Applications due to Prescribed Dose Reductions
Planned applications are calculated as the number of days between start date and stop date of each 
Subject’s c
trifarotene 50 
compliance and vehicle c
Video compliance will be calculated on a per-subject basis as follows:
Video Compliance = 100
Actual Videos
Planned Videos
Missed Videos due to Prescribed Dose Reductions
Planned videos are calculated as the number of days between start date and stop date of each 
compliance evaluation period
Treatment compliance will be summarized at each analysis visit and overall using descriptive 
statistics (n, mean, standard deviation, median, first and third quartile, min and max) by treatment 
side 
 and overall 
Frequencies and pro
treatment 
 
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 and overall in
Video compliance will be summarized at each analysis visit and overall using descriptive statistics 
(n, mean, standard deviation, median, first and third quartile, min and max) in the ITT population
video 
in
Treatment compliance, video compliance
6.2.7.3
Prescribed Dose Reductions
Descriptive statistics (n, mean, standard deviation, median, first and third quartile, min and max) 
will be presented at each analysis visit for drugs in the ITT population for the following:
Subjects with Prescribed Dose Reduction since the Last Scheduled Visit
Reasons for Prescribed Dose Reduction
Duration of Prescribed Dose Reduction (days) 
Missed Applications due to Prescribed Dose Reductions 
Duration of the prescribed dose reduction will be calculated as Dose Reduction End Date minus 
Listings for
6.2.7.4
Non-Investigational Products
-investigational products during the 
study will be summarized by 
in the ITT 
All non-investigational products used 
6.3
Efficacy Analysis
Subjects will be summarized and analyzed according to the treatment sides they were randomized 
to and all efficacy d
6.3.1
Missing Data Pattern
Distinct missing data patterns of acne atrophic scar counts with their corresponding frequencies 
 
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versus vehicle) in order to establish whether they are monotone or non-
6.3.2
Efficacy Data Summary
A summary based on observed case (OC) will be provided for all primary and secondary efficacy 
endpoints and 
-Reported Outcomes For these summaries, no data will be 
 
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Statistical Analysis Plan
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6.3.3
Analysis of Primary Endpoint 
The hypothesis test for the primary endpoint can be formally defined as follows:
: 
= 0
:
0 
where µDiff is the mean of the differences in change from baseline in total atrophic acne scar count 
The hypothesis test for the primary endpoint will be evaluated on the ITT population at the two- 
the primary endpoint is statistically significant with a p-
 
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The bilateral difference between the trifarotene side and the vehicle side in absolute change from 
baseline in total atrophic acne scar counts 
the Student's t-
assumption is not met, the appropriate non-parametric statistical method (
signed rank
test, Hodges-Lehmann estimate of location shift and asymptotic confidence interval) 
For analysis of change from baseline in total atrophic acne scar counts to 
It is expected that the pattern of missing data will be monotonic, with slight deviations being 
corrected by the Markov Chain Monte Carlo (M
Separate 
imputations by treatment group will be carried out Linear regression will be employed to model 
the missing acne counts, with the following covariates included in the imputation model: non-
missing total atrophic acne scar counts from earlier time points (see Section
for further 
6.3.4
Sensitivity Analysis of Primary Endpoint
To assess the robustness of the primary efficacy results, the following sensitivity analyses will be 
conducted: 
1) Jump-to-Reference (J2R) approach under Missing Not At Random (MNAR) assumption, by 
2) Missing data of primary endpoint will be imputed using Last Observation Carried Forward 
3)
6.3.5
Analysis of Secondary Endpoints
6.3.5.1
Atrophic Acne Scar Counts up to Week 20
The hypothesis test for the absolute change in total atrophic acne scar count per half-face from 
Baseline up
 can be formally defined as follows: 
: 
= 0
:
0 
where µDiff is the mean of the differences 
 16 and 20
The hypothesis tests for the absolute change in total atrophic acne scar count per half-face from 
baseline up
will be evaluated on the ITT population at the two-sided significance level 
(the management of multiplicity is described in Section 
)
 
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p-values and 
The bilateral difference between the trifarotene side and the vehicle side in absolute change from 
baseline in total atrophic acne scar counts 
will be analyzed on the 
ITT population using the Student's t-
not met, the appropriate non-parametric statistical method
(
signed rank test, Hodges-Lehmann estimate of location shift and asymptotic confidence
interval) 
The bilateral difference between the trifarotene side and the vehicle side in percent change from 
baseline in total atrophic acne scar count at each post-baseline visit will be analyzed on the ITT 
population using the Student's t-
-parametric statistical method 
, Hodges-Lehmann estimate of location shift and asymptotic confidence
interval
For analysis of change from baseline in total atrophic acne scar counts to 
eeks 
and 20, missing counts will be imputed using Multiple Imputation (MI) under the Missing At 
t the pattern of missing data will be monotonic, with 
slight deviations being corrected by the Markov Chain Monte Carlo (MCMC) method of the SAS 
Separate imputations by treatment group will be carried out Linear regression will 
be employed to model the missing acne counts, with the following covariates included in the 
imputation model: non-missing total atrophic acne scar counts from earlier time points (see Section
 
