A Phase 3, Multicenter, Randomized, Double-Blind, Vehicle-Controlled Study to Evaluate the Safety and Efficacy of Cortexolone 17α-Propionate (CB-03-01) Cream, 1% Applied Twice Daily for 12 Weeks in Subjects With Facial Acne Vulgaris
Phase: PHASE3
Conditions: Acne Vulgaris
Sponsor: Cassiopea SpA

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. 
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 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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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. 
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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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: 
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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 
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 
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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