Clinical trial NCT02682264
Conditions: Acne Vulgaris
Keywords: acne clascoterone anti-androgen
Sponsor: Cassiopea SpA
Start date: 2016-03-09; Completion date: 2018-08-31
Enrollment: 609 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to determine the long-term safety of CB-03-01 cream, 1% applied twice daily for an additional nine months in study participants with acne vulgaris that participated in the Phase 3 pivotal studies for a total treatment of up to 12 months.

Detailed description:
This was a multicenter, open label, long-term extension study for CB-03-01 cream, 1% focused on safety in male and female participants, 9 years or older who completed one of the Phase 3 pivotal studies \[CB-03-01/25 and CB-03-01/26\]. Participants applies the active medication (CB-03-01 cream, 1%) twice daily to the entire face and, if designated by investigator AND desired by the participant, truncal acne for nine additional months of treatment. Thus, overall participants were exposed to CB-03-01 cream, 1% for a total treatment of up to 12 months (0 or 3 months in the Phase 3 pivotal study and an additional nine months in this long-term safety study).

Participants treated facial acne per protocol for nine months. Treatment of truncal acne was discussed by the investigator and participant. Treatment on the face and/or trunk was discontinued if/when acne clears and re-started if/when acne worsens, according to the assessment of the investigator for each respective treatment area (i.e., face and trunk).

Participants were rolled over from the Phase 3 pivotal studies \[CB-03-01/25 and CB-03-01/26\] into this long-term, safety study in order to achieve at least 300 participants on-study at 6 months and 100 participants on-study at 12 months.

Arms: arm 1: CB-03-01 (cortexolone 17α-propionate) Cream, 1%, applied twice daily to whole face (about 1 gram) and affected areas of trunk (if applicable) for up to an additional 9 months. Over the course of the study, treatment on the face and/or trunk may be discontinued if/when acne clears and re-started if/when acne worsens, according to the assessment of the investigator for each respective treatment area.
Interventions: intervention 1: CB-03-01 cream, 1%
Intervention descriptions: intervention 1: Cortexolone 17α-propionate (USAN/INN: clascoterone) is a steroidal antiandrogen that is being developed as a 1% cream for the topical treatment of acne vulgaris.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
Page 1 of 53 
TI SOP 305-A Protocol Template, Version 06 
AN OPEN-LABEL, LONG-TERM EXTENSION STUDY TO EVALUATE  
THE SAFETY OF CORTEXOLONE 17α-PROPIONATE (CB-03-01) CREAM, 1% 
APPLIED TWICE DAILY IN SUBJECTS WITH ACNE VULGARIS 
PROTOCOL NUMBER: 
CB-03-01/27 
TI PROJECT NUMBER: 
171-7151-305 
REGULATORY FILING NUMBER: 
IND #112,137 
EUDRACT NUMBER 
2015-002637-21 
ORIGINAL PROTOCOL: 
September 9, 2015 
FILENAME: 
CB-03-01_27_pro_09Sep2015_v1.0 
SPONSOR: 
Cassiopea S.p.A. 
Via C. Colombo 1 
20020 Lainate (MI), Italy 
SPONSOR REPRESENTATIVES: 
Luigi Moro, Ph.D., Chief Scientific Officer 
Louise Dube, Ph.D., Global Director of R&D 
MEDICAL MONITORS: 
Daniel Piacquadio, M.D. (Therapeutics, Inc.) 
858-571-1800, ext. 107 (office) 
858-571-1234 (facsimile) 
619-889-7058 (cell) 
danp@therapeuticsinc.com (email) 
Oriele Sarno, M.D. (Innopharma S.r.l.) 
+39 329 594 9920 (cell) 
+39 342 91 46 120 (cell) 
o.sarno@inoopharma.it (email)
PROJECT MANAGERS: 
Marietta Radona (Therapeutics, Inc.) 
858-571-1800, ext. 171 (office) 
858-571-1234 (facsimile) 
mradona@therapeuticsinc.com (email) 
Nicoletta Coceani (Innopharma S.r.l.) 
+39 (0362) 57 31 28+ (office) 
+39-0362 54 42 11 (facsimile) 
n.coceani@innopharma.it (email)
24 Hour Emergency Telephone Number 
US: 619-889-7058, EU: +39 342 91 46 120 
Therapeutics, Incorporated 
9025 Balboa Avenue, Suite 100, San Diego, CA 92123 
The information contained in this document is confidential and proprietary 
property of Cassiopea S.p.A. 




Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 3 of 53 
TI SOP 305-A Protocol Template, Version 06 
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 Name of Principal Investigator 
 
____________________________________ 
 
_____________________ 
Investigator Signature  
 
 
 
 
Date 
 
Protocol number: 
CB-03-01/27  
 
 
Site number:   ____ 
 
Version: 1.0 
 
Date of final version: September 9, 2015 
 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 4 of 53 
TI SOP 305-A Protocol Template, Version 06 
PROTOCOL SYNOPSIS 
Title 
An Open-Label, Long-Term Extension Study to Evaluate the Safety of 
Cortexolone 17α-Propionate (CB-03-01) Cream, 1% Applied Twice-Daily 
in Subjects with Acne Vulgaris 
Study Type 
Phase 3 
Test Article / 
Investigational Product 
CB-03-01 cream containing 1% cortexolone 17α-propionate 
Study Objective 
The primary objective of this study is to determine the long-term safety of 
CB-03-01 cream, 1% applied twice daily for an additional nine months in 
subjects with acne vulgaris that participated in the Phase 3 pivotal studies for 
a total treatment of up to 12 months.  
Study Design 
Multicenter, open label study. 
Treatment Groups 
All subjects will apply CB-03-01 cream, 1% twice daily (BID) to the entire 
face and, if designated by investigator AND desired by subject, truncal acne 
for an additional nine months of treatment. 
Duration of Treatment 
9 additional months. 
 
All subjects will apply the active medication (CB-03-01 cream, 1%) twice 
daily (BID) for an additional nine months of treatment (for a total of up to 
12 months; 0 or 3 months in the Phase 3 pivotal study [CB-03-01/25 and CB-
03-01/26] and an additional 9 months in this open-label long-term extension 
study). Treatment on face and/or trunk may be discontinued if/when acne 
clears (achieves an IGA of grade 0 or “minimal” grade 1) and re-instated 
if/when acne worsens (IGA ≥2) according to the assessment of the 
investigator for each respective treatment area. 
Duration of Study 
Each subject’s participation will be for nine (9) months. 
Study Population 
Male and female subjects 9 years or older who were enrolled and completed 
participation in one of the Phase 3 pivotal studies [CB-03-01/25 and CB-03-
01/26]. 
Total Number of 
Subjects 
Approximately 600 subjects will be enrolled in this trial to achieve at least 
300 subjects on-study at 6 months and 100 subjects on-study at 12 months.  
These treatment durations include the 0 or 3 months of active treatment in 
the Phase 3 pivotal studies (CB-03-01/25 and CB-03-01/26). 
 
Enrollment will be competitive; upon enrollment of about 600 subjects in 
this study, the option for rollover will not be offered to other subjects in the 
Phase 3 pivotal studies (CB-03-01/15 and CB-03-01/26), even if those 
subjects are eligible. 
Number of Sites 
Approximately 78 sites that are participating in either Phase 3 pivotal study 
[CB-03-01/25 and CB-03-01/26] will also participate in this study. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 5 of 53 
TI SOP 305-A Protocol Template, Version 06 
Inclusion Criteria 
To enter the study, a subject must meet the following criteria: 
 
1. Subject must have been enrolled in one of the Phase 3 pivotal studies 
(CB-03-01/25 and CB-03-01/26), completed the assigned treatment 
regimen without any material non-compliance with study requirements 
or test article dosing (compliance ≥80%), and completed the final study 
visit (Visit 4-Pivotal). 
2. Subject agrees to treat his/her facial acne and truncal acne (if designated 
by investigator AND desired by subject) during the nine month study 
period per protocol. Note: Subjects who are clear (IGA=0) at Visit 4-
Pivotal are also eligible for this study.  
3. Females must be post-menopausal1, surgically sterile2, or using highly 
effective birth control methods.3,4 Women of childbearing potential 
(WOCBP)5 must have a negative urine pregnancy test (UPT) at Visit 4-
LTF (or Visit 4-Pivotal, if the visits occur on the same day). 
4. 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 the study, the 
subject must provide written informed consent at that time to continue 
study participation. 
5. Subject is willing to comply with study instructions and return to the 
clinic for required visits. 
Exclusion Criteria 
A subject is ineligible to enter the study if he/she meets one or more of the 
following 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 
safety evaluation of the test products or requires the use of interfering 
topical or systemic therapy (see Section 8.1: Prohibited Medications and 
Therapies). 
3. Subject has any condition which, in the investigator’s opinion, would 
make it unsafe or unsuitable for the subject to participate in this research 
study. 
4. Subject plans to use any other investigational drug or device during 
participation in this study. 
                                                 
1 Defined as amenorrhea greater than 12 consecutive months. 
2 Hysterectomy, bilateral tubal ligation (at least six 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 for at least two complete cycles (i.e.; eight to twelve weeks) prior to it being considered 
highly effective, c) intrauterine device (IUD) for at least one week prior to it being considered highly 
effective, d) partner vasectomy (performed at least six 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]. 
4 WOCBP taking hormonal therapy for any reason must not change their dosing regimen during the study. 
5 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. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 6 of 53 
TI SOP 305-A Protocol Template, Version 06 
5. Subject, and parent/guardian if required, is unable to communicate or 
cooperate with the investigator due to language problems, poor mental 
development, or impaired cerebral function. 
6. Subject may be unreliable for the study including subjects who engage 
in excessive alcohol intake or drug abuse, or subject who is unable to 
return for scheduled follow-up visits. 
7. Subject has known hypersensitivity or previous allergic reaction to any 
of the active or inactive components of the test article. 
8. Subject is or plans to use any topical anti-acne preparations (excluding 
CB-03-01 cream) or procedures on the face (or trunk, if applicable) or 
any systemic anti-acne medications (as detailed in Section 8.1: 
Prohibited Medications and Therapies) during the study. 
Study Procedures 
The study will consist of a Baseline Visit, follow-up visits at LTF-Months 1, 
3, 6, and 9, and follow-up phone calls at LTF-Months 4.5 and 7.5. For 
subjects in the Phase 3 pivotal studies randomized to active (CB-03-01 
cream, 1% twice daily), the total treatment period will be 12 (3+9) months; 
whereas for those subjects in the Phase 3 pivotal studies randomized to 
vehicle, the total treatment period will be 9 (0+9) months. 
 
For this Long-Term Follow-Up (LTF) study, subjects must rollover from the 
Phase 3 pivotal study (CB-03-01/25 and CB-03-01/26) into this study AT or 
WITHIN THREE (3) DAYS of Visit 4-Pivotal. 
 
During the LTF study, subjects will treat facial acne per protocol for nine 
months. Treatment of truncal acne is optional and will be discussed by the 
investigator and subject (see Section 10.3). If truncal acne is to be treated, 
the subject must continue to treat the designated treatment area for the 
remainder of the study as detailed in Section 6.2. Treatment on face and/or 
trunk for a subject may be discontinued if/when acne is under successful 
control (achieves an IGA of grade 0 or “minimal” grade 1) and re-instated 
if/when acne worsens (IGA ≥2) according to the assessment of the 
investigator for each respective treatment area. Subjects must be seen by the 
investigator via a scheduled or unscheduled visit to change (i.e., restart or 
stop) test article dosing. Acne will be managed per protocol as detailed in 
Section 6.2 and Section 8.2. 
 
