Conditions: Acne Vulgaris
Keywords: acne clascoterone anti-androgen
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 732
Healthy volunteers: no

Brief summary:
The primary objective of this study is to determine the safety and efficacy of CB-03-01 cream, 1%, versus the vehicle cream applied twice daily for 12 weeks in subjects with facial acne vulgaris.

Detailed description:

Arms:
arm 1: CB-03-01 cream, 1% applied twice daily for 12 weeks arm 2: Vehicle cream applied twice daily for 12 weeks

Interventions: intervention 1: CB-03-01 cream, 1% intervention 2: Vehicle cream
Intervention descriptions: intervention 1: CB-03-01 (cortexolone 17α-propionate) is a steroidal antiandrogen that is being developed as a 1% cream for the topical treatment of acne vulgaris. intervention 2: Vehicle cream manufactured to mimic look and feel of CB-03-01 but without the active ingredient cortexolone 17α-propionate.

Protocol document:
Prot_000.pdf: 
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, VEHICLE-
CONTROLLED STUDY TO EVALUATE THE SAFETY AND EFFICACY OF 
CORTEXOLONE 17a-PROPIONATE (CB-03-01) 1% CREAM APPLIED 
TWICE-DAILY FOR 12 WEEKS IN SUBJECTS WITH 
FACIAL ACNE VULGARIS 
SPONSOR PROTOCOL NUMBER: 
CB-03-01126 
REGULATORY FILING NUMBER: 
IND #112,137 
ORIGINAL PROTOCOL: 
June 11,2015 
EUDRACT NUMBER 
2015-002623-26 
SPONSOR: 
Cassiopea S.p.A. 
Via C. Colombo 1, 
20020 Lainate (MI), Italy 
SPONSOR REPRESENTATIVE: 
Luigi Moro, Ph.D. 
Chief Scientific Officer 
CRO: 
InnoPharma Sri 
PROJECT MANAGER: 
c/o Polo Tecnologico Brianza 
Via Lavoratori Autobianchi, I 
Edificio 9 - Ufficio 14 - Piano Terra 
20832 Desio (MB) - !TAL Y 
Sara V enturati 
Phone: +39-0362 1869144 
Fax: 
+ 39-0362 54 42 II 
s. venturati@innopharma. it 
The information contained in this document is confidential and proprietary 
property of Cassiopea S.p.A. 
CONFIDENTIAL 
Page I of 56 


Product Name: Cortexolone !?a-Propionate (CB-03-01) 
Protocol: CB-03-01126 
Sponsor Name: Cassiopea S,p.A. 
Protocol Date: June ll, 2015 
PROTOCOL APPROVAL 
The following individuals approve version 1.0 of the CB-03-01/26 protocol dated June 
11, 2015. All changes to this version ofthe protocol must have prior written approval and 
require an amendment or administratiVe letter. 
Cassiopea S.p.A. Representative(s): 
Luigi Moro, Ph.D. 
Chief Scientific Officer 
ffi-re c/ 
Matteo Rossini, M.Sc. 
Biometry Manager, CROSS Metrics SA 
Signature: t1Jt_; j 2....,...,.._::. 
Innopharma S.r .1. Representative: 
Sara Venturati, B.Sc 
Clinical Project Manager 
CONFIDENTIAL 
Page2of56 
Date: A 3 ··kJ 2a>l5 


Product Name: Cortexolone 17u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
STUDY ACKNOWLEDGEMENT 
I understand this protocol contains information that is confidential and proprietary to 
Cassiopea S.p.A., the Sponsor. 
I have read this protocol and agree that it contains all the details necessary to conduct the 
study as described. I will conduct this study following this protocol and will make a 
reasonable effort to complete the study in the time noted. 
I will provide the contents of this protocol to study staff under my direct supervision that 
need to know the contents to conduct the study. I will discuss this information with the 
study staff to ensure they are fully informed about the study and the test articles. I will 
provide the contents of the protocol to the responsible Institutional Review Board(s). 
These disclosures may be made; providing the contents are not used in any other clinical 
study and they are not disclosed to any other person or entity without prior written 
consent from Cassiopea S.p.A. This condition does not apply to disclosure required by 
government regulations or laws; however, I agree to give prompt notice to Cassiopea 
S.p.A. of any such disclosure. 
I understand the study may be terminated or enrollment suspended at any time by 
Cassiopea S.p.A., with or without cause, or by me if it becomes necessary to protect the 
interests of the study subjects. 
Any additional information added to this protocol is also confidential and proprietary to 
Cassiopea S.p.A. and must be treated in the same manner as the contents of this protocol. 
Printed N arne of Principal Investigator 
Investigator Signature 
Date 
Protocol number: 
CB-03-01/26 
Site number: 
Version: 1.0 
Date of final version: June II, 2015 
CONFIDENTIAL 
Page 3 of 56 


Product Name: Cortexolone 17u-Propionate (CB-03-0 l) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
PROTOCOL SYNOPSIS 
Title 
A Phase 3, Multicenter, Randomized, Double-Blind, Vehicle-Controlled Study 
to Evaluate the Safety and Efficacy of Cortexolone !?a-Propionate (CB-03-01) 
I% Cream Applied Twice-Daily for 12 Weeks in Subjects with Facial Acne 
Vulgaris 
Study Type 
Phase 3 
Test Articles 
I. 
CB-03-0 I ( cortexolone !?a-propionate) cream, I% 
2. 
Vehicle cream 
Study Objective 
The primary objective of this study is to determine the safety and efficacy of 
CB-03-01 cream, 1%, versus the vehicle cream applied twice daily for 12 
weeks in subjects with facial acne vulgaris. 
Study Design 
Multicenter, randomized, double-blind, vehicle-controlled, parallel group 
comparison study. 
A separate open-label long-term extension study is planned. Subjects 
completing the treatment-phase of this trial will be offered the opportunity to 
participate in this follow-on study (CB-03-01/27: An Open-Label, Long-Term 
Extension Study to Evaluate the Safety of Cortexolone !?a-Propionate (CB-
03-01) Cream, 1% Applied Twice Daily for up to 12 Months in Subjects with 
Facial Acne Vulgaris). In this open label study, all subjects will apply the 
active medication (cortexolone 17a-propionate cream, 1%) twice daily for up 
to 9 additional months of treatment (for a total of up to 12 months; 0 or 3 
months in the pivotal Phase 3 trial and an additional 9 months in the open-label 
long-term extension study). 
Treatment Groups 
Eligible subjects will be randomized (1:1) to one of two treatment groups: (I) 
CB-03-0 I cream, I% or (2) vehicle cream. All subjects (with supervision from 
parent/guardian, if needed) will apply the assigned test article twice-daily to 
the entire face for 12 weeks. 
Duration of Treatment 
12 weeks 
Duration of Study 
12 weeks 
Study Population 
Male and female subjects 9 years or older with facial acne vulgaris (Grade 3 or 
4 on Investigator's Global Assessment (IGA]). 
Total Number of 
At least 700 subjects; 350 subjects per treatment group. 
Subjects 
Number of Sites 
Approximately 40 sites will participate in this study. 
CONFIDENTIAL 
Page 4 of 56 


Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
Inclusion Criteria 
To enter the study, a subject must meet the following criteria: 
I. Subject is male or non-pregnant female, 9 years of age or older. Females 
must be post-menopausal 1, surgically sterile2, or using highly effective 
birth control methods 3 •4 WOCBP must have a negative urine pregnancy 
test (UPT) at the Screening/Baseline Visit. 
2. 
Subject has provided written and verbal informed consent/assent. A subject 
under 18 years of age must provide written informed assent and be 
accompanied by the parent or legal guardian at the time of assent/consent 
signing. The parent or legal guardian must provide informed consent for 
the subject. If a subject becomes 18 years of age during the study, the 
subject must provide written informed consent at that time to continue 
study participation. 
3. 
Subject has an Investigator's Global Assessment (IGA) score of 3 or 4 [0 
(clear) to 4 (severe) scale]. 
4. 
Subject has facial acne vulgaris, which can include the nose, with at least 
30 to a maximum of 75 inflammatory lesions (papules, pustules, and 
nodules) and 30 to a maximum of!OO non-inflammatory lesions (open and 
closed comedones). 
5. 
Subject and parent/guardian (if applicable) are willing to comply with 
study instructions and return to the clinic for required visits. 
6. 
Subject has used the same type and brand of make-up, other facial products 
(exclusive of RX/OTC acne cleansers) and hair products (e.g., shampoo, 
gel, hair spray, mousse, etc.) for at least one (I) month prior to the Baseline 
Visit and agrees to continue his/her other general skin and hair care 
products and regimen for the entire study. 
Exclusion Criteria 
A subject is ineligible to enter the study if he/she meets one or more of the 
following criteria: 
I. Subject is pregnant, lactating, or is planning to become pregnant during the 
study. 
2. 
Subject has any skin pathology or condition that could interfere with the 
evaluation of the test products or requires the use of interfering topical or 
systemic therapy. 
3. 
Subject has greater than two (2) facial nodules. 
4. 
Subject has nodulocystic acne. 
5. 
Subject has any condition which, in the investigator's opinion, would make 
1 Defined as amenorrhea greater than 12 consecutive months. 
2 Hysterectomy, bilateral tubal ligation (at least six (6) months prior to study entry), or bilateral 
oophorectomy. 
3 Highly effective contraception includes a) total abstinence, b) oral, injected, or implanted hormonal 
methods of contraception, c) intrauterine device (IUD), d) partner vasectomy (performed at least six (6) 
months prior to study entry), or e) double barrier methods of contraception [barrier methods include male 
or female condom, diaphragm with spermicidal foam/gel/film/vaginal suppository, cervical cap with 
spennicides, or contraceptive sponge]. 
4 Women of childbearing potential (WOCBP) taking hormonal therapy for any reason exclusive for the 
treatment of acne (e.g., as contraception, etc.) must be on the same treatment for at least 12 weeks prior to 
study entry and must not change their dosing regimen during the study. Those who have used hormonal 
therapy prior to study entry must have discontinued use at least eight (8) weeks prior to the start of the 
study. 
CONFIDENTIAL 
Page 5 of 56 


Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June 11, 2015 
Study Procedures 
it unsafe for the subject to participate in this research study. 
6. 
Subject is currently enrolled in an investigational drug or device study. 
7. 
Subject has received an investigational drug or has been treated with an 
investigational device within 30 days prior to the initiation of treatment 
(Baseline). 
8. 
Subject has facial hair that could interfere with the study assessments in the 
opinion of the investigator. 
9. 
Subject and parent/guardian (if applicable) are unable to communicate or 
cooperate with the investigator due to language problems, poor mental 
development, or impaired cerebral function. 
10. Subject may be unreliable for the study including subjects who engage in 
excessive alcohol intake or drug abuse, or subjects who are unable to 
return for scheduled follow-up visits. 
II. Subject has known hypersensitivity or previous allergic reaction to any of 
the active or inactive components of the test articles (see Section 6.1). 
12. Subject has the need or plans to be exposed to artificial tanning devices or 
excessive sunlight during the trial. 
13. Subject has used any of the following topical anti-acne preparations or 
procedures on the face: 
• 
Topical anti-acne treatments including, but not limited to, over-the-
counter (OTC) acne cleansers or treatments, benzoyl peroxide, 
antibiotics, azelaic acid, sulfa based products, corticosteroids and 
salicylic acid within two (2) weeks of the initiation of treatment. 
" 
Retinoids, including tazarotene, adapalene, tretinoin, within four (4) 
weeks of the initiation of treatment. 
• 
Light treatments, microdermabrasion, or chemical peels within eight (8) 
weeks of the initiation of treatment. 
14. Subject has used the following systemic anti-acne medications: 
• Corticosteroids (including intramuscular and intralesional injections) 
within four (4) weeks of the initiation of treatment. Inhaled, intranasal, 
or ocular corticosteroids are allowed if use is stable (stable use is 
defined as dose and frequency unchanged for at least four (4) weeks 
prior to the initiation of treatment). 
• 
Antibiotics within four (4) weeks of the initiation of treatment with the 
exception of five (5) days or less of antibiotic therapy during this 
period, BUT with no antibiotics use permitted within one (I) week 
prior to the initiation oftreatment. 
• 
Spironolactone within eight (8) weeks of the initiation of treatment with 
the exception of five (5) days or less of spironolactone therapy during 
this period, BUT with no spironolactone use permitted within one (I) 
week prior to the initiation of treatment. 
• 
Retinoid therapy within six (6) months of the initiation of treatment. 
• 
Other systemic therapy which may materially affect the subject's acne 
in the opinion of the investigator. 
The study will consist of a Screening/Baseline Visit and three (3) scheduled 
visits. 
1. 
Visit I (Screening/Baseline): At Visit I, study staff will explain the study 
procedures and an informed consent/assent must be signed prior to the 
initiation of any study-related procedures. At this visit, consenting subjects 
will have their medical and dermatological history, dermatologic exam, 
CONFIDENTIAL 
Page 6 of 56 


Product Name: Cortexolone l7u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
Study Measurements 
CONFIDENTIAL 
and inclusion/exclusion criteria reviewed to determine subject eligibility. 
Subjects that require a "washout" period prior to enrollment to meet 
inclusion/exclusion criteria requirements will be required to return to the 
clinic within 45 days to complete the remaining activities. Subjects who 
require "washout" for longer than 45 days will be re-consented. A brief 
physical examination including vital signs, UPT (if applicable), 
electrocardiogram (ECG), Fitzpatrick Skin Type assessment, clinical 
evaluations (lesions counts, IGA, as well as baseline local skin reactions 
(LSRs) pre-application), and photographs will be performed at this visit. 
Prior and concomitant therapy and concomitant medications/procedures 
will be reviewed. Subjects will be randomized and assigned a test article 
kit number. Test article and Subject Diary will be dispensed. Subjects and 
parent/guardian (if applicable) will be instructed on how to apply the test 
article and to record applications in the Subject Diary. The first dose will 
be applied during this visit under supervision of the investigator. Adverse 
events (AEs) and LSRs post-application will be assessed. The subject will 
be scheduled for the first follow-up visit. 
2. 
Visits 2 and 3 (Weeks 4 & 8): Subjects will return after the initial 
treatment for clinical evaluations (lesion counts, IGA, AEs, and LSRs), 
UPT (if applicable), and review of concomitant medications/procedures. 
Test article application and compliance will be reviewed (from Subject 
Diary), test article and Subject Diary will be dispensed/returned (as 
required), and photography will be performed. The subject will be 
scheduled for the next follow-up visit. 
3. 
Visit 4 (Final Visit. Week 12 & Early Termination): Subjects will return 
for the final visit for review of concomitant medications/procedures, UPT 
(if applicable), ECG, clinical evaluations (lesion counts, IGA, AEs, and 
LSRs), and photography. All test article will be returned and compliance 
documented (from Subject Diary). 
Efficacy will be assessed by the investigator as follows: 
• Investigator's Global Assessment OGA): Overall severity of acne using 
a five-point scale from 0 = clear to 4 = severe will be conducted at each 
visit. This is a static morphological scale that refers to a point in time 
and not a comparison to Baseline. 
• Acne Lesion Counts: Total lesions, including inflammatory lesions 
(papules, pustules, and nodules) and non-inflammatory lesions (open 
and closed comedones), on the face will be accurately counted, but 
recorded separately at each visit. 
Assessment of subject satisfaction with the treatment will be obtained using a 
four-point scale from 
(very satisfied) to 
(not satisfied at 
all) at the final visit (Week 12). 
Safety will be assessed by the investigator via the evaluation of local and 
systemic AEs and UPTs at each visit (Baseline, Weeks 4, 8, and 12, or at the 
end of treatment). ECGs will also be assessed at Baseline and Week 12. 
LSRs including telangiectasia, skin atrophy, striae rubrae, erythema, edema, 
and scaling/dryness will be assessed by the investigator at each visit using a 
Page 7 of 56 


Product Name: Cortexolone 17u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
Study Endpoints 
Sample Size 
Calculations and Power 
Considerations 
CONFIDENTIAL 
five-point ordinal scale (0 
none, I 
trace, 2 
mild, 3 
moderate, and 4 
severe). Subjects will be asked to rate the severity of stinging/burning and 
pruritus using a four-point scale (0 
none, I 
mild, 2 
moderate, and 3 
severe) at each visit (Baseline [pre· and post-application], and Weeks 4, 8, and 
12). 
Efficacy Endpoints: 
Primary Endpoints (Hierarchical) 
• 
Pl: Proportion of subjects in each treatment group achieving 
"success" at Week 12, with "success" defined as an IGA score of 
"clear (score=O)" or "almost clear (score=l)" AND at least a two-
point reduction in IGA compared to Baseline. 
• 
P2: Absolute change from Baseline in non-inflammatory lesion 
counts in each treatment group at Week 12. 
• 
P3: Absolute change from Baseline in inflammatory lesion counts in 
each treatment group at Week 12. 
Secondary Endpoints (Hierarchical) 
• 
Sl: Absolute change from Baseline in total lesions counts in each 
treatment group at Week 12. 
• 
S2: Percent change from Baseline in total lesions counts in each 
treatment group at Week 12. 
• 
S3: Percent change from Baseline in non-inflammatory lesions count 
in each treatment group at Week 12. 
• 
S4: Percent change from Baseline in inflammatory lesions count in 
each treatment group at Week 12. 
Safety Endpoints: 
• 
Local and systemic AEs at every visit (Baseline, Weeks 4, 8, and 12). 
• 
LSRs: telangiectasia, skin atrophy, striae rubrae, erythema, edema, 
scaling/dryness, stinging/burning, and pruritus scored by frequency 
and severity at every visit (Baseline, Weeks 4, 8, and 12). 
• 
UPTs in all WOCBP at every visit (Baseline, Weeks 4, 8, and 12). 
• 
Material changes from Baseline in ECGs at Week 12. 
Assumptions used for sample size calculations were estimated from Phase 2 
Dose Escalation Study (171-7151-201), using a subset of subjects with 30-75 
inflammatory lesions and 30-100 non-inflammatory lesions at Baseline. 
All the hypothesis tests for the primary endpoints have to be performed at the 
same significance level 
two-sided and the failure to reject a null 
hypothesis will imply the failure of rejecting all of the subsequent null 
hypotheses. 
In order to keep the overall Type II error 
for the whole study, the sample 
size for the three hypothesis tests on the primary endpoints will be calculated 
considering an individual Type II error 
For an IGA success rate of(continuity corrected) 14.00% for CB-03-01 cream 
and 2.17% for vehicle cream (odds 
sample size was estimated to be 
202 subjects per treatment group. 
Page 8 of 56 


Product Name: Cortexolone !?a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
Statistical Methods 
CONFIDENTIAL 
For a mean absolute change from Baseline in non-inflammatory lesion counts 
of -22 for CB-03-0 I cream and -1 for vehicle cream (standard 
17), 
sample size was calculated to be 19 subjects per treatment group. 
For a mean absolute change from Baseline in inflammatory lesion counts of-
15 for CB-03-01 cream and -10 for vehicle cream (standard 
sample size was calculated to be 334 subjects per treatment group. 
The hypothesis test for the secondary endpoints will be performed at the same 
significance level 
two-sided of the primary endpoints if and only if all 
the null hypotheses on the primary endpoints are rejected. 
For a mean absolute change from Baseline in total lesion counts of -35 for CB-
03-01 cream and -13 for vehicle cream (standard 
sample size 
was calculated to be 13 subjects per treatment group. 
For a mean percent change from Baseline in total lesion counts of -35 for CB-
03-01 cream and -14 for vehicle cream (standard 
sample size 
was calculated to be 77 subjects per treatment group. 
For a mean percent change from Baseline in non-inflammatory lesion counts of 
-33 for CB-03-01 cream and -5 for vehicle cream (standard 
sample size was calculated to be 43 subjects per treatment group. 
For a mean percent change from Baseline in inflammatory lesion counts of -37 
for CB-03-01 cream and -23 for vehicle cream (standard 
sample 
size was calculated to be 172 subjects per treatment group. 
Based on those assumptions, at least 350 subjects in each treatment group (CB-
03-01 cream, I% BID and vehicle BID) will be included into each Phase 3 
study to provide sufficient power (90%) with the chosen primary endpoints. 
All statistical processing will be performed using SAS® unless otherwise stated. 
Summary tables (descriptive statistics and/or frequency tables) will be 
provided for baseline variables, efficacy variables, and safety variables. 
Continuous variables will be described by descriptive statistics (n, mean, 
standard deviation, CV%, minimum, median, and maximum). Frequency 
counts and percentage of subjects within each category are provided for 
categorical data. Summaries will be provided for each treatment group. 
Study Sets: 
The Safety set will include all subjects who received at least one application of 
the test article. The intent-to-treat (ITT) set will include all randomized 
subjects. The per-protocol (PP) set will be a subset of the ITT set and will 
include subjects who completed the study without any significant protocol 
deviations. The analysis of safety will be conducted on the Safety set. The 
analysis of efficacy will be conducted on both the ITT and PP sets, with the 
ITT set considered as the primary set for statistical analysis. Multiple 
imputation will be used to impute missing values for the primary endpoints and 
absolute change in total lesions count (S I) in the ITT analyses. Sensitivity 
Page 9 of 56 


Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
CONFIDENTIAL 
analyses will be performed to investigate the robustness of the results obtained 
on the ITT set for the primary endpoints (change from Baseline in non-
inflammatory and inflammatory lesion counts and IGA "success" at Week 12). 
Missing values for the other secondary endpoints (i.e., S2-S4: percent change 
in lesions counts) will be calculated using the values obtained from the 
multiple imputation of the primary efficacy endpoints and secondary efficacy 
endpoint #1 (Sl). 
Efficacy Analyses: 
Primarv Efficacv Analvsis 
Hypothesis tests on the primary endpoints will be conducted in hierarchical 
order for P 1 through P3. 
Pl: A logistic regression model with treatment and analysis center as fixed 
effects will be used to compare the proportion of subjects achieving "success" 
in each treatment group at Week 12, where "success" is defined as an IGA 
score of"clear (score=O)" or "almost clear (score=l)" AND at least a 
improvement in IGA compared to Baseline. 
P2: An analysis of covariance (ANCOV A) will be used to compare the 
absolute change from Baseline in non-inflammatory lesion counts in each 
treatment group at Week 12, with treatment and analysis center as fixed effects 
and the Baseline non-inflammatory lesion count as the covariate. 
P3: An ANCOV A will be used to compare the absolute change from Baseline 
in inflammatory lesion counts in each treatment group at Week 12, with 
treatment and analysis center as fixed effects and the Baseline inflammatory 
lesion count as the covariate. 
Secondary Efficacy Analysis 
Hypothesis tests on the secondary endpoints will be conducted in hierarchical 
order for S I through S4. 
Sl: An ANCOV A will be used to compare the absolute change from Baseline 
in total lesion counts in each treatment group at Week 12, with treatment and 
analysis center as fixed effects and the Baseline total lesion count as the 
covariate. 
S2: An AN COY A will be used to compare the percent change from Baseline 
in total lesion counts in each treatment group at Week 12, with treatment and 
analysis center as fixed effects and the Baseline total lesion count as the 
covariate. 
S3: An ANCOV A will be used to compare the percent change from Baseline 
in non-inflammatory lesion counts in each treatment group at Week 12, with 
treatment and analysis center as fixed effects and the Baseline non-
inflammatory lesion count as the covariate. 
S4: An ANCOV A will be used to compare the percent change from Baseline 
in inflammatory lesion counts in each treatment group at Week 12, with 
treatment and analysis center as fixed effects and the Baseline inflammatory 
lesion count as the covariate. 
Page 10 of 56 


Product Name: Cortexolone !?a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
CONFIDENTIAL 
Treatment Compliance and Extent of Exposure Analyses: 
Treatment Compliance 
Compliance to the test article will be evaluated at each visit and overall 
according to the following formula: 
Number of actual applications 
100 x Number of scheduled applications 
Non-compliance will be defined as a compliance value less than 80%. 
Descriptive statistics will be used to summarize test article compliance at each 
visit and overall for the ITT and PP sets. The proportion of compliant and non-
compliant subjects will be summarized by table of frequencies at each visit and 
overall for the ITT and PP sets. Subjects with an overall compliance not 
evaluable (due to missing data) or less than 80% will be excluded from the PP 
set. 
Extent of Exposure 
Descriptive statistics will be used to summarize exposure to test article for the 
ITT, PP, and Safety sets. The total amount oftest article used (grams applied) 
will be calculated for each subject from the weights of the returned test articles. 
The mean daily amount of test article applied (total amount of test article 
used/number of days of treatment) will be calculated for each subject. 
Safety Analyses: 
Local Skin Reactions CLSRsi 
LSRs (telangiectasia, skin atrophy, 
striae rubrae, erythema, edema, 
scaling/dryness, stinging/burning, and pruritus) will be summarized by the 
frequency of each individual LSR by treatment group and severity at each visit. 
Adverse Events (AEs) 
Pre-treatment AEs (PTAEs) and Treatment Emergent AEs (TEAEs) will be 
coded using the MedDRA coding dictionary. TEAEs will be summarized by 
treatment group and overall. The number and proportion of subjects with any 
TEAE and the number of TEAEs will be tabulated by MedDRA system organ 
class (SOC) and preferred term (PT), seriousness, relationship to test article, 
and severity. 
Electrocardiograms (ECGs) 
ECGs will be evaluated for any material change during the study period. 
Results (normal/borderline/abnormal) of the ECG and descriptive statistics will 
be provided by treatment group at each visit for heart rate, RR duration, PR 
duration, QRS duration, QT duration including Bazett's and Fridericia's 
corrections, and P axis for the Safety set. Changes in overall interpretation 
(normal/abnormal/borderline) of the ECG from Baseline to Week 12 will be 
examined using shift tables. 
Page II of 56 


Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
SCHEDULE OF EVENTS 
Visit 1 
Visit2 
Visit 3 
Visit 4 
PROCEDlJlU;S 
• 
Screeni!!g/ 
Week121 
· 
.. 
Week4 
WeekS 
(Day29±5) (Day 57 ±7) 
(Day85± 10) 
. 
Informed Consent/ Assent' 
X' 
Medical/Dermatological History 
X 
Demographics 
X 
Inclusion/Exclusion Criteria 
X 
Dermatologic & Limited Physical 
X 
Exam 
Fitzpatrick Skin Type Assessment 
X 
Urine Pregnancy Testsj 
X 
X 
X 
X 
Electrocardiograms 
X 
X 
Photographs 
X 
X 
X 
X 
Lesion Counts 
X 
X 
X 
X 
Investigator's Global Assessment 
X 
X 
X 
X 
X 
Local Skin Reaction Assessment 
(pre- & post-
X 
X 
X 
aoolication) 
Review of Concomitant 
X 
X 
X 
X 
Medications & Procedures 
Study Medication and Diary 
X 
X 
X 
X 
Dispensed & Collected'·' 
Review of Compliance 
X 
X 
X 
Adverse Events Evaluation 
X 
X 
X 
X 
1 Subjects who terminate early shall complete all final visit activities designated at Week 12. 
2· ConsenVassent may be performed up to 45 days prior to the Baseline Visit. Subjects who require 
"washout" for longer than 45 days will be re-consented. 
3· Testing to be conducted on all WOCBP (see Section 5.1.1 for definition). UPT minimal sensitivity is 
25 mill/mL. 
4· Instruct subject and the subject's parent/guardian on test article application and provide instruction sheet 
after assessing the subject's use of the test article with respect to the amount and number of doses applied 
since the last visit. 
5· Dispense Subject Diary at initial and subsequent visits, as needed. 
CONFIDENTIAL 
Page 12 of 56 


Product Name: Cortexolone 17u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
ABBREVIATIONS 
AE 
ANCOVA 
BID 
CB-03-01 
CLIA 
CFR 
CRF 
CRO 
CV% 
ECG 
EDC 
FDA 
GCP 
HPA 
IGA 
IND 
IRB 
ITT 
IUD 
LSR 
MedORA 
OTC 
PK 
pp 
PT 
PTAE 
QA 
QD 
RX 
SAE 
SAS 
soc 
TEAE 
UPT 
WOCBP 
CONFIDENTIAL 
Adverse Event 
Analysis of Covariance 
Twice a day 
Cortexolone 17u-propionate 
Clinical Laboratory Improvement Amendments 
Code of Federal Regulations 
Case Report Form 
Contract Research Organization 
Percent Coefficient of Variation 
Electrocardiogram 
Electronic Data Capture 
Food and Drug Administration 
Good Clinical Practices 
Hypothalamic-Pituitary-Adrenal 
Investigator's Global Assessment 
Investigational New Drug 
Institutional Review Board 
Intent-to-Treat 
Intrauterine Device 
Local Skin Reaction 
Medical Dictionary for Regulatory Activities 
Over-the-Counter 
Pharmacokinetics 
Per-Protocol 
Preferred Term 
Pre-Treatment Adverse Event 
Quality Assurance 
Once a day 
Prescription 
Serious Adverse Event 
Statistical Analysis Software 
System Organ Class 
Treatment Emergent Adverse Event 
Urine Pregnancy Test 
Women of Childbearing Potential 
Page 13 of 56 


Product Name: Cortexolone 17a-Propionate (CB-03-0!) 
Protocol: CB-03-0!/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June!!, 20!5 
TABLE OF CONTENTS 
Protocol Approval ............................................................................................................... 2 
Study Acknowledgement .................................................................................................... 3 
Protocol Synopsis ................................................................................................................ 4 
Schedule ofEvents ............................................................................................................ 12 
Abbreviations .................................................................................................................... 13 
Table of Contents .............................................................................................................. !4 
I. 
Background ....................................................................................................... !6 
2. 
Rationale ........................................................................................................... 17 
3. 
Objective ........................................................................................................... 17 
4. 
Study Design ..................................................................................................... !7 
5. 
Study Population ............................................................................................... 18 
5.1 
Subject Eligibility ............................................................................................. 18 
5.!.1 
Inclusion Criteria ....................................................................................... !8 
5.!.2 
Exclusion Criteria ...................................................................................... 19 
6. 
7. 
8. 
5.1.3 
6.! 
6.2 
6.3 
8.1 
8.2 
9. 
9.! 
9.2 
9.3 
10. 
10.1 
10.2 
10.3 
10.4 
!!. 
12. 
12.1 
!3. 
!3.1 
13.2 
Subject Withdrawal Criteria ...................................................................... 20 
Test Articles and Regimen ................................................................................ 20 
Description ........................................................................................................ 20 
Instructions for Use and Application ................................................................ 2! 
Warnings, Precautions and Contraindications .................................................. 21 
Randomization Assignment .............................................................................. 22 
Prior and Concomitant Therapies ..................................................................... 22 
Prohibited Medications or Therapies ................................................................ 22 
Allowed Medications or Therapies ................................................................... 23 
Study Procedures .............................................................................................. 24 
Visit I (Day I): Screening/Baseline ................................................................. 24 
Visits 2 (Week 4) and 3 (Week 8) .................................................................... 25 
Visit 4 (Week 12): End of Study ....................................................................... 26 
Clinical Evaluations .......................................................................................... 27 
Investigator's Global Assessment (IGA) .......................................................... 27 
Acne Lesion Counting ...................................................................................... 27 
Fitzpatrick Skin Type Assessment. ................................................................... 28 
Local Skin Reactions (LSRs) ............................................................................ 28 
Photography ...................................................................................................... 30 
Laboratory Tests ............................................................................................... 31 
Urine Pregnancy Tests (UPTs) ......................................................................... 31 
End of Study Criteria ........................................................................................ 31 
Completion of the Study ................................................................................... 31 
Subject Discontinuation .................................................................................... 31 
CONFIDENTIAL 
Page !4of56 


Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
13.3 
Study Termination ............................................................................................ 32 
14. 
Adverse Event Reporting .................................................................................. 32 
14.1 
Adverse Event (AE) .......................................................................................... 33 
14.2 
Serious Adverse Event (SAE) ........................................................................... 36 
14.3 
Pregnancy .......................................................................................................... 38 
15. 
Blinding/Unblinding ......................................................................................... 39 
16. 
Clinical Supplies ............................................................................................... 39 
16.1 
Test Article Information ................................................................................... 39 
16.2 
Supplies Provided by CRO ............................................................................... 39 
16.3 
Supplies Provided by Investigator .................................................................... 39 
17. 
Statistical Considerations .................................................................................. 39 
17.1 
Study Endpoints ................................................................................................ 39 
17.1.1 
Efficacy Endpoints .................................................................................... 39 
17.1.2 
Safety Endpoints ........................................................................................ 40 
17.2 
Sample Size Calculations and Power Considerations ....................................... 40 
17.3 
Statistical Methods ............................................................................................ 41 
17.3.1 
Efficacy Analyses ...................................................................................... 42 
17.3.2 
Treatment Compliance and Extent of Exposure Analyses ........................ 44 
17.3.3 
Safety Analyses ......................................................................................... 45 
17.4 
18. 
18.1 
18.2 
18.3 
18.4 
18.5 
18.6 
18.7 
18.8 
18.9 
Interim Analyses ............................................................................................... 46 
Ethical and Regulatory Considerations ............................................................. 46 
Compliance with Good Clinical Research Practice .......................................... 46 
Institutional Review Board (IRB) and Informed Consent/ Assent.. .................. 46 
Protocol Compliance ......................................................................................... 47 
Protocol Revisions ............................................................................................ 47 
Study Monitoring .............................................................................................. 47 
Case Report Form Requirements: Electronic Data Capture (EDC) .................. 47 
Reports to Institutional Review Board .............................................................. 48 
Quality Assurance Audits ................................................................................. 48 
Records Retention ............................................................................................. 48 
18.10 Record Confidentiality ...................................................................................... 48 
19. 
References ......................................................................................................... 49 
Appendix I 
Sample Subject and Parent/Guardian Instruction sheet... .......................... 50 
Appendix 2 
Sample Subject Diary ................................................................................ 52 
Appendix 3 
Test Article Packaging and Labeling ......................................................... 54 
CONFIDENTIAL 
Page15of56 


Product Name: Cortexolone !?a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
1. 
BACKGROUND 
CB-03-01 (cortexolone !?a-propionate) is a steroidal antiandrogen that is being 
developed as a I% cream for the topical treatment of acne vulgaris, an androgen-
dependent skin disorder. CB-03-01 binds to the human androgen receptor displacing the 
androgenic hormones and acts as an androgen antagonist. In human plasma, CB-03-01 is 
rapidly metabolized to parent cortexolone so that its systemic bioavailability after topical 
application is anticipated to be low. Cortexolone, the main by-product, is a physiological 
component of the pool of endogenous corticosteroids, and is an intermediate in the 
synthesis of glucocorticoids, but it only exhibits weak glucocorticoid properties [I]. 
In single-dose studies in mouse and in rat, and following repeated subcutaneous 
administration in rats, and dermal administration in rabbits and minipigs, the drug was 
well tolerated with no significant local or unexpected systemic effects. CB-03-0 I is not 
mutagenic in the Ames test or in the human chromosome aberration test, and it is not a 
skin sensitizer. 
To date, four Phase I and three Phase 2 clinical studies have been completed with CB-03-
01 cream in Europe and the United States, with over 500 subjects exposed to CB-03-01 
creams. All studies were conducted using CB-03-01 cream, 1%; additional concentrations 
of CB-03-01 cream (0.1% and 0.5%) were also used in the most-recent Phase 2 Dose-
Escalating study. The studies included: 
I. A Phase I Single Dose Pharmacokinetics (PK) Study in 24 healthy volunteers 
[randomized, double-blind, vehicle-controlled, single-ascending dose], 
2. A Phase I Repeat Dose PK Study in 24 healthy volunteers [randomized, vehicle-
controlled, 14-day repeat-dose], 
3. A Phase I Steady State PK Study in 8 subjects with acne vulgaris [single center, 
open-label, pilot, 6-week repeat-dose] 
4. A Phase I Three-week Cumulative Skin Irritation Study in 36 healthy volunteers, 
5. A Phase 2 Hypothalamic-Pituitary-Adrenal axis (HPA)/PK study in 42 subjects 
with acne vulgaris [open-label, 14-day repeat-dose] 
6. A Phase 2 Comparator Proof of Concept Study in 72 adult subjects with facial 
acne 
[randomized, double-blind, vehicle-controlled, active-comparator 
(Retin-A [tretinoin] 0.05% cream), 8-week repeat-dose], and 
7. A Phase 2 Dose-Escalating Study in 363 subjects with facial acne vulgaris [multi-
center, randomized, double-blind, vehicle controlled, 12-week repeat-dose] 
Overall, the data that resulted from the completion of the aforementioned studies has 
demonstrated that CB-03-01 creams selected for clinical development (a) are well 
tolerated locally, (b) result in minimal systemic exposure when applied topically, (c) have 
a clinical safety profile without any concern and similar to the placebo, and (d) at I% 
CONFIDENTIAL 
Page 16 of 56 


Product Name: Cortexolone l7a-Propionate (CB-03-01) 
Protocol: CB-03-01126 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
concentration applied BID are significantly more effective than its vehicle at reducing 
inflammatory and non-inflammatory lesions counts in adolescent and adult subjects. 
CB-03-0 I could offer advantages over existing products for acne vulgaris due to its 
potential 
efficacy and 
lack of systemic antiandrogen 
activity. 
Because its 
pharmacological action appears to be limited to the local site of application, use of CB-
03-0 I may be able to mitigate the side effects related to systemic exposure to hormonal 
agents currently used in the treatment of acne. 
2. 
RATIONALE 
The concentration ofCB-03-01 selected for the initial clinical studies(!%) was based on 
antiandrogenic activity in the hamster flank organ test in which the best effective 
concentration was 0.8% [!]. The results of the Phase 2 Dose Escalation Study 
demonstrated that CB-03-0 I cream, I% applied BID had more favorable results than 
other treatments (0.1% BID, 0.5% BID, and I% QD) and no material safety issues were 
noted with any of the concentrations of CB-03-01 cream [2]. Based on the collective 
findings of the previous Phase I and Phase 2 studies, CB-03-01 cream, 1% BID appears 
to be the best treatment candidate to advance for further clinical study and development 
as a topical treatment for acne vulgaris. Thus, the present Phase 3 study has been 
designed to determine and compare the efficacy of treatment with CB-03-01 cream, I% 
and the vehicle cream applied twice daily for 12 weeks in subjects with moderate to 
severe facial acne vulgaris. 
3. 
OBJECTIVE 
The primary objective of this study is to determine the safety and efficacy of CB-03-0 I 
cream, I% versus the vehicle cream applied twice daily for 12 weeks in subjects with 
facial acne vulgaris. 
4. 
STUDY DESIGN 
This is a multicenter, randomized, double-blind, vehicle-controlled, parallel-group 
comparison study of safety and efficacy for CB-03-01 cream, I% in male and female 
subjects, 9 years or older with moderate to severe acne vulgaris on the face. Eligible 
subjects must have acne vulgaris of the face (which can include the nose) with an 
Investigator's Global Assessment (IGA) score of 3 or 4, at least 30 to a maximum of 75 
inflammatory lesions (papules, pustules, and nodules), and at least 30 to a maximum of 
100 non-inflammatory lesions (open and closed comedones). At least 700 subjects will be 
enrolled at approximately 40 sites. Subjects will be randomized in a I: I ratio to one of 
two treatment groups: 
I. CB-03-01 (cortexolone 17a-propionate) cream, 1% 
2. Vehicle cream 
CONFIDENTIAL 
Page 17 of 56 


Product Name: Cortexolone !?a-Propionate (CB-03-01) 
Protocol: CB-03-01126 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
All subjects will apply the assigned test article to the face twice daily for 12 weeks (see 
Section 6). 
In addition, a separate open-label long-term extension study is planned. Subjects 
completing the treatment-phase of this trial will be offered the opportunity to participate 
in this follow-on study (CB-03-01127: An Open-Label, Long-Term Extension Study to 
Evaluate the Safety of Cortexolone !?a-Propionate (CB-03-01) Cream, 1% Applied 
Twice Daily for up to 12 Months in Subjects with Facial Acne Vulgaris). In this open 
label study, all subjects will apply the active medication (cortexolone !?a-propionate 
cream, 1%) twice daily for up to 9 additional months of treatment (for a total of up to 12 
months; 0 or 3 months in the pivotal Phase 3 trial and an additional 9 months in the open-
labellong-term extension study). 
5. 
STUDY POPULATION 
5.1 
Subject Eligibility 
To be included in the study, subjects must meet the following inclusion criteria and none 
of the exclusion criteria. 
5. 1.1 
Inclusion Criteria 
I. Subject is male or non-pregnant female, 9 years of age or older. Females must be 
post-menorausal5, surgically sterile6, or using highly effective birth control 
methods.7• WOCBP must have a negative urine pregnancy test (UPT) at the 
Screening/Baseline Visit. 
2. Subject has provided written informed consent/assent. A subject under 18 years of 
age must provide written informed assent and be accompanied by the parent or legal 
guardian at the time of assent/consent signing. The parent or legal guardian must 
provide informed consent for the subject. If a subject becomes 18 years of age during 
5 Defined as amenorrhea greater than 12 consecutive months. 
6 Hysterectomy, bilateral tubal ligation (at least six (6) months prior to study entry), or bilateral 
oophorectomy. 
7 Highly effective contraception includes a) total abstinence, b) oral, injected, or implanted hormonal 
methods of contraception, c) intrauterine device (IUD), d) partner vasectomy (performed at least six (6) 
months prior to study entry), or e) double barrier methods of contraception [barrier methods include male 
or female condom, diaphragm with spermicidal foam/gel/film/vaginal suppository, cervical cap with 
spermicides, or contraceptive sponge]. 
8 Women of childbearing potential (WOCBP) include any female who has experienced menarche or is 10 
years of age or older and who has not undergone successful surgical sterilization (hysterectomy, bilateral 
tubal ligation or bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea> 12 consecutive 
months]. WOCBP taking hormonal therapy for any reason exclusive of the treatment for acne (e.g., as 
contraception, etc.) must be on the same treatment for at least 12 weeks prior to study entry and must not 
change their dosing regimen during the study. Those who have used hormonal therapy prior to study entry 
must have discontinued use at least eight (8) weeks prior to the start of the study. 
CONFIDENTIAL 
Page 18 of 56 


Product Name: Cortexolone 17u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
the study the subject must provide written informed consent at that time to continue 
study participation. 
3. Subject has an Investigator's Global Assessment (IGA) score of 3 or 4 [0 (clear) to 4 
(severe) scale]. 
4. Subject has facial acne vulgaris, (which can include the nose), with at least 30 to a 
maximum of 75 inflammatory lesions (papules, pustules, and nodules) and 30 to a 
maximum of 100 non-inflammatory lesions (open and closed comedones). 
5. Subject and parent/guardian (if applicable) are willing to comply with study 
instructions and return to the clinic for required visits. 
6. Subject has used the same type and brand of make-up, other facial products 
(exclusive of RX/OTC acne cleansers) and hair products (e.g., shampoo, gel, hair 
spray, mousse, etc.) for at least one (1) month prior to the Baseline Visit and agrees to 
continue his/her other general skin and hair care products and regimen for the entire 
study. 
5.1.2 
Exclusion Criteria 
1. Subject is pregnant, lactating, or is planning to become pregnant during the study. 
2. Subject has any skin pathology or condition that could interfere with the evaluation of 
the test products or requires the use of interfering topical or systemic therapy. 
3. Subject has greater than two (2) facial nodules. 
4. Subject has nodulocystic acne. 
5. Subject has any condition which, in the investigator's opinion, would make it unsafe 
for the subject to participate in this research study. 
6. Subject is currently enrolled in an investigational drug or device study. 
7. Subject has received an investigational drug or has been treated with an 
investigational device within 30 days prior to the initiation of treatment (Baseline). 
8. Subject has facial hair that could interfere with the study assessments in the opinion of 
the investigator. 
9. Subject and parent/guardian (if applicable) are unable to communicate or cooperate 
with the investigator due to language problems, poor mental development, or 
impaired cerebral function. 
I 0. Subject may be unreliable for the study including subjects who engage in excessive 
alcohol intake or drug abuse, or subjects who are unable to return for scheduled 
follow-up visits. 
II. Subject has known hypersensitivity or previous allergic reaction to any of the active 
or inactive components of the test articles (see Section 6.1). 
12. Subject has the need or plans to be exposed to artificial tanning devices or excessive 
sunlight during the trial. 
13. Subject has used any of the following topical anti-acne preparations or procedures on 
the face: 
• Topical anti-acne treatments including, but not limited to, over-the-counter (OTC) 
acne cleansers or treatments, benzoyl peroxide, antibiotics, azelaic acid, sulfa 
CONFIDENTIAL 
Page 19 of 56 


Product Name: Cortexolone 17u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
based products, corticosteroids and salicylic acid within two (2) weeks of the 
initiation of treatment. 
• Retinoids, including tazarotene, adapalene, tretinoin, within four ( 4) weeks of the 
initiation of treatment. 
• Light treatments, microdermabrasion, or chemical peels within eight (8) weeks of 
the initiation of treatment. 
14. Subject has used the following systemic anti-acne medications: 
• Corticosteroids (including intramuscular and intralesional injections) within four 
( 4) weeks of the initiation of treatment. Inhaled, intranasal or ocular corticosteroids 
are allowed if use is stable (stable use is defined as dose and frequency unchanged 
for at least four (4) weeks prior to the initiation of treatment). 
• Antibiotics within four ( 4) weeks of the initiation of treatment with the exception 
of five (5) days or less of antibiotic therapy during this period, BUT with no 
antibiotics use permitted within one (I) week prior to the initiation of treatment. 
• Spironolactone within eight (8) weeks of the initiation of treatment with the 
exception of five (5) days or less of spironolactone therapy during this period, 
BUT with no spironolactone use permitted within one (I) week prior to the 
initiation of treatment. 
• Retinoid therapy within six (6) months of the initiation of treatment. 
• Other systemic therapy which may materially affect the subject's acne in the 
opinion of the investigator. 
5.1.3 
Subject Withdrawal Criteria 
Procedures for handling subjects who are discontinued from the study are described in 
Section 13.2. Subjects who are discontinued will not be replaced. 
6. 
TEST ARTICLES AND REGIMEN 
6.1 
Description 
Test article name: 
Active ingredient: 
Other ingredients: 
Placebo name: 
Ingredients: 
CONFIDENTIAL 
CB-03-0 I Cream, I% 
Cortexolone 17u-propionate (11-deoxy-hydrocortisone-17u-
propionate). 
Cetyl alcohol, glycerol monostearate, liquid paraffin, propylene 
glycol, tocopherol, sodium edetate, polysorbate 80, citric acid, 
purified water. 
Vehicle Cream 
Cetyl alcohol, glycerol monostearate, liquid paraffin, propylene 
glycol, tocopherol, sodium edetate, polysorbate 80, citric acid, 
purified water. 
Page 20 of 56 


Product Name: Cortexolone !?a-Propionate (CB-03-01) 
Protocol: CB-03-01126 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
6.2 
Instructions for Use and Application 
At the first visit, the subjects will be instructed to wash their entire face (the area to be 
treated) with mild soap and water and then dry the area gently. The study staff will then 
instruct the subject and parent/guardian (if applicable) on how to dispense the cream, how 
much of the test article to use, and where to apply the assigned test article. The first 
application of cream should be applied in the office at Visit I under supervision of the 
study staff after subject has been deemed eligible. Typically, about I gram of the cream 
will be dispensed onto a fingertip and applied to the face by dabbing small amounts 
gently on multiple regions of the face (e.g., forehead, nose, cheeks, chin). Using a 
fingertip, the cream will be spread to provide a thin, uniform layer of the cream over the 
entire face. 
Subjects and parents/guardians (if applicable) will be instructed to apply the cream to the 
whole face twice daily (morning and in the evening) for 12 weeks. The subject should 
ideally allow at least eight (8) hours between applications. All subjects should not wash 
the treated area for at least four (4) hours following test article application; and MUST 
NOT APPLY THE TEST ARTICLE WITHIN FOUR (4) HOURS PRIOR TO ANY 
STUDY VISIT. 
Subjects will be provided with a Subject Diary to record the dates and time of 
application. Subjects will be instructed to only apply the study cream to the face as 
instructed by the investigator or designated study personnel. Note: The dispensing, 
recording, and application of the test article by the subject may require adult 
supervision by the subject's parent/guardian. 
Subject and parent/guardian (if applicable) will also be provided with a Subject 
Instruction Sheet providing them with instructions on how to use and store the cream at 
home during the study period. 
Subject and parent/guardian (if applicable) will be instructed to bring all the containers of 
cream (used and unused) and their completed diaries to each visit. The study staff will 
weigh all the returned containers and will record the weights on the appropriate study 
medication accountability logs and case report forms (CRFs). 
Subjects who are not compliant with applying the creams as instructed (determined from 
subject diaries and/or the weight of test article used) may be discontinued from the study. 
6.3 
Warnings, Precautions and Contraindications 
These test articles are for topical use only. Care should be taken to avoid contact with 
eyes and all mucous membranes. If contact with eyes occurs, rinse thoroughly with water. 
Subjects with a known sensitivity to any of the ingredients in the test articles should not 
participate in this study. 
CONFIDENTIAL 
Page 21 of 56 


Product Name: Cortexolone !?a-Propionate (CB-03-01) 
Protocol: CB-03-01126 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
Should skin irritation or rash develop, subjects should discontinue use and contact the 
study site. 
In case of accidental ingestion, subjects should contact the investigator immediately. 
The effects of the test article in nursing mothers, pregnant women and their unborn 
children are unknown. WOCBP must not be pregnant or planning a pregnancy during the 
study period. 
7. 
RANDOMIZATION ASSIGNMENT 
Subjects who are eligible for enrollment into the study will be randomized to receive CB-
03-01 cream or vehicle cream in a 1:1 ratio. The randomization scheme will be blocked 
by investigational site. At each site, subject kits will be dispensed according to the kit 
number assigned by an IVRS/IWRS system as subjects are enrolled. At each site, the 
study staff will add the site number (provided to each site) and the subject number 
(starting with 001) to each kit label. The kit number dispensed to each subject will also be 
recorded on the source documents and CRFs. Treatment group designation will remain 
blinded until the final database is locked (unless unblinding is required as described in 
Section 15). Subjects who withdraw prematurely from the study will not be replaced. 
8. 
PRIOR AND CONCOMITANT THERAPIES 
Current medications and any medications taken in the 30 days prior to the start of the 
study (Screening, Visit l) will be recorded on the appropriate CRFs with the 
corresponding indication. The medications to be recorded include RX and OTC 
medications (except vitamins and dietary supplements not used to treat a medical 
condition). All medications taken on a regular basis should be recorded on this page prior 
to commencing the use of the test article. 
Therapies (medication and non-medication therapies) not restricted by the protocol may be 
used during the study for the treatment or prevention of disease or to maintain good health. 
Vitamins and mineral supplements are permitted at dosages considered by the investigator 
as reasonable for maintaining good health. Non-prohibited chronic therapies being used at 
Visit I may be continued. Any changes in concomitant therapies during the study must be 
recorded on the Concomitant Therapy Form. The reason for any change in concomitant 
therapies should be evaluated and, if appropriate, reported as, or in conjunction with, an 
adverse event. 
8.1 
Prohibited Medications or Therapies 
Medications or therapies that are prohibited during the duration of the study are as 
follows: 
CONFIDENTIAL 
Page 22 of 56 


Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-01126 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
Prior to entry into the study, subjects must not use the medications and/or procedures 
on the face as specified in Section 5 .1.2. 
During the study, subjects must not use the following products and/or procedures on the 
face: 
• 
Topical anti-acne treatments including, but not limited to, OTC acne cleansers or 
treatments, benzoyl peroxide, antibiotics, azelaic acid, sulfa based products, 
corticosteroids, and salicylic acid. 
• 
Retinoids including tazarotene, adapalene, and tretinoin. 
• 
Light treatments (including artificial tanning devices), microdermabrasion, or 
chemical peels. 
• 
Any other investigational drug or use of any investigational device 
• 
Systemic medications with potential anti-acne effects including: 
• 
Corticosteroids (including intramuscular and intralesional injections). Inhaled, 
intranasal, or ocular corticosteroids are allowed (see Section 8.2). 
• 
Antibiotics 
• 
Spironolactone 
• 
Retinoid therapy 
• 
The addition of hormonal contraception 
• 
Change to pre-existing hormonal contraception 
• 
Other systemic therapy, which may materially affect the subject's acne in the 
opinion of the investigator. 
Other chronic medications being used at the time of Baseline Visit can be continued at 
the discretion of the investigator. The reason for any changes in such concomitant 
therapies should be reported as, or in conjunction with, an AE. 
8.2 
Allowed Medications or Therapies 
Subjects must be on a consistent skin care program (make-up, moisturizers, soap, 
sunscreen, etc. of their choice, exclusive ofRX/OTC acne cleansers) for at least one (I) 
month prior to enrollment. The subject's skin care regimen will be reviewed and 
approved prior to their randomization. This skin care program should not contain any 
OTC products with significant levels of anti-acne ingredients such as retinol or alpha-
hydroxy acids (i.e., lactic acid, glycol acid, etc. at greater than 5%). 
No additional medications, including OTC preparations, should be used without the 
knowledge and, if possible, permission of the investigator. Vitamins and mineral 
supplements are permitted at dosages considered by the investigator as reasonable for 
maintaining good health. The addition, discontinuation, or dose change of any 
concomitant medications will be documented in the source documents. 
CONFIDENTIAL 
Page 23 of 56 