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6.3.6
Statistical/Analytical Issues
6.3.6.1
Adjustments for Covariates
No adjustment for covariates is planned for the primary, secondary and exploratory efficacy 
6.3.6.2
Handling of Dropouts or Missing Data 
Missing data for atrophic acne scar counts will be imputed using Multiple Imputation (MI) under 
The missing data pattern of atrophic acne scar counts
tern is non-
chain method will be used, with 200 burn-
In case of lack of convergence with the single chain method, the multiple chain method will be 
by treatment group will be carried out The minimum values for 
imputed variables will be set to 0, in order to force PROC MI to redraw another value for 
imputation when an intended imputed value is
If the MCMC method of step 1 was previously employed, one imputation will be made using 
each of the fifty (50) MCMC-
previously employed, fifty (50) imputations will be created assuming the data are Missing At 
R
A linear regression model will be used with 
covariates for non-missing atrophic acne scar counts from earlier scheduled time points 
 
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In case of lack of convergence with linear regression model, a predictive 
mean matching method
Separate imputations by treatment group will be carried 
out The minimum values for imputed variables will be set to 0, in order to force PROC MI to 
atrophic acne scar counts will be derived from the corresponding imputed lesion counts
The imputed datasets will be analyzed as specified in sections 
and 
The resulting analysis on the imputed datasets will then be combined to produce a single set of 
The number of fifty (50) imputations was selected in order to prevent a power falloff due to 
choosing a number of imputations too small [1
As sensitivity analysis of the primary endpoint, the primary analysis will be repeated on the ITT 
population by imputing atrophic acne scar counts on the basis of a Jump-to-Reference (J2R) 
approach under the Missing Not At Random (MNAR) assumption Missing values of bilateral 
difference in atrophic acne scar counts between the trifarotene side and the vehicle side will be 
imputed as zero (0)
As additional sensitivity analysis of the primary endpoint, the primary analysis will be repeated on 
the ITT population by imputing missing data using Last Observation Carried Forward 
case no post-
case no post-baseline value is available, baseline value will be ca
will be calculated from the imputed ordinal 
Moreover, 
imputed using 
6.3.6.3
Interim Analyses and Data Monitoring
A blinded sample size re-estimation will be performed after 
additional subjects to be 
randomized (see Section 
6.3.6.4
Multicenter Study
6.3.6.5
Multiple Comparison/Multiplicity
The hypothesis test for the primary endpoint will be evaluated on the ITT population at the 
 
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The hypothesis tests for the scar secondary efficacy endpoints will be evaluated on the ITT 
moving to the next hypothesis test only after a success on the pr
1)
2)
3)
5)
6)
7) Absolute change from Baseline in t
This approach does not inflate the Type I error rate as long as the hypothesis tests for the secondary 
efficacy endpoints are conditional on the success of the primary, there is a prospective specification 
of the testing sequence and no further testing is performed once the sequence breaks, that is, further 
testing stops as soon as there is a failure of a hypothesis test in the sequence to show significance 
No hypothesis test will be ev
p-values and 
6.3.6.6
Use of an Efficacy Subset of Subjects
The classification of the protocol deviations and the exclusion of subjects from the Per Protocol 
(PP) population will be determined prior to breaking the study blind (see Section
The analysis on the PP population will allow evaluating the impact of major protocol deviations on 
the estimati
6.3.6.7
Active-Control Studies Intended to Show Equivalence
6.3.6.8
Examination of Subgroups
6.3.6.9
Analysis Visits Definition
Efficacy and safety by-visit summaries and analyses will use
unscheduled visits (including early termination visit) will be windowed based on the following 
 
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Analysis Visit
Target Study Day
Analysis Visit Window
Baseline
1 
<= 1
Week 1
8 
4 - 11
Week 2
15
12 - 19
Week 4
29
22 - 36
Week 8
57
50 - 64
Week 12
85
75 - 95
Week 16
113
103 - 123
Week 20
141
131 - 151
Week 24
169
>= 159
If two or more assessments (include both scheduled and unscheduled assessments) are available 
for the analysis visits then all assessments will be listed and the following rules will be applied for 
Efficacy assessments: the assessment taken closest to the target study day will be used for the 
Safety assessments, excluding clinical laboratory tests: the assessment taken closest to the 
Clinical laboratory tests: the latest assessment will be used for the summari
6.4
Safety Analysis 
6.4.1
Extent of Exposure 
The mean daily amount of drug applied will be calculated as the difference between the weight (in 
grams) of dispensed pumps and the weight (in grams) of returned pumps (missing pumps not 
returned by the s
for EU and Canada sites - the nominal fill weight of drug - for the aim of this calculation, supposing 
their content was completely used) divided by the number of days of use of the pumps (calculated 
The date of compliance assessment will be used instead of the actual pumps return date in order to 
avoid an overestimation of the number of days of use in case of delayed return of the pumps and to 
between weights of dispensed and returned pumps are deemed due to weighting errors and thus are 
The mean daily amount of drug applied will be listed and summarized at each analysis visit using 
descriptive statistics (n, mean, standard deviation, median, first and third quartile, min and max) 
by treatment 
 