Visit 4-LTF (Baseline): At Visit 4-LTF, 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, inclusion/exclusion 
criteria will be reviewed to determine subject eligibility. Demographics and 
medical/dermatological history data will be used from the Phase 3 pivotal 
study. A brief physical examination including vital signs and a UPT (if 
applicable) will be performed. Note: If Visit 4-Pivotal and Visit 4-LTF occur 
on the same day, the results of the UPT performed during the End of Study 
(EOS) visit of the Phase 3 pivotal study can be used as Baseline data. IGA 
for the face and local skin reactions (LSRs) [pre-application for the face] 
performed during the EOS Visit of the Phase 3 pivotal study (Visit 4-Pivotal) 
will be used as Baseline data. Treatment of truncal acne will be discussed by 
the investigator and subject. If the subject desires, the truncal treatment area 
will be defined and agreed upon by the investigator and the subject, with the 
percent body surface area (BSA) to be treated recorded. If the investigator 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 7 of 53 
TI SOP 305-A Protocol Template, Version 06 
and subject designate a treatment area for truncal acne, the subject must 
continue to treat this area for the duration of the study with dosing 
adjustments per protocol as detailed in Section 6.2. If the investigator and 
subject do not designate a treatment area for truncal acne at this visit, one 
may be designated at subsequent visits (e.g., if acne worsens in the truncal 
area); however, once treatment begins in such truncal treatment area, the 
subject must continue to treat this area for the remainder of the study as 
detailed in Section 6.2. If applicable, IGA and LSRs [pre-application] for the 
trunk will also be assessed at this visit. Ongoing concomitant medications 
and procedures will be reviewed. The subject (and parent/guardian, if 
applicable) will be instructed on how to apply the investigational test article 
(ITA). ITA and subject diary will be dispensed. The first dose will be applied 
during this visit under supervision of the investigator, except for those 
subjects with clear facial acne and no truncal acne. LSRs post-application 
(for both face and trunk separately, as applicable) and adverse events (AEs) 
will be assessed. The subject will be scheduled for the first follow-up visit.  
NOTE: If a subject’s acne is totally clear (i.e., IGA=0) on face and/or trunk, 
the subject will not receive or apply the ITA at home for the first month of 
the study and be reassessed at Visit 5 or earlier (after an unscheduled visit), 
if acne worsens (be it on the face and/or the trunk) before Visit 5. 
 
Visits 5 (LTF Month 1), 6 (LTF Month 3), and 8 (LTF Month 6): Subjects 
will return to the clinic. IGA, LSRs, and AEs will also be assessed. 
Concomitant medications and procedures and ITA compliance will be 
reviewed. A UPT (if applicable) will be performed at Visit 8. Assessment of 
the subject’s acne will be made on face and trunk to determine if the subject 
requires on-going therapy or if treatment needs to be started (i.e., for subjects 
with an IGA=0 at Baseline [Visit 4-LTF]) or restarted (after a previous 
discontinuation due to acne clearing). Based on this determination, ITA and 
a subject diary will be dispensed/returned (as required). For subjects starting 
treatment at this visit, the first dose of the ITA will be applied under 
supervision of the investigator. The subject will be scheduled for a follow-
up visit (at Visit 5 and Visit 6) or end of study (EOS) visit (at Visit 8). 
 
Visit 7: Phone Call 1 (LTF Month 4.5) and Visit 9: Phone Call 2 (LTF Month 
7.5): The site staff will contact the subject by telephone to review any 
changes in concomitant medications and procedures as well as test article 
compliance. Site staff will query the subject about any AEs and will confirm 
the next appointment. In the event there is: 
 
a) improving or worsening of the subject’s acne such that the treatment may 
be discontinued or restarted, respectively, OR 
 
b) a concern regarding an AE or the subject’s progress based upon the Phone 
Call visit, 
 
the subject may be seen in the clinic as an unscheduled visit at the discretion 
of the investigator. However, to change (i.e., restart or stop) test article 
dosing on either treatment area (face and/or trunk), the subject must be seen 
and evaluated in person by the investigator or designee. 
 
Visit 10 (Month 9): End of Study (EOS) Visit & Early Termination. Subjects 
will return to the clinic for the final visit. UPT (if applicable) will be 
performed. IGA, LSRs, and AEs will be assessed. Concomitant medications 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 8 of 53 
TI SOP 305-A Protocol Template, Version 06 
and procedures will be reviewed. ITA and subject diary will be returned. The 
subject will exit the study. 
 
Unscheduled Visit: [If/As Needed]. Note: Subjects must be seen by the 
investigator via a scheduled or an unscheduled visit to change (i.e., restart 
or stop) test article dosing on either treatment area (face and/or trunk). 
Subjects may return to the clinic at the discretion of the investigator. LSRs, 
AEs, and any changes in concomitant medications and procedures will be 
assessed, 
as 
needed. 
In 
addition, 
IGA, 
to 
document 
acne 
improvement/clearance (i.e., achieves an IGA of grade 0 or “minimal” grade 
1) or significant worsening (IGA ≥2), shall also be assessed to support 
treatment modifications. ITA will be dispensed/returned (as required). The 
next regular follow-up visit will be confirmed prior to the end of the 
unscheduled visit. 
Study Measurements 
Safety will be assessed by the investigator via the evaluation of local and 
systemic AEs at each visit/phone call. 
 
LSRs including telangiectasia, skin atrophy, striae rubrae, erythema, edema, 
and scaling/dryness will be assessed by the investigator for each treatment 
area (face and trunk) using a five-point ordinal scale from 0=none to 
4=severe at each visit (Visit 4-LTF [post-application, if applicable], and 
Visits 5, 6, 8, and 10, and any Unscheduled Visits, as needed). Subjects will 
be asked to rate the severity of stinging/burning and pruritus for each 
treatment area (face and trunk) using a four-point scale from 0=none to 
3=severe at each visit (Visit 4-LTF [post-application, if applicable], and 
Visits 5, 6, 8, and 10, and any Unscheduled Visits, as needed). 
 
Efficacy will be assessed by the investigator using an IGA. IGA performed 
on the face during the End of Study (EOS) Visit of the Phase 3 pivotal study 
(i.e., Visit 4-Pivotal) and IGA performed on the trunk at Visit 4-LTF will be 
used as Baseline data. If treatment of the trunk begins post-Visit4-LTF, the 
Baseline data will be assessed at the visit where treatment is first applied. 
 
Investigator’s Global Assessment (IGA): Overall severity of acne using a 
five-point scale from 0=clear to 4=severe will be conducted at Visits 5, 6, 8, 
and 10 for each treatment area (face and trunk) and any Unscheduled Visits, 
as needed. This is a static morphological scale that refers to a point in time 
and not a comparison to Baseline. 
Study Endpoints 
Safety Endpoints: 
• 
Incidence of any local and systemic treatment emergent AEs 
(TEAEs). 
• 
Number of subjects with presence (and severity) of each individual 
LSR (telangiectasia, skin atrophy, striae rubrae, erythema, edema, 
scaling/dryness, stinging/burning, and pruritus) for each treatment 
area, as applicable, at each time point collected (Baseline, and LTF-
Months 1, 3, 6, and 9, and any Unscheduled Visits). 
• 
UPT results in all WOCBP at Baseline, LTF-Month 6, and EOS. 
 
Efficacy Endpoints: 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 9 of 53 
TI SOP 305-A Protocol Template, Version 06 
• 
Number of subjects with each IGA severity score for each treatment 
area, as applicable, at each time point collected (Baseline and LTF-
Months 1, 3, 6, and 9). 
Sample Size 
Calculations 
For large samples, the two-sided confidence interval for a single proportion 
extends a distance ω= 𝑧𝑧1−𝛼𝛼
2ට𝜋𝜋(1−𝜋𝜋)
𝑛𝑛
 from the observed proportion in both 
directions. An incidence no greater than 1% of important AEs out of 100 
subjects will provide the estimate of no greater than a 3% prevalence of 
important AEs at the 95% confidence level with a much larger number of 
subjects exposed for the same duration (i.e., 12 months). Applying the same 
approach, an incidence no greater than 1% of important AEs out of 300 
subjects will provide the estimate of no greater than a 2.1% prevalence of 
important AEs at the 95% confidence level with a much larger number of 
subjects exposed for the same duration (i.e., 6 months). 
 
Approximately six hundred (600) subjects will be enrolled in order to have 
300 subjects on-study at 6 months and 100 subjects on-study at 12 months.  
These treatment durations include the 0 or 3 months of active treatment in 
the Phase 3 pivotal studies (CB-03-01/25 and CB-03-01/26). 
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. 
 
Study Sets: 
Subjects who complete 6 months or 12 months on-study without material 
non-compliance with test article (CB-03-01 cream, 1%) dosing per protocol 
will count towards the desired 300 subjects at 6 months and 100 subjects at 
12 months. 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 
enrolled 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. 
 
Safety Analyses: 
Extent of Exposure 
Descriptive statistics will be used to summarize exposure to test article for 
the Safety, ITT, and PP 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. The number of applications and days dosed for each treatment area 
(face and/or trunk from Subject Diary) will also be summarized. 
 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 10 of 53 
TI SOP 305-A Protocol Template, Version 06 
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 and severity at each clinic visit for face 
and trunk, separately. 
 
Adverse Events (AEs) 
AEs will be coded using the MedDRA coding dictionary summarized by 
relationship to test article and severity. 
 
Efficacy Analyses: 
Investigator’s Global Assessment 
Frequency distributions of IGA scores will be summarized at Baseline (EOS-
Pivotal), and LTF Months 1, 3, 6, and 9 for face and trunk, separately. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 11 of 53 
TI SOP 305-A Protocol Template, Version 06 
SCHEDULE OF EVENTS 
Visit 
Visits 1-4 
Pivotal 
Phase 3 
Visit 4-
LTF 
Baseline 
Visit 5 
 
 
Visit 6 
 
 
Visit 7 
Phone 
Call 1 
Visit 8 
 
 
Visit 9 
Phone  
Call 2 
Visit 101 
EOS 
 
Unscheduled 
 
 
Long-Term Follow-Up (LTF): Month 
Day 
 
0 
12 
1 
29 ± 10 
3 
85 ± 15 
4.5 
137 ± 15 
6 
183 ± 15 
7.5 
228 ± 15 
9 
274 ± 21  
If/As Needed 
Overall CB-03-01 Exposure: Month3 
0 or 3 
0 or 3 
1 or 4 
3 or 6 
4.5 or 7.5 
6 or 9 
7.5 or 10.5 
9 or 12 
 
PROCEDURES 
See Phase 3 
 
 
 
 
 
 
 
 
Informed Consent/Assent4 
 
X4 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
Demographics 
 
From 
Phase 35 
 
 
 
 
 
 
 
Medical/Dermatological History  
 
From 
Phase 35 
 
 
 
 
 
 
 
Physical Exam with Vital Signs 
 
X 
 
 
 
 
 
 
 
UPT for WOCBP 
 
X6 
 
 
 
X 
 
X 
 
IGA  
(Face and Trunk, separately) 
 
Face: 
From 
Phase 37 
Trunk: X8 
X 
X 
 
X 
 
X 
X 
Determination of Test Article Dosing 
 
X 
X 
X 
 
X 
 
X 
X 
LSRs Assessment  
(Face and Trunk, separately) 
 