Product Name: Cortexolone 17u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
Medications will be permitted, at the discretion of the investigator, to treat local skin 
reactions, if applicable. 
Intranasal, inhaled, and ophthalmic steroids used for the management of allergies, 
pulmonary disorders, or other conditions exclusive of acne are NOT considered 
prohibited medications, but should be recorded on the Concomitant Medication Form. 
WOCBP taking per protocol allowed hormonal contraception therapy at enrollment 
must remain on the same treatment for the duration of the trial. 
Any changes in concomitant therapies during the study must be recorded on the CRFs. The 
reason for any changes in concomitant medications or therapies/procedures should be 
reported and should reflect either a baseline medical condition documented in the medical 
history of the CRF or an AE. 
9. 
STUDY PROCEDURES 
The study will consist of a Screening/Baseline Visit and three (3) scheduled visits. 
Specific activities for each study visit are listed below. 
9.1 
Visit 1 (Day 1): Screening/Baseline 
Subjects can be screened for the study up to 45 days before Visit I. During screening, the 
study requirements will be reviewed, written informed consent/assent obtained, and 
eligibility confirmed. If applicable, the washout from prohibited medications or 
treatments will be determined and implemented. Subjects who require "washout" for 
longer than 45 days will be re-consented. 
At Screening, the investigator or designee will: 
• 
Obtain a signed, written informed consent (unless the subject signed a consent 
within the past 45 days). Note: a subject under 18 years of age must provide 
written informed assent and be accompanied by the parent or legal guardian at the 
time of assent/consent signing. The parent or legal guardian must provide 
informed consent for the subject. If a subject becomes 18 years of age during the 
study, the subject must provide written informed consent at that time to continue 
study participation. 
• 
Complete review and documentation of the subject's medical and dermatological 
history and demographic information. 
• 
Record any concomitant medications and therapies. 
• 
Confirm the subject meets the inclusion/exclusion criteria. 
• 
Have subject complete washout from any prohibited medications, if necessary. 
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Product Name: Cortexolone !?a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
Once the Screening procedures have been completed, the investigator or designee will: 
• 
Perform a dermatologic exam and brief physical exam (including vital signs, 
height, and weight). 
• 
Perform a Fitzpatrick Skin Type assessment (see Section 10.3). 
• 
Perform a UPT for all WOCBP (see Section 5.1.1 for definition). The results must 
be negative for the subject to be enrolled into the study. 
• 
Perform an ECG. 
• 
Perform IGA (see Section 10.1) and acne lesion counts (see Section 10.2) prior to 
the first application of the test article. 
• 
Record Baseline LSRs (prior to application of the test article) (see Section 10.4). 
• 
Perform photography for all subjects at all sites (see Section II). 
• 
If the subject meets the inclusion/exclusion criteria, randomize the subject to the 
next available (lowest) subject number. 
• 
Weigh and dispense initial tube(s) of test article. 
• 
Complete the Study Medication Accountability Log. 
• 
Dispense the Subject Instruction Sheet to the subject and parent/guardian (if 
applicable) (Appendix 1). 
• 
Dispense the Subject Diary (Appendix 2) to the subject and parent/guardian (if 
applicable) and provide completion instructions. 
• 
Instruct the subject and parent/guardian (if applicable) where and how to apply 
the initial dose of test article to the acne lesions on the face following the 
procedures in Section 6.2. The first application should occur in the office under 
supervision of the study staff. 
• 
Record any AEs and LSRs (see Section 10.4) after the initial application of the 
test article. 
• 
Instruct the subject and parent/guardian (if applicable) to apply the test article 
(about I gram) to the whole face twice per day, with at least eight (8) hours 
between applications. 
• 
Update the Screening and Enrollment Log. 
• 
Schedule Visit 2 (Week 4). 
9.2 
Visits 2 (Week 4) and 3 (Week 8) 
The visit windows for Visits 2 and 3 are Day 29 ± 5 and Day 57± 7, respectively. 
At these visits, the investigator or designee will: 
• 
Observe/query the subject about any changes in his/her health since the previous 
study visit, including concomitant medications/therapies, and document the 
findings. 
• 
Assess any LSRs associated with the subject's acne or the topical application of 
the test article (see Section I 0.4 ). 
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Product Name: Cortexolone 17u-Propionate (CB-03-01) 
Protocol: CB-03-0l/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June 11,2015 
• 
Initiate/update the appropriate AE form, if applicable. 
• 
Perform a UPT for all WOCBP (see Section 5.1.1 for definition). 
• 
Perform photography (see Section II). 
• 
Perform IGA (see Section 10.1) and acne lesion counts (see Section 10.2). 
• 
Collect and dispense another (new) Subject Diary, if necessary (Appendix 2). 
• 
Collect and weigh used tubes of test article and weigh/dispense additional tubes, 
if necessary (see Appendix 3). If subject is under or over utilizing the test article 
remember to re-educate them regarding proper use and application. 
• 
Complete the Study Medication Accountability Log. 
• 
Review subject instructions on the proper application of the test article (Appendix 
I) with the subject and parent/guardian (if applicable) and the recommended 
amount of test article per application, as well as review and discuss any 
discrepancies or concerns with the subject regarding their use of the diary in 
addition to the amount of test article used since the last visit, if applicable. 
Subjects who have missed multiple applications of the test article may be 
discontinued from the study, at the discretion of the investigator. 
• 
Instruct the subject and parent/guardian (if applicable) to continue application of 
the test article (about I gram) to the whole face twice per day, with at least eight 
(8) hours between applications. 
• 
Schedule the next visit. 
9.3 
Visit 4 (Week 12): End of Study 
The visit window for Visit 4 is Day 85 ± 10. 
At this visit, the investigator or designee will: 
• 
Observe/query the subject about any changes in his/her health since the previous 
study visit, including concomitant medications/therapies, and document the 
findings. 
• 
Assess any LSRs associated with the subject's acne or the topical application of 
the test article (see Section I 0.4). 
• 
Initiate/update the appropriate AE form, if applicable. 
• 
Perform a UPT for all WOCBP (see Section 5.1.1 for definition). 
• 
Perform an ECG. 
• 
Perform photography (see Section II). 
• 
Perform IGA (see Section 10.1) and acne lesion counts (see Section 10.2). 
• 
Collect the Subject Diary (Appendix 2). 
• 
Collect and weigh used and unused tubes of test articles (see Appendix 3). 
• 
Complete the Study Medication Accountability Log. 
• 
Complete End of Study Form and discharge subject from the study. 
CONFIDENTIAL 
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Product Name: Cortexolone !?a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June ll, 2015 
10. 
CLINICAL EVALUATIONS 
The following clinical evaluations will be performed according to the schedules indicated 
during the study. The same investigator should complete the evaluations for a given 
subject throughout the study. If this becomes impossible a sub-investigator with 
overlapping experience with the subject and the study should complete the evaluations. 
10.1 
Investigator's Global Assessment (IGA) 
At every study visit, overall severity of acne using a five-point scale from 0 = clear to 
4 = severe will be conducted at each visit. This is a static morphological scale that refers 
to a point in time and not a comparison to Baseline. Subjects must have an IGA score of 
3 (moderate) or 4 (severe) at Baseline. 
0 
Clear 
Absence of active disease with no inflammatory or non-
inflammatory lesions. 
1 
Almost Clear Rare non-inflammatory lesions with no more than one small 
inflammatory lesions. 
2 
Mild 
Some non-inflammatory lesions with no more than a few 
inflammatory lesions (papules/pustules only; no nodular/cystic 
lesions). 
3 
Moderate 
Up to many non-inflammatory lesions and may have some 
inflammatory lesions but no more than one nodular/cystic lesion. 
4 
Severe 
Up to many non-inflammatory lesions and inflammatory lesions 
but no more than a few nodular/cystic lesions. 
10.2 
Acne Lesion Counting 
The number of inflammatory lesions (papules, pustules, and nodules) and non-
inflammatory lesions (open and closed comedones) on the face vertically from the 
hairline to mandible rim and horizontally from ear to ear, including those on the nose will 
be counted to determine subject eligibility at Visit 1. Subjects must have at least 30 to a 
maximum of 75 inflammatory lesions and 30 to a maximum of 100 non-inflammatory 
lesions on the face (which can include the nose) at Baseline. 
Lesions are defined as follows: 
• 
Comedones- open (blackheads) and closed (whiteheads). 
• 
Papules- raised inflammatory lesions with no visible purulent material. 
• 
Pustules- raised inflammatory lesions with visible purulent material. 
• 
Nodules- Any circumscribed, inflammatory masses greater or equal to 5 mm in 
diameter with or without cystic changes. 
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Product Name: Cortexolone 17u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
10.3 
Fitzpatrick Skin Type Assessment 
At Visit I, the investigator or designee will document the subject's skin phototype (I-VI) 
using the Fitzpatrick Skin Type Assessment as described below: 
FITZPATRICK SKIN TYPE 
Skin 
Typical Features 
Tanning ability 
Phototype 
I 
Pale white skin, blue/hazel eyes, Always burns, does not tan 
blond/red hair 
II 
Fair skin, blue eyes 
Burns easily, tans poorly 
III 
Darker white skin 
Tans after initial burn 
IV 
Light brown skin 
Burns minimally, tans easily 
v 
Brown skin 
Rarely bums, tans darkly easily 
VI 
Dark brown or black skin 
Never burns, always tans darkly 
10.4 
Local Skin Reactions (LSRs) 
At every study visit, the investigator or designee will document the severity of the 
following LSRs known to be associated with application of topical steroids: 
• 
Telangiectasia 
• 
Skin atrophy 
• 
Striae rubrae 
A five-point ordinal scale will be used to assess the severity of these reactions (0 =none, 
I =trace, 2 =mild, 3 =moderate, and 4 = severe). 
In addition, the investigator or designee will evaluate the severity of the following LSRs 
known to be associated with acne vulgaris, using the five-point ordinal scales described 
below: 
• 
Erythema 
• 
Edema 
• 
Scaling/dryness 
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Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-01126 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June 11,2015 
Erythema: 
0 
None 
1 
Minimal -barely perceptible erythema 
2 
Mild- predominantly minimal erythema (pink) in the treated area with or without 
a few isolated areas of more intense erythema 
3 
Moderate - predominantly moderate erythema (red) in the treated area with or 
without a few isolated areas of intense erythema (bright red) 
4 
Severe - predominantly intense erythema (bright red) in the treated area with or 
without a few isolated areas of very intense (fiery red) erythema 
Edema· 
0 
None 
1 
Minimal - scant, rare edema 
2 
Mild -
easily seen edema, minimally palpable, involving up to 113 of the 
Treatment Area 
3 
Moderate - easily seen edema and typically palpable, involving between 113 to 
2/3 of the Treatment Area 
4 
Severe - easily seen edema, indurated in some areas, involving over 2/3 of the 
Treatment Area 
Scaling/dryness· 
0 
None 
1 
Minimal -barely perceptible desquamation 
2 
Mild -limited areas of fine desquamation in up to 1/3 of the treatment area 
3 
Moderate- fine desquamation involving 113 to 2/3 of the treatment area or limited 
areas of coarser scaling 
4 
Severe - coarser scaling involving more than 2/3 of the treatment area or limited 
areas of very coarse scaling 
In addition, subjects will be asked to rate the severity of the following LSRS that 
occurred in the treatment area since the last visit, using the four-point ordinal scales 
described below: 
• 
Stinging/burning 
• 
Pruritus 
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Product Name: Cortexolone 17u-Propionate (CB-03-01) 
Protocol: CB-03-01126 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
Stinging/burning: 
0 
None 
I 
Minimal, barely perceptible- tolerable and little discomfort 
2 
Moderate- tolerable, but causes some discomfort 
3 
Severe- very uncomfortable or intolerable 
Pruritus (itching)· 
0 
None - no evidence of itching 
I 
Mild - only aware of itching at times, only present when relaxing, not present 
when focused on other activities 
2 
Moderate - often aware of itching, annoying, sometimes disturbs sleep and daytime 
activities 
3 
Severe -constant itching, distressing; frequent sleep disturbance, interferes with 
activities 
These LSRs will be collected independently of AEs. Only LSRs that require medical 
intervention (e.g., prescription medication) or require withholding the application of the 
test articles will be documented as AEs. Any LSRs that are not listed above will be 
recorded as AEs. 
11. 
PHOTOGRAPHY 
Photography documentation is required in this study. Photographs taken as part of this 
study will be used to document the effects of treatment, AEs, or other findings during the 
trial. Color photographs (both sides of the face and the front of the face) of the areas with 
acne lesions of all enrolled subjects will be performed at the Baseline Visit prior to 
application of the test articles and at Visits 2, 3, and 4. The study sites will be provided 
with suggested guidelines to assist them in taking standardized photographs. In addition, 
investigators at all study sites may take photos as they deem appropriate to document the 
clinical status of the subject (e.g., an AE, etc.). Photographs taken for this study are for 
informational purposes only and are not to assist in grading or for any other assessment. 
Note: Subjects may decline to have photographs taken during the conduct of the study. If 
a subject initially consents to photographs, then declines further photography, the 
Sponsor may use the photographs taken under consent for the purposes noted above. 
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Product Name: Cortexolone l7u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
12. 
LABORATORY TESTS 
12.1 
Urine Pregnancy Tests (UPTs) 
The UPT will be performed at the study site if the site is registered and conforms to 
Clinical Laboratory Improvement Amendments (CLIA) regulations for such testing (site 
possesses at a minimum a current valid CLIA Certificate of Waiver) or at an 
appropriately registered reference laboratory. A UPT will be performed at every visit on 
all WOCBP (see Section 5.1.1 for definition). The investigator will report the UPT results 
on the CRFs, in the subject's medical records and, if applicable, in independent records 
maintained at the study site. The UPT used must have a minimum sensitivity of 25 miU 
of 13-HCG/mL of urine. 
13. 
END OF STUDY CRlTERlA 
At the end of each subject's participation in the study, the investigator will complete an 
End of Study form for all completed and discontinued subjects. 
13.1 
Completion of the Study 
Each subject who completes the 12-week course of treatment as specified in this protocol 
will have completed the study. 
13.2 
Subject Discontinuation 
A subject may be withdrawn from the study prior to completion for any of the following 
reasons: 
• 
Whenever the subject or the subject's parent/guardian decides it is in the subject's 
best interest to be withdrawn, Note: if the subject or parent/guardian decides to 
withdraw from the study due to an AE then it should be classified as withdrawal 
due to an AE. 
• 
Whenever the investigator decides it is in the subject's best interest to be 
withdrawn 
• 
AEs 
• 
Worsening of condition or treatment failure (in the opinion of the investigator) 
• 
Noncompliance 
• 
Pregnancy 
• 
Lost to follow-up 
• 
Sponsor administrative reasons 
If a subject withdraws prematurely during the 12-week treatment period for any reason, 
the Visit 4 procedures should be completed at that time. Subjects who withdraw 
prematurely will not be replaced. When a subject is withdrawn from the study for a 
treatment-related AE (i.e., possibly, probably or definitely related as defined in Section 
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Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
14), when possible, the subject should be followed until resolution or stabilization of the 
AE. 
13.3 
Study Termination 
The study may be terminated by the investigator or the Sponsor. If, in the opinion of the 
investigator, clinical observations made during the study suggest that it may be unwise to 
continue, he or she may stop the study. A study termination by the investigator will be 
reported to the Sponsor. 
In addition, a written statement fully documenting the reasons for this action will be 
submitted to the Sponsor by the investigator within five (5) working days. 
In the event that the Sponsor chooses to discontinue or terminate the study, appropriate 
notification will be given to the investigator. 
14. 
ADVERSE EVENT REPORTING 
An adverse event (AE) is any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
An AE (also referred to as an adverse experience) can be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a drug, without any judgment about causality. An AE can arise from any 
use of the drug (e.g., off-label use, use in combination with any drug) and from any route 
of administration, formulation, or dose, including an overdose. 
Information on the medical condition of subjects should begin following the subject's 
written consent/assent to participate in the study and a medical history should be taken at 
screening. During any wash out and baseline periods, any changes in the health of 
subjects should be recorded as changes in medical history unless the event occurred as a 
result of a study-related procedure and is unanticipated, in such cases, the event should be 
recorded as an AE and reported to the Institutional Review Board (IRB) as an 
"unanticipated problem" in accordance with local procedures. Other changes in subject 
health information becomes AE data when the subject begins dosing with the test article 
and therefore AE data should be collected from the date of the first dose oftest article. 
These data are considered treatment-emergent AEs. 
Timely and complete reporting of all AEs assists CRO m identifying any untoward 
medical occurrence, thereby allowing: 
I) protection of the safety of study subjects; 
2) a greater understanding of the overall safety profile of the test article; 
3) recognition of dose-related test article toxicity; 
4) appropriate modification of study protocols; 
5) improvements in study design or procedures; and 
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Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-0!126 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June ll, 2015 
6) adherence to worldwide regulatory requirements. 
Test article is defined as a pharmaceutical form of an active ingredient or vehicle/placebo 
being tested or used as a reference in the study, whether blinded or unblinded. AEs may 
be either spontaneously reported or elicited during questioning and examination of a 
subject. All AEs must be completely recorded on the AE CRF. If known, the investigator 
should report the diagnosis of the underlying illness or disorder, rather than its individual 
symptoms. Subjects experiencing AEs that cause interruption or discontinuation of test 
article, or those experiencing AEs that are present at the end of their participation in the 
study should receive follow-up as appropriate. If possible, report the outcome of any AE 
that caused permanent discontinuation or that was present at the end of the study 
particularly if the AE is considered by the investigator to be treatment-related (i.e., 
definitely, probably, or possibly related to test article). 
14.1 
Adverse Event (AE) 
All AEs must be recorded on the AE CRF. AEs should be followed to resolution or 
stabilization (if possible), and reported as serious adverse events (SAEs) if they become 
serious. 
LSRs that have been reported in subjects treated with CB-03-01 creams (0.1 %-1% 
concentration) include (with decreasing frequency) erythema, pruritus, scaling/dryness, 
skin atrophy, striae rubrae, stinging/burning, edema, and telangiectasia; however most 
LSRs were typically of minimal to mild severity. No subjects discontinued treatment due 
to these LSRs. 
AEs that have been reported in subjects treated with CB-03-01 creams (0.1-l% 
concentration) 
were 
minimal, 
typically 
mild 
in 
severity, 
and 
most 
were 
recovered/resolved without sequelae at the end of the study. Only two AEs in one (1) 
subject were judged as probably or possibly related to treatment; both of these treatment-
related AEs (burning and cold at application site) were mild in severity. Two SAEs have 
been reported to date; both were not related to treatment and were resolved at the end of 
the study. In addition, one subject discontinued early from the study due to an AE 
(urinary tract infection), which was not related to treatment. 
The investigator will instruct the subject to report any AEs that may occur during the 
study. At each visit, the investigator should ask the subject, in non-directive fashion, 
about any change in the subject's overall condition since the previous visit. 
The severity of each AE, as judged by the investigator, will be recorded on the 
appropriate AE CRF and will be graded according to the following scale: 
Mild -The AE is transient and easily tolerated by the subject. 
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Product Name: Cortexolone !?a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
Moderate - The AE causes the subject discomfort and interrupts the subject's 
usual activities. 
Severe - The AE causes considerable interference with the subject's usual 
activities, and may be incapacitating or life-threatening. 
The investigator must determine the relationship of the AE to the test article according to 
the following categories: 
Definite - An event that follows a reasonable temporal sequence from 
administration of the test article; that follows a known or expected response 
pattern to the test article; and that is confirmed by improvement on stopping or 
reducing the dosage, and reappearance of the event on repeated exposure (re-
challenge). 
Probable - An event that follows a reasonable temporal sequence from 
administration of the test article; that follows a known or expected response 
pattern to the test article; and that is confirmed by improvement on stopping or 
reducing the dosage of the test article; and that is unlikely to have been caused by 
concurrent/underlying illness or other drugs, procedures, or other causes. 
Possible - An event that follows a reasonable temporal sequence from 
administration of the test article; that follows a known or expected response 
pattern to the test article; but may have been caused by concurrent/underlying 
illness, other drug, procedure, or other causes. 
Unlikely - An event that does not follow a reasonable temporal sequence from 
administration of the test article; that does not follow a known or expected 
response pattern to the test article, or most likely was caused by 
concurrent/underlying illness, other drug, procedure, or other causes, because of 
their known effects. 
Not Related - An event almost certainly caused by concurrent/underlying illness, 
other drug, procedure, or other causes. 
The investigator should categorize the outcome of the AE according to the following 
categories: 
Fatal - Termination of life as a result of an AE. 
Not Recovered/Not Resolved - AE has not improved or the subject has not 
recuperated. 
Recovered/Resolved - AE has improved or the subject has recuperated. 
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Product Name: Cortexolone 17u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
Recovered/Resolved with Sequelae - subject recuperated but retained the 
pathological conditions resulting from the prior disease or injury. 
Recovering/Resolving - AE is improving or the subject is recuperating. 
Unknown -Not known, not observed, not recorded or subject refused. 
The investigator should report the action taken with the test article due to the AE 
according to the following categories: 
Dose Not Changed - An indication that a medication schedule was maintained. 
Dose Increased - An indication that a medication schedule was modified by 
addition; either by changing the frequency, strength or amount. 
Dose Reduced - An indication that a medication schedule was modified by 
subtraction, either by changing the frequency, strength or amount. 
Drug Interrupted - An indication that a medication schedule was modified by 
temporarily terminating a prescribed regimen of medication. 
Drug Withdrawn - An indication that a medication schedule was modified 
through termination of a prescribed regimen of medication. 
Not Applicable - Determination of a value is not relevant in the current context. 
Unknown- Not known, not observed, not recorded, or refused. 
The investigator should report any other action taken due to the AE. 
An adverse reaction is any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the 
event. For the purposes of prescription drug labeling, the term adverse reaction means an 
undesirable effect, reasonably associated with the use of a drug that may occur as part of 
its pharmacological action or may be unpredictable in its occurrence. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that 
the drug caused the event. 
For the purposes of IND safety reporting, "reasonable possibility" means there is 
evidence to suggest a causal relationship between the drug and the AE. A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any AE caused by a drug. 
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Product Name: Cortexolone !?a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
An AE or suspected adverse reaction is considered "unexpected" if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; 
or, if an investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current 
application. For example, under this definition, hepatic necrosis would be unexpected (by 
virtue of greater severity) if the investigator brochure referred only to elevated hepatic 
enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would 
be unexpected (by virtue of greater specificity) if the investigator brochure listed only 
cerebral vascular accidents. "Unexpected," as used in this definition, also refers to AEs or 
suspected adverse reactions that are mentioned in the investigator brochure as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, 
but are not specifically mentioned as occurring with the particular drug under 
investigation. 
14.2 
Serious Adverse Event (SAE) 
An event that is serious must be recorded on the AE CRF and on the CRO SAE Report 
Form, and requires expeditious handling to comply with regulatory requirements. 
An AE or suspected adverse reaction is considered "serious" if, in the opinion of either 
the investigator or Sponsor, it results in any of the following outcomes: 
• 
Death. 
• 
Life-threatening event. 
• 
Inpatient hospitalization or prolongation of existing hospitalization. 
• 
Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• 
Congenital anomaly/birth defect. 
• 
Is an important medical event- defined as a medical event(s) that may not result 
in death, be life-threatening, or require hospitalization but, based upon appropriate 
medical judgment, may jeopardize the patient/subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in the definition above. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
Events NOT considered to be SAEs are: 
• 
Hospitalizations for the treatment, which was elective or pre-planned, of a pre-
existing condition that did not worsen, and 
• 
Treatment on an emergency, outpatient basis, for an event not fulfilling any of the 
definitions of "serious" given above and not resulting in hospital admission. 
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Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June 11, 2015 
AEs classified as "serious" by either the investigator or the Sponsor require expeditious 
handling and reporting to CRO to comply with regulatory requirements. All serious AEs, 
whether related or unrelated to test article, must be immediately reported by 
telephone to the Medical Monitor and, in the event that he/she is unavailable, to the 
Project Manager. Written notification of all SAEs should be sent to the Project Manager 
by email or confirmed facsimile transmission. These include those SAEs listed in the 
protocol or investigator brochure and must include an assessment of whether there is a 
reasonable possibility that the drug caused the event. 
Study endpoints that are SAEs (e.g., all-cause mortality) must be reported in accordance 
with the protocol unless there is evidence suggesting a causal relationship between the 
drug and the event (e.g., death from anaphylaxis). In this case, the investigator must 
immediately report the event to the Sponsor. In addition, such information should also be 
provided to the site's respective IRB per their governing guidelines for SAE reporting. 
If only limited information is initially available, follow-up reports are required. Should 
the investigator become aware of an SAE (regardless of its relationship to test article) that 
occurs within 30 days after stopping the test article, the SAE must be reported in 
accordance with procedures specified in this protocol. In the event of death, if an autopsy 
is performed, a copy of the report should be sent to Sponsor, if available. 
As required, CRO will notify participating investigators of all suspected adverse reactions 
that are serious and unexpected. This notification will be in the form of an IND safety 
report of potential serious risks as soon as possible but no later than 15 calendar days 
after the Sponsor determines that the information is "reportable" according to the criteria 
listed in 21 CFR Section 312.32. These are: 
i) Serious and unexpected suspected adverse reactions, 
ii) Findings from other studies including epidemiological studies, pooled 
analyses, or other clinical studies that suggest a significant risk in humans 
exposed to the test articles, 
iii) Findings from animal or in vitro tests that suggest a significant risk to 
humans exposed to the test articles or reports of significant organ toxicity 
at or near the expected human exposure, and 
iv) Clinically important increases in the rate of occurrence of serious 
suspected adverse reactions. 
Upon receiving such notices, the investigator must review and retain the notice with the 
Investigator Brochure and immediately submit a copy of this information to the 
responsible IRB according to local regulations. The investigator and IRB will determine 
if the informed consent/assent requires revision. The investigator should also comply 
with the IRB procedures for reporting any other safety information. Where required, 
submission of safety updates by the investigator to Health Authorities should be handled 
according to local regulations. 
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Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June 11, 2015 
14.3 
Pregnancy 
WOCBP (see Section 5.1.1 for definition) must have a negative UPT prior to study 
enrollment and must use a highly effective method of birth control during the course of 
the study, in a manner such that risk of failure is minimized. Prior to study enrollment, 
WOCBP must be advised of the importance of avoiding pregnancy during trial 
participation and the potential risk factors for an unintentional pregnancy. The subject 
and parent/guardian must sign an informed consent/assent form documenting this 
discussion. 
During the study, all WOCBP should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period). 
WOCBP enrolling into the study must have a pregnancy test prior to study therapy, and 
monthly throughout the course of the study. The study therapy must be withheld until the 
results oflaboratory pregnancy testing are known, and a negative UPT must be confirmed 
to continue in the trial. If pregnancy is confirmed during screening, the subject must not 
receive test article and must not be enrolled in the study. 
If a subject or investigator suspects that a subject may be pregnant at any time during the 
study, the test article must be withheld until the results of laboratory pregnancy testing 
are available. If pregnancy is confirmed, the subject must not apply further test article and 
must be discontinued from the study. 
If following initiation of study treatment, it is subsequently discovered that a trial subject 
was pregnant or may have been pregnant at the time of test article exposure, the 
investigator must immediately notify the Medical Monitor of this event, and record the 
pregnancy on the appropriate pregnancy surveillance form. The form will be sent to 
CRO. The investigator must notify the IRB of any pregnancy associated with the study 
therapy and keep careful source documentation of the event. 
Protocol-required procedures for those subjects that are discontinued from the study must 
be performed on the subject unless contraindicated by pregnancy (e.g., x-ray studies). 
Other appropriate pregnancy follow-up procedures should be considered if indicated, 
including counseling of the subject by the investigator and her managing physician or 
health care provider (e.g., obstetrician). In addition, the investigator must report to CRO, 
on the appropriate pregnancy surveillance form(s), any follow-up information regarding 
the course of the pregnancy, including perinatal and neonatal outcome. Although 
pregnancy itself is not an AE, any complications during pregnancy should be recorded as 
AEs (or SAEs, ifthey fulfill the SAE criteria). Abortion, whether accidental, therapeutic, 
or spontaneous should be reported as an SAE. Offspring should be followed for a 
minimum of eight weeks. Any congenital anomaly/birth defect in a child born to a 
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Product Name: Cortexolone !?a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June 11,2015 
subject exposed to the test article(s) should be recorded as an SAE and details 
documented in the pregnancy surveillance form. 
15. 
BLINDING/UNBLINDING 
Blinding is important for the integrity of this clinical drug trial. However, the blind may 
be broken in the event of a medical emergency in a subject, in which knowledge of the 
test article identity is critical to the subject's management. Before breaking the blind for a 
subject, the investigator should determine that the information is necessary (i.e., that it 
will alter the subject's immediate management). In many cases, particularly when the 
emergency is clearly not test article related, the problem may be effectively managed by 
assuming that the subject is receiving active product without the need for unblinding. The 
need to break the blind should first be discussed with the responsible Medical Monitor 
and the best method to do this will be determined. 
16. 
CLINICAL SUPPLIES 
16.1 
Test Article Information 
Test articles will be packaged and labeled by the Sponsor or designee. Detailed 
information on the packaging/labeling, blinding/unblinding, storage and preparation, 
dispensing, accountability etc. is included in Appendix 3. 
16.2 
Supplies Provided by CRO 
• 
CRFs 
• 
Source document draft templates 
• 
Site regulatory binder or document filing system 
• 
UPT kits 
• 
Weighing scales (if necessary) 
• 
High quality digital camera and any associated software (if needed) 
16.3 
Supplies Provided by Investigator 
• 
Urine collection containers for UPTs 
• 
Computer to store and view photographs of subjects 
17. 
STATISTICAL CONSIDERATIONS 
17.1 
Study Endpoints 
17.1.1 
Efficacy Endpoints 
Primary Endpoints (Hierarchical): 
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Product Name: Cortexolone 17a-Propionate (CB-03-0l) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
o 
Pl: Proportion of subjects in each treatment group achieving "success" at Week 
12, with "success" defined as an IGA score of "clear (score=O)" or "almost clear 
(score=!)" AND at least a two-point reduction in IGA compared to Baseline. 
o 
P2: Absolute change from Baseline in non-inflammatory lesion counts in each 
treatment group at Week 12. 
o 
P3: Absolute change from Baseline in inflammatory lesion counts in each 
treatment group at Week 12. 
Secondary Endpoints (Hierarchical): 
o Sl: Absolute change from Baseline in total lesion counts (including inflammatory 
and non-inflammatory) in each treatment group at Week 12. 
o S2: Percent change from Baseline in total lesion counts (including inflammatory 
and non-inflammatory) in each treatment group at Week 12. 
o S3: Percent change from Baseline in non-inflammatory lesions count in each 
treatment group at Week 12. 
o S4: Percent change from Baseline in inflammatory lesions count in each treatment 
group at Week 12. 
17.1.2 
Safety Endpoints 
o 
Local and systemic AEs at every visit (Baseline, Weeks 4, 8, and 12). 
o 
LSRs: 
telangiectasia, 
skin 
atrophy, 
striae 
rubrae, 
erythema, 
edema, 
scaling/dryness, stinging/burning, and pruritus scored by frequency and severity 
at every visit (Baseline, Weeks 4, 8, and 12). 
o 
UPTs in all WOCBP at every visit (Baseline, Weeks 4, 8, and 12). 
o 
Material changes from Baseline in ECGs at Week 12. 
17.2 
Sample Size Calculations and Power Considerations 
Assumptions used for sample size calculation were estimated from Phase 2 Dose 
Escalation Study (171-7151-201) [2], using a subset of subjects with 30-75 inflammatory 
lesions and 30-100 non-inflammatory lesions at Baseline. Sample size calculations were 
performed on the basis of the formulas for testing superiority in terms of mean 
differences and odds ratio of Wang and Chow. 
All the hypothesis tests for the primary endpoints have to be performed at the same 
significance level a=0.05 two-sided and the failure to reject a null hypothesis will imply 
the failure of rejecting all of the subsequent null hypotheses. 
In order to keep the overall Type II error p=O.l for the whole study, the sample size for 
the three hypothesis tests on the primary endpoints will be calculated considering an 
individual Type II error P=0.033. 
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Product Name: Cortexolone 17u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
For an IGA success rate of(continuity corrected) 14.00% for CB-03-01 cream and 2.17% 
for vehicle cream (odds ratio=7), sample size was estimated to be 202 subjects per 
treatment group. 
For a mean absolute change from Baseline in non-inflammatory lesion counts of -22 for 
CB-03-0 I cream and -I for vehicle cream (standard deviation= 17), sample size was 
calculated to be 19 subjects per treatment group. 
For a mean absolute change from Baseline in inflammatory lesion counts of -14 for CB-
03-01 cream and -11 for vehicle cream (standard deviation=l7), sample size was 
calculated to be 334 subjects per treatment group. 
The hypothesis test for the secondary endpoints will be performed at the same 
significance level u=0.05 two-sided of the primary endpoints if and only if all the null 
hypotheses on the primary endpoints are rejected. 
For a mean absolute change from Baseline in total lesion counts of -35 for CB-03-0 I 
cream and -13 for vehicle cream (standard deviation=17), sample size was calculated to 
be 13 subjects per treatment group. 
For a mean percent change from Baseline in total lesion counts of -35 for CB-03-01 
cream and -14 for vehicle cream (standard deviation=40), sample size was calculated to 
be 77 subjects per treatment group. 
For a mean percent change from Baseline in non-inflammatory lesion counts of -33 for 
CB-03-0 I cream and -5 for vehicle cream (standard deviation=40), sample size was 
calculated to be 43 subjects per treatment group. 
For a mean percent change from Baseline in inflammatory lesion counts of -37 for CB-
03-01 cream and -23 for vehicle cream (standard deviation=40), sample size was 
calculated to be 172 subjects per treatment group. 
Based on those assumptions, at least 350 subjects in each treatment group (CB-03-01 
cream, I% BID and vehicle BID) will be included in each Phase 3 study to provide 
sufficient power (90%) with the chosen primary endpoints. 
17.3 
Statistical Methods 
All statistical processing will be performed using SAS® unless otherwise stated. 
Summary tables (descriptive statistics and/or frequency tables) will be provided for 
baseline variables, efficacy variables, and safety variables. Continuous variables will be 
described by descriptive statistics (n. mean, standard deviation, CV%, minimum, median, 
and maximum). Frequency counts and percentage of subjects within each category are 
provided for categorical data. Summaries will be provided for each treatment group. 
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Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
The Safety set will include all subjects who received at least one application of the test 
article. The ITT set will include all randomized subjects. The PP set will be a subset of 
the ITT set and will include subjects who completed the study without any significant 
protocol deviations. The analysis of safety will be conducted on the Safety set. The 
analysis of efficacy will be conducted on both the ITT and PP sets, with the ITT set 
considered as the primary set for statistical analysis. Multiple imputation will be used to 
impute missing values for the primary endpoints and absolute change in total lesions 
count (S I) in the ITT analyses. Sensitivity analyses will be performed to investigate the 
robustness of the results obtained on the ITT set for the primary endpoints (change from 
Baseline in non-inflammatory and inflammatory lesion counts and IGA "success" at 
Week 12). Missing values for the other secondary endpoints (i.e., S2-S4: percent change 
in lesions counts) will be calculated using the values obtained from the multiple 
imputation of the primary efficacy endpoints and secondary efficacy endpoint #I (SI). 
17.3.1 
Efficacy Analyses 
17.3.1.1 
Primary Efficacy Analysis 
Hypothesis tests on the primary endpoints will be conducted in hierarchical order for PI 
through P3. 
Pl: A logistic regression model with treatment and analysis center as fixed effects will be 
used to compare the proportion of subjects achieving "success" in each treatment group 
at Week 12, where "success" is defined as an IGA score of "clear" (score=O) or "almost 
clear" (score= I) AND at least a two-point improvement in IGA compared to Baseline. 
P2: An analysis of covariance (AN COY A) will be used to compare the absolute change 
from Baseline in non-inflammatory lesion count in each treatment group at Week 12, 
with treatment and analysis center as fixed effects and the Baseline non-inflammatory 
lesion count as the covariate. 
P3: An ANCOVA will be used to compare the absolute change from Baseline in 
inflammatory lesion count in each treatment group at Week 12, with treatment and 
analysis center as fixed effects and the Baseline inflammatory lesion count as the 
covariate. 
17.3.1.2 
Secondary Efficacy Analysis 
Hypothesis tests on the secondary endpoints will be conducted in hierarchical order for 
Sl through S4. 
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Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June 11,2015 
Sl: An ANCOVA will be used to compare the absolute change from Baseline in total 
lesion counts in each treatment group at Week 12, with treatment and analysis center as 
fixed effects and the Baseline total lesion count as the covariate. 
S2: An ANCOV A will be used to compare the percent change from Baseline in total 
lesion counts in each treatment group at Week 12, with treatment and analysis center as 
fixed effects and the Baseline total lesion count as the covariate. 
S3: An ANCOV A will be used to compare the percent change from Baseline in non-
inflammatory lesion counts in each treatment group at Week 12, with treatment and 
analysis center as fixed effects and the Baseline non-inflammatory lesion count as the 
covariate. 
S4: An ANCOV A will be used to compare the percent change from Baseline in 
inflammatory lesion counts in each treatment group at Week 12, with treatment and 
analysis center as fixed effects and the Baseline inflammatory lesion count as the 
covariate. 
17 .3.1.3 
Imputation of Missing Data 
Missing values for the primary endpoint in the ITT analyses will be imputed by 
o 
Multiple imputation using missing at random assumption; 
o 
Missing at worst value (for the entire set); 
o 
Worst case; 
o 
Last observation carried forward; and 
o 
Baseline observation carried forward. 
17 .3.1.4 
Sensitivity Analyses 
Sensitivity analyses will be performed to investigate the robustness of the results obtained 
on the ITT set for the primary endpoints. The first sensitivity analysis will be the Per 
Protocol analysis. Four additional sensitivity analyses will be performed using different 
methods of imputation on the ITT set. On a per-subject basis, missing values for the 
primary endpoints will be imputed with the 
I) Worst value (for the entire set); 
2) Worst case; 
3) Last observation carried forward; and 
4) Baseline observation carried forward. 
17.3.1.5 
Multicenter Studies 
Each center will conduct the clinical study under a common protocol. Consistency in 
study execution at each center will be emphasized. The study is to be conducted in such a 
manner as to have a minimum of eight ITT subjects enrolled in each of the treatment 
groups at each center (i.e., 16 ITT subjects enrolled overall per study center). In the event 
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Product Name: Cortexolone 17u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
that there are too few subjects in a treatment arm for a center, then this center's data will 
be combined with another center's data in order to achieve the desired minimum number 
of subjects per treatment arm. The combining of data across centers will be accomplished 
by combining data from two or more centers based on geographical and climatic 
similarities until the minimum number of subjects per treatment arm is achieved. The 
sequence of combination will be based on the total number of subjects enrolled in each 
center (combining the lowest with second lowest and so on). Combining center data to 
achieve sufficient subjects per treatment arm will result in combined centers. These 
combined centers, as well as individual centers with sufficient subjects per treatment arm, 
will be referred to as "analysis centers" in the statistical analysis. 
17 .3.!.6 
Multiple Comparisons/Multiplicity 
All the hypothesis tests for the primary endpoints have to be performed at the same 
significance level u=0.05 two-sided and the failure to reject a null hypothesis will imply 
the failure of rejecting of all the subsequent null hypotheses. This approach inflates the 
overall type II error p, which in the worst case scenario is equal to the sum of the Type II 
error p connected with the individual hypothesis tests. 
The hypothesis test for the secondary endpoints will be performed at the same 
significance level u=0.05 two-sided of the primary endpoints if and only if all the null 
hypotheses on the primary endpoints are rejected. 
17.3.!.7 
Subgroup Analyses 
No subgroup analyses are planned. 
17.3.2 
Treatment Compliance and Extent of Exposure Analyses 
17.3.2.1 
Treatment Compliance 
Compliance to the test article will be evaluated at each visit and overall according to the 
following formula: 
Number of actual applications 
100 X 
. 
. 
Number of scheduled applrcatwns 
Non-compliance will be defined as a compliance value less than 80%. 
Descriptive statistics will be used to summarize test article compliance at each visit and 
overall for the ITT and PP sets. The proportion of compliant and non-compliant subjects 
will be summarized by table of frequencies at each visit and overall for the ITT and PP 
sets. Subjects with an overall compliance not evaluable (due to missing data) or less than 
80% will be excluded from the PP set. 
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Product Name: Cortexolone l7u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June ll, 2015 
17 .3.2.2 
Extent of Exposure 
Descriptive statistics will be used to summarize exposure to test article for the ITT, PP 
and Safety sets. The total amount of test article used (grams applied) will be calculated 
for each subject from the weights of the returned test articles. The mean daily amount of 
test article applied (total amount of test article used/number of days of treatment) will be 
calculated for each subject and summarized by treatment using descriptive statistics. 
17.3.3 
Safety Analyses 
17.3.3.1 
Local Skin Reactions (LSRs) 
LSRs (telangiectasia, skin atrophy, striae rubrae, erythema, edema, scaling/dryness, 
stinging/burning, and pruritus) will be summarized by the frequency of each individual 
LSR by treatment group and severity at each visit. 
17.3.3.2 
Adverse Events (AEs) 
Pre-treatment AEs (PTAEs) and Treatment Emergent AEs (TEAEs) will be coded using 
the MedORA coding dictionary. TEAEs will be summarized by treatment group and 
overall. The number and proportion of subjects with any TEAE and the number of 
TEAEs will be tabulated by MedORA SOC and PT, seriousness, relationship to test 
article, and severity. 
17.3.3.3 
Electrocardiograms (ECGs) 
ECGs will be evaluated for any material change during the study period. Results 
(normal/borderline/abnormal) of the ECG and descriptive statistics will be provided by 
treatment group at each visit for heart rate, RR duration, PR duration, QRS duration, QT 
duration including Bazett's and Fridericia's corrections, and P axis for the Safety set. 
Changes in overall interpretation (normal/abnormal/borderline) of the ECG from 
Baseline to Week 12 will be examined using shift tables. 
17.3.3.4 
VitalSigns 
Vital signs will be listed and summarized by treatment group. Descriptive statistics 
(mean, standard deviation, CV%, minimum, median, and maximum) will be presented. 
17.3.3.5 
Urine Pregnancy Tests 
The results of UPTs monthly at Visit I (Baseline), Visit 2 (Week 4), Visit 3 (Week 8), 
and Visit 4 (Week 12 I end of treatment), or if the subject withdraws prematurely, will be 
listed. 
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Product Name: Cortexolone 17o.-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
17.4 
Interim Analyses 
No interim statistical analyses are planned. 
18. 
ETHICAL AND REGULATORY CONSIDERATIONS 
18.1 
Compliance with Good Clinical Research Practice 
This study will be conducted in compliance with the principles of the Declaration of 
Helsinki, with the current Good Clinical Practice (GCP) guidelines and with other 
applicable regulations. The investigator and all study staff will conduct the study in 
compliance with this protocol. The protocol, informed consent/assent documents, 
recruitment advertisements and any amendments to these items will have IRB approval 
prior to study initiation. Voluntary informed consent/assent will be given by every 
subject and the subject's parent/guardian prior to the initiation of any study-related 
procedures. The rights, safety, and well-being of the study subjects are the most 
important considerations and prevail over the interests of science and society. All 
personnel involved in the conduct of this study must be qualified by education, training, 
and experience to perform their assigned responsibilities. 
18.2 
Institutional Review Board (IRB) and Informed Consent/Assent 
Before study initiation, the investigator must have written and dated approval from the 
IRB for the protocol, consent/assent form, subject recruitment materials/process (e.g., 
advertisements), and any other written information to be provided to subjects and the 
subject's parent/guardian. The investigator should also provide the IRB with a copy of 
the product labeling, information to be provided to subjects/care givers and any updates. 
The investigator will submit documentation of the IRB approval to CRO. 
The IRB approved consent/assent form must include all elements required by FDA, state, 
and local regulations, and may include appropriate additional elements. 
The investigator/designee will explain the study to each potential subject and the 
subject's parent/guardian. The subject must indicate voluntary consent/assent by signing 
and dating the approved informed consent/assent form. The parent or legal guardian must 
provide written informed consent for the subject. The investigator must provide the 
subject with a copy of the consent/assent form, in a language the subject understands. 
The investigator will maintain documentation that informed consent/assent was obtained 
prior to the initiation of any study-specific procedures. 
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Product Name: Cortexolone 17u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June 11,2015 
18.3 
Protocol Compliance 
The IRB approved protocol must be followed except in the case of a change that is 
intended to eliminate an immediate risk to subjects. All protocol deviations must be 
documented. 
18.4 
Protocol Revisions 
CRO must prepare all protocol revisions. All protocol amendments must receive IRB 
approval prior to implementation. All administrative letters must be submitted to the IRB 
for their information. Copies of all correspondence with the IRB regarding this study 
must be sent to CRO. 
New or altered consent/assent forms required by the IRB due to a protocol change must 
be signed by all subjects and the subject's parent/guardian currently enrolled in the study 
and must be used for any subsequent subject enrollment. 
18.5 
Study Monitoring 
Representatives of CRO and/or the Sponsor must be allowed to visit all study sites, to 
review study records, and to directly compare them with source documents (including, 
but not limited to patient and hospital records), to discuss the study conduct with the 
investigator and study staff, and to verify that the investigator, study staff, and facilities 
remain acceptable for the conduct of the study. 
Representatives of government regulatory authorities may also evaluate the study 
records, source documents, investigator, study staff, and facilities. 
The investigator should immediately notify CRO of any audits of this study by any 
regulatory agency and must promptly provide copies of any audit reports. 
18.6 
Case Report Form Requirements: Electronic Data Capture (EDC) 
The study will utilize validated 21 CFR Part II compliant EDC software to collect CRF 
data. All requested information must be entered on the CRFs in the areas provided in a 
timely manner. When changes or corrections are made in the CRF, the EDC system will 
maintain a complete audit trail of the person making the changes, the date and time of the 
change, and the reason for the change. Only individuals listed on the Delegation of 
Responsibilities Log with responsibility for CRF completion may make entries on the 
CRFs. Usernames and passwords will be provided to each authorized user to allow access 
to the training module. Access to additional features and functions will not be enabled 
until the user has successfully completed the training. 
The investigator or physician sub-investigator must electronically sign and date each 
subject's CRF. Individuals who will be providing electronic signatures must first submit 
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Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
documentation with a handwritten signature acknowledging that their electronic signature 
is a legally binding equivalent to their handwritten signature. 
18.7 
Reports to Institutional Review Board 
The investigator should provide the IRB with reports, updates, and other information 
(e.g., safety updates, protocol amendments, and administrative letters) according to 
regulatory requirements or Institution procedures. 
18.8 
Quality Assurance Audits 
Representatives from CRO and/or the Sponsor or a third party selected by the Sponsor 
may conduct a quality assurance (QA) audit of this study. During the audit, the 
investigator must provide the auditor with direct access to all relevant documents and 
discuss any findings with the auditor. 
In the event of an inspection by the FDA or other regulatory authorities, the investigator 
must give the inspector direct access to relevant documents and to discuss any findings 
with the inspector. The investigator must notify CRO in the event of a FDA site audit. 
18.9 
Records Retention 
The investigator must maintain all study records (including test article disposition, 
informed consents/assents, CRFs and data clarification forms, if paper CRFs, source 
documents, correspondence, regulatory documents, contracts, etc.) for the maximum 
period required by CRO or the institution where the study is conducted, whichever is 
longer. The original Label Pages and Study Medication Accountability Logs will be 
collected at the end of the study and kept with the study records. Copies of these pages 
and logs will be kept at the sites. 
The investigator must contact CRO or the Sponsor prior to destroying any records 
associated with this study. 
If the investigator withdraws from the study, the records shall be transferred to a mutually 
agreed upon designee. Written notification of such a transfer must be given to CRO. 
18.10 
Record Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified 
in a manner designed to maintain subject confidentiality. All records will be kept in a 
secure storage area with limited access. Clinical information will not be released without 
the written permission of the subject or the subject's parent/guardian (if appropriate), 
except as necessary for monitoring by CRO or the Sponsor, the FDA or other regulatory 
authority, or the IRB. 
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Product Name: Cortexolone !?a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
The investigator and all employees and coworkers involved with this study shall not 
disclose or use for any purpose other than performance ofthe study, any data, records, or 
other unpublished, confidential information disclosed to those individuals for the purpose 
of the study. Prior written agreement from CRO or the Sponsor must be obtained for the 
disclosure of any said confidential information to other parties. 
19. 
REFERENCES 
I. Celasco G, Moro, L, Bozzella R, Ferraboschi P, Bartorelli L, Quattrocchi C, Nicoletti 
F. Biological profile of cortexolone !?a-propionate (CB-03-01), a new topical and 
peripherally selective androgen antagonist. Arzneim.-Forsch. 2004; 54, 881-886. 
2. 171-7151-201. A Phase 2, Multicenter, Randomized, Double-Blind, Vehicle-
Controlled, Dose Escalating Study to Evaluate the Safety and Efficacy of Cortexolone 
!?a-Propionate (CB-03-01) Cream Applied Once or Twice-Daily for 12 Weeks in 
Subjects with Facial Acne Vulgaris. Intrepid Therapeutics, Inc., 2014. 
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Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June 11,2015 
APPENDIX 1 
SAMPLE 
SUBJECT 
INSTRUCTION SHEET 
AND 
PARENT/GUARDIAN 
Copies of the Subject Instruction Sheet on the next page will be provided to each study 
site. This sample instruction sheet may be used or modified by the investigator. If the 
instruction sheet is modified other than to reflect appropriate contact information specific 
to the site, the Subject Instruction Sheet will need to be reviewed and approved by the 
governing IRB prior to use as it will differ from the form included here which as part of 
the protocol is subject to IRB review and approval. 
The investigator should provide a copy of the Subject Instruction Sheet to each subject 
and the subject's parent/guardian at Visit 1 prior to dispensing the containers of the test 
article(s). 
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Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Protocol: CB-03-01126 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
SAMPLE SUBJECT AND PARENT/GUARDIAN INSTRUCTION SHEET 
Please follow these instructions carefully. If you do not understand anything in these 
instructions, ask your parent or guardian for help. Contact/ask your parent or guardian to 
contact the study staff at the telephone number noted below if you have any questions 
about the study: 
Contact: 
At: ________ _ 
STUDY MEDICATION APPLICATION: 
o 
YOU WILL BE INSTRUCTED HOW TO APPLY THE STUDY MEDICATION IN THE 
CLINIC TWICE-DAILY: Once in the morning and once in the evening daily with 
approximately eight (8) hours or more between applications. 
• 
WASH YOUR ENTIRE FACE WITH MILD SOAP AND WATER AND GENTLY DRY 
THE AREA TO BE TREATED. 
o 
WASH YOUR HANDS BEFORE AND AFTER APPLYING THE CREAM. 
• 
DISPENSE ABOUT I GRAM OF CREAM ONTO ONE OF YOUR FINGERTIPS AND 
THEN BEGIN TO APPLY THE CREAM TO YOUR ENTIRE FACE BY DABBING 
SMALL AMOUNTS GENTLY ON TO MULTIPLE FACIAL REGIONS (FOREHEAD, 
CHEEKS, NOSE, AND CHIN). 
• 
SPREAD THE CREAM EVENLY WITH YOUR FINGERTIP TO COVER YOUR ENTIRE 
FACE WITH A VERY THIN EVEN COAT OF THE CREAM AS DIRECTED BY THE 
STUDY STAFF. 
• 
RECORD DATE AND TIME OF STUDY MEDICATION APPLICATION IN YOUR 
SUBJECT DIARY. 
o 
DO NOT WASH THE TREATED AREA FOR AT LEAST FOUR (4) HOURS AFTER 
APPLICATION OR COVER OR WRAP AREAS WHERE STUDY MEDICATION WAS 
APPLIED. 
o 
CONTINUE USE OF THE STUDY MEDICATION AS DIRECTED BY THE STUDY 
DOCTOR. 
BEFORE EACH STUDY VISIT: 
• 
DO NOT APPLY THE STUDY MEDICATION WITHIN FOUR (4) HOURS OF 
YOUR SCHEDULED STUDY VISIT. 
ADDITIONAL REMINDERS: 
• 
Store the study medications according to the instructions on the label. 
• 
Bring this sheet, the Subject Diary, and ALL your containers (used and unused) of study 
medication with you to every study visit. 
• 
Do not allow anyone else to use the study medications and keep the containers of study 
medication away from children/pets. 
• 
Discontinue use if skin irritation or rash develop and contact the study site. 
STUDY VISIT SCHEDULE· 
VISIT2: 
VISIT3: 
Date: 
Time: 
Date: 
Time: 
VISIT4: 
Date: 
Time: 
CONFIDENTIAL 
Page 51 of 56 


Product Name: Cortexolone l7u-Propionate (CB-03-01) 
Protocol: CB-03-01/26 
Sponsor Name: Cassiopea S.p.A. 
Protocol Date: June II, 2015 
APPENDIX2 
SAMPLE SUBJECT DIARY 
A copy of the Subject Diary will be provided to each study site. The investigator should 
provide a copy of the Subject Diary to each subject and parent/guardian (if applicable) at 
Visit I (Day l, Baseline) and all follow-up visits as necessary. 
CONFIDENTIAL 
Page 52 of 56 


Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Sponsor Name: Cassiopea S.p.A. 
Protocol: CB-03-01/26 
Protocol Date: June 11, 2015 
SAMPLE SUBJECT DIARY for PROTOCOL CB-03-01/26 
Apply the study medication as prescribed. After dosing, record the date and time. If you miss a dose, write MISSED in the space for time. 
Return this diary, your used AND unused medication tubes at each visit AS REQUIRED, PARENT/GUARDIAN SHOULD ASSIST IN 
RECORDING THE SUBJECT DIARY. 
If you have any questions, call: Name: 
Telephone: 
Date 
Dose 
Date 
Dose 
'"· 
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ldd, 
I time of dav) 
I 
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_pm 
Next appointment: 
I 
I ___ at 
am/pm 
Week Day 
dd 
MMM 
yy 
Site Use Only: 
Diary Dispensed at Visit: 
Date Dispensed: 
Date Returned: 
D 1 (Baseline) D 2 (Week 4) D 3 (Week 8) 
CONFIDENTIAL 
Page 53 of 56 


Product Name: Cortexolone 17a-Propionate (CB-03-01) 
Sponsor Name: Cassiopea S.p.A. 
Protocol: CB-03-01/26 
Protocol Date: June II, 2015 
APPENDIX3 
TEST ARTICLE PACKAGING AND LABELING 
The test articles will be packaged and labeled by the Sponsor or designee. CB-03-0 I 
cream, I% will be packaged in blind-end epoxy lined aluminum tubes, with a 
polypropylene cap closure, containing 30 grams of test article. Each subject will be 
assigned a subject number and provided with sufficient test article in standard packaging 
for the designated treatment period during the trial. 
Subject Boxes and Labels 
The randomization scheme will be blocked by investigational site. The box label will, at a 
minimum, contain the following information: protocol number, subject identifiers 
(subject number), the contents, an investigational test article disclaimer (e.g for US., 
Caution: New Drug Limited by United States law to investigational use), and the 
appropriate storage conditions for the test article. 
Subject Kits and Labels 
Each Subject Kit label will, at a minimum, contain the following information: protocol 
number, subject identifiers (subject number and subject initials to be filled in), the 
contents, the kit number, an investigational test article disclaimer (e.g. for US, Caution: 
New Drug Limited by United States law to investigational use), and the appropriate 
storage conditions for the test article. In the event of an emergency, the contents of the kit 
can be unblinded using the proper procedures as outlined in the protocol and by 
instructions provided to the site. 
Kits will be dispensed at Baseline, Visit 2 (Week 4), and Visit 3 (Week 8). Subjects 
should not have more than one (I) kit at any time. When the kits are dispensed to 
subjects, the Subject Kit label should be completed entirely with the necessary 
information recorded in the Study Medication Accountability Log at the investigative 
site. 
Tube Labels 
Each tube will contain, at a minimum, the following information: the protocol number, 
subject identifiers (subject number), the contents, the tube number (with test article batch 
number and retest date), an investigational test article disclaimer (e.g. for US, Caution: 
New Drug Limited by United States law to investigational use), and the appropriate 
storage conditions for the test article. 
A 3.1 Test Article Storage and Preparation 
Test articles will be stored under secure conditions until they are dispensed to the 
subjects. Test articles should be stored in accordance with the temperature specified on 
the box, kit, and tube labels. 
CONFIDENTIAL 
Page 54 of 56 


Product Name: Cortexolone 17u-Propionate (CB-03-01) 
Sponsor Name: Cassiopea S.p.A. 
A 3.2 Dispensing Test Article 
Protocol: CB-03-01/26 
Protocol Date: June II, 2015 
Sites will receive shipments of one or more blocks of test articles. Subjects who are 
eligible for enrollment into the study will be assigned a three digit subject number by the 
study staff in ascending order beginning with the lowest available number. 
The test article must be dispensed only to study subjects and only at study sites specified 
on the form FDA 1572 by authorized personnel as required by applicable regulations and 
guidelines. 
On dispensing the test article for the first time on Day I, provide each subject with 
sufficient test article for the designated treatment period and record the information on 
the Study Medication Accountability Log. Each tube contains approximately 30 grams of 
test article and should last for approximately two weeks. 
The subject will also be instructed to bring all the tubes (used and unused) to each clinic 
visit. When a subject returns each used tube oftest article, record the date of return, and 
initials of the individual accepting the return for each tube of test article on the same line 
of the Study Medication Accountability Log as the dispensing information. 
At Visit 2 and Visit 3 (Week 4 and Week 8), visually check the tubes of test article to 
determine if the subject has applied correctly the test article and, if necessary, review the 
application instructions with the subject. Any discrepancies or concerns with the subject 
regarding the use of the diary to record test article compliance should be addressed. 
At Visits 2, 3, and 4 (Weeks 4, 8 and 12), record the weights of all returned tubes to the 
nearest tenth gram (0.1 gram). At each visit, all tubes should be collected and additional 
tubes dispensed to the subject to ensure each subject has sufficient test article for the 
designated treatment period. Make every effort to obtain the return of all dispensed tubes 
of test article. If these efforts fail, make a detailed note of the reason for the failure in the 
source documents and on the Comments page of the CRFs. 
A 3.3 Test Article Supply Records at Study Sites 
It is the responsibility of the investigator to ensure that a current record of test article 
disposition is maintained. Records or logs must comply with applicable regulations and 
guidelines, and should include: 
• 
Amount received placed in storage area. 
• 
Amount currently in storage area. 
• 
Label lD number (subject kit number). 
• 
Dates and initials of the person responsible for each product inventory 
entry/movement. 
• 
Amount dispensed to and returned by each subject, including unique subject 
identifiers. 
CONFIDENTIAL 
Page 55 of 56 


Product Name: Cortexolone !?a-Propionate (CB-03-01) 
Sponsor Name: Cassiopea S.p.A. 
Protocol: CB-03-01/26 
Protocol Date: June ll, 2015 
o 
Amount transferred to another area for dispensing or storage. 
o 
Non-study disposition (e.g., lost, wasted, broken). 
o 
Amount returned to Sponsor or third party (if applicable). 
o 
Amount destroyed at study site, if applicable. 
CRO will provide forms to facilitate inventory control if the staff at the study site does 
not have an established system that meets these requirements. 
A 3.4 Dose Modifications 
The subject should not modify the treatment regimen without consultation with the 
investigator. Subjects should be instructed to discontinue use if skin irritation or rash 
develops and to contact the study site. In the event that the investigator believes dose 
modification is necessary (e.g., problems with tolerance), the subject's care should be 
discussed with the Medical Monitor prior to making any dose modifications. All dose 
modifications must be reported on the appropriate CRF. 
A 3.5 Documentation of Application and Compliance 
The date and time of the first application of test article will be recorded on the 
appropriate CRF. A CRF will also be used to record any changes from the application 
specified in the protocol (e.g., missed applications, investigator directed reduction in 
application frequency, etc.). The date and time of the last application of the test article 
will be recorded on a CRF. 
A Subject Diary will be dispensed to subjects to record the dates and times of all 
application doses and to record any missed doses of the test article (Appendix 2). 
Subjects will be instructed to bring the diary with them to each study visit. 
A 3.6 Return and Destruction of Test Article Supplies 
Upon completion or termination of the study, all test article tubes must be accounted for 
and any missing tubes of test article must be explained on the completed Study 
Medication Accountability Log. All returned tubes will be weighed to the nearest tenth 
gram (O.lg) in order to document extent of subject exposure. Unless instructed otherwise 
by the Sponsor, the study site will keep the original Study Medication Accountability Log 
and copies of the CRF Label Pages containing the Subject Kit labels in the study file. A 
copy of the Study Medication Accountability Log and the CRF Label Pages with the 
original labels from the subject kits will be returned to the Sponsor. All tubes of test 
article will then either be a) returned to the study Sponsor orb) emptied and provided to a 
sponsor-identified third party vendor for appropriate destruction, according to applicable 
regulations with the provision of a certificate of destruction. 
CONFIDENTIAL 
Page 56 of 56 

SAP_001.pdf: 
CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/26 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 29MAY2018 
CROSS Metrics S.A.  
Page 1 of 41 
STATISTICAL ANALYSIS PLAN 
 
CRO study code CRO-MT-15-013 - Sponsor code CB-03-01/26 
 
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-
BLIND, VEHICLE-CONTROLLED STUDY TO EVALUATE 
THE SAFETY AND EFFICACY OF CORTEXOLONE 17α-
PROPIONATE (CB-03-01) 1% CREAM APPLIED TWICE-
DAILY FOR 12 WEEKS IN SUBJECTS WITH FACIAL ACNE 
VULGARIS 
 
Multicenter, randomized, double-blind, vehicle-controlled, parallel group comparison study 
 
IND number: 112,137 
 
EudraCT number: 2015-002623-26 
 
Test product: 
CB-03-01 cream containing 1% cortexolone 17α-propionate (BID) 
Placebo product: 
Vehicle cream (BID) 
Sponsor: 
Cassiopea S.p.A. 
Via C. Colombo 1  
20020 Lainate (MI), Italy 
Sponsor Representative: 
 
  
Development phase: 
Phase 3 
Version and date: 
Final version 1.0, 29MAY2018 
 
This study was conducted in accordance with Good Clinical Practice (GCP), ICH topic E6 
 
Property of the sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the sponsor 
 
This document comprises 41 pages plus appendices 
 






CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/26 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 29MAY2018 
  
Page 4 of 41 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN 
1 
STATISTICAL ANALYSIS PLAN APPROVAL 
2 
TABLE OF CONTENTS 
4 
STUDY SCHEDULE 
7 
LIST OF ABBREVIATIONS 
8 
1. 
INTRODUCTION 
9 
1.1 
Changes with respect to the study protocol 
9 
2. 
STUDY DESCRIPTION 
9 
2.1 
Background 
9 
2.2 
Rationale 
10 
2.3 
Study Objectives 
10 
2.4 
Study Design 
10 
2.5 
Study Population 
11 
2.5.1 
Subject Eligibility 
11 
2.5.2 
Subject Withdrawal Criteria 
11 
2.6 
Randomization Assignment 
11 
3. 
CLINICAL EVALUATIONS AND LABORATORY TESTS 
12 
3.1 
Investigator’s Global Assessment (IGA) 
12 
3.2 
Acne Lesions Counting 
12 
3.3 
Fitzpatrick Skin Type Assessment 
13 
3.4 
Local Skin Reactions (LSRs) 
13 
3.5 
Urine Pregnancy Tests (UPTs) 
15 
4. 
STATISTICAL CONSIDERATIONS 
16 
4.1 
Study Endpoints 
16 
4.1.1 
Efficacy Endpoints 
16 
4.1.1.1 
Primary Efficacy Endpoints 
16 
4.1.1.2 
Secondary Efficacy Endpoints 
16 
4.1.2 
Safety Endpoints 
16 
4.2 
Hypothesis Tests 
16 
4.2.1 
Superiority of TEST vs. VEHICLE in terms of the proportion of subjects with at least a two-
point reduction in IGA compared to Baseline AND an IGA score of 0 (clear) or 1 (almost 
clear) at Week 12 
17 
4.2.2 
Superiority of TEST vs. VEHICLE in terms of absolute change from Baseline in NILC at 
Week 12 
18 
4.2.3 
Superiority of TEST vs. VEHICLE in terms of absolute change from Baseline in ILC at Week 
12 
18 
4.2.4 
Superiority of TEST vs. VEHICLE in terms of absolute change from Baseline in TLC at Week 
12 
18 
4.2.5 
Superiority of TEST vs. VEHICLE in terms of percent change from Baseline in TLC at Week 
12 
18 
4.2.6 
Superiority of TEST vs. VEHICLE in terms of percent change from Baseline in NILC at Week 
12 
19 
4.2.7 
Superiority of TEST vs. VEHICLE in terms of percent change from Baseline in ILC at Week 
12 
19 


CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/26 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 29MAY2018 
  
Page 5 of 41 
4.3 
Sample Size Calculations and Power Considerations 
19 
4.3.1 
Proportion of subjects in each treatment group with at least a two-point reduction in IGA 
compared to Baseline AND an IGA score of 0 (clear) or 1 (almost clear) at Week 12 
20 
4.3.2 
Absolute change from baseline in NILC in each treatment group at Week 12 
20 
4.3.3 
Absolute change from Baseline in ILC in each treatment group at Week 12 
21 
4.3.4 
Absolute change from Baseline in TLC at Week 12 
22 
4.3.5 
Percent change from Baseline in TLC at Week 12 
22 
4.3.6 
Percent change from Baseline in NILC at Week 12 
23 
4.3.7 
Percent change from Baseline in ILC at Week 12 
23 
5. 
BLINDING/UNBLINDING AND BLIND REVIEW 
25 
6. 
STATISTICAL METHODS 
25 
6.1 
Tables, Listings and Figures layout 
25 
6.2 
Analysis sets 
26 
6.2.1 
Exclusion from the Per Protocol Set 
26 
6.3 
Evaluation of Treatment Compliance 
27 
6.4 
Handling of missing data 
27 
6.4.1 
Methods for replacing missing data 
27 
6.4.2 
Replacement rules for each analysis set 
28 
6.5 
Analysis centers 
29 
6.6 
Demographic, baseline and background characteristics and other study information 
30 
6.6.1 
Subjects’ disposition 
30 
6.6.2 
Analysis sets 
30 
6.6.3 
Subjects excluded from efficacy and/or safety analysis 
30 
6.6.4 
Discontinued subjects 
30 
6.6.5 
Protocol deviations 
30 
6.6.6 
Blind breaking 
30 
6.6.7 
Mismatches of assigned and received IMPs 
30 
6.6.8 
Demography 
30 
6.6.9 
Inclusion/Exclusion criteria 
31 
6.6.10 
Fitzpatrick Skin Type Assessment 
31 
6.6.11 
Medical and dermatological history 
31 
6.6.12 
Dermatological examination and brief physical examination 
31 
6.6.13 
Prior and concomitant medications 
31 
6.6.14 
Concurrent Therapies and Procedures 
32 
6.6.15 
Photographs 
32 
6.6.16 
Subjects study visits 
32 
6.7 
Efficacy analysis 
32 
6.7.1 
Primary efficacy analysis 
32 
6.7.1.1 
Proportion of subjects in each treatment group with at least a two-point reduction in IGA 
compared to Baseline AND an IGA score of 0 (clear) or 1 (almost clear) at Week 12 - ITT 
32 
6.7.1.2 
Absolute change from Baseline in NILC at Week 12 - ITT 
33 
6.7.1.3 
Absolute change from Baseline in ILC at Week 12 - ITT 
33 
6.7.2 
Secondary efficacy analysis 
33 
6.7.2.1 
Absolute change from Baseline in TLC at Week 12 - ITT 
33 
6.7.2.2 
Percent change from Baseline in NILC at Week 12 - ITT 
33 
6.7.2.3 
Percent change from Baseline in ILC at Week 12 - ITT 
34 
6.7.2.4 
Percent change from Baseline in TLC at Week 12 - ITT 
34 
6.7.3 
Sensitivity analyses 
34 
6.7.3.1 
Per Protocol analysis 
34 
6.7.3.1.1 
Proportion of subjects in each treatment group with at least a two-point reduction in IGA 
compared to Baseline AND an IGA score of 0 (clear) or 1 (almost clear) at Week 12 - PP 
34 
6.7.3.1.2 
Absolute change from Baseline in NILC at Week 12 - PP 
35 


CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/26 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 29MAY2018 
  
Page 6 of 41 
6.7.3.1.3 
Absolute change from Baseline in ILC at Week 12 - PP 
35 
6.7.3.2 
Missing as worst value analysis 
35 
6.7.3.3 
Worst case analysis 
35 
6.7.3.4 
LOCF analysis 
35 
6.7.3.5 
BOCF analysis 
35 
6.7.4 
Center by treatment interaction 
35 
6.7.4.1 
Analysis center by treatment interaction 
36 
6.7.4.2 
Original center by treatment interaction 
36 
6.8 
Subgroup Analyses 
37 
6.9 
Treatment compliance and extent of exposure analyses 
37 
6.9.1 
Treatment compliance 
37 
6.9.2 
Extent of exposure 
37 
6.10 
Safety analysis 
38 
6.10.1 
Local Skin Reactions (LSRs) 
38 
6.10.2 
Adverse events 
38 
6.10.3 
Electrocardiograms (ECGs) 
39 
6.10.4 
Vital signs 
39 
6.10.5 
Pregnancy tests 
39 
6.11 
Interim Analyses 
39 
7. 
ANALYSIS DATASETS 
39 
8. 
REFERENCES 
40 
9. 
APPENDICES 
41 
 


CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/26 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 29MAY2018 
  
Page 7 of 41 
STUDY SCHEDULE 
 
PROCEDURES 
Visit 1 
Screening/ 
Baseline 
Day 1 
Visit 2 
 
Week 4 
(Day 29 ± 5) 
Visit 3 
 
Week 8 
(Day 57 ± 7) 
Visit 4 
 
Week 121 
(Day 85 ± 10) 
Informed Consent/Assent2 
X2 
 
 
 
Medical/Dermatological History  
X 
 
 
 
Demographics 
X 
 
 
 
Review of Prior & Concomitant Therapy 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
Dermatologic & Limited Physical  Exam 
X 
 
 
 
Fitzpatrick Skin Type Assessment 
X 
 
 
 
Urine Pregnancy Tests3  
X 
X 
X 
X 
Photographs 
X 
X 
X 
X 
Lesion Counts 
X 
X 
X 
X 
Investigator’s Global Assessment 
X 
X 
X 
X 
Local Skin Reaction Assessment 
X 
(pre- & post-
application) 
X 
X 
X 
Electrocardiograms 
X 
 
 
X 
Review of Concomitant Medications & 
Procedures 
X 
X 
X 
X 
Study Medication Dispensed & Collected4,5 
X 
X 
X 
X 
Review of Compliance  
 
X 
X 
X 
Adverse Events Evaluation 
X 
X 
X 
X 
 
1. 
Subjects who terminate early shall complete all final visit activities designated at Week 12. 
2. 
Consent/assent may be performed up to 45 days prior to the Baseline Visit. Subjects who require 
“washout” for longer than 45 days were re-consented. 
3. 
Testing to be conducted on all WOCBP. UPT minimal sensitivity is 25 mIU/mL. 
4. 
Instruct subject and the subject’s parent/guardian on test article application and provide instruction sheet 
after assessing the subject’s use of the test article with respect to the amount and number of doses applied 
since the last visit. 
5. 
Dispense subject diary at initial and subsequent visits, as needed. 
 


CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/26 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 29MAY2018 
  
Page 8 of 41 
LIST OF ABBREVIATIONS 
 
ADaM 
Analysis Data Model 
ADS 
Analysis Datasets Specification 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical classification system 
BID 
Twice a day 
BOCF 
Baseline Observation Carried Forward 
CB-03-01 
Cortexolone 17α-propionate 
CDISC 
Clinical Data Interchange Standards Consortium 
CRF 
Case Report Form 
CV% 
Percent Coefficient of Variation 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
HPA 
Hypothalamic-Pituitary-Adrenal  
ICH 
International Conference of Harmonization 
IGA 
Investigator’s Global Assessment 
ILC 
Inflammatory Lesions Count 
IND 
Investigational New Drug 
ITT 
Intent-to-Treat 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
LSR 
Local Skin Reaction 
MAR 
Missing at Random 
MWV 
Missing as Worst Value 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
NILC 
Non-Inflammatory Lesions Count 
OR 
Odds Ratio 
PP 
Per-Protocol 
PT 
Preferred Term 
PTAE 
Pre-Treatment Adverse Event 
π2p(0,1) 
Proportion of subjects achieving at least a two-point reduction in IGA 
compared to Baseline AND an IGA score of 0 (clear) or 1 (almost clear) 
at Week 12 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TLC 
Total Lesions Count 
UPT 
Urine Pregnancy Test 
WC 
Worst Case 
WOCBP 
Women of Childbearing Potential 
 


CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/26 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 29MAY2018 
  
Page 9 of 41 
1. 
INTRODUCTION 
 
Statistical analysis will be performed by the 
. The present 
Statistical Analysis Plan (SAP) specifies the analyses of the data from clinical study protocol 
CB-03-01/26. The endpoints and methods of analysis specified in this SAP are consistent with 
ICH E9 guidelines (1), with the FDA draft guidance for industry on Ance Vulgaris (2) and 
with the study protocol (4). The SAP has been compiled by the 
 
, reviewed by the Sponsor and finalized before the EDC database lock. 
 
1.1 
Changes with respect to the study protocol 
 
No change with respect to the study protocol. 
 
2. 
STUDY DESCRIPTION 
 
2.1 
Background 
 
CB-03-01 (cortexolone 17α-propionate) is a steroidal antiandrogen that is being developed as 
cream for the topical treatment of acne vulgaris, an androgen-dependent skin disorder. CB-03-
01 binds to the human androgen receptor displacing the androgenic hormones and acts as an 
androgen antagonist. In human plasma, CB-03-01 is rapidly metabolized to parent 
cortexolone so that its systemic bioavailability after topical application is anticipated to be 
low. Cortexolone, the main by-product, is a physiological component of the pool of 
endogenous corticosteroids, and is an intermediate in the synthesis of glucocorticoids, but it 
only exhibits weak glucocorticoid properties (5). 
 
In single-dose studies in mouse and in rat, and following repeated subcutaneous 
administration in rats, and dermal administration in rabbits and minipigs, the drug was well 
tolerated with no significant local or unexpected systemic effects. CB-03-01 is not mutagenic 
in the Ames test or in the human chromosome aberration test, and it is not a skin sensitizer.  
 
To date, four Phase 1 and three Phase 2 clinical studies have been completed with CB-03-01 
cream in Europe and the United States, with over 500 subjects exposed to CB-03-01 creams. 
All studies were conducted using CB-03-01 cream, 1%; additional concentrations of CB-03-
01 cream (0.1% and 0.5%) were also used in the most-recent Phase 2 Dose-Escalating study.  
 
The studies included: 
 
1. 
A Phase 1 Single Dose Pharmacokinetics (PK) Study in 24 healthy volunteers 
[randomized, double-blind, vehicle-controlled, single-ascending dose], 
2. 
A Phase 1 Repeat Dose PK Study in 24 healthy volunteers [randomized, vehicle-
controlled, 14-day repeat-dose], 
3. 
A Phase 1 Steady State PK Study in 8 subjects with acne vulgaris [single center, open-
label, pilot, 6-week repeat-dose] 
4. 
A Phase 1 Three-week Cumulative Skin Irritation Study in 36 healthy volunteers, 
5. 
A Phase 2 Hypothalamic-Pituitary-Adrenal axis (HPA)/PK study in 42 subjects with 
acne vulgaris [open-label, 14-day repeat-dose], 


CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/26 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 29MAY2018 
  
Page 10 of 41 
6. 
A Phase 2 Comparator Proof of Concept Study in 72 adult subjects with facial acne 
vulgaris [randomized, double-blind, vehicle-controlled, active-comparator (Retin-A® 
[tretinoin] 0.05% cream), 8-week repeat-dose], and 
7. 
A Phase 2 Dose-Escalating Study in 363 subjects with facial acne vulgaris [multi-
center, randomized, double-blind, vehicle controlled, 12-week repeat-dose]. 
 
Overall, the data that resulted from the completion of the aforementioned studies has 
demonstrated that CB-03-01 creams selected for clinical development 
 
1. 
are well tolerated locally, 
2. 
result in minimal systemic exposure when applied topically, 
3. 
have a clinical safety profile without any concern and similar to the placebo, and  
4. 
at 1% concentration applied BID are significantly more effective than its vehicle at 
reducing inflammatory and non-inflammatory lesions counts in adolescent and adult 
subjects. 
 
CB-03-01 could offer advantages over existing products for acne vulgaris due to its potential 
efficacy and lack of systemic antiandrogen activity. Because its pharmacological action 
appears to be limited to the local site of application, use of CB-03-01 may be able to mitigate 
the side effects related to systemic exposure to hormonal agents currently used in the 
treatment of acne. 
 
2.2 
Rationale 
 
The concentration of CB-03-01 selected for the initial clinical studies (1%) was based on 
antiandrogenic activity in the hamster flank organ test in which the best effective 
concentration was 0.8% (5). The results of the Phase 2 Dose Escalation Study demonstrated 
that CB-03-01 cream, 1% applied BID had more favorable results than other treatments (0.1% 
BID, 0.5% BID, and 1% QD) and no material safety issues were noted with any of the 
concentrations of CB-03-01 cream (6). Based on the collective findings of the previous Phase 
1 and Phase 2 studies, CB-03-01 cream, 1% BID appears to be the best treatment candidate to 
advance for further clinical study and development as a topical treatment for acne vulgaris. 
Thus, the present Phase 3 study has been designed to determine and compare the efficacy of 
treatment with CB-03-01 cream, 1% and the vehicle cream applied twice daily for 12 weeks 
in subjects with moderate to severe facial acne vulgaris. 
 
2.3 
Study Objectives 
 
The primary objective of this study is to determine the safety and efficacy of CB-03-01 
cream, 1% versus the vehicle cream applied twice daily for 12 weeks in subjects with facial 
acne vulgaris. 
 
2.4 
Study Design 
 
This is a multicenter, randomized, double-blind, vehicle-controlled, parallel-group 
comparison study of safety and efficacy for CB-03-01 cream, 1% in male and female subjects 
9 years or older with moderate to severe acne vulgaris on the face. Eligible subjects must have 
acne vulgaris of the face (which can include the nose) with an Investigator’s Global 
Assessment (IGA) score of 3 or 4, at least 30 to a maximum of 75 inflammatory lesions 


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(papules, pustules, and nodules) and at least 30 to a maximum of 100 non-inflammatory 
lesions (open and closed comedones). 732 subjects were enrolled at 48 sites (5 sites included 
into the study did not enroll any subject). Subjects were randomized in a 1:1 ratio to one of 
two treatment groups: 
 
1. 
CB-03-01 cream containing 1% cortexolone 17α-propionate 
2. 
Vehicle cream 
 
All subjects had to apply the assigned test article to the face twice daily for 12 weeks. Refer to 
section 6 of the study protocol (4). 
 
2.5 
Study Population 
 
Male and female subjects 9 years or older with facial acne vulgaris (Grade 3 or 4 on 
Investigator’s Global Assessment [IGA]). 
 
732 subjects were included into the study and 53 sites participated in this study (5 sites did 
not enroll any subject). 
 
2.5.1 
Subject Eligibility 
 
To be included in the study, subjects had to meet the inclusion criteria and none of the 
exclusion criteria reported in the section 5.1.1 and 5.1.2 of the study protocol (4). 
 
2.5.2 
Subject Withdrawal Criteria 
 
Procedures for handling subjects who were discontinued from the study are described in 
section 13.2 of the study protocol (4). Subjects who were discontinued were not replaced. 
 
2.6 
Randomization Assignment 
 
Subjects who were eligible for enrollment into the study were randomized to receive CB-03-
01 cream or vehicle cream in a 1:1 ratio. The randomization scheme was blocked by 
investigational site with a block size of 4. At each site, subject kits were dispensed according 
to the kit number assigned by an IVRS/IWRS system as subjects were enrolled. At each site, 
the study staff added the site number (provided to each site) and the subject number (starting 
with 001) to each kit label. The kit number dispensed to each subject was also recorded on the 
source documents and CRFs. Treatment group designation will remain blinded until the final 
database is locked, unless unblinding is required as described in section 15 of the study 
protocol (4). Subjects who withdrew prematurely from the study were not replaced. 
 
 


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3. 
CLINICAL EVALUATIONS AND LABORATORY TESTS 
 
The following clinical evaluations were performed according to the schedules indicated 
during the study. The same investigator should have completed the evaluations for a given 
subject throughout the study. If this became impossible a sub-investigator with overlapping 
experience with the subject and the study should have completed the evaluations. 
 
3.1 
Investigator’s Global Assessment (IGA) 
 
At every study visit, overall severity of acne using a five-point scale from 0 (clear) to 
4 (severe) was assessed. This is a static morphological scale that refers to a point in time and 
not a comparison to Baseline. Subjects had to have an IGA score of 3 (moderate) or 4 (severe) 
at Baseline. 
 
Score Assessment 
Description 
0 
Clear 
Absence of active disease with no inflammatory or non-inflammatory 
lesions 
1 
Almost Clear Rare non-inflammatory lesions with no more than one small 
inflammatory lesions 
2 
Mild 
Some non-inflammatory lesions with no more than a few 
inflammatory lesions (papules/pustules only; no nodular/cystic 
lesions) 
3 
Moderate 
Up to many non-inflammatory lesions and may have some 
inflammatory lesions but no more than one nodular/cystic lesion 
4 
Severe 
Up to many non-inflammatory lesions and inflammatory lesions but 
no more than a few nodular/cystic lesions 
 
3.2 
Acne Lesions Counting 
 
The number of inflammatory lesions (papules, pustules, and nodules) and non-inflammatory 
lesions (open and closed comedones) on the face vertically from the hairline to mandible rim 
and horizontally from ear to ear, including those on the nose were counted to determine 
subject eligibility at Visit 1. Subjects must have at least 30 to a maximum of 75 inflammatory 
lesions and 30 to a maximum of 100 non-inflammatory lesions on the face (which can include 
the nose) at Baseline. 
 
Lesions are defined as follows: 
 
1. 
Comedones - open (blackheads) and closed (whiteheads). 
2. 
Papules - raised inflammatory lesions with no visible purulent material. 
3. 
Pustules - raised inflammatory lesions with visible purulent material. 
4. 
Nodules - Any circumscribed, inflammatory masses greater or equal to 5 mm in 
diameter with or without cystic changes. 
 
 


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3.3 
Fitzpatrick Skin Type Assessment 
 
At Visit 1, the investigator or designee had to document the subject’s skin phototype (I-VI) 
using the Fitzpatrick Skin Type Assessment as described below:  
 
Skin 
Phototype Typical Features 
Tanning ability 
I 
Pale white skin, blue/hazel eyes, blond/red hair Always burns, does not tan 
II 
Fair skin, blue eyes 
Burns easily, tans poorly 
III 
Darker white skin 
Tans after initial burn 
IV 
Light brown skin 
Burns minimally, tans easily 
V 
Brown skin 
Rarely burns, tans darkly easily 
VI 
Dark brown or black skin 
Never burns, always tans darkly 
 
3.4 
Local Skin Reactions (LSRs) 
 
At every study visit, the investigator or designee had to document the severity of the 
following LSRs known to be associated with application of topical steroids: 
 
1. 
Telangiectasia 
 
2. 
Skin atrophy 
 
3. 
Striae rubrae 
 
A five-point ordinal scale was used to assess the severity of these reactions: 
 
Score 
Assessment 
0 
None 
1 
Trace 
2 
Mild 
3 
Moderate 
4 
Severe 
 
In addition, the investigator or designee had to evaluate the severity of the following LSRs 
known to be associated with acne vulgaris, using the five-point ordinal scales described 
below: 
 
4. 
Erythema 
 
5. 
Edema 
 
6. 
Scaling/dryness 
 
 


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Erythema Score 
Assessment 
0 
None 
1 
Minimal - barely perceptible erythema 
2 
Mild - predominantly minimal erythema (pink) in the treated 
area with or without a few isolated areas of more intense 
erythema 
3 
Moderate - predominantly moderate erythema (red) in the 
treated area with or without a few isolated areas of intense 
erythema (bright red) 
4 
Severe - predominantly intense erythema (bright red) in the 
treated area with or without a few isolated areas of very intense 
(fiery red) erythema 
 
Edema Score 
Assessment 
0 
None 
1 
Minimal - scant, rare edema 
2 
Mild - easily seen edema, minimally palpable, involving up to 
1/3 of the Treatment Area 
3 
Moderate - easily seen edema and typically palpable, involving 
between 1/3 to 2/3 of the Treatment Area 
4 
Severe - easily seen edema, indurated in some areas, involving 
over 2/3 of the Treatment Area 
 
Scaling/dryness Score 
Assessment 
0 
None 
1 
Minimal - barely perceptible desquamation 
2 
Mild - limited areas of fine desquamation in up to 1/3 of the 
treatment area 
3 
Moderate - fine desquamation involving 1/3 to 2/3 of the 
treatment area or limited areas of coarser scaling 
4 
Severe - coarser scaling involving more than 2/3 of the 
treatment area or limited areas of very coarse scaling 
 
In addition, subjects were asked to rate the severity of the following LSRS that occurred in 
the treatment area since the last visit, using the four-point ordinal scales described below: 
 
7. 
Stinging/burning 
 
8. 
Pruritus 
 
 


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Stinging/burning Score 
Assessment 
0 
None 
1 
Minimal, barely perceptible - tolerable and little discomfort 
2 
Moderate - tolerable, but causes some discomfort 
3 
Severe - very uncomfortable or intolerable 
 
Pruritus (itching) Score 
Assessment 
0 
None - no evidence of itching 
1 
Mild - only aware of itching at times, only present when 
relaxing, not present when focused on other activities 
2 
Moderate - often aware of itching, annoying, sometimes 
disturbs sleep and daytime activities 
3 
Severe - constant itching, distressing; frequent sleep 
disturbance, interferes with activities 
 
These LSRs were collected independently of AEs. Only LSRs that require medical 
intervention (e.g., prescription medication) or require withholding the application of the test 
articles had to be documented as AEs. Any LSRs that are not listed above had to be recorded 
as AEs. 
 
3.5 
Urine Pregnancy Tests (UPTs) 
 
The UPT had to be performed at the study site if the site is registered and conforms to Clinical 
Laboratory Improvement Amendments (CLIA) regulations for such testing (site possesses at a 
minimum a current valid CLIA Certificate of Waiver) or at an appropriately registered 
reference laboratory. A UPT had to be performed on all WOCBP at Visit 1 (Baseline), Visit 
2, Visit 3 and Visit 4 (or end of treatment if the subject withdraws prematurely). The 
investigator had to report the UPT results on the CRFs, in the subject’s medical records and, if 
applicable, in independent records maintained at the study site. The UPT used must have a 
minimum sensitivity of 25mIU of β-HCG/mL of urine.  
 
 


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4. 
STATISTICAL CONSIDERATIONS 
 
4.1 
Study Endpoints 
 
4.1.1 
Efficacy Endpoints 
 
4.1.1.1 
Primary Efficacy Endpoints 
 
P1: Proportion of subjects in each treatment group with at least a two-point reduction in 
IGA compared to Baseline AND an IGA score of 0 (clear) or 1 (almost clear) at Week 
12 (π2p(0,1)); 
P2: Absolute change from Baseline in non-inflammatory lesions count (NILC) in each 
treatment group at Week 12; 
P3: Absolute change from Baseline in inflammatory lesions count (ILC) in each treatment 
group at Week 12. 
 
4.1.1.2 
Secondary Efficacy Endpoints 
 
S1: Absolute change from Baseline in total lesions count (TLC, including inflammatory and 
non-inflammatory lesions) in each treatment group at Week 12; 
S2: Percent change from Baseline in total lesions count (TLC, including inflammatory and 
non-inflammatory lesions) in each treatment group at Week 12; 
S3: Percent change from Baseline in non-inflammatory lesions count (NILC) in each 
treatment group at Week 12; 
S4: Percent change from Baseline in inflammatory lesions count (ILC) in each treatment 
group at Week 12. 
 
4.1.2 
Safety Endpoints 
 
SF1: Local and systemic AEs at every visit (Baseline, Weeks 4, 8, and 12); 
SF2: Local Skin Reactions (telangiectasia, skin atrophy, striae rubrae, erythema, edema, 
scaling/dryness, stinging/burning and pruritus) scored by frequency and severity at 
every visit (Baseline, Weeks 4, 8 and 12); 
SF3: UPTs in all WOCBP at Visit 1 (Baseline), Visit 2, Visit 3 and Visit 4 (or end of 
treatment if the subject withdraws prematurely); 
SF4: Material changes from Baseline in ECGs at Week 12. 
 
4.2 
Hypothesis Tests 
 
Hypothesis tests on the primary endpoints will be conducted according to the following 
hierarchical order: 
 
HT1: Superiority of TEST vs. VEHICLE in terms of the proportion of subjects in each 
treatment group with at least a two-point reduction in IGA compared to Baseline AND 
an IGA score of 0 (clear) or 1 (almost clear) at Week 12 (π2p(0,1)); 
HT2: Superiority of TEST vs. VEHICLE in terms of absolute change from Baseline in non-
inflammatory lesions count (NILC) at Week 12; 
HT3: Superiority of TEST vs. VEHICLE in terms of absolute change from Baseline in 
inflammatory lesions count (ILC) at Week 12. 


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The null hypotheses of the three hypothesis tests on the primary endpoints have all to be 
rejected in order to claim superiority of of TEST vs. VEHICLE.  
 
In order to keep an overall Type I error α=0.05 two-sided for the whole study, all the 
hypothesis tests have to be performed at the same significance level α=0.05 two-sided and the 
failure to reject a null hypothesis will imply the failure of rejecting of all the subsequent null 
hypotheses. 
 
This approach inflates the overall Type II error β, which in the worst case scenario is equal to 
the sum of the Type II error β connected with the individual hypothesis tests. This inflation 
must be taken into account for a proper estimation of the sample size (3). 
 
Hypothesis tests on the secondary endpoints will be conducted according to the following 
hierarchical order: 
 
HT4: Superiority of TEST vs. VEHICLE in terms of absolute change from Baseline in total 
lesions count (TLC) at Week 12; 
HT5: Superiority of TEST vs. VEHICLE in terms of percent change from Baseline in total 
lesions count (TLC) at Week 12; 
HT6: Superiority of TEST vs. VEHICLE in terms of percent change from Baseline in non-
inflammatory lesions count (NILC) at Week 12; 
HT7: Superiority of TEST vs. VEHICLE in terms of percent change from Baseline in 
inflammatory lesions count (ILC) at Week 12. 
 
The hypothesis test for the secondary endpoints will be performed at the same significance 
level α=0.05 two-sided of the primary endpoints if and only if all the null hypotheses on the 
primary endpoints are rejected and the failure to reject a null hypothesis will imply the failure 
of rejecting of all the subsequent null hypotheses. 
 
4.2.1 
Superiority of TEST vs. VEHICLE in terms of the proportion of subjects with at 
least a two-point reduction in IGA compared to Baseline AND an IGA score of 
0 (clear) or 1 (almost clear) at Week 12 
 
π2p(0,1),TEST:  
Proportion of subjects in TEST treatment group achieving “success” at 
Week 12, with “success” defined as at least a two-point reduction in IGA 
compared to Baseline AND an IGA score of 0 (clear) or 1 (almost clear) 
 
π2p(0,1),VEHICLE: Proportion of subjects in VEHICLE treatment group achieving “success” at 
Week 12, with “success” defined as at least a two-point reduction in IGA 
compared to Baseline AND an IGA score of 0 (clear) or 1 (almost clear) 
 
𝐎𝐑𝟐𝐩(𝟎,𝟏),𝐓𝐕=
𝛑𝟐𝐩(𝟎,𝟏),𝐓𝐄𝐒𝐓൫𝟏−𝛑𝟐𝐩(𝟎,𝟏),𝐕𝐄𝐇𝐈𝐂𝐋𝐄൯
𝛑𝟐𝐩(𝟎,𝟏),𝐕𝐄𝐇𝐈𝐂𝐋𝐄൫𝟏−𝛑𝟐𝐩(𝟎,𝟏),𝐓𝐄𝐒𝐓൯  
 
𝐇𝐓𝟏: ൜𝐇𝟎: 𝐎𝐑𝟐𝐩(𝟎,𝟏),𝐓𝐕≤𝟏
𝐇𝐚: 𝐎𝐑𝟐𝐩(𝟎,𝟏),𝐓𝐕> 𝟏 
 


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4.2.2 
Superiority of TEST vs. VEHICLE in terms of absolute change from Baseline 
in NILC at Week 12 
 
µNILC,TEST: 
Mean absolute change from baseline of NILC at Week 12 in TEST treatment 
group 
 
µNILC,VEHICLE: Mean absolute change from baseline of NILC at Week 12 in VEHICLE 
treatment group 
 
𝐇𝐓𝟐: ൜𝐇𝟎: µ𝐍𝐈𝐋𝐂,𝐓𝐄𝐒𝐓−µ𝐍𝐈𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄≤𝟎
𝐇𝐚: µ𝐍𝐈𝐋𝐂,𝐓𝐄𝐒𝐓−µ𝐍𝐈𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄> 𝟎 
 
4.2.3 
Superiority of TEST vs. VEHICLE in terms of absolute change from Baseline 
in ILC at Week 12 
 
µILC,TEST: 
Mean absolute change from baseline of ILC at Week 12 in TEST treatment 
group 
 
µILC,VEHICLE: Mean absolute change from baseline of ILC at Week 12 in VEHICLE 
treatment group 
 
𝐇𝐓𝟑: ൜𝐇𝟎: µ𝐈𝐋𝐂,𝐓𝐄𝐒𝐓−µ𝐈𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄≤𝟎
𝐇𝐚: µ𝐈𝐋𝐂,𝐓𝐄𝐒𝐓−µ𝐈𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄> 𝟎 
 
4.2.4 
Superiority of TEST vs. VEHICLE in terms of absolute change from Baseline 
in TLC at Week 12 
 
µTLC,TEST: 
Mean absolute change from baseline of TLC at Week 12 in TEST treatment 
group 
 
µTLC,VEHICLE: Mean absolute change from baseline of TLC at Week 12 in VEHICLE 
treatment group 
 
𝐇𝐓𝟒: ൜𝐇𝟎: µ𝐓𝐋𝐂,𝐓𝐄𝐒𝐓−µ𝐓𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄≤𝟎
𝐇𝐚: µ𝐓𝐋𝐂,𝐓𝐄𝐒𝐓−µ𝐓𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄> 𝟎 
 
4.2.5 
Superiority of TEST vs. VEHICLE in terms of percent change from Baseline in 
TLC at Week 12 
 
PTLC,TEST: 
Mean percent change from baseline of TLC at Week 12 in TEST treatment 
group 
 
PTLC,VEHICLE: Mean percent change from baseline of TLC at Week 12 in VEHICLE treatment 
group 
 
𝐇𝐓𝟓: ൜𝐇𝟎: 𝐏𝐓𝐋𝐂,𝐓𝐄𝐒𝐓−𝐏𝐓𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄≤𝟎
𝐇𝐚: 𝐏𝐓𝐋𝐂,𝐓𝐄𝐒𝐓−𝐏𝐓𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄> 𝟎 
 


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4.2.6 
Superiority of TEST vs. VEHICLE in terms of percent change from Baseline in 
NILC at Week 12 
 
PNILC,TEST: 
Mean percent change from baseline of NILC at Week 12 in TEST treatment 
group 
 
PNILC,VEHICLE: Mean percent change from baseline of NILC at Week 12 in VEHICLE 
treatment group 
 
𝐇𝐓𝟔: ൜𝐇𝟎: 𝐏𝐍𝐈𝐋𝐂,𝐓𝐄𝐒𝐓−𝐏𝐍𝐈𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄≤𝟎
𝐇𝐚: 𝐏𝐍𝐈𝐋𝐂,𝐓𝐄𝐒𝐓−𝐏𝐍𝐈𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄> 𝟎 
 
4.2.7 
Superiority of TEST vs. VEHICLE in terms of percent change from Baseline in 
ILC at Week 12 
 
PTLC,TEST: 
Mean percent change from baseline of ILC at Week 12 in TEST treatment 
group 
 
PTLC,VEHICLE: Mean percent change from baseline of ILC at Week 12 in VEHICLE treatment 
group 
 
𝐇𝐓𝟕: ൜𝐇𝟎: 𝐏𝐈𝐋𝐂,𝐓𝐄𝐒𝐓−𝐏𝐈𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄≤𝟎
𝐇𝐚: 𝐏𝐈𝐋𝐂,𝐓𝐄𝐒𝐓−𝐏𝐈𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄> 𝟎 
 
4.3 
Sample Size Calculations and Power Considerations 
 
Assumptions used for sample size calculation were estimated from Phase 2 Dose Escalation 
Study 171-7151-201 (6). 
 
Sample size calculations were performed on the basis of the formulas for testing superiority in 
term of means difference and odds ratio of Wang and Chow (7, 8). 
 
All the hypothesis tests for the primary endpoints have to be performed at the same 
significance level α=0.05 two-sided and the failure to reject a null hypothesis will imply the 
failure of rejecting of all the subsequent null hypotheses. 
 
In order to keep the overall Type II error β=0.1 for the whole study, the sample sizes for the 
three hypothesis tests on the primary endpoints were calculated considering an individual 
Type II error β=0.033 (3). 
 
The hypothesis tests for the secondary endpoint will be performed at the same significance 
level α=0.05 two-sided of the primary endpoints if and only if all the null hypotheses on the 
primary endpoints are rejected and the failure to reject a null hypothesis will imply the failure 
of rejecting of all the subsequent null hypotheses. The sample sizes for the four hypothesis 
tests on the secondary endpoints were calculated considering an individual Type II error 
β=0.1. 
 
Based on the previous assumptions, at least 350 subjects in each treatment group (CB-03-01 
1% BID and vehicle BID) were included into each Phase 3 study to provide sufficient power 
(90%) with the chosen primary endpoints as this approach would: 


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1. 
allow a reasonable allowance for non-completers and to provide a more meaningful 
number of subjects exposed to CB-03-01 cream in the safety population of the program 
and  
2. 
be adequate for investigating with a sufficient power the secondary endpoint. 
 
Details of the calculations are reported in the following sections. 
 
4.3.1 
Proportion of subjects in each treatment group with at least a two-point 
reduction in IGA compared to Baseline AND an IGA score of 0 (clear) or 1 
(almost clear) at Week 12 
 
𝐍𝐓𝐄𝐒𝐓= 𝐍𝐕𝐄𝐇𝐈𝐂𝐋𝐄= 
൫𝐳𝛂𝟐
⁄ + 𝐳𝛃൯
𝟐
ቀ𝐥𝐨𝐠൫𝐎𝐑𝟐𝐩(𝟎,𝟏)൯ቁ
𝟐ቆ
𝟏
𝛑𝟐𝐩(𝟎,𝟏),𝐓𝐄𝐒𝐓൫𝟏−𝛑𝟐𝐩(𝟎,𝟏),𝐓𝐄𝐒𝐓൯+
𝟏
𝛑𝟐𝐩(𝟎,𝟏)𝐕𝐄𝐇𝐈𝐂𝐋𝐄൫𝟏−𝛑𝟐𝐩(𝟎,𝟏),𝐕𝐄𝐇𝐈𝐂𝐋𝐄൯ቇ 
 
A post-hoc analysis of the data collected in the Phase 2 Dose Escalation Study 171-7151-201 
(6) performed only for the subjects with 30-75 inflammatory lesions and 30-100 non-
inflammatory lesions at baseline provided the following results for the proportion of success 
and the related sample size estimation. 
 