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6.4.2
Adverse Events
All Adverse Events (AEs) will be coded using MedDRA dictionary (version 
(localized to right or left side) will be presented by side (
) and 
t are subject specific will be presented overall only
Treatment-Emergent Adverse Events (TEAEs) are defined as the adverse events that occurred, or 
classified on the basis of the imputed start date (see imputation rules of Section
) 
Pre-Treatment Adverse Events (PTAEs) are defined as the 
Missing relationships to study drug or study procedures will be imputed with the closest 
-19 will be imputed with the closest 
with any TEAE and frequencies (n) of TEAEs will be summarized by treatment side (trifarotene 
and overall in the Safety population according to the following categories:
Subjects with any TEAE due to COVID-
Subjects with any TEAE by Closest Relationship to Study Drug: 
Subjects with any 
Subjects with any TEAE by Closest Relationship to Study Procedures: 
Subjects with any TEAE whose closest relationship to Study Procedures
Subjects with any TEAE whose closest relationship to Study Procedures 
Subjects with any TEAE whose greatest severity is Sev
 
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Subjects with any Serious TEAE due to COVID-
Subjects with any Serious TEAE by Closest Relationship to Study Drug: 
Subjects with any Serious TEAE by Closest Relationship to Study Procedures: 
Subjects with any Serious TEAE whose closest relationship to Study Procedures
Subjects with any Serious TEAE whose closest relationship to Study Procedures is Not 
TEAE and frequencies (n) of TEAEs will 
be summarized by 
and overall in the Safety 
Summary of Subjects with any TEAE and Frequency of TEAEs by System Organ Class and 
Summary of Subjects with any TEAE and Frequency of TEAEs that occurred in >1
Summary of Subjects with any TEAE of Special Interest and Frequency of TEAEs of Special 
Summary of Subjects with any TEAE due to COVID-19 and Frequency of TEAEs due to 
COVID-
Summary of Subjects with any TEAE related to Study Drug and Frequency of TEAEs related 
to
Summary of Subjects with any TEAE related to Study Procedures and Frequency of TEAEs 
related to Study Procedures
Summary of Sub
Summary of Subjects with any TEAE leading to Study Drug Discontinuation and Frequency 
of TEAEs Leading to Study Drug Discontinuation by System Organ Cla
Summary of Subjects with any TEAE Leading to Study Discontinuation and Frequency of 
and frequencies (n) of 
serious TEAEs will be summarized by
and 
Summary of Subjects with any Serious TEAE and Frequency of Serious TEAEs by System 
 
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Summary of Subjects with any Serious TEAE of Special Interest and Frequency of Serious 
Summary of Subjects with any Serious TEAE due to COVID-19 and Frequency of Serious 
TEAEs due to COVID-
Summary of Subjects with any Serious TEAE related to Study Drug and Frequency of Serious 
TEAEs related to
Summary of Subjects with any Serious TEAE related to Study Procedures and Frequency of 
TEAEs related to
Summary of Subjects with any Serious TEAE leading to Study Drug Discontinuation and 
Frequency of Serious TEAEs Leading to Study Drug Discontinuation by System Organ Class 
Summary of Subjects with any Serious TEAE Leading to Study Discontinuation and Frequency 
of Serious TEAEs Leading to Study Discontinuation by System Organ Class and Preferred 
6.4.3
Deaths, Other Serious Adverse Events and Other Significant Adverse Events
The following listings for all subjects included in the Safety population will be provided: 
Treatment-
Adverse Events due to COVID-
Treatment-Emergent Adverse Events leading to Study Drug 
Treatment-
6.4.4
Clinical Laboratory Evaluation 
6.4.5
Vital Signs
6.4.6
Physical Findings
Not applic
 
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6.4.10
Re-Challenge Patch Test and Ingredient Patch Test
Listing of re-challenge patch test and ingredient patch test results wil
7
CHANGES FROM THE PROTOCOL ANALYSIS PLAN
If the blind review suggests changes to the principal features stated in the protocol, these have to 
be documented in a protocol am
8
SHELLS OF TABLES, FIGURES AND LISTINGS AND REPORTING 
OUTPUT (GENERAL FEATURES)
landscape orientation and with the following margins:
Top: 
 
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Bottom:
Left:
Right: 
Courier New, 8-point font will be used for TLF contents (excluding column headers) and TLF 
Courier New, 8-point, bold font will be used for page headers and footers, TLF title, TLF headers, 
A clear, accurate and complete programming code will be developed to generate the statistical 
titles and footnotes will be made to improve the understanding of summaries and document any 
fications including but not limited to the SAS code will be 
The final list of tables, figures and listings and their shells for the reporting of this study will be 
available in a separate document that will be developed and will 
 
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9
REFERENCES
8:206-213 
-007-0070-9 
 
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