X9 
X 
X 
 
X 
 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications & Procedures 
 
From 
Phase 310 
X 
X 
X 
X 
X 
X 
X 
Dispense & Collect ITA11,12 
 
X 
X 
X 
 
X 
 
X 
X 
Review of Compliance  
 
 
X 
X 
X 
X 
X 
 
X 
1 Subjects who terminate early shall complete all final visit activities. 
2 For this LTF study, subjects must rollover from the Phase 3 pivotal study (CB-03-01/25 and CB-03-01/26) into this study AT or WITHIN THREE (3) DAYS of 
Visit 4-Pivotal. 
3Given that the Phase 3 pivotal trial is randomized (1:1) between active (CB-03-01 cream, 1%) and vehicle, upon entering the LTF study, some subjects will have 
an overall exposure to CB-03-01 cream, 1% of 3 months and others will have 0 months (i.e., subjects were treated with vehicle in the Pivotal study). 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 12 of 53 
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4 Consent/assent may be performed up to 45 days prior to the Baseline Visit. 
5 Demographics and medical/dermatological history will be used from the Phase 3 pivotal study (Visit 1-Pivotal). 
6 If Visit 4-Pivotal and Visit 4-LTF occur on the same day, the results of the UPT performed during the End of Study (EOS) visit of the Phase 3 pivotal study can 
be used as Baseline data. 
7IGA performed at the EOS Visit of the Phase 3 pivotal trial will be used as Baseline data (Visit 4-Pivotal). 
8 If truncal acne is to be treated (as designated by the investigator AND desired by subject), identify the percent body surface area (BSA) to be treated. BSA will 
be estimated based on the assumption that 1% BSA is equivalent to the area of the subject’s hand with fingers held together. 
9 LSRs assessed at the EOS Visit of the Phase 3 pivotal trial (Visit 4-Pivotal) will be used as pre-application data for face. LSRs [pre-application] will be assessed 
for trunk at Visit 4-LTF. After ITA application in the clinic, LSRs will be assessed post-application (Visit 4-LTF) for face and trunk, as applicable. 
10 Any ongoing concomitant medications and procedures will be reviewed at Visit 4-LTF. 
11 Instruct subject (and parent/guardian, if applicable) on ITA application and provide instruction sheet. Review compliance with respect to the amount and number 
of doses applied since the last visit. 
12 Dispense subject diary, as needed. 
 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
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ABBREVIATIONS 
AE 
Adverse Event 
BID 
Twice a day 
BSA 
Body Surface Area 
CB-03-01 
Cortexolone 17α-propionate 
CLIA 
Clinical Laboratory Improvement Amendments 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CV% 
Percent Coefficient of Variation 
EDC 
Electronic Data Capture 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
IGA 
Investigator’s Global Assessment 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITA 
Investigational Test Article 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
LSR 
Local Skin Reaction 
LTF 
Long-Term Follow-Up 
MedDRA 
Medical Dictionary for Regulatory Activities 
OTC 
Over-the-Counter 
PP 
Per-Protocol 
QA 
Quality Assurance 
RX 
Prescription 
SAE 
Serious Adverse Event 
TEAE 
Treatment Emergent Adverse Event 
TI 
Therapeutics, Incorporated 
UPT 
Urine Pregnancy Test 
WOCBP 
Women of Childbearing Potential 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
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TABLE OF CONTENTS 
Protocol Approval ............................................................................................................... 2 
Study Acknowledgement .................................................................................................... 3 
Protocol Synopsis................................................................................................................ 4 
Schedule of Events ............................................................................................................ 11 
Abbreviations .................................................................................................................... 13 
Table of Contents .............................................................................................................. 14 
1. 
Background ....................................................................................................... 16 
2. 
Rationale ........................................................................................................... 16 
3. 
Objective ........................................................................................................... 16 
4. 
Study Design ..................................................................................................... 16 
5. 
Study Population ............................................................................................... 17 
5.1 
Subject Eligibility ............................................................................................. 17 
5.1.1 
Inclusion Criteria ....................................................................................... 17 
5.1.2 
Exclusion Criteria ...................................................................................... 18 
5.1.3 
Subject Withdrawal Criteria ...................................................................... 19 
6. 
Test Articles and Regimen ................................................................................ 19 
6.1 
Description ........................................................................................................ 19 
6.2 
Instructions for Use and Application ................................................................ 19 
6.3 
Warnings, Precautions and Contraindications .................................................. 21 
7. 
Randomization Assignment .............................................................................. 21 
8. 
Prior and Concomitant Therapies ..................................................................... 21 
8.1 
Prohibited Medications or Therapies ................................................................ 22 
8.2 
Allowed Medications or Therapies ................................................................... 22 
9. 
Study Procedures .............................................................................................. 23 
9.1 
Visit 4-LTF Baseline (LTF-Day 1) [Visit 4-Pivotal + 3 days] ......................... 23 
9.2 
Visit 5 (LTF-Month 1) [Day 29 ± 10], Visit 6 (LTF-Month 3) [Day 85±15], and 
Visit 8 (LTF-Month 6) [Day 183±15] .............................................................. 25 
9.3 
Visit 7: Phone Call 1 (LTF-Month 4.5) [Day 137±15] and Visit 9: Phone Call 2 
(LTF-Month 7.5) [Day 228±15] ....................................................................... 26 
9.4 
Visit 10 (LTF-Month 9) [Day 274 ± 21]: EOS & Early Termination .............. 27 
9.5 
Unscheduled Visit ............................................................................................. 27 
10. 
Clinical Evaluations .......................................................................................... 29 
10.1 
Investigator’s Global Assessment (IGA) .......................................................... 29 
10.2 
Local Skin Reactions (LSRs) ............................................................................ 30 
10.3 
Truncal Body Surface Area (BSA) ................................................................... 32 
11. 
Photography ...................................................................................................... 32 
12. 
Laboratory Tests ............................................................................................... 32 
12.1 
Urine Pregnancy Tests (UPTs) ......................................................................... 32 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 15 of 53 
TI SOP 305-A Protocol Template, Version 06 
13. 
End of Study Criteria ........................................................................................ 32 
13.1 
Completion of the Study ................................................................................... 33 
13.2 
Subject Discontinuation .................................................................................... 33 
13.3 
Study Termination ............................................................................................ 33 
14. 
Adverse Event Reporting .................................................................................. 33 
14.1 
Adverse Event (AE) .......................................................................................... 34 
14.2 
Serious Adverse Event (SAE) ........................................................................... 37 
14.3 
Pregnancy .......................................................................................................... 39 
15. 
Blinding/Unblinding ......................................................................................... 40 
16. 
Clinical Supplies ............................................................................................... 40 
16.1 
Test Article Information ................................................................................... 40 
16.2 
Supplies Provided by CRO ............................................................................... 40 
16.3 
Supplies Provided by Investigator .................................................................... 40 
17. 
Statistical Considerations .................................................................................. 41 
17.1 
Sample Size ....................................................................................................... 41 
17.2 
Endpoints .......................................................................................................... 41 
17.2.1 
Safety Endpoints ........................................................................................ 41 
17.2.2 
Efficacy Endpoints .................................................................................... 41 
17.3 
Statistical Methods ............................................................................................ 41 
17.3.1 
Safety Analyses ......................................................................................... 42 
17.3.2 
Efficacy Analyses ...................................................................................... 42 
17.4 
Subgroup Analyses ........................................................................................... 42 
17.5 
Interim Analyses ............................................................................................... 42 
18. 
Ethical and Regulatory Considerations ............................................................. 43 
18.1 
Compliance with Good Clinical Research Practice .......................................... 43 
18.2 
Institutional Review Board (IRB)/ Ethics Committee and Informed 
Consent/Assent ................................................................................................. 43 
18.3 
Protocol Compliance ......................................................................................... 43 
18.4 
Protocol Revisions ............................................................................................ 44 
18.5 
Study Monitoring .............................................................................................. 44 
18.6 
Case Report Form (CRF) Requirements: Electronic Data Capture (EDC) ...... 44 
18.7 
Reports to Institutional Review Board .............................................................. 45 
18.8 
Quality Assurance Audits ................................................................................. 45 
18.9 
Records Retention ............................................................................................. 45 
18.10 Record Confidentiality ...................................................................................... 45 
19. 
References ......................................................................................................... 46 
Appendix 1 
Sample Subject Instruction Sheet .............................................................. 47 
Appendix 2 
Sample Subject Diary ................................................................................ 49 
Appendix 3 
Test Article Information ............................................................................ 51 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 16 of 53 
TI SOP 305-A Protocol Template, Version 06 
1. 
BACKGROUND 
CB-03-01 (cortexolone 17α-propionate) is a steroidal antiandrogen that is being developed 
as a 1% cream for the topical treatment of acne vulgaris, 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 [1]. 
 
CB-03-01 could offer advantages over existing products for acne vulgaris due to its 
potential efficacy and lack of systemic antiandrogen activity. Because its pharmacological 
action appears to be limited to the local site of application, use of CB-03-01 may be able 
to mitigate the side effects related to systemic exposure to hormonal agents currently used 
in the treatment of acne. 
2. 
RATIONALE 
To date, CB-03-01 cream has been used for treatment of acne vulgaris for up to 12 weeks 
with no material safety issues to note. Given that acne vulgaris is a chronic condition which 
typically waxes and wanes over time and often requires extended (and sometimes 
intermittent) treatment, this study is designed to investigate the long-term safety of CB-03-
01 cream, 1%. 
3. 
OBJECTIVE 
The primary objective of this study is to determine the long-term safety of CB-03-01 cream, 
1% applied twice daily for an additional nine months in subjects with acne vulgaris that 
participated in the Phase 3 pivotal studies for a total treatment of up to 12 months. 
4. 
STUDY DESIGN 
This is a multicenter, open label, long-term extension study for CB-03-01 cream, 1% 
focused on safety in male and female subjects, 9 years or older who completed one of the 
Phase 3 pivotal studies [CB-03-01/25 and CB-03-01/26]. Subjects will apply the active 
medication (CB-03-01 cream, 1%) twice daily to the entire face and, if designated by 
investigator AND desired by subject, truncal acne for nine additional months of treatment. 
Thus, overall subjects will be exposed to CB-03-01 cream, 1% for a total treatment of up 
to 12 months (0 or 3 months in the Phase 3 pivotal study and an additional nine months in 
this long-term safety study). 
 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 17 of 53 
TI SOP 305-A Protocol Template, Version 06 
For this Long-Term Follow-Up (LTF) study, subjects must rollover from the Phase 3 
pivotal study (CB-03-01/25 and CB-03-01/26) into this study AT or WITHIN THREE (3) 
DAYS of Visit 4-Pivotal. 
 
Subjects will treat facial acne per protocol for nine months. Treatment of truncal acne will 
be discussed by the investigator and subject. If the subject desires, the truncal treatment 
area will be defined and agreed upon by the investigator and the subject. If the investigator 
and subject designate a treatment area for truncal acne, the subject must continue to treat 
this area for the duration of the study per protocol as detailed in Section 6.2. If the 
investigator and subject do not designate a treatment area for truncal acne at Baseline 
[Visit 4-LTF], one may be designated at subsequent visits (e.g., if acne worsens in the 
truncal area), but once treatment begins in such treatment area, the subject must continue 
to treat this area per protocol for the remainder of the study. 
 
Treatment on the face and/or trunk may be discontinued if/when acne clears (achieves an 
IGA of grade 0 or “minimal” grade 1) and re-instated if/when acne worsens (IGA ≥2), 
according to the assessment of the investigator for each respective treatment area (i.e., face 
and trunk). Note: Subjects must be seen by the investigator via a routinely scheduled study 
visit or an unscheduled visit to change (i.e., restart or stop) test article dosing on either 
treatment area (i.e., face and trunk). 
 
Subjects (approximately 600) will be rolled over from the Phase 3 pivotal studies [CB-03-
01/25 and CB-03-01/26] into this long-term, safety study in order to achieve at least 300 
subjects on-study at 6 months and 100 subjects on-study at 12 months. These treatment 
durations include the 0 or 3 months of active treatment in the Phase 3 pivotal studies (CB-
03-01/25 and CB-03-01/26). 
5. 
STUDY POPULATION 
5.1 
Subject Eligibility 
To be included in the study, subjects must meet the following inclusion and none of the 
exclusion criteria. 
5.1.1 Inclusion Criteria 
1. Subject must have been enrolled in one of the Phase 3 pivotal studies [CB-03-01/25 
and CB-03-01/26], completed the assigned treatment regimen without any material 
non-compliance with study requirements or test article dosing (compliance≥80%), and 
completed the final study visit (Visit 4-Pivotal). 
2. Subject agrees to treat his/her facial acne and truncal acne (if designated by investigator 
AND desired by subject) during the nine month study period per protocol. Note: 
Subjects who are clear (IGA=0) at Visit 4-Pivotal are also eligible for the study. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 18 of 53 
TI SOP 305-A Protocol Template, Version 06 
3. Females must be post-menopausal6, surgically sterile7, or using highly effective birth 
control methods.8,9 Women of childbearing potential (WOCBP)10 must have a negative 
urine pregnancy test (UPT) at Visit 4-LTF (or Visit4-Pivotal, if the visits occur on the 
same day). 
4. 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 
the study, the subject must provide written informed consent at that time to continue 
study participation. 
5. Subject is willing to comply with study instructions and return to the clinic for required 
visits. 
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 safety 
evaluation of the test products or requires the use of interfering topical or systemic 
therapy (see Section 8.1: Prohibited Medications and Therapies). 
3. Subject has any condition which, in the investigator’s opinion, would make it unsafe 
or unsuitable for the subject to participate in this research study. 
4. Subject plans to use any other investigational drug or device during participation in this 
study. 
5. Subject, and parent/guardian if required, is unable to communicate or cooperate with 
the investigator due to language problems, poor mental development, or impaired 
cerebral function. 
6. 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. 
7. Subject has known hypersensitivity or previous allergic reaction to any of the active or 
inactive components of the test article. 
8. Subject is or plans to use any topical anti-acne preparations (excluding CB-03-01 
cream) or procedures on the face (or trunk, if applicable) or any systemic anti-acne 
                                                 
6 Defined as amenorrhea greater than 12 consecutive months. 
7 Hysterectomy, bilateral tubal ligation (at least six months prior to study entry), or bilateral oophorectomy. 
8 Highly effective contraception includes a) total abstinence, b) oral, injected, or implanted hormonal methods 
of contraception for at least two complete cycles (i.e., eight to twelve weeks) prior to it being considered 
highly effective, c) intrauterine device (IUD) for at least one week prior to it being considered highly 
effective, d) partner vasectomy (performed at least six 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]. 
9 WOCBP taking hormonal therapy for any reason must not change their dosing regimen during the study. 
10 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. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 19 of 53 
TI SOP 305-A Protocol Template, Version 06 
medications (as detailed in Section 8.1: Prohibited Medications and Therapies) during 
the study 
5.1.3 Subject Withdrawal Criteria 
Procedures for handling subjects who are discontinued from the study are described in 
Section 13.2. 
6. 
TEST ARTICLES AND REGIMEN 
6.1 
Description 
Test article name: 
CB-03-01 Cream, 1% 
Active ingredient: 
Cortexolone 17α-propionate (11-deoxy-hydrocortisone-17α-
propionate). 
Other ingredients: 
Cetyl alcohol, glycerol monostearate, liquid paraffin, propylene 
glycol, tocopherol, sodium edetate, polysorbate 80, citric acid, 
purified water. 
6.2 
Instructions for Use and Application 
Subjects will treat facial acne per protocol for nine months. Treatment of truncal acne will 
be discussed by the investigator and subject. If the subject desires, the truncal treatment 
area will be defined and agreed upon by the investigator and the subject. If the investigator 
and subject designate a treatment area for truncal acne, the subject must continue to treat 
this area per protocol for the duration of the study as detailed below. If the investigator and 
subject do not designate a treatment area for truncal acne at Baseline (Visit 4-LTF), one 
may be designated at subsequent visits (e.g., if acne worsens in the truncal area), but once 
treatment begins in such treatment area, the subject must continue to treat this area per 
protocol for the remainder of the study. 
 