 
TEST 
VEHICLE 
Success 
3 (12.50%) 
0 (0.00%) 
Failure 
21 (87.50%) 
22 (100.00%) 
 
Since the number of success is zero for VEHICLE, a continuity correction (Haldane 
correction) was applied to each cell in the previous table in order to calculate the odds ratio: 
 
 
TEST 
VEHICLE 
Success 
3.5 (14.00%) 
0.5 (2.17%) 
Failure 
21.5 (86.00%) 
22.5 (97.83%) 
 
𝐎𝐑𝟐𝐩(𝟎,𝟏),𝐓𝐕= 𝛑𝟐𝐩(𝟎,𝟏),𝐓𝐄𝐒𝐓൫𝟏−𝛑𝟐𝐩(𝟎,𝟏),𝐕𝐄𝐇𝐈𝐂𝐋𝐄൯
𝛑𝟐𝐩(𝟎,𝟏),𝐕𝐄𝐇𝐈𝐂𝐋𝐄൫𝟏−𝛑𝟐𝐩(𝟎,𝟏),𝐓𝐄𝐒𝐓൯= 𝟕. 𝟑𝟐𝟓𝟔  
 
𝛂= 𝟎. 𝟎𝟓 𝐭𝐰𝐨−𝐬𝐢𝐝𝐞𝐝, 𝛃= 𝟎. 𝟎𝟑𝟑⇒𝐍𝐓𝐄𝐒𝐓= 𝐍𝐕𝐄𝐇𝐈𝐂𝐋𝐄= 𝟐𝟎𝟐 
 
202 subjects per group should be enrolled in order to have 202 subjects per group included 
into the ITT Set. 
 
4.3.2 
Absolute change from baseline in NILC in each treatment group at Week 12 
 
𝐍𝐓𝐄𝐒𝐓= 𝐍𝐕𝐄𝐇𝐈𝐂𝐋𝐄=
𝟐𝛔𝟐൫𝐳𝛂𝟐
⁄ + 𝐳𝛃൯
𝟐
൫µ𝐍𝐈𝐋𝐂,𝐓𝐄𝐒𝐓−µ𝐍𝐈𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄൯
𝟐 
 


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A post-hoc analysis of the data collected in the Phase 2 Dose Escalation Study 171-7151-201 
(6) performed only for the subjects with 30-75 inflammatory lesions and 30-100 non-
inflammatory lesions at baseline provided the following results for the least square means (i.e. 
the means obtained after having controlled for the fixed effects and the covariate of the 
ANCOVA) of the absolute change from baseline in non-inflammatory lesions count and for 
the related sample size estimation. 
 
 
Number of subjects 
Least Square Mean 
TEST 
24 
-22.398746 
VEHICLE 
22 
-0.924803 
 
Considering a mean absolute change from baseline in non-inflammatory lesions count of -22 
for TEST treatment group and -1 for VEHICLE treatment group and a common standard 
deviation of 17, we obtain the following estimate of the sample size. 
 
𝛂= 𝟎. 𝟎𝟓 𝐭𝐰𝐨−𝐬𝐢𝐝𝐞𝐝, 𝛃= 𝟎. 𝟎𝟑𝟑, µ𝐈𝐋𝐂,𝐓𝐄𝐒𝐓= −𝟐𝟐, µ𝐈𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄= −𝟏, 𝛔= 𝟏𝟕 
 
𝐍𝐓𝐄𝐒𝐓= 𝐍𝐕𝐄𝐇𝐈𝐂𝐋𝐄= 𝟏𝟗 
 
19 subjects per group should be enrolled in order to have 19 subjects per group included into 
the ITT Set. 
 
4.3.3 
Absolute change from Baseline in ILC in each treatment group at Week 12 
 
𝐍𝐓𝐄𝐒𝐓= 𝐍𝐕𝐄𝐇𝐈𝐂𝐋𝐄=
𝟐𝛔𝟐൫𝐳𝛂𝟐
⁄ + 𝐳𝛃൯
𝟐
൫µ𝐈𝐋𝐂,𝐓𝐄𝐒𝐓−µ𝐈𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄൯
𝟐 
 
A post-hoc analysis of the data collected in the Phase 2 Dose Escalation Study 171-7151-201 
(6) performed only for the subjects with 30-75 inflammatory lesions and 30-100 non-
inflammatory lesions at baseline provided the following results for the least square means (i.e. 
the means obtained after having controlled for the fixed effects and the covariate of the 
ANCOVA) of the absolute change from baseline in inflammatory lesions count and for the 
related sample size estimation. 
 
 
Number of subjects 
Least Square Mean 
TEST 
24 
-14.473098 
VEHICLE 
22 
-10.621723 
 
Considering a mean absolute change from baseline in inflammatory lesions count of -15 for 
TEST treatment group and -10 for VEHICLE treatment group and a common standard 
deviation of 17, we obtain the following estimate of the sample size. 
 
𝛂= 𝟎. 𝟎𝟓 𝐭𝐰𝐨−𝐬𝐢𝐝𝐞𝐝, 𝛃= 𝟎. 𝟎𝟑𝟑, µ𝐈𝐋𝐂,𝐓𝐄𝐒𝐓= −𝟏𝟓, µ𝐈𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄= −𝟏𝟎, 𝛔= 𝟏𝟕 
 
𝐍𝐓𝐄𝐒𝐓= 𝐍𝐕𝐄𝐇𝐈𝐂𝐋𝐄= 𝟑𝟑𝟒 
 


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334 subjects per group should be enrolled in order to have 334 subjects per group included 
into the ITT Set. 
 
4.3.4 
Absolute change from Baseline in TLC at Week 12 
 
𝐍𝐓𝐄𝐒𝐓= 𝐍𝐕𝐄𝐇𝐈𝐂𝐋𝐄=
𝟐𝝈𝟐൫𝐳𝛂𝟐
⁄ + 𝐳𝛃൯
𝟐
൫µ𝐓𝐋𝐂,𝐓𝐄𝐒𝐓−µ𝐓𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄൯
𝟐 
 
A post-hoc analysis of the data collected in the Phase 2 Dose Escalation Study 171-7151-201 
(6) performed only for the subjects with 30-75 inflammatory lesions and 30-100 non-
inflammatory lesions at baseline provided the following results for the least square means (i.e. 
the means obtained after having controlled for the fixed effects and the covariate of the 
ANCOVA) of the absolute change from baseline in total lesions count and for the related 
sample size estimation. 
 
 
Number of subjects 
Least Square Mean 
TEST 
24 
-35.7127562 
VEHICLE 
22 
-13.0667959 
 
Considering a mean absolute change from baseline in total lesions count of -35 for TEST 
treatment group and -13 for VEHICLE treatment group and a common standard deviation of 
17, we obtain the following estimate of the sample size. 
 
𝛂= 𝟎. 𝟎𝟓 𝐭𝐰𝐨−𝐬𝐢𝐝𝐞𝐝, 𝛃= 𝟎. 𝟏, µ𝐓𝐋𝐂,𝐓𝐄𝐒𝐓= −𝟑𝟓, µ𝐓𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄= −𝟏𝟑, 𝛔= 𝟏𝟕 
 
𝐍𝐓𝐄𝐒𝐓= 𝐍𝐕𝐄𝐇𝐈𝐂𝐋𝐄= 𝟏𝟑 
 
13 subjects per group should be enrolled in order to have 13 subjects per group included into 
the ITT Set. 
 
4.3.5 
Percent change from Baseline in TLC at Week 12 
 
𝐍𝐓𝐄𝐒𝐓= 𝐍𝐕𝐄𝐇𝐈𝐂𝐋𝐄=
𝟐𝝈𝟐൫𝐳𝛂𝟐
⁄ + 𝐳𝛃൯
𝟐
൫𝐏𝐓𝐋𝐂,𝐓𝐄𝐒𝐓−𝐏𝐓𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄൯
𝟐 
 
A post-hoc analysis of the data collected in the Phase 2 Dose Escalation Study 171-7151-201 
(6) performed only for the subjects with 30-75 inflammatory lesions and 30-100 non-
inflammatory lesions at baseline provided the following results for the least square means (i.e. 
the means obtained after having controlled for the fixed effects and the covariate of the 
ANCOVA) of the percent change from baseline in total lesions count and for the related 
sample size estimation. 
 
 
Number of subjects 
Least Square Mean 
TEST 
24 
-35.455503 
VEHICLE 
22 
-14.144333 
 


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Considering a mean percent change from baseline in total lesions count of -35 for TEST 
treatment group and -14 for VEHICLE treatment group and a common standard deviation of 
40, we obtain the following estimate of the sample size. 
 
𝛂= 𝟎. 𝟎𝟓 𝐭𝐰𝐨−𝐬𝐢𝐝𝐞𝐝, 𝛃= 𝟎. 𝟏, µ𝐓𝐋𝐂,𝐓𝐄𝐒𝐓= −𝟑𝟓, µ𝐓𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄= −𝟏𝟒, 𝛔= 𝟒𝟎 
 
𝐍𝐓𝐄𝐒𝐓= 𝐍𝐕𝐄𝐇𝐈𝐂𝐋𝐄= 𝟕𝟕 
 
77 subjects per group should be enrolled in order to have 77 subjects per group included into 
the ITT Set. 
 
4.3.6 
Percent change from Baseline in NILC at Week 12 
 
𝐍𝐓𝐄𝐒𝐓= 𝐍𝐕𝐄𝐇𝐈𝐂𝐋𝐄=
𝟐𝝈𝟐൫𝐳𝛂𝟐
⁄ + 𝐳𝛃൯
𝟐
൫𝐏𝐍𝐈𝐋𝐂,𝐓𝐄𝐒𝐓−𝐏𝐍𝐈𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄൯
𝟐 
 
A post-hoc analysis of the data collected in the Phase 2 Dose Escalation Study 171-7151-201 
(6) performed only for the subjects with 30-75 inflammatory lesions and 30-100 non-
inflammatory lesions at baseline provided the following results for the least square means (i.e. 
the means obtained after having controlled for the fixed effects and the covariate of the 
ANCOVA) of the percent change from baseline in non-inflammatory lesions count and for 
the related sample size estimation. 
 
 
Number of subjects 
Least Square Mean 
TEST 
24 
-33.718297 
VEHICLE 
22 
-5.133111 
 
Considering a mean percent change from baseline in non-inflammatory lesions count of -33 
for TEST treatment group and -5 for VEHICLE treatment group and a common standard 
deviation of 40, we obtain the following estimate of the sample size. 
 
𝛂= 𝟎. 𝟎𝟓 𝐭𝐰𝐨−𝐬𝐢𝐝𝐞𝐝, 𝛃= 𝟎. 𝟏, µ𝐓𝐋𝐂,𝐓𝐄𝐒𝐓= −𝟑𝟑, µ𝐓𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄= −𝟓, 𝛔= 𝟒𝟎 
 
𝐍𝐓𝐄𝐒𝐓= 𝐍𝐕𝐄𝐇𝐈𝐂𝐋𝐄= 𝟒𝟑 
 
43 subjects per group should be enrolled in order to have 43 subjects per group included into 
the ITT Set. 
 
4.3.7 
Percent change from Baseline in ILC at Week 12 
 
𝐍𝐓𝐄𝐒𝐓= 𝐍𝐕𝐄𝐇𝐈𝐂𝐋𝐄=
𝟐𝝈𝟐൫𝐳𝛂𝟐
⁄ + 𝐳𝛃൯
𝟐
൫𝐏𝐈𝐋𝐂,𝐓𝐄𝐒𝐓−𝐏𝐈𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄൯
𝟐 
 
A post-hoc analysis of the data collected in the Phase 2 Dose Escalation Study 171-7151-201 
(6) performed only for the subjects with 30-75 inflammatory lesions and 30-100 inflammatory 
lesions at baseline provided the following results for the least square means (i.e. the means 
obtained after having controlled for the fixed effects and the covariate of the ANCOVA) of 


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the percent change from baseline in inflammatory lesions count and for the related sample 
size estimation. 
 
 
Number of subjects 
Least Square Mean 
TEST 
24 
-37.657976 
VEHICLE 
22 
-23.450604 
 
Considering a mean percent change from baseline in inflammatory lesions count of -37 for 
TEST treatment group and -23 for VEHICLE treatment group and a common standard 
deviation of 40, we obtain the following estimate of the sample size. 
 
𝛂= 𝟎. 𝟎𝟓 𝐭𝐰𝐨−𝐬𝐢𝐝𝐞𝐝, 𝛃= 𝟎. 𝟏, µ𝐓𝐋𝐂,𝐓𝐄𝐒𝐓= −𝟑𝟕, µ𝐓𝐋𝐂,𝐕𝐄𝐇𝐈𝐂𝐋𝐄= −𝟐𝟑, 𝛔= 𝟒𝟎 
 
𝐍𝐓𝐄𝐒𝐓= 𝐍𝐕𝐄𝐇𝐈𝐂𝐋𝐄= 𝟏𝟕𝟐 
 
172 subjects per group should be enrolled in order to have 172 subjects per group included 
into the ITT Set. 
 
 
 


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5. 
BLINDING/UNBLINDING AND BLIND REVIEW 
 
Blinding is important for the integrity of this clinical drug trial. However, the blind may be 
broken in the event of a medical emergency in a subject, in which knowledge of the test 
article identity is critical to the subject’s management. Before breaking the blind for a subject, 
the investigator should determine that the information is necessary (i.e., that it alters the 
subject’s immediate management). In many cases, particularly when the emergency is clearly 
not test article related, the problem may be effectively managed by assuming that the subject 
is receiving active product without the need for unblinding. The need to break the blind had 
first to be discussed with the responsible Medical Monitor and the best method to do this was 
be determined. 
 
Data collected during the study will be revised in blind, the assignment of subjects to the 
analysis sets (ITT, PP and Safety) and the definition of the analysis centers (see section 6.5) 
will be performed before the database lock during the blind review meeting/conference. 
 
The review team will be composed only of people not directly involved in the clinical phase 
of the trial in order to safeguard their blindness to the administered treatments. 
 
6. 
STATISTICAL METHODS 
 
All statistical analysis will be performed using SAS for Windows Version 9.3 (TS1M1) (9) 
(or higher). 
The data documented in this trial and the parameters measured will be summarised using 
classic descriptive statistics: mean, standard deviation, percent coefficient of variation 
(CV%), minimum, median and maximum values for quantitative variables. Frequency counts 
and percentage of subjects within each category are provided for categorical data. Summaries 
will be provided for each treatment group. Data not available will be managed according to 
the procedure described in the paragraph 6.4. 
 
6.1 
Tables, Listings and Figures layout 
 
Tables and Listings will be provided according to the following settings:  
 
 
Background: White 
 
Foreground: Black 
 
Font face: Times 
 
Font style: Roman 
 
Font size: 10 pt 
 
Font weight: Medium (data, footers and notes), Bold (titles and headers) 
 
Font width: Normal 
 
Layout: Landscape 
 
Top Margin: 0.8 cm 
 
Bottom Margin: 0.8 cm 
 
Left Margin: 0.8 cm 
 
Right Margin: 0.8 cm 
 
Test label: CB-03-01 
 
Placebo label: Vehicle 
 
Date format: ddMMMyyyy 


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 
Means, standard deviations, percent coefficient of variations, medians, lower confidence 
limits and upper confidence limits will be rounded to one digit more than the original 
data 
 
Minima and maxima will keep the same number of decimal digits as the source values 
 
p-values will be rounded to the fourth decimal digit and will be flagged by an asterisk 
(*) in case of statistical significance (i.e. p-value < 0.05 or, in case of center by 
treatment interaction, p-value < 0.10). p-values lower than 0.0001 will be reported as 
“<.0001 *”. 
 
The data and results of CB-03-01 will be presented before the data and results of Vehicle in 
all listings and tables. 
 
6.2 
Analysis sets 
 
The following analysis sets will be defined: 
 
1. 
Intent-to-Treat Set (ITT): all randomised subjects. This analysis set will be used for 
primary analyses and sensitivity analyses. 
 
2. 
Per Protocol Set (PP): all randomised subjects who will fulfil the study protocol 
requirements in terms of investigational medicinal product intake and collection of 
primary efficacy data, will not have any inclusion/exclusion criteria violation and with 
no major deviations that may affect study results. This analysis set will be used for 
sensitivity analyses. 
 
3. 
Safety Set: all subjects who will receive at least one dose of the test article. This 
analysis set will be used for safety analyses. 
 
6.2.1 
Exclusion from the Per Protocol Set 
 
Reasons for the exclusion from the Per Protocol Set include the following: 
 
1. 
lack of compliance to the test article (subjects with an overall compliance not evaluable 
due to missing data or less than 80% as defined in paragraph 6.3); 
2. 
exposure to an test article different from the one assigned to the subject; 
3. 
lack of the primary variables assessments at Baseline or at Week 12; 
4. 
failure to satisfy any inclusion/exclusion criteria (eligibility violations); 
5. 
intake of prohibited medications. 
 
The precise reasons for excluding subjects from the per protocol set will be fully defined and 
documented in the blind review meeting/conference report before breaking the blind. 
 


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6.3 
Evaluation of Treatment Compliance 
 
Compliance to the test article will be evaluated at each visit and overall according to the 
following formula: 
𝐂𝐨𝐦𝐩𝐥𝐢𝐚𝐧𝐜𝐞= 𝟏𝟎𝟎×
𝐍𝐮𝐦𝐛𝐞𝐫 𝐨𝐟 𝐚𝐜𝐭𝐮𝐚𝐥 𝐚𝐩𝐩𝐥𝐢𝐜𝐚𝐭𝐢𝐨𝐧𝐬
𝐍𝐮𝐦𝐛𝐞𝐫 𝐨𝐟 𝐬𝐜𝐡𝐞𝐝𝐮𝐥𝐞𝐝 𝐚𝐩𝐩𝐥𝐢𝐜𝐚𝐭𝐢𝐨𝐧𝐬 
 
Non-compliance will be defined as a compliance value less than 80% and subjects with an 
overall compliance not evaluable due to missing data or less than 80% will be excluded from 
the Per Protocol Set (see paragraph 6.2.1). 
 
6.4 
Handling of missing data 
 
6.4.1 
Methods for replacing missing data 
 
1. 
Multiple imputation (MI) under missing at random (MAR) assumption: multiple 
imputation is a general approach to the problem of missing data that aims to allow for 
the uncertainty about the missing data by creating several different plausible imputed 
data sets and appropriately combining results obtained from each of them. Missing at 
random (MAR) approach assumes that any systematic difference between the missing 
values and the observed values can be explained by differences in observed data. The 
use of multiple imputation under MAR assumption provides unbiased estimations of the 
parameters and allows to evaluate the uncertainty of parameters’ estimation due to the 
presence of missing data. 
 
A Markov Chain Monte Carlo (MCMC) method that assumes multivariate normality 
will be used to impute all the missing values. In order to prevent a power falloff due to 
choosing a number of imputations too small, 10 imputations will be performed (10). 
 
The multiple imputation procedure will be implemented by using the MI procedure of 
the SAS system with the following options: 
 
 
NIMPUTE=10 
 
SEED=1 
 
ROUND=0 
 
MINMAXITER=10000000 
 
and the following MCMC statement: 
 
 
MCMC IMPUTE=FULL CHAIN=SINGLE INITIAL=EM (BOOTSTRAP=0.9 
CONVERGE=1E-6 ITPRINT MAXITER=1000) 
 
A unique imputation process will be performed without taking into account the 
treatment arm. 
 
The imputed data sets will be then analysed with the MIANALYZE procedure of the 
SAS system with the following options: 
 
 
ALPHA=0.05 
 
EDF=number of subjects of the ITT set - number of 
estimated parameters (including intercept)] 
 


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Type-III analyses obtained from multiple imputations will be combined according to the 
method proposed by Binhuan Wang and Yixin Fang (11). 
 
2. 
Missing as Worst Value (MWV): for each subject, missing values of a variable will be 
replaced with the worst value (failure in case of dichotomous variables or the higher 
value collected in the study for lesions counting) of that variable regardless of the 
treatment arm. 
 
3. 
Worst Case (WC): for each subject, missing values of a variable will be replaced with 
the worst value (failure in case of dichotomous variables or the higher value collected in 
the study for lesions counting) of that variable if the subject is assigned to the CB-03-01 
arm and with the best value of that variable (success in case of dichotomous variables or 
the lower value collected in the study for lesions counting) if the subject is assigned to 
the Vehicle arm. 
 
4. 
Last Observation Carried Forward (LOCF): for each subject, missing values of a 
variable are replaced by the last observed value of that variable. 
 
5. 
Baseline Observation Carried Forward (BOCF): for each subject, missing values of a 
variable are replaced by the baseline observed value of that variable. 
 
6.4.2 
Replacement rules for each analysis set 
 
1. 
Intent-to-Treat Set (ITT): all missing values of the primary endpoints will be replaced 
according to the MI under MAR assumption method for the primary analysis and 
according to the MWV, WC, LOCF and BOCF methods in order to perform four 
distinct sensitivity analyses. Missing values of the secondary endpoints will be replaced 
according to the MI under MAR assumption method. 
 
2. 
Per Protocol Set (PP): no replacement of missing data is required for the primary and 
secondary endpoints. 
 
3. 
Safety Set: no replacement of missing data is required for the safety endpoints. 
 
 


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6.5 
Analysis centers 
 
Each center conducted the clinical study under a common protocol.  Consistency in study 
execution at each center was emphasized.  The study had to be conducted in such a manner as 
to have a minimum of 8 ITT subjects enrolled in each of the treatment groups at each center 
(i.e. 16 ITT subjects enrolled overall).  In the event that there are too few subjects in a 
treatment arm for a center, then this center’s data will be combined with another center’s data 
in order to achieve the desired minimum number of subjects per treatment arm. The 
combining of data across centers will be accomplished by combining data from two or more 
centers based on geographic and climatic similarities until the minimum number of subjects 
per treatment arm is achieved. The sequence of combination will be based on the total number 
of subjects enrolled in each center (combining lowest to 2nd lowest and so on).  Combining 
center data to achieve sufficient subjects per treatment arm will result in the combined 
centers.  These combined centers, as well as individual centers with sufficient subjects per 
treatment arm, will be referred to as “analysis centers” in the statistical analyses. 
 
Supposing to have N geographic and climatic areas with Mi (i=1..N) centers for each area, we 
can write the set of all centers as 
 
൛𝐶𝑖𝑗ൟ𝑖=1..𝑁,𝑗=1..𝑀𝑖 
 
and the set of ordered centers according to the ascending number of enrolled subjects within 
each geographic and climatic area as 
 
൛𝐶𝑖𝑗(𝑘)ൟ𝑖=1..𝑁,𝑘=1..𝑀𝑖 | ∀ 𝑖 , 𝑚< 𝑛⇒#൫𝐶𝑖𝑗(𝑚)൯≤#൫𝐶𝑖𝑗(𝑛)൯ 
 
Using this notation, each geographic and climatic area i can have up to Ai (∀ i=1..N, Ai ≤ Mi) 
analysis centers 
൛𝐴𝐶𝑖𝑗ൟ𝑖=1..𝑁,𝑗=1..𝐴𝑖 
 
For example 
𝐴𝐶𝑖1 = 𝐶𝑖𝑗(1) 𝑈 𝐶𝑖𝑗(2) 𝑈 𝐶𝑖𝑗(3) 
𝐴𝐶𝑖2 = 𝐶𝑖𝑗(4) 𝑈 𝐶𝑖𝑗(5) 
𝐴𝐶𝑖3 = 𝐶𝑖𝑗(6) 
… 
𝐴𝐶𝑖𝐴𝑖= 𝐶𝑖𝑗(𝑀𝑖) 
 
The definition of the analysis centers will be performed before the database lock during the 
blind review meeting/conference. 


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6.6 
Demographic, baseline and background characteristics and other study 
information 
 
Demographic, baseline and background characteristics will be reported for all the enrolled 
subjects and analyses will be performed according to the treatment the subjects actually 
received (PP and Safety) and according to the treatment they were assigned (ITT). 
 
6.6.1 
Subjects’ disposition 
 
The disposition of all subjects enrolled in the study will be listed and summarised by 
treatment group (CB-03-01 and Vehicle). The number and percentage of subjects completing 
the study, the number and percentage of withdrawals and the reasons for withdrawal will be 
presented (Listing 16.2.4.1, Table 14.1.1.1). 
 
6.6.2 
Analysis sets 
 
The subjects included in each analysis sets will be listed and summarised by treatment group 
(CB-03-01 and Vehicle) (Listing 16.2.4.2, Table 14.1.1.2).  
 
6.6.3 
Subjects excluded from efficacy and/or safety analysis 
 
All subjects excluded from the efficacy and/or safety analysis will be listed and the reasons 
for exclusion will be reported (Listing 16.2.3.1). 
 
6.6.4 
Discontinued subjects 
 
All subjects who discontinued the clinical trial will be listed. Sex, age, last visit performed 
before discontinuation, type of discontinuation, date of premature discontinuation and primary 
reason for subject premature discontinuation will be reported (Listing 16.2.1.1). 
 