At the first visit, the subjects will be instructed to wash the area to be treated (entire face 
and trunk, if applicable) 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 test article, how much of the test article to use, and where to apply the assigned test 
article. The first application of the test article should be applied in the office at Visit 4-LTF 
under supervision of the study staff after the treatment areas have been determined, except 
for those subjects with clear facial acne and no truncal acne. For subjects starting treatment 
at subsequent visits, the first dose of the test article will be applied at that visit under 
supervision of the study staff. Typically, for the face, about one (1) gram of the test article 
will be dispensed onto a fingertip and applied by gently dabbing small amounts of the test 
article on multiple regions of the face (e.g., forehead, nose, cheeks, chin). Using a fingertip, 
the test article will be spread to provide a thin, uniform layer of the test article over the 
entire face. In addition, if applicable, subjects who choose (with investigator’s approval) 
to treat truncal acne should apply a thin uniform application of the test article to the 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 20 of 53 
TI SOP 305-A Protocol Template, Version 06 
designated area(s) of the trunk (e.g., the shoulders, chest, and/or back).  Note: one (1) gram 
of cream will cover approximately a 8.5” x 11” (~22 cm x 28 cm) area. 
 
Subject and parent/guardian (if applicable) will also be provided with a Subject Instruction 
Sheet (Appendix 1) providing them with instructions on how to use and store the cream at 
home during the study period. Subjects and parents/guardians (if applicable) will be 
instructed to apply the test article to the whole face and trunk, if applicable, twice daily 
(morning and in the evening) for nine additional months. The subject should ideally allow 
at least eight hours between applications. All subjects should not wash the treated area for 
at least four hours following test article application and should not apply the test article 
within four hours prior to any study visit. 
 
If a subject’s acne is totally clear (i.e., IGA=0) on face and/or trunk at Visit 4-LTF, the 
subject will not apply the test article to the area(s) that is clear at home for the first month 
of the study and be reassessed at Visit 5 or earlier (after an unscheduled visit), if acne 
worsens (in either area) before Visit 5. If acne is totally clear on the face and the trunk has 
not been designated for treatment, the subject will not be dispensed the test article at Visit 
4-LTF. For subjects whose acne is not totally clear (i.e., IGA>0) at Visit 4-LTF, the subject 
should apply the test article at home twice daily (morning and evening) as instructed by 
the study staff. 
 
Over the course of the study, treatment on the face and/or trunk may be discontinued 
if/when acne clears (achieves an IGA of grade 0 or “minimal” grade 1) and re-instated 
if/when acne worsens (IGA≥2), according to the assessment of the investigator for each 
respective treatment area. If treatment is discontinued on face and trunk, all containers of 
the test article should be collected. If treatment is re-instated, sufficient test article will be 
dispensed to the subject; previously returned test article should NOT be re-dispensed, 
rather new containers of the test article will be dispensed as needed to the subject. Note: 
Subjects must be seen by the investigator via a scheduled or an unscheduled visit to change 
(i.e., restart or stop) the test article dosing on either treatment area (face and trunk). If the 
subject feels that his/her acne has cleared, he/she should continue to apply the test 
article to the designated treatment area (face and/or trunk) as instructed by the 
investigator and call the investigator for an unscheduled visit. The subject should 
NOT change his/her dosing regimen until the investigator has documented acne 
clearance or significant worsening to support a change in the treatment. 
 
Subjects will be provided with a Subject Diary (Appendix 2) to record the dates and time 
of application, along with where the test article was applied. Subjects will be instructed to 
only apply the test article to the face and/or trunk 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 be instructed to bring all the containers of 
cream (used and unused) and their completed diaries to each visit. The study staff will 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 21 of 53 
TI SOP 305-A Protocol Template, Version 06 
weigh all the returned containers and will record the weights on the appropriate study 
medication accountability logs and case report forms (CRFs). Test articles that are returned 
should NOT be re-dispensed to the subject. 
 
Subjects who are not compliant with applying the test article 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 
The test article is 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 article should not 
participate in this study. 
 
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 
There is no randomization assignment in this study. This is an open label, extension study 
in which all eligible subjects will be treated with CB-03-01 cream, 1% (i.e., the test article). 
About 600 subjects will be enrolled in this extension study to achieve at least 300 subjects 
on-study at 6 months and 100 subjects on-study at 12 months. These treatment durations 
include the 0 or 3 months of active treatment in the Phase 3 pivotal studies (CB-03-01/25 
and CB-03-01/26). Enrollment will be competitive; upon enrollment of about 600 subjects 
in this study, the option for rollover will not be offered to other subjects in the Phase 3 
pivotal studies (CB-03-01/15 and CB-03-01/26), even if those subjects are eligible. 
Enrolled subjects will be provided with labeled test article during the study period, as 
needed. Subject numbers will be carried over from the Phase 3 pivotal study [CB-03-01/25 
or CB-03-01/26].  
8. 
PRIOR AND CONCOMITANT THERAPIES 
Current medications taken at the start of this study (Visit 4-LTF) 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 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 22 of 53 
TI SOP 305-A Protocol Template, Version 06 
the Concomitant Medications form prior to commencing the use of the test article. Any 
medications that were used prior to the start of this study would have been recorded as part 
of the Phase 3 pivotal study [CB-03-01/25 or CB-03-01/26]. 
 
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 4-LTF 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 AE. 
8.1 
Prohibited Medications or Therapies 
During the study, subjects must not use the following products and/or procedures on the 
face or trunk: 
• Any other investigational drug or use of any investigational device; 
• Light treatments (including artificial tanning devices, blue light, laser, etc.), 
microdermabrasion, or chemical peels; 
• Systemic spironolactone; 
• Systemic retinoid therapy; 
• All topical acne therapies not allowed per Section 8.2 (e.g. retinoids, azelaic acid, 
dapsone, etc.). 
 
Other chronic medications being used at the time of Visit 4-LTF can be continued at the 
discretion of the investigator. The reason for any changes in such concomitant medications 
and/or therapies should be reported as, or in conjunction with, an AE. 
8.2 
Allowed Medications or Therapies 
All allowed concurrent acne medications and/or therapies must be given IN 
ADDITION to the test article and NOT IN PLACE of the test article. 
 
During the study, if control of acne is insufficient, the following supplemental products 
and/or procedures may be used at the discretion of the investigator on the face or trunk: 
• Hormonal contraceptives11; 
• Occasional use of systemic antibiotics for acne (not to exceed 12 continuous weeks) 
or for other medical needs; 
• Systemic corticosteroids (for other medical needs); 
• Occasional use of intralesional corticosteroid injections for nodular or cystic acne 
lesions (low dose, e.g., ~2 mg triamcinolone / cc) or for other medical needs; 
                                                 
11 If hormonal contraception is initiated as concurrent acne therapy, the method of highly effective birth 
control used at Visit 4-LTF must be continued for at least two complete cycles (i.e., eight to twelve weeks). 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
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• Occasional use of TOPICAL steroids or TOPICAL antibiotics for up to 10 
continuous days (for other medical needs) within the treatment area (face and/or 
trunk); 
• TOPICAL anti-acne cleansers (not leave-on products) that have benzoyl peroxide 
(≤5%) OR salicylic acid (≤2%) as their only active ingredient within the treatment 
area (face and/or trunk). 
 
Acne Management: The intent of the study is to limit the use of other acne medications 
to facilitate the safety assessment of long-term use of the investigational test article over a 
one year period of time.  In the event that the study drug does not sufficiently control the 
subject’s acne, the Investigator, at their election, may prescribe select additional 
medication(s)12 that can be taken in addition to the investigational test article. Ideally these 
measures should be used only for brief period(s) of time, if medically necessary, to 
reasonably control the subject’s acne, during the study.  These medications are limited to 
certain products (e.g., topical anti-acne cleansers, oral antibiotics, or intralesional steroid 
injections for cyst/nodular lesions) as detailed in the list of allowed medications or 
therapies above. 
9. 
STUDY PROCEDURES 
The study will consist of a Baseline Visit, follow-up visits at Months 1, 3, 6, and 9, and 
follow-up phone calls at Months 4.5 and 7.5. For subjects in the Phase 3 pivotal studies 
randomized to active (CB-03-01 cream, 1% twice daily), the total treatment period will be 
12 (3+9) months; whereas for those subjects in the Phase 3 pivotal studies randomized to 
vehicle, the total treatment period will be 9 (0+9) months. 
 
During the LTF study, treatment on face and/or trunk for a subject may be discontinued 
if/when acne is under successful control (achieves an IGA of grade 0 or “minimal” grade 
1) and re-instated if/when acne worsens (IGA≥2), according to the assessment of the 
investigator for each respective treatment area. Subjects MUST be seen by the investigator 
via a scheduled or unscheduled visit to change (i.e., restart or stop) test article dosing). 
 
Specific activities for each study visit are listed below. 
9.1 
Visit 4-LTF Baseline (LTF-Day 1) [Visit 4-Pivotal + 3 days] 
Informed consent/assent can be obtained up to 45 days before Visit 4-LTF. Note: 
Consent/assent for this extension study should not be signed at Baseline of the Phase 3 
pivotal study (i.e., Visit 1). For this LTF study, subjects must rollover from the Phase 3 
pivotal study (CB-03-01/25 and CB-03-01/26) into this study AT or WITHIN THREE (3) 
DAYS of Visit 4-Pivotal. 
                                                 
12 For US sites: OTC acne cleanser containing 2% salicylic acid or 5% benzoyl peroxide and doxycycline 
will be provided by the investigator. The subject will be responsible for other additional acne medications 
that may be prescribed by the investigator. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
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At this visit, 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. 
• Confirm the subject meets the inclusion/exclusion criteria. 
• Confirm demographics and medical / dermatological history were collected in the 
Phase 3 pivotal study (Visit 1-Pivotal). 
• Review any ongoing concomitant medications and procedures. 
• Perform a brief physical exam (including vital signs, height, and weight). 
• Perform a UPT for all WOCBP (see Section 5.1 for definition). The results must be 
negative for the subject to be enrolled. Note: If Visit 4-Pivotal and Visit 4-LTF 
occur on the same day, the results of the UPT performed during the End of Study 
(EOS) visit of the Phase 3 pivotal study can be used. 
• Confirm that an IGA was performed and LSRs were assessed for the face at Visit 
4-Pivotal. 
• Discuss with the subject if truncal acne will be treated. If applicable, identify the 
truncal treatment area and record the percent BSA of the truncal treatment area (see 
Section 10.3). Note: If the investigator and the subject designate a treatment area 
for truncal acne, the subject must continue to treat this area per protocol for the 
duration of the study as detailed in Section 6.2. 
• Prior to the first application of the test article, for the trunk (if applicable). 
o Perform IGA (see Section 10.1); and 
o Perform LSR assessment (see Section 10.2). 
• Determine if the subject requires ongoing therapy based on IGA scores of the face 
and trunk. Note: If a subject’s acne is totally clear (IGA=0) on face and/or trunk, 
the subject will not receive or apply the ITA for the first month of the study and will 
be reassessed at Visit 5 or earlier (after an unscheduled visit), if acne worsens (be 
it on the face and/or the trunk) before Visit 5. 
• Dispense the Subject Instruction Sheet to the subject and parent/guardian (if 
applicable) (Appendix 1), as required. 
• Dispense the Subject Diary to the subject and parent/guardian (if applicable) and 
provide completion instructions (Appendix 2), as required. 
• Weigh and dispense the test article and complete the Study Medication 
Accountability Log, as required (Appendix 3). 
• Instruct the subject and parent/guardian (if applicable) where and how to apply the 
initial dose of the test article following the procedures in Section 6.2. The first 
application should occur in the office under supervision of the study staff, except 
for those subjects with clear facial acne and no truncal acne. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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• Record any AEs. 
• Assess LSRs post-application for face AND trunk, separately, and as applicable 
(see Section 10.2). 
• Instruct the subject and parent/guardian (if applicable) to apply the test article to 
the designated treatment areas (i.e., face and/or trunk) twice per day, with at least 
eight hours between applications. 
• Remind the subject that if the subject feels that his/her acne has cleared or 
significantly worsened (for those subjects with IGA=0), the subject should contact 
the investigator for an unscheduled visit. Note: Subjects MUST be seen by the 
investigator via a scheduled or an unscheduled visit to change (i.e., start or stop) 
test article dosing on either treatment area (face and trunk). 
• Schedule Visit 5 (LTF-Month 1). 
9.2 
Visit 5 (LTF-Month 1) [Day 29 ± 10], Visit 6 (LTF-Month 3) [Day 85±15], and 
Visit 8 (LTF-Month 6) [Day 183±15] 
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 AEs and concomitant medications/therapies, and document 
the findings. 
• Perform a UPT for all WOCBP (see Section 5.1 for definition) (Visit 8 ONLY). 
• Perform IGA for face AND trunk, separately, and as applicable (see Section 10.1). 
• Assess LSRs for face AND trunk, separately, and as applicable (see Section 10.2). 
• Determine if the subject requires ongoing therapy or if treatment needs to be 
(re)started based on IGA scores of the face and trunk. Note: Treatment on the face 
and/or trunk may be discontinued if/when acne clears (achieves an IGA of grade 0 
or “minimal” grade 1) and re-instated if/when acne worsens (IGA≥2) according to 
the assessment of the investigator for each respective treatment area. Also, if a 
treatment area for truncal acne was not identified at Baseline (Visit 4-LTF), one 
may be designated at a subsequent visit (e.g., if acne worsens in the truncal area), 
but once treatment begins in such treatment area, the subject must continue to treat 
the designated area per protocol for the remainder of the study as detailed in 
Section 6.2. 
• Review test article compliance based on Subject Diary and weights of the test 
article. Remind the subject to apply the test article to the designated treatment areas 
(i.e., face and/or trunk) twice per day, with at least eight hours between 
applications. 
• Dispense an updated (or new) Subject Instruction Sheet to the subject and 
parent/guardian (if applicable) (Appendix 1), if the subject is starting treatment at 
this visit. 
• Collect the old and dispense a new Subject Diary to the subject and parent/guardian 
and provide completion instructions (Appendix 2), if applicable (i.e., acne 
treatment on the face and/or trunk shall continue per protocol as detailed in Section 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 26 of 53 
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6.2). Any noteworthy discrepancies in the Subject Diary should be queried and 
documented. 
• Collect all previously dispensed test article and complete the Study Medication 
Accountability Log (Appendix 3). 
• Weigh and dispense [only if applicable (i.e., acne treatment on the face and/or trunk 
shall continue per protocol)] new containers of the test article and complete the 
Study Medication Accountability Log (Appendix 3). Note: For subjects that were 
totally clear (IGA=0) at Baseline, if their acne on the face and/or trunk remains 
totally clear (IGA=0), then do not dispense the test article. If treatment shall not 
continue per protocol as detailed in Section 6.2, collect all containers of the test 
article. PREVIOUSLY RETURNED TEST ARTICLE SHOULD NOT BE RE-
DISPENSED.  
• If treatment is started for the first time (in this LTF study) on the face and/or trunk, 
o Discuss with the subject if truncal acne will be treated. If applicable, 
identify the truncal treatment area and record the percent BSA of the truncal 
treatment area (see Section 10.3). Note: If the investigator and the subject 
designate a treatment area for truncal acne, the subject must continue to 
treat this area per protocol for the remainder of the study. 
o Instruct the subject and parent/guardian (if applicable) where and how to 
apply the initial dose of the test article following the procedures in Section 
6.2. The first application should occur in the office under supervision of the 
study staff. 
o Record any AEs. 
o Instruct the subject and parent/guardian (if applicable) to apply the test 
article to the designated treatment areas (i.e., face and/or trunk) twice per 
day, with at least eight hours between applications. 
• Remind the subject that if the subject feels that his/her acne has cleared or 
significantly worsened (for those subjects with IGA=0), the subject should contact 
the investigator for an unscheduled visit. Acne will be managed per Section 6.2 and 
Section 8.2. Note: Subjects MUST be seen by the investigator via a scheduled or 
an unscheduled visit to change (i.e., start or stop) test article dosing on either 
treatment area (face and trunk). 
• Schedule follow-up visit (at Visit 5 and 6) or an end of study (EOS) visit (at Visit 8). 
9.3 
Visit 7: Phone Call 1 (LTF-Month 4.5) [Day 137±15] and Visit 9: Phone Call 2 
(LTF-Month 7.5) [Day 228±15] 
The investigator or designee will contact the subject by telephone to: 
• Review any changes in his/her health, with the subject or parent/guardian (as 
appropriate), since the previous study visit, including AEs and concomitant 
medications/therapies, and document the findings. 
• Review test article compliance. 
• Emphasize need to maintain the Subject Diary daily with each application. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 27 of 53 
TI SOP 305-A Protocol Template, Version 06 
• In the event that either of the following occur prior to the next scheduled visit, the 
subject may be seen in the clinic as an unscheduled visit at the discretion of the 
investigator: 
o Improving (appears to have achieved an IGA of grade 0 or “minimal” grade 
1) or worsening (IGA≥2 after treatment was stopped) of the subject’s acne 
such that the treatment may be discontinued or restarted, respectively; OR 
o A concern regarding an AE or the subject’s progress; OR 
o Other item of note from the investigator’s perspective. 
• Note: Subjects MUST be seen by the investigator via a scheduled or an unscheduled 
visit to change (i.e., start or stop) test article dosing on either treatment area (face 
and trunk). 
• In the event an in-office visit is required, the site should schedule an unscheduled 
visit for evaluation in a timely fashion. 
• Confirm the next scheduled visit. 
9.4 
Visit 10 (LTF-Month 9) [Day 274 ± 21]: EOS & Early Termination 
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 AEs and concomitant medications/therapies, and document 
the findings. 
• Perform a UPT for all WOCBP (see Section 5.1 for definition). 
• Perform IGA for face AND trunk, separately, as needed (see Section 10.1). 
• Assess LSRs for face AND trunk, separately, as needed (see Section 10.2). 
• Review and collect the Subject Diary.  Any noteworthy discrepancies in the diary 
should be queried and documented. 
• Collect and weigh all used and unused test article and complete the Study 
Medication Accountability Log, as required (Appendix 3). 
• Complete the End of Study Form and discharge the subject from the study. 
9.5 
Unscheduled Visit 
The subject may be seen in the clinic as an unscheduled visit at the discretion of the 
investigator in the event there is (a) improving or worsening of the subject’s acne such that 
the treatment may be discontinued or restarted, respectively, or (b) a concern regarding an 
AE or the subject’s progress based upon the Phone Call visit.  
 
Subjects MUST be seen by the investigator via an unscheduled visit to change (i.e., 
start or stop) test article dosing on either treatment area (face and trunk). 
 
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 AEs and concomitant medications/therapies, and document 
the findings. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 28 of 53 
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• Perform IGA for face AND trunk, separately, as needed (see Section 10.1). 
• Assess LSRs for face AND trunk, separately, as needed (see Section 10.2). 
• Determine if the subject requires ongoing therapy or if treatment needs to be 
(re)started based on IGA scores of the face and trunk. Note: Treatment on the face 
and/or trunk may be discontinued if/when acne clears (achieves an IGA of grade 0 
or “minimal” grade 1) and re-instated if/when acne worsens (IGA≥2) according to 
the assessment of the investigator for each respective treatment area. Also, if a 
treatment area for truncal acne was not identified at Baseline (Visit 4-LTF), one 
may be designated at a subsequent visit (e.g., if acne worsens in the truncal area), 
but once treatment begins in such treatment area, the subject must continue to treat 
the designated area per protocol for the remainder of the study as detailed in 
Section 6.2. 
• Review test article compliance based on Subject Diary and weights of the test 
article. Remind the subject to apply the test article to the designated treatment areas 
(i.e., face and/or trunk) twice per day, with at least eight hours between 
applications. 
• Dispense an updated (or new) Subject Instruction Sheet to the subject and 
parent/guardian (if applicable) (Appendix 1), as required. 
• Collect the old and dispense a new Subject Diary to the subject and parent/guardian 
and provide completion instructions (Appendix 2), if applicable (i.e., acne 
treatment on the face and/or trunk shall continue per protocol). Any noteworthy 
discrepancies in the Subject Diary should be queried and documented. 
• Collect all previously dispensed test article and complete the Study Medication 
Accountability Log (Appendix 3). 
• Weigh and dispense [only if applicable (i.e., acne treatment on the face and/or trunk 
shall continue per protocol)] new containers of the test article and complete the 
Study Medication Accountability Log (Appendix 3). Note: If treatment shall not 
continue per protocol as detailed in Section 6.2, collect all containers of the test 
article. PREVIOUSLY RETURNED TEST ARTICLES SHOULD NOT BE RE-
DISPENSED. 
• If treatment is started for the first time (in this LTF study) on the face and/or trunk, 
o Discuss with the subject if truncal acne will be treated. If applicable, 
identify the truncal treatment area and record the percent BSA of the truncal 
treatment area (see Section 10.3). Note: If the investigator and the subject 
designate a treatment area for truncal acne, the subject must continue to 
treat this area per protocol for the remainder of the study as detailed in 
Section 6.2. 
o Instruct the subject and parent/guardian (if applicable) where and how to 
apply the initial dose of the test article following the procedures in Section 
6.2. The first application should occur in the office under supervision of the 
study staff. 
o Record any AEs. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 29 of 53 
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o Instruct the subject and parent/guardian (if applicable) to apply the test 
article to the designated treatment areas (i.e., face and/or trunk) twice per 
day, with at least eight hours between applications. 
• Remind the subject that if the subject feels that his/her acne has cleared or 
significantly worsened (for those subjects with IGA=0), the subject should contact 
the investigator for a scheduled or an unscheduled visit. Acne will be managed per 
Section 6.2 and Section 8.2. Note: Subjects MUST be seen by the investigator via 
an unscheduled visit to change (i.e., start or stop) test article dosing on either 
treatment area (face and trunk). 
• Confirm the next scheduled visit. 
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) 
Overall severity of acne using a five-point scale from 0=clear to 4=severe will be evaluated 
for the face and trunk, separately. This is a static morphological scale that refers to a point 
in time and not a comparison to Baseline. IGA performed on the face during the End of 
Study (EOS) Visit of the Phase 3 pivotal study (i.e., Visit 4-Pivotal) and IGA performed 
on the trunk at Visit 4-LTF will be used as Baseline data. 
 
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 lesion. 
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. 
 
IGA, to document acne improvement (i.e., achieves an IGA of grade 0 or “minimal” grade 
1) or worsening (IGA≥2), should also be assessed to support treatment recommendations 
at regularly scheduled visits and any unscheduled visits, as needed. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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10.2 
Local Skin Reactions (LSRs) 
At every in-clinic study visit and unscheduled visits, the investigator or designee will 
document the severity of the following LSRs known to be associated with application of 
topical steroids in the treatment areas (face and trunk, separately): 
• Telangiectasia 
• Skin atrophy 
• Striae rubrae 
 
A five-point ordinal scale will be used to assess the severity of these reactions (0=none, 
1=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 in the treatment areas (face and trunk, 
separately), using the five-point ordinal scales described below: 
• Erythema 
• Edema 
• Scaling/dryness  
 
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 1/3 of the 
Treatment Area 
3 
Moderate – easily seen edema and typically palpable, involving between 1/3 to 
2/3 of the Treatment Area 
4 
Severe – easily seen edema, indurated in some areas, involving over 2/3 of the 
Treatment Area 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
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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 1/3 to 2/3 of the treatment area or limited 
areas of coarser scaling 
4 
Severe – coarser scaling involving more than 2/3 of the treatment area or limited 
areas of very coarse scaling 
 
In addition, subjects will be asked to rate the severity of the following LSRs that occurred 
in the treatment areas (face and trunk, separately) since the last visit, using the four-point 
ordinal scales described below: 
• Stinging/burning 
• Pruritus 
 
Stinging/burning: 
0 
None 
1 
Minimal, barely perceptible – tolerable and little discomfort 
2 
Moderate – tolerable, but causes some discomfort 
3 
Severe – very uncomfortable or intolerable 
 
Pruritus (itching): 
0 
None - no evidence of itching 
1 
Mild - only aware of itching at times, only present when relaxing, not present when 
focused on other activities 
2 
Moderate - often aware of itching, annoying, sometimes disturbs sleep and daytime 
activities 
3 
Severe -constant itching, distressing; frequent sleep disturbance, interferes with 
activities 
 
These LSRs 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. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
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10.3 
Truncal Body Surface Area (BSA) 
Treatment of truncal acne will be discussed by the investigator and subject. If the subject 
desires, the truncal treatment area will be defined and agreed upon by the investigator and 
the subject with the percent BSA to be treated recorded. Percent BSA to be treated will be 
estimated using the assumption that 1% BSA is equivalent to the area of the subject’s hand 
with fingers held together. Once this truncal treatment area has been defined, the subject 
must continue to treat this area for the remainder of the study until the area is clear (an IGA 
of grade 0 or “minimal” grade 1) as determined by the investigator and then re-initiate 
treatment (as/if required) per protocol for worsening (see Section 6.2). 
11. 
PHOTOGRAPHY 
Photography documentation is not required in this study. However, the investigator may 
elect to photograph the subject to document the effects of treatment, AEs or other findings 
during the trial. All photographs taken as part of 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. 
12. 
LABORATORY TESTS 
12.1 
Urine Pregnancy Tests (UPTs) 
The UPT will be performed at the study site if the site meets local country requirements to 
perform the testing (e.g., United States sites 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 Visit 4-LTF (or Visit 4-Pivotal, if the 
visits occur on the same day) (i.e., Baseline), Visit 8 (LTF-Month 6), and Visit 10 (EOS) 
on all WOCBP (see Section 5.1 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 
β-HCG/mL of urine. 
13. 
END OF STUDY CRITERIA 
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. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
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13.1 
Completion of the Study 
Each subject who completes the nine month treatment period and the required study visits 
(Visits 4-LTF and Visits 5-10) 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 nine month treatment period for any reason, 
the Visit 10 (EOS) procedures should be completed at that time. When a subject is 
withdrawn from the study for a treatment-related AE (i.e., possibly, probably or definitely 
related as defined in Section 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.  
 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 34 of 53 
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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. 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 of test article. These data are considered treatment-emergent AEs.  
 
Timely and complete reporting of all AEs assists the contract research organization (CRO) 
in identifying any untoward medical occurrence, thereby allowing:  
1) 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  
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. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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AEs that have been reported in subjects treated with CB-03-01 creams (0.1-1% 
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. 
 
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. 
 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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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. 
 
 
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. 
 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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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 (and other national health authority) 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.  
 
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. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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• 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. 
 
AEs classified as “serious” by either the investigator or the Sponsor require expeditious 
handling and reporting to the 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 listed on the first page of the protocol. 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 the CRO, if available. 
 
As required, the 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 
(and other national health authority) 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, 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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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. 
14.3 
Pregnancy 
WOCBP (see Section 5.1 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 at 
EOS. The study therapy must be withheld until the results of laboratory 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 the CRO. The 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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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 the 
CRO, on the appropriate CRO 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, if they 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 subject exposed 
to the test article(s) should be recorded as an SAE and details documented in the pregnancy 
surveillance form. 
15. 
BLINDING/UNBLINDING 
This study is an open label study. There is no blinding of the test article. 
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, storage and preparation, dispensing, accountability etc. is 
included in Appendix 2. 
16.2 
Supplies Provided by CRO 
• EDC (e.g. access to e-CRFs, etc.) 
• Subject Diaries 
• Source document draft templates 
• Site regulatory binder 
• UPT kits 
• Weighing scales (if necessary) 
• Medications for Additional Acne Management: OTC acne cleanser containing 2% 
salicylic acid or 5% benzoyl peroxide and doxycycline (for US sites only) 
16.3 
Supplies Provided by Investigator 
• Urine collection containers for UPTs 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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17. 
STATISTICAL CONSIDERATIONS 
17.1 
Sample Size 
For large samples, the two-sided confidence interval for a single proportion extends a 
distance ω= 𝑧𝑧1−𝛼𝛼
2ට𝜋𝜋(1−𝜋𝜋)
𝑛𝑛
 from the observed proportion in both directions. An incidence 
no greater than 1% of important AEs out of 100 subjects will provide the estimate of no 
greater than a 3% prevalence of important AEs at the 95% confidence level with a much 
larger number of subjects exposed for the same duration (i.e., 12 months). Applying the 
same approach, an incidence no greater than 1% of important AEs out of 300 subjects will 
provide the estimate of no greater than a 2.1% prevalence of important AEs at the 95% 
confidence level with a much larger number of subjects exposed for the same duration (i.e., 
6 months). 
 
Approximately six hundred (600) subjects will be enrolled in order to have 300 subjects 
on-study at 6 months and 100 subjects on-study at 12 months. These treatment durations 
include the 0 or 3 months of active treatment in the Phase 3 pivotal studies (CB-03-01/25 
and CB-03-01/26). 
17.2 
Endpoints 
17.2.1 Safety Endpoints 
Safety endpoints will include: 
• Incidence of any local and systemic treatment emergent AEs (TEAEs). 
• Number of subjects with presence (and severity) of each individual LSR 
(telangiectasia, skin atrophy, striae rubrae, erythema, edema, scaling/dryness, 
stinging/burning, and pruritus) for each treatment area, as applicable, at each time 
point collected (Baseline, and LTF-Months 1, 3, 6, and 9, and any Unscheduled 
Visits). 
• UPT results in all WOCBP at Baseline, LTF-Month 6, and EOS. 
17.2.2 Efficacy Endpoints 
Efficacy Endpoints will include: 
• Number of subjects with each IGA severity score for each treatment area, as 
applicable, at each time point collected (Baseline and LTF-Months 1, 3, 6, and 9). 
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 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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maximum). Frequency counts and percentage of subjects within each category are provided 
for categorical data. 
 
Subjects who complete 6 months or 12 months on-study without material non-compliance 
with test article (CB-03-01 cream, 1%) dosing per protocol will count towards the desired 
300 subjects at 6 months and 100 subjects at 12 months. 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 enrolled 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. 
17.3.1 Safety Analyses 
Extent of Exposure 
Descriptive statistics will be used to summarize exposure to test article for the Safety, ITT, 
and PP 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. The number of applications and days dosed for each treatment 
area (face and/or trunk from Subject Diary) will also be summarized. 
 
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 and severity at each clinic visit for face and trunk, separately. 
 
Adverse Events (AEs) 
AEs will be coded using the MedDRA coding dictionary summarized by relationship to 
test article and severity. 
17.3.2 Efficacy Analyses 
Investigator’s Global Assessment (IGA) 
Frequency distributions of IGA scores will be summarized at Baseline (EOS-Pivotal), and 
LTF Months 1, 3, 6, and 9 for face and trunk, separately. 
17.4 
Subgroup Analyses 
No subgroup analyses are planned. 
17.5 
Interim Analyses 
No interim analysis is planned. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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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)/ Ethics Committee 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 the CRO. 
 
The IRB approved consent/assent form must include all elements required by FDA (or 
other national health authority), state, and local country 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. 
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. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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18.4 
Protocol Revisions 
The 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 the 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 the 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 the 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 (CRF) Requirements: Electronic Data Capture (EDC) 
The study will utilize validated 21CFR Part 11 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 
documentation with a handwritten signature acknowledging that their electronic signature 
is a legally binding equivalent to their handwritten signature. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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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 the 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 national health or 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 the CRO in the event of a 
FDA or other national health authority 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 the CRO or the institution where the study is conducted, whichever is 
longer. The Study Medication Accountability Logs will be collected at the end of the study 
and kept with the study records at the sites. 
 
The investigator must contact the 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 the 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 the CRO or the Sponsor, the FDA or other national health 
or regulatory authority, or the IRB. 
 
The investigator and all employees and coworkers involved with this study shall not 
disclose or use for any purpose other than performance of the study, any data, records, or 
other unpublished, confidential information disclosed to those individuals for the purpose 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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of the study. Prior written agreement from the CRO or the Sponsor must be obtained for 
the disclosure of any said confidential information to other parties. 
19. 
REFERENCES 
1. Celasco G, Moro, L, Bozzella R, Ferraboschi P, Bartorelli L, Quattrocchi C, Nicoletti 
F. Biological profile of cortexolone 17α-propionate (CB-03-01), a new topical and 
peripherally selective androgen antagonist.  Arzneim.-Forsch. 2004; 54, 881-886. 
 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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APPENDIX 1 
SAMPLE SUBJECT INSTRUCTION SHEET 
A sample Subject Instruction Sheet is provided on the next page.  The investigator should 
provide a copy of the Subject Instruction Sheet to each subject and the subject’s 
parent/guardian at Visit 4-LTF prior to dispensing the containers of the test article(s). 
 
 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
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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: 
Contact: 
 
 
 
 
 
 
At: 
 
 
 
 
 
THE AREA(S) TO BE TREATED ARE (CIRCLE ALL THAT APPLY):      FACE      TRUNK 
 
STUDY MEDICATION APPLICATION: 
• 
You will be instructed how to apply the cream in the clinic. 
• 
You should apply the cream TWICE DAILY to your face and/or trunk as directed by the 
study doctor: once in the morning and once in the evening daily with approximately eight 
(8) hours or more between applications. 
• 
Wash the area to be treated with mild soap and water; gently dry. 
• 
Wash your hands before and after applying the cream. 
• 
For your FACE: 
O Dispense about 1 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). 
O 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. 
• 
For your TRUNK (optional, to be determined by you and the investigator): 
O To cover each 8.5 x 11 inch (~22 x 28 cm) area dispense about 1 gram of cream onto one 
of your fingertips and then begin to apply the cream to the designated areas of your trunk 
(shoulders, chest, and back) with acne (as needed) by dabbing small amounts over multiple 
regions of the area affected with acne. 
O Spread the cream evenly with your fingertip to apply a very thin even coat of the cream 
over the designated truncal region as directed by the study staff. 
• 
Record date and time of cream application (and areas that were treated) in your subject diary 
for the face and/or trunk. 
• 
Do not wash the treated area(s) for at least four (4) hours after application or cover or wrap 
areas where the cream was applied.  
• 
Continue use of the cream as directed by the study doctor. 
• 
If you think your acne has cleared, DO NOT STOP APPLYING THE CREAM. Continue to 
apply the cream and contact the study doctor to be seen in the clinic. 
 