6.6.5 
Protocol deviations 
 
All the protocol deviations reported during the clinical trial will be listed by subject and 
summarised by treatment group (CB-03-01 and Vehicle); the number and percentage of 
subjects for each deviation will be reported (Listing 16.2.2.1, Table 14.1.1.8, Table 14.1.1.9). 
 
6.6.6 
Blind breaking 
 
In case of any blind breaking, whether the unblinding was confirmed or not and the reason for 
unblinding will be listed by treatment group (Listing 16.2.2.2). 
 
6.6.7 
Mismatches of assigned and received IMPs 
 
In case of any mismatches of assigned and received IMPs, the assigned and actually received 
IMPs will be listed (Listing 16.2.2.3). 
 
 
6.6.8 
Demography 
 


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Demographic data will be listed and summarised by treatment group (CB-03-01 and Vehicle). 
The number and percentage of subjects in each category of categorical variables (e.g. sex) and 
the descriptive statistics (mean, standard deviation, CV%, minimum, median and maximum) 
of continous variables (e.g. age) will be presented (Listing 16.2.4.3, Table 14.1.1.3, Table 
14.1.1.4, Table 14.1.1.5). 
 
6.6.9 
Inclusion/Exclusion criteria 
 
All the unmet inclusion/exclusion criteria will be listed and summarised by treatment group 
(CB-03-01 and Vehicle). The number and percentage of subjects for each skin type will be 
reported (Listing 16.2.4.4, Table 14.1.1.6, Table 14.1.1.7).  
 
6.6.10 
Fitzpatrick Skin Type Assessment 
 
The Fitzpatrick skin type assessments will be listed and summarised by treatment group (CB-
03-01 and Vehicle). The number and percentage of subjects for each skin type will be 
reported (Listing 16.2.10.1, Table 14.1.1.10, Table 14.1.1.11). 
 
6.6.11 
Medical and dermatological history 
 
All the findings of medical history of all subjects enrolled in the study will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) and listed  (Listing 16.2.10.2). The 
version of the dictionary used for coding will be reported in the clinical study report. 
 
The findings of medical history will be summarised by treatment group (CB-03-01 and 
Vehicle). The number and percentage of subjects with any findings will be presented by PT 
and SOC (Table 14.1.1.12). 
 
6.6.12 
Dermatological examination and brief physical examination 
 
Whether the dermatological examination was performed or not and, if performed, the date of 
examination and the presence of facial acne vulgaris, hypopigmentation, hyperpigmentation 
and other dermatological findings on face and whether the physical examination was 
performed or not and, if performed, the date of examination will be listed  (Listing 16.2.10.3). 
 
6.6.13 
Prior and concomitant medications 
 
All prior and concomitant medications will be coded using the World Health Organization 
Drug Dictionary Enhanced (WHO DDE) and listed (Listing 16.2.10.4). The version of the 
dictionary used for coding will be reported in the clinical study report. 
 
Prior and concomitant medications will be listed and summarized by treatment group (CB-03-
01 and Vehicle). The number and percentage of subjects with any concomitant medication 
will be presented by and ATC 4th level (or the higher available ATC level if 4th level is 
missing) and standardised drug name (Table 14.1.1.13, Table 14.1.1.14). 
 


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6.6.14 
Concurrent Therapies and Procedures 
 
Non medication concurrent therapies and procedures will be listed (Listing 16.2.10.5) by 
treatment group (CB-03-01 and Vehicle). 
 
6.6.15 
Photographs 
 
Whether photographs were taken or not and, as applicable, the reason for not collecting them 
or the date of collection will be listed (Listing 16.2.10.6) by treatment group (CB-03-01 and 
Vehicle). 
 
6.6.16 
Subjects study visits 
 
The dates of all subjects study visits will be listed (Listing 16.2.10.7) by treatment group (CB-
03-01 and Vehicle). 
 
6.7 
Efficacy analysis 
 
Subjects will be analysed according to the analysis center they will be assigned to and to the 
treatment they were assigned to (ITT, PP). 
 
The original clinical center of the subjects will be used only for the the investigation of 
center-to-center variability. 
 
The investigator's global assessment scores will be listed (Listing 16.2.6.1) and summarised 
by treatment group (CB-03-01 and Vehicle) using contingency tables (Table 14.2.1.1, Table 
14.2.1.2). 
 
The proportion of subjects with at least a two-point reduction in IGA AND an IGA score of 0 
(clear) or 1 (almost clear) will be summarised by treatment group (CB-03-01 and Vehicle) 
using contingency tables (Table 14.2.1.3, Table 14.2.1.4). 
 
The acne lesion counts will be listed by treatment group (Listing 16.2.6.2); the values of 
NILC and ILC and their changes from baseline will be summarised by treatment group (CB-
03-01 and Vehicle) using descriptive statistics (Table 14.2.1.5, Table 14.2.1.6). 
 
6.7.1 
Primary efficacy analysis 
 
6.7.1.1 
Proportion of subjects in each treatment group with at least a two-point 
reduction in IGA compared to Baseline AND an IGA score of 0 (clear) or 1 
(almost clear) at Week 12 - ITT 
 
A logistic regression model with treatment and analysis center as fixed effects will be used to 
compare the proportion of subjects in each treatment group with at least a two-point reduction 
in IGA AND an IGA score of 0 (clear) or 1 (almost clear) at Week 12 (π2p(0,1)). Subjects will 
be analysed according to the treatment they were assigned to (ITT) and missing data will be 
replaced using a multiple imputation (MI) under missing at random (MAR) assumption. 
 


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The adjusted odds ratio of the comparison of π2p(0,1) between CB-03-01 and Vehicle and its 
95% confidence interval will be derived from the regression model (Table 14.2.2.1). 
 
6.7.1.2 
Absolute change from Baseline in NILC at Week 12 - ITT 
 
An analysis of covariance (ANCOVA) will be used to compare the absolute change from 
Baseline in NILC in each treatment group at Week 12, with treatment and analysis center as 
fixed effects and the Baseline NILC as covariate. Subjects will be analysed according to the 
treatment they were assigned to (ITT) and missing data will be replaced using a multiple 
imputation (MI) under missing at random (MAR) assumption. 
 
The adjusted means difference of the comparison of NILC between CB-03-01 and Vehicle 
and its 95% confidence interval will be derived from the regression model (Table 14.2.2.2). 
 
6.7.1.3 
Absolute change from Baseline in ILC at Week 12 - ITT 
 
An ANCOVA will be used to compare the absolute change from Baseline in ILC in each 
treatment group at Week 12, with treatment and analysis center as fixed effects and the 
Baseline ILC as covariate. Subjects will be analysed according to the treatment they were 
assigned to (ITT) and missing data will be replaced using a multiple imputation (MI) under 
missing at random (MAR) assumption. 
 
The adjusted means difference of the comparison of ILC between CB-03-01 and Vehicle and 
its 95% confidence interval will be derived from the regression model (Table 14.2.2.3). 
 
6.7.2 
Secondary efficacy analysis 
 
6.7.2.1 
Absolute change from Baseline in TLC at Week 12 - ITT 
 
An analysis of covariance (ANCOVA) will be used to compare the absolute change from 
Baseline in TLC in each treatment group at Week 12, with treatment and analysis center as 
fixed effects and the Baseline TLC as covariate. Subjects will be analysed according to the 
treatment they were assigned to (ITT) and missing data will be replaced using a multiple 
imputation (MI) under missing at random (MAR) assumption. 
 
The adjusted means difference of the comparison of TLC between CB-03-01 and Vehicle and 
its 95% confidence interval will be derived from the regression model (Table 14.2.2.4). 
 
6.7.2.2 
Percent change from Baseline in NILC at Week 12 - ITT 
 
An analysis of covariance (ANCOVA) will be used to compare the percent change from 
Baseline in NILC in each treatment group at Week 12, with treatment and analysis center as 
fixed effects and the Baseline NILC as covariate. Subjects will be analysed according to the 
treatment they were assigned to (ITT) and missing percent changes will be calculated using 
the values obtained from the multiple imputation (MI) under missing at random (MAR) 
assumption performed for the NILC (see paragraph 6.7.1.2). 
 


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The adjusted percent means difference of the comparison of NILC between CB-03-01 and 
Vehicle and its 95% confidence interval will be derived from the regression model (Table 
14.2.2.5). 
 
6.7.2.3 
Percent change from Baseline in ILC at Week 12 - ITT 
 
An analysis of covariance (ANCOVA) will be used to compare the percent change from 
Baseline in ILC in each treatment group at Week 12, with treatment and analysis center as 
fixed effects and the Baseline ILC as covariate. Subjects will be analysed according to the 
treatment they were assigned to (ITT) and missing percent changes will be calculated using 
the values obtained from the multiple imputation (MI) under missing at random (MAR) 
assumption performed for the ILC (see paragraph 6.7.1.3). 
 
The adjusted percent means difference of the comparison of ILC between CB-03-01 and 
Vehicle and its 95% confidence interval will be derived from the regression model (Table 
14.2.2.6). 
 
6.7.2.4 
Percent change from Baseline in TLC at Week 12 - ITT 
 
An analysis of covariance (ANCOVA) will be used to compare the percent change from 
Baseline in TLC in each treatment group at Week 12, with treatment and analysis center as 
fixed effects and the Baseline TLC as covariate. Subjects will be analysed according to the 
treatment they were assigned to (ITT) and missing percent changes will be calculated using 
the values obtained from the multiple imputation (MI) under missing at random (MAR) 
assumption performed for the TLC (see paragraph 6.7.2.1). 
 
The adjusted percent means difference of the comparison of TLC between CB-03-01 and 
Vehicle and its 95% confidence interval will be derived from the regression model (Table 
14.2.2.7). 
 
6.7.3 
Sensitivity analyses 
 
The robustness of the result obtained on the ITT set for the primary endpoints will be tested 
by performing the following sensitivity analyses. 
 
6.7.3.1 
Per Protocol analysis 
 
6.7.3.1.1 
Proportion of subjects in each treatment group with at least a two-point 
reduction in IGA compared to Baseline AND an IGA score of 0 (clear) or 1 
(almost clear) at Week 12 - PP 
 
A logistic regression model with treatment and analysis center as fixed effects will be used to 
compare the proportion of subjects in each treatment group with at least a two-point reduction 
in IGA AND an IGA score of 0 (clear) or 1 (almost clear) at Week 12 (π2p(0,1)). Subjects will 
be analysed according to the treatment they were assigned to (PP). 
 
The adjusted odds ratio of the comparison of π2p(0,1) between CB-03-01 and Vehicle and its 
95% confidence interval will be derived from the regression model (Table 14.2.3.1). 
 


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6.7.3.1.2 
Absolute change from Baseline in NILC at Week 12 - PP 
 
An analysis of covariance (ANCOVA) will be used to compare the absolute change from 
Baseline in NILC in each treatment group at Week 12, with treatment and analysis center as 
fixed effects and the Baseline NILC as covariate. Subjects will be analysed according to the 
treatment they were assigned to (PP). 
 
The adjusted means difference of the comparison of NILC between CB-03-01 and Vehicle 
and its 95% confidence interval will be derived from the regression model (Table 14.2.3.2). 
 
6.7.3.1.3 
Absolute change from Baseline in ILC at Week 12 - PP 
 
An ANCOVA will be used to compare the absolute change from Baseline in ILC in each 
treatment group at Week 12, with treatment and analysis center as fixed effects and the 
Baseline ILC as covariate. Subjects will be analysed according to the treatment they were 
assigned to (PP). 
 
The adjusted means difference of the comparison of ILC between CB-03-01 and Vehicle and 
its 95% confidence interval will be derived from the regression model (Table 14.2.3.3). 
 
6.7.3.2 
Missing as worst value analysis 
 
The analyses of sections 6.7.1.1, 6.7.1.2 and 6.7.1.3 will be repeated by replacing missing 
data according to the Missing as Worst Value (MWV) approach. Subjects will be analysed 
according to the treatment they were assigned to (ITT) (Table 14.2.3.4, Table 14.2.3.5, Table 
14.2.3.6). 
 
6.7.3.3 
Worst case analysis 
 
The analyses of sections 6.7.1.1, 6.7.1.2 and 6.7.1.3 will be repeated by replacing missing 
data according to the Worst Case (WC) approach. Subjects will be analysed according to the 
treatment they were assigned to (ITT) (Table 14.2.3.7, Table 14.2.3.8, Table 14.2.3.9). 
 
6.7.3.4 
LOCF analysis 
 
The analyses of sections 6.7.1.1, 6.7.1.2 and 6.7.1.3 will be repeated by replacing missing 
data according to the Last Observation Carried Forward (LOCF) approach. Subjects will be 
analysed according to the treatment they were assigned to (ITT) (Table 14.2.3.10, Table 
14.2.3.11, Table 14.2.3.12). 
 
6.7.3.5 
BOCF analysis 
 
The analyses of sections 6.7.1.1, 6.7.1.2 and 6.7.1.3 will be repeated by replacing missing 
data according to the Baseline Observation Carried Forward (BOCF) approach. Subjects will 
be analysed according to the treatment they were assigned to (ITT) (Table 14.2.3.13, Table 
14.2.3.14, Table 14.2.3.15). 
 
6.7.4 
Center by treatment interaction 
 


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An analysis of the center by treatment interaction will be performed in order to evaluate the 
presence of a significant interaction and, in case of a significant interaction is observed, in 
order to ensure that the primary efficacy results are not driven by extreme centers. Two 
different analysis of the center by treatment interaction for the primary efficacy results will be 
performed, one for the analysis centers and one for the original centers. 
 
6.7.4.1 
Analysis center by treatment interaction 
 
The analyses of sections 6.7.1.1, 6.7.1.2 and 6.7.1.3 will be repeated by adding the analysis 
center by treatment interaction as fixed effect. The reference levels for the effects of the 
analysis model will be the analysis center with the highest number of subjects and the vehicle 
treatment, respectively (Table 14.2.3.16, Table 14.2.3.17, Table 14.2.3.18). 
 
If the analysis center by treatment interaction factor is significant (Wald p-value < 0.10) a 
sensitivity analysis that excludes analysis centers with the extreme efficacy results will be 
performed to determine the robustness of the treatment effect. Otherwise, the data will be 
considered to be free of the impact of extreme analysis centers. 
 
The identification of the extreme analysis centers will be based on the Wald p-values of the 
analysis center by treatment interaction terms. 
 
Analysis centers will be excluded one by one according to the significance of the interaction 
term (starting from the one with the most significant interaction term). After each exclusion, 
the analysis will be repeated on the remaining centers until the analysis center by treatment 
interaction factor is not significant (Wald p-value ≥ 0.10). 
 
Upon identification of the extreme analysis center(s), the analyses of sections 6.7.1.1, 6.7.1.2 
and 6.7.1.3 will be repeated considering only the remaining analysis centers. Inferences will 
be based on this analyses in addition to observations regarding the extreme analysis center(s). 
Conclusions will be presented as appropriate to the findings of the sensitivity analysis. 
 
6.7.4.2 
Original center by treatment interaction 
 
The analyses of sections 6.7.1.1, 6.7.1.2 and 6.7.1.3 will be repeated considering the original 
center as fixed effect and by adding the original center by treatment interaction as fixed effect. 
The reference levels for the effects of the analysis model will be the center with the highest 
number of subjects and the vehicle treatment, respectively (Table 14.2.3.19, Table 14.2.3.20, 
Table 14.2.3.21). 
 
If the original center by treatment interaction factor is significant (Wald p-value < 0.10) a 
sensitivity analysis that excludes original centers with the extreme efficacy results will be 
performed to determine the robustness of the treatment effect. Otherwise, the data will be 
considered to be free of the impact of extreme centers. 
 
The identification of the extreme centers will be based on the Wald p-values of the center by 
treatment interaction terms. 
 
Centers will be excluded one by one according to the significance of the interaction term 
(starting from the one with the most significant interaction term). After each exclusion, the 


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analysis will be repeated on the remaining original centers until the original center by 
treatment interaction factor is not significant (Wald p-value ≥ 0.10). 
 
Upon identification of the extreme original center(s), the analyses of sections 6.7.1.1, 6.7.1.2 
and 6.7.1.3 will be repeated considering only the remaining original centers. Inferences will 
be based on this analyses in addition to observations regarding the extreme original center(s). 
Conclusions will be presented as appropriate to the findings of the sensitivity analysis. 
 
6.8 
Subgroup Analyses 
 
No subgroup analysis is planned. 
 
6.9 
Treatment compliance and extent of exposure analyses 
 
6.9.1 
Treatment compliance 
 
The dispensation date, the weight of the dispensed article, the return date, the weight of the 
returned article, the number of applied doses, the number of expected doses and compliance 
rate will be listed (Listing 16.2.5.1) by treatment group (CB-03-01 and Vehicle). 
 
Descriptive statistics will be used to summarize the test article compliance at each visit and 
overall by treatment group (CB-03-01 and Vehicle) for the ITT and PP sets. The proportion of 
compliant (i.e. with a compliance ≥ 80%) and non-compliant (i.e. with a compliance < 80%) 
subjects will be summarized by table of frequencies at each visit and overall by treatment 
group (CB-03-01 and Vehicle) for the ITT and PP sets (Table 14.2.4.1, Table 14.2.4.2). 
Subjects with an overall compliance not evaluable (due to missing data) or less than 80% will 
be excluded from the PP set (see section 6.2.1). 
 
6.9.2 
Extent of exposure 
 
The date/time of first and last application, the total amount of test article used (calculated as 
number of grams applied for each subject from the weights of the returned test articles) and 
the mean daily amount of test article applied (calculated as the total amount of test article 
used divided by the number of days of treatment) will be listed (Listing 16.2.5.2) by treatment 
group (CB-03-01 and Vehicle). 
 
Descriptive statistics will be used to summarize exposure to the test article at each visit and 
overall by treatment group (CB-03-01 and Vehicle) for the ITT, PP and Safety sets (Table 
14.2.4.3, Table 14.2.4.4, Table 14.2.4.5). 
 


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6.10 
Safety analysis 
 
All safety analyses will be performed on subjects of the Safety set. Subjects will be analysed 
according to the treatment they actually received. 
 
6.10.1 
Local Skin Reactions (LSRs) 
 
LSRs (telangiectasia, skin atrophy, striae rubrae, erythema, edema, scaling/dryness, 
stinging/burning, and pruritus) will be listed (Listing 16.2.9.1) and summarized by the 
frequency of each individual LSR by treatment group (CB-03-01 and Vehicle) and severity at 
each visit (Table 14.3.5.1).  
 
6.10.2 
Adverse events 
 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
listed. The version of the dictionary used for coding will be reported in the clinical study 
report. 
 
AEs will be classified as Pre-Treatment AEs (PTAEs) and Treatment Emergent AEs 
(TEAEs), according to the period of occurrence, as follows: 
 
• 
PTAEs: all AEs occurring before the first dose of the test article and not worsening after 
the first dose of the test article; 
• 
TEAEs: all AEs occurring or worsening after the first dose of the test article. 
 
Individual TEAEs and PTAEs will be listed by treatment group (Listing 16.2.7.1, Listing 
16.2.7.2). 
 
No summary table will be provided for PTAEs. 
 
TEAEs will be summarised by treatment group and overall. 
 
• 
The number and percentage of subjects with any TEAE and the number of TEAEs will be 
presented overall (Table 14.3.1.1) and by SOC and PT (Table 14.3.1.2); 
• 
The number and percentage of subjects with any TEAE by relationship and the number of 
TEAEs by relationship will be presented (Table 14.3.1.1); 
• 
The number and percentage of subjects with any TEAE related to the IMP and the number 
of TEAEs related to the IMP will be presented by SOC and PT (Table 14.3.1.3); 
• 
The number and percentage of subjects with any TEAE by severity and the number of 
TEAEs by severity will be presented overall (Table 14.3.1.1) and by SOC and PT (Table 
14.3.1.4); 
• 
The number and percentage of subjects with any TEAE leading to discontinuation and the 
number of TEAEs leading to discontinuation will be presented (Table 14.3.1.1). 
 
Serious TEAEs will be summarised by treatment group and overall. 
 
• 
The number and percentage of subjects with any Serious TEAE and the number of Serious 
TEAEs will be presented overall (Table 14.3.1.1) and by SOC and PT (Table 14.3.1.5); 


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• 
The number and percentage of subjects with any Serious TEAE by relationship and the 
number of Serious TEAEs by relationship will be presented (Table 14.3.1.1); 
• 
The number and percentage of subjects with any Serious TEAE related to the IMP and the 
number of Serious TEAEs related to the IMP will be presented by SOC and PT (Table 
14.3.1.6); 
• 
The number and percentage of subjects with any Serious TEAE leading to discontinuation 
and the number of Serious TEAEs leading to discontinuation will be presented (Table 
14.3.1.1). 
• 
The number and percentage of subjects with any Serious TEAE leading to death and the 
number of Serious TEAEs leading to death will be presented (Table 14.3.1.1). 
 
All Serious TEAEs will be listed and all TEAEs leading to discontinuation will be listed 
(Table 14.3.2.1). 
 
6.10.3 
Electrocardiograms (ECGs) 
 
ECGs will be evaluated for any material change during the study period. Overall 
interpretation (normal/borderline/abnormal) of the ECG will be listed (Listing 16.2.9.2) and 
summarised by treatment group (CB-03-01 and Vehicle) at each visit using contingency 
tables (Table 14.3.5.2). Values for heart rate, RR duration, PR duration, QRS duration, QT 
duration including Bazett’s and Fridericia’s corrections, P axis and their changes from 
baseline will be listed and summarised by treatment group (CB-03-01 and Vehicle) at each 
visit (Table 14.3.5.2) using descriptive statistics (mean, standard deviation, CV%, minimum, 
median and maximum). Changes in overall interpretation (normal/borderline/abnormal) of the 
ECG from Baseline to Visit 4 (Day 85 ± 10) will be examined using shift tables (Table 
14.3.5.3). 
 
6.10.4 
Vital signs 
 
Vital signs will be listed (Listing 16.2.9.3) and summarised by treatment group (CB-03-01 
and Vehicle). Descriptive statistics (mean, standard deviation, CV%, minimum, median and 
maximum) will be presented (Table 14.3.5.4). 
 
6.10.5 
Pregnancy tests 
 
The results of pregnancy test at Visit 1 (Baseline), Visit 2 (Day 29 ± 5), Visit 3 (Day 57 ± 7) 
and Visit 4 (Day 85 ± 10) or end of treatment if the subject withdraws prematurely will be 
listed (Listing 16.2.8.1). 
 
6.11 
Interim Analyses 
 
No interim statistical analysis is planned. 
 
7. 
ANALYSIS DATASETS 
 
Analysis datasets will be created according to the ADaM model of CDISC (12). 
 
 


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Final version 1.0, 29MAY2018 
  
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8. 
REFERENCES 
 
1. 
ICH Topic E9: Statistical principles for clinical trials. CPMP/ICH/363/96 
2. 
Guidance for Industry - Acne Vulgaris: Developing Drugs Treatment - Draft version, 
September 2005 
3. 
EMA - Points to consider in multiplicity issues in clinical trials - 19 September 2002 
4. 
CB-03-01/26. A Phase 3, Multicenter, Randomized, Double-Blind, Vehicle-Controlled 
Study to Evaluate the Safety and Efficacy of Cortexolone 17α-Propionate (CB-03-01) 
1% Cream Applied Twice-Daily for 12 Weeks in Subjects with Facial Acne Vulgaris. 
Cassiopea SpA, June 11, 2015 
5. 
Celasco G, Moro, L, Bozzella R, Ferraboschi P, Bartorelli L, Quattrocchi C, Nicoletti F. 
Biological profile of cortexolone 17α-propionate (CB-03-01), a new topical and 
peripherally selective androgen antagonist.  Arzneim.-Forsch. 2004; 54, 881-886 
6. 
171-7151-201. A Phase 2, Multicenter, Randomized, Double-Blind, Vehicle-Controlled, 
Dose Escalating Study to Evaluate the Safety and Efficacy of Cortexolone 17α-
Propionate (CB-03-01) Cream Applied Once or Twice-Daily for 12 Weeks in Subjects 
with Facial Acne Vulgaris. Intrepid Therapeutics, Inc., 2014 
7. 
Hansheng Wang, Shein-Chung Chow, "SAMPLE SIZE CALCULATION FOR 
COMPARING MEANS", Wiley Encyclopedia of Clinical Trials, Copyright © 2007, 
John Wiley & Sons, Inc. 
8. 
Hansheng Wang, Shein-Chung Chow, "SAMPLE SIZE CALCULATION FOR 
COMPARING PROPORTIONS", Wiley Encyclopedia of Clinical Trials, Copyright © 
2007, John Wiley & Sons, Inc. 
9. 
SAS/STAT® 9.3 User’s Guide 
10. 
John W. Graham, Allison E. Olchowski, Tamika D. Gilreath, "How Many Imputations 
are Really Needed? Some Practical Clarifications of Multiple Imputation Theory", Prev 
Sci (2007) 8:206-213 DOI 10.1007/s11121-007-0070-9 
11. 
Binhuan Wang, New York University School of Medicine; Yixin Fang, New York 
University School of Medicine; Man Jin, Forest Research Institute; "Combining Type-
III Analyses from Multiple Imputations"; Paper 1543-2014 
12. 
Analysis Data Model (ADaM) - Implementation Guide - Final version 1.0, December 
17, 2009 
 
 


CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/26 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 29MAY2018 
  
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9. 
APPENDICES 
 
Appendix 1. Section 14 - Tables Shells 
Appendix 2. Section 16.2 - Individual Subject Data Listings Shells