BEFORE EACH STUDY VISIT: Do not apply the cream within 4 hours of your 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:  
VISIT 5: Date:                   Time:              VISIT 6: Date:                    Time:                
VISIT 8: Date:                   Time:              VISIT 10: Date:                  Time:                


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 49 of 53 
TI SOP 305-A Protocol Template, Version 06 
APPENDIX 2 
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 4-LTF (Day 1, Baseline) and all follow-up visits, as necessary. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 50 of 53 
TI SOP 305-A Protocol Template, Version 06 
SAMPLE SUBJECT DIARY FOR PROTOCOL CB-03-01/27 
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 AND all tubes of cream (used and unused) at EVERY VISIT. ASK YOUR PARENT/GUARDIAN FOR HELP. 
If you have any questions, call NAME: _____________________________  
AT:________________________________ 
 
Date  
(dd-MMM-yy) 
Time of Dose 
(HH:MM) 
Areas Treated 
Date  
(dd-MMM-yy) 
Time of Dose 
(HH:MM) 
Areas Treated 
___ / _____ / ___ ____ : ____ AM 
____ : ____ PM  Face  Trunk ___ / _____ / ___ ____ : ____ AM ____ : ____ PM  Face  Trunk 
___ / _____ / ___ ____ : ____ AM 
____ : ____ PM  Face  Trunk ___ / _____ / ___ ____ : ____ AM ____ : ____ PM  Face  Trunk 
___ / _____ / ___ ____ : ____ AM 
____ : ____ PM  Face  Trunk ___ / _____ / ___ ____ : ____ AM ____ : ____ PM  Face  Trunk 
___ / _____ / ___ ____ : ____ AM 
____ : ____ PM  Face  Trunk ___ / _____ / ___ ____ : ____ AM ____ : ____ PM  Face  Trunk 
___ / _____ / ___ ____ : ____ AM 
____ : ____ PM  Face  Trunk ___ / _____ / ___ ____ : ____ AM ____ : ____ PM  Face  Trunk 
___ / _____ / ___ ____ : ____ AM 
____ : ____ PM  Face  Trunk ___ / _____ / ___ ____ : ____ AM ____ : ____ PM  Face  Trunk 
___ / _____ / ___ ____ : ____ AM 
____ : ____ PM  Face  Trunk ___ / _____ / ___ ____ : ____ AM ____ : ____ PM  Face  Trunk 
___ / _____ / ___ ____ : ____ AM 
____ : ____ PM  Face  Trunk ___ / _____ / ___ ____ : ____ AM ____ : ____ PM  Face  Trunk 
___ / _____ / ___ ____ : ____ AM 
____ : ____ PM  Face  Trunk ___ / _____ / ___ ____ : ____ AM ____ : ____ PM  Face  Trunk 
___ / _____ / ___ ____ : ____ AM 
____ : ____ PM  Face  Trunk ___ / _____ / ___ ____ : ____ AM ____ : ____ PM  Face  Trunk 
___ / _____ / ___ ____ : ____ AM 
____ : ____ PM  Face  Trunk ___ / _____ / ___ ____ : ____ AM ____ : ____ PM  Face  Trunk 
___ / _____ / ___ ____ : ____ AM 
____ : ____ PM  Face  Trunk ___ / _____ / ___ ____ : ____ AM ____ : ____ PM  Face  Trunk 
___ / _____ / ___ ____ : ____ AM 
____ : ____ PM  Face  Trunk ___ / _____ / ___ ____ : ____ AM ____ : ____ PM  Face  Trunk 
___ / _____ / ___ ____ : ____ AM 
____ : ____ PM  Face  Trunk ___ / _____ / ___ ____ : ____ AM ____ : ____ PM  Face  Trunk 
 
 
Site Use Only: Diary Dispensed at: 
 
 Visit 4-LTF  Visit 5    Visit 6  
 Visit 8 
 Visit 10    Unscheduled 
Date Dispensed: _________________________ 
Date Returned:  __________________________ 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 51 of 53 
TI SOP 305-A Protocol Template, Version 06 
APPENDIX 3 
TEST ARTICLE INFORMATION 
A 3.1 Test Article Packaging and Labeling 
The test articles will be packaged and labeled by the Sponsor or designee. CB-03-01 cream, 
1% will be packaged in blind-end epoxy lined aluminum tubes, with a polypropylene cap 
closure, containing 30 grams or 60 grams of the test article. Each subject will be assigned 
a subject number (carried over from Phase 3 pivotal study [CB-03-01/25 or CB-03-01/26]) 
and provided with sufficient test article in standard packaging for the designated treatment 
period during the study. 
 
Tube Labels 
Each tube will contain, at a minimum, the following information: the study/protocol 
number, subject identifiers (e.g., subject number [to be filled in]), the contents, the tube 
number (to be filled in) with test article batch number), an investigational test article 
disclaimer (e.g., Caution: New Drug Limited by United States law to investigational use), 
and the appropriate storage conditions for the test article. 
A 3.2 Test Article Storage and Preparation 
The test articles will be stored under secure conditions until they are dispensed to the 
subjects. Test articles should be stored in accordance with the tube labels. 
A 3.3 Dispensing Test Article 
The test article must be dispensed only to study subjects and only at study sites specified 
on the form FDA 1572 (or other documents required by the governing national health 
authority) by authorized personnel as required by applicable regulations and guidelines. 
 
Sufficient test article will be provided to each subject as needed for the designated 
treatment period. For those subjects with clear facial acne and no truncal acne at Baseline 
(Visit 4-LTF), the test article will NOT be dispensed and the subject will be reassessed at 
Visit 5 or earlier (after an unscheduled visit), if acne worsens (be it on the face and/or the 
trunk) before Visit 5. 
 
As test article is dispensed and collected at clinic visits, tubes will be weighed to the nearest 
tenth gram (0.1 gram) and information should be recorded on the Study Medication 
Accountability Log. If treatment is discontinued on the face and trunk, all containers of the 
test article should be collected. If treatment is re-instated, sufficient test article will be 
dispensed to the subject; previously returned test article should NOT be re-dispensed, 
rather new containers of the test article will be dispensed as needed to the subject. Every 
effort to obtain the return of all dispensed tubes of the test article should be made. If these 
efforts fail, the reason should be recorded on the drug accountability CRF and a detailed 
note of the reason for failure should be made in the source documents. 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 52 of 53 
TI SOP 305-A Protocol Template, Version 06 
A 3.4 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 ID number (tube numbers). 
• 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. 
• Amount transferred to another area for dispensing or storage. 
• Non-study disposition (e.g., lost, wasted, broken). 
• Amount returned to Sponsor or third party, if applicable. 
• Amount destroyed at study site, if applicable. 
 
The 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 3.5 Dose Modifications 
The subject should not modify the treatment regimen without consultation with the 
investigator. If the subject feels that his/her acne has cleared, he/she should continue to 
apply the test article to the designated treatment area (face and/or trunk) as instructed by 
the investigator and call the investigator for an unscheduled visit. The subject should NOT 
change his/her dosing regimen until the investigator has documented acne improvement or 
worsening to support a change in the treatment recommendations. 
 
Treatment on the face and/or trunk may be discontinued if/when acne clears (achieves an 
IGA of grade 0 or “minimal” grade 1) and re-instated if/when acne worsens (IGA≥2) 
according to the assessment of the investigator for each respective treatment area. 
 
If skin irritation or rash develops, subject should discontinue use and contact the study site. 
In the event that the investigator believes dose modification is necessary due to tolerability 
issues (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 3.6 Documentation of Application and Compliance 
A Subject Diary will be dispensed to the subject to record the dates and times of all 
application doses and any missed doses of the test article (Appendix 2). Subjects will be 


Product Name: Cortexolone 17α-Propionate (CB-03-01) 
Protocol: CB-03-01/27 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: September 9, 2015 
 
CONFIDENTIAL 
Page 53 of 53 
TI SOP 305-A Protocol Template, Version 06 
instructed to bring the diary with them to each study visit. The date and time of the first 
and last application of the test article will be recorded on the appropriate CRF. 
A 3.7 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 the test article must be explained on the completed Study 
Medication Accountability Log. All returned tubes will be weighed to the nearest tenth 
gram (0.1 gram) 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 in the study file. A copy of the Study Medication Accountability Log 
will be returned to the Sponsor. All tubes of test article will then either be a) returned to 
the study Sponsor or b) 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. 

SAP_001.pdf: 
CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/27 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 27NOV2018 
 
Page 1 of 23 
STATISTICAL ANALYSIS PLAN 
 
CRO study code CRO-MT-15-014 - Sponsor code CB-03-01/27 
 
AN OPEN-LABEL, LONG-TERM EXTENSION STUDY TO 
EVALUATE 
THE 
SAFETY 
OF 
CORTEXOLONE 
17α-
PROPIONATE (CB-03-01) CREAM, 1% APPLIED TWICE 
DAILY IN SUBJECTS WITH ACNE VULGARIS 
 
Multicenter, open-label, long-term extension study 
 
IND number: 112,137 
 
EudraCT number: 2015-002637-21 
 
Test product: 
CB-03-01 cream containing 1% cortexolone 17α-propionate (BID) 
Sponsor: 
Cassiopea S.p.A. 
Via C. Colombo 1  
20020 Lainate (MI), Italy 
Sponsor Representative: 
 
  
Development phase: 
Phase 3 
Version and date: 
Final version 1.0, 27NOV2018 
 
This study was conducted in accordance with Good Clinical Practice (GCP), ICH topic E6 
 
Property of the sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the sponsor 
 
This document comprises 23 pages plus appendices 
 






CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/27 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 27NOV2018 
 
Page 4 of 23 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN 
1 
STATISTICAL ANALYSIS PLAN APPROVAL 
2 
TABLE OF CONTENTS 
4 
STUDY SCHEDULE 
6 
LIST OF ABBREVIATIONS 
8 
1. 
INTRODUCTION 
9 
1.1 
Changes with respect to the study protocol 
9 
2. 
STUDY DESCRIPTION 
9 
2.1 
Background 
9 
2.2 
Rationale 
9 
2.3 
Study Objectives 
9 
2.4 
Study Design 
10 
2.5 
Study Population 
10 
2.5.1 
Subject Eligibility 
10 
2.5.2 
Subject Withdrawal Criteria 
10 
2.6 
Randomization Assignment 
10 
3. 
CLINICAL EVALUATIONS 
11 
3.1 
Investigator’s Global Assessment (IGA) 
11 
3.2 
Local Skin Reactions (LSRs) 
11 
3.3 
Truncal Body Surface Area (BSA) 
13 
4. 
PHOTOGRAPHY 
14 
5. 
LABORATORY TESTS 
14 
5.1 
Urine Pregnancy Tests (UPTs) 
14 
6. 
STATISTICAL CONSIDERATIONS 
15 
6.1 
Study Endpoints 
15 
6.1.1 
Safety Endpoints 
15 
6.1.2 
Efficacy Endpoints 
15 
6.2 
Hypothesis Tests 
15 
6.3 
Sample Size Calculations 
15 
7. 
STATISTICAL METHODS 
16 
7.1 
Tables, Listings and Figures layout 
16 
7.2 
Analysis sets 
16 
7.2.1 
Exclusion from the Per Protocol Set 
17 
7.3 
Evaluation of Treatment Compliance 
17 
7.4 
Handling of missing data 
17 
7.5 
Demographic, baseline and background characteristics and other study information 
17 
7.5.1 
Subjects’ disposition 
17 
7.5.2 
Analysis sets 
17 
7.5.3 
Subjects on-study 
17 
7.5.4 
Subjects excluded from efficacy and/or safety analysis 
18 


CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/27 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 27NOV2018 
 
Page 5 of 23 
7.5.5 
Discontinued subjects 
18 
7.5.6 
Demography 
18 
7.5.7 
Inclusion/Exclusion criteria 
18 
7.5.8 
Protocol deviations 
18 
7.5.9 
Medical and dermatological history 
18 
7.5.10 
Brief physical examination 
18 
7.5.11 
Prior and concomitant medications 
18 
7.5.12 
Concurrent Therapies and Procedures 
19 
7.5.13 
Subjects study visits 
19 
7.6 
Efficacy analysis 
19 
7.7 
Subgroup Analyses 
19 
7.8 
Treatment compliance and extent of exposure analyses 
19 
7.8.1 
Treatment compliance 
19 
7.8.2 
Extent of exposure 
19 
7.8.3 
Treated areas and dose adjustments 
20 
7.8.4 
Dosing 
20 
7.9 
Safety analysis 
20 
7.9.1 
Local Skin Reactions (LSRs) 
20 
7.9.2 
Adverse events 
20 
7.9.3 
Vital signs 
21 
7.9.4 
Pregnancy tests 
21 
7.10 
Interim Analyses 
21 
8. 
ANALYSIS DATASETS 
21 
9. 
REFERENCES 
22 
10. 
APPENDICES 
23 
 


CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/27 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 27NOV2018 
  
Page 6 of 23 
STUDY SCHEDULE 
 
Visit 
Visits 1-4 
Pivotal 
Phase 3 
Visit 4- 
LTF 
Baseline 
Visit 5 
Visit 6 
Visit 7 
Phone 
Call 1 
Visit 8 
Visit 9 
Phone 
Call 2 
Visit 101 
EOS 
Unscheduled 
Long-Term Follow-Up (LTF): Month 
Day 
 
0 
12 
1 
29 ± 10 
3 
85 ± 15 
4.5 
137 ± 15 
6 
183 ± 15 
7.5 
228 ± 15 
9 
274 ± 21 
If/As Needed 
Overall CB-03-01 Exposure: Month3 
0 or 3 
0 or 3 
1 or 4 
3 or 6 
4.5 or 7.5 
6 or 9 
7.5 or 10.5 
9 or 12 
 
PROCEDURES 
See Phase 3 
 
 
 
 
 
 
 
 
Informed Consent/Assent4 
 
X4 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
Demographics 
 
From Phase 35 
 
 
 
 
 
 
 
Medical/Dermatological History 
 
From Phase 35 
 
 
 
 
 
 
 
Physical Exam with Vital Signs 
 
X 
 
 
 
 
 
 
 
UPT for WOCBP 
 
X6 
 
 
 
X 
 
X 
 
IGA (Face and Trunk, separately) 
 
Face: 
From Phase 37 
Trunk: X8 
X 
X 
 
X 
 
X 
X 
Determination of Test Article Dosing 
 
X 
X 
X 
 
X 
 
X 
X 
LSRs Assessment (Face and Trunk, separately) 
 
X9 
X 
X 
 
X 
 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications & Procedures 
 
From Phase 310 
X 
X 
X 
X 
X 
X 
X 
Dispense & Collect ITA11,12 
 
X 
X 
X 
 
X 
 
X 
X 
Review of Compliance 
 
 
X 
X 
X 
X 
X 
 
X 


CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/27 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 27NOV2018 
  
Page 7 of 23 
1 
Subjects who terminate early shall complete all final visit activities. 
2 
For this LTF study, subjects must rollover from the Phase 3 pivotal study (CB-03-01/25 and CB-03-01/26) into this study AT or WITHIN THREE (3) DAYS of Visit 4-Pivotal. 
3 
Given that the Phase 3 pivotal trial is randomized (1:1) between active (CB-03-01 cream, 1%) and vehicle, upon entering the LTF study, some subjects had an overall exposure to CB-03-01 
cream, 1% of 3 months and others had 0 months (i.e., subjects were treated with vehicle in the Pivotal study). 
4 
Consent/assent may be performed up to 45 days prior to the Baseline Visit. 
5 
Demographics and medical/dermatological history were used from the Phase 3 pivotal study (Visit 1-Pivotal). 
6 
If Visit 4-Pivotal and Visit 4-LTF occur on the same day, the results of the UPT performed during the End of Study (EOS) visit of the Phase 3 pivotal study can be used as Baseline data. 
7 
IGA performed at the EOS Visit of the Phase 3 pivotal trial were used as Baseline data (Visit 4-Pivotal). 
8 
If truncal acne is to be treated (as designated by the investigator AND desired by subject), identify the percent body surface area (BSA) to be treated. BSA was estimated based on the 
assumption that 1% BSA is equivalent to the area of the subject’s hand with fingers held together. 
9 
LSRs assessed at the EOS Visit of the Phase 3 pivotal trial (Visit 4-Pivotal) were used as pre-application data for face. LSRs [pre-application] were assessed for trunk at Visit 4-LTF. After 
ITA application in the clinic, LSRs were assessed post-application (Visit 4-LTF) for face and trunk, as applicable. 
10 
Any ongoing concomitant medications and procedures were reviewed at Visit 4-LTF. 
11 
Instruct subject (and parent/guardian, if applicable) on ITA application and provide instruction sheet. Review compliance with respect to the amount and number of doses applied since the last 
visit. 
12 
Dispense subject diary, as needed. 
 
 
 


CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/27 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 27NOV2018 
  
Page 8 of 23 
LIST OF ABBREVIATIONS 
 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical classification system 
BID 
Twice a day 
BSA 
Body Surface Area 
CB-03-01 
Cortexolone 17α-propionate 
CDISC 
Clinical Data Interchange Standards Consortium 
CRF 
Case Report Form 
CV% 
Percent Coefficient of Variation 
EDC 
Electronic Data Capture 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
HPA 
Hypothalamic-Pituitary-Adrenal  
ICH 
International Conference of Harmonization 
IGA 
Investigator’s Global Assessment 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITA 
Investigational Test Article 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
LSR 
Local Skin Reaction 
LTF 
Long-Term Follow-Up 
MedDRA 
Medical Dictionary for Regulatory Activities 
OTC 
Over-the-Counter 
PP 
Per-Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
UPT 
Urine Pregnancy Test 
WOCBP 
Women of Childbearing Potential 
 


CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/27 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 27NOV2018 
  
Page 9 of 23 
1. 
INTRODUCTION 
 
Statistical analysis will be performed by the 
. The present 
Statistical Analysis Plan (SAP) specifies the analyses of the data from clinical study protocol 
CB-03-01/27. The endpoints and methods of analysis specified in this SAP are consistent with 
ICH E9 guidelines (1), with the FDA draft guidance for industry on Ance Vulgaris (2) and 
with the study protocol (3). The SAP has been compiled by the 
 
 reviewed by the Sponsor and finalized before the EDC database lock. 
 
1.1 
Changes with respect to the study protocol 
 
No change with respect to the study protocol. 
 
2. 
STUDY DESCRIPTION 
 
2.1 
Background 
 
CB-03-01 (cortexolone 17α-propionate) is a steroidal antiandrogen that is being developed as 
a 1% 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 (4). 
 
CB-03-01 could offer advantages over existing products for acne vulgaris due to its potential 
efficacy and lack of systemic antiandrogen activity. Because its pharmacological action 
appears to be limited to the local site of application, use of CB-03-01 may be able to mitigate 
the side effects related to systemic exposure to hormonal agents currently used in the 
treatment of acne. 
 
2.2 
Rationale 
 
To date, CB-03-01 cream has been used for treatment of acne vulgaris for up to 12 weeks 
with no material safety issues to note. Given that acne vulgaris is a chronic condition which 
typically waxes and wanes over time and often requires extended (and sometimes 
intermittent) treatment, this study is designed to investigate the long-term safety of CB-03-01 
cream, 1%. 
 
2.3 
Study Objectives 
 
The primary objective of this study is to determine the long-term safety of CB-03-01 cream, 
1% applied twice daily for an additional nine months in subjects with acne vulgaris that 
participated in the Phase 3 pivotal studies for a total treatment of up to 12 months. 
 


CONFIDENTIAL 
 
Statistical analysis plan 
 
Sponsor code CB-03-01/27 
Cortexolone 17-α Propionate - Acne Vulgaris 
Final version 1.0, 27NOV2018 
  
Page 10 of 23 
2.4 
Study Design 
 
This is a multicenter, open label, long-term extension study for CB-03-01 cream, 1% focused 
on safety in male and female subjects, 9 years or older who completed one of the Phase 3 
pivotal studies [CB-03-01/25 and CB-03-01/26]. Subjects applied the active medication (CB-
03-01 cream, 1%) twice daily to the entire face and, if designated by investigator AND 
desired by subject, truncal acne for nine additional months of treatment. Thus, overall subjects 
were exposed to CB-03-01 cream, 1% for a total treatment of up to 12 months (0 or 3 months 
in the Phase 3 pivotal study and an additional nine months in this long-term safety study). 
 
For this Long-Term Follow-Up (LTF) study, subjects must rollover from the Phase 3 pivotal 
study (CB-03-01/25 and CB-03-01/26) into this study AT or WITHIN THREE (3) DAYS of 
Visit 4-Pivotal. 
 
Refer to section 4 of the study protocol (3) for further details. 
 
2.5 
Study Population 
 
Male and female subjects 9 years or older with facial acne vulgaris who were enrolled in one 
of the Phase 3 pivotal studies (CB-03-01/25 and CB-03-01/26), completed the assigned 
treatment regimen without any material non-compliance with study requirements or test 
article dosing (compliance ≥ 80%) and completed the final study visit. 
 
609 subjects were included into the study and 75 sites participated in this study. 
 
2.5.1 
Subject Eligibility 
 
To be included in the study, subjects had to meet the inclusion criteria and none of the 
exclusion criteria reported in the section 5.1.1 and 5.1.2 of the study protocol (3). 
 
2.5.2 
Subject Withdrawal Criteria 
 
Procedures for handling subjects who were discontinued from the study are described in 
section 13.2 of the study protocol (3). 
 
2.6 
Randomization Assignment 
 
There is no randomization assignment in this study. This is an open label, extension study in 
which all eligible subjects are treated with CB-03-01 cream, 1% (i.e., the test article). 609 
subjects were enrolled in this extension study in order to achieve at least 300 subjects on-
study at 6 months and 100 subjects on-study at 12 months. These treatment durations include 
the 0 or 3 months of active treatment in the Phase 3 pivotal studies (CB-03-01/25 and CB-03-
01/26). Enrollment was competitive; upon enrollment of 600 subjects in this study, the option 
for rollover was not offered to other subjects in the Phase 3 pivotal studies (CB-03-01/25 and 
CB-03-01/26), even if those subjects were eligible. Enrolled subjects were provided with 
labeled test article during the study period, as needed. Subject numbers were carried over 
from the Phase 3 pivotal study (CB-03-01/25 or CB-03-01/26). 


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3. 
CLINICAL EVALUATIONS 
 
The following clinical evaluations were 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. 
 
3.1 
Investigator’s Global Assessment (IGA) 
 
Overall severity of acne using a five-point scale from 0=clear to 4=severe was evaluated for 
the face and trunk, separately. This is a static morphological scale that refers to a point in time 
and not a comparison to Baseline. IGA performed on the face during the End of Study (EOS) 
Visit of the Phase 3 pivotal study (i.e., Visit 4-Pivotal) and IGA performed on the trunk at 
Visit 4-LTF were used as Baseline data. 
 
Score Assessment 
Description 
0 
Clear 
Absence of active disease with no inflammatory or non-inflammatory 
lesions 
1 
Almost Clear Rare non-inflammatory lesions with no more than one small 
inflammatory lesions 
2 
Mild 
Some non-inflammatory lesions with no more than a few 
inflammatory lesions (papules/pustules only; no nodular/cystic 
lesions) 
3 
Moderate 
Up to many non-inflammatory lesions and may have some 
inflammatory lesions but no more than one nodular/cystic lesion 
4 
Severe 
Up to many non-inflammatory lesions and inflammatory lesions but 
no more than a few nodular/cystic lesions 
 
IGA, to document acne improvement (i.e., achieves an IGA of grade 0 or “minimal” grade 1) 
or worsening (IGA ≥ 2), was also assessed to support treatment recommendations at regularly 
scheduled visits and any unscheduled visits, as needed. 
 
3.2 
Local Skin Reactions (LSRs) 
 
At every in-clinic study visit and unscheduled visits, the investigator or designee documented 
the severity of the following LSRs known to be associated with application of topical steroids 
in the treatment areas (face and trunk, separately): 
 
1. 
Telangiectasia 
 
2. 
Skin atrophy 
 
3. 
Striae rubrae 
 
A five-point ordinal scale was used to assess the severity of these reactions: 
 
Score 
Assessment 
0 
None 
1 
Trace 


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Score 
Assessment 
2 
Mild 
3 
Moderate 
4 
Severe 
 
In addition, the investigator or designee evaluated the severity of the following LSRs known 
to be associated with acne vulgaris in the treatment areas (face and trunk, separately), using 
the five-point ordinal scales described below: 
 
4. 
Erythema 
 
5. 
Edema 
 
6. 
Scaling/dryness 
 
Erythema Score 
Assessment 
0 
None 
1 
Minimal - barely perceptible erythema 
2 
Mild - predominantly minimal erythema (pink) in the treated 
area with or without a few isolated areas of more intense 
erythema 
3 
Moderate - predominantly moderate erythema (red) in the 
treated area with or without a few isolated areas of intense 
erythema (bright red) 
4 
Severe - predominantly intense erythema (bright red) in the 
treated area with or without a few isolated areas of very intense 
(fiery red) erythema 
 
Edema Score 
Assessment 
0 
None 
1 
Minimal - scant, rare edema 
2 
Mild - easily seen edema, minimally palpable, involving up to 
1/3 of the Treatment Area 
3 
Moderate - easily seen edema and typically palpable, involving 
between 1/3 to 2/3 of the Treatment Area 
4 
Severe - easily seen edema, indurated in some areas, involving 
over 2/3 of the Treatment Area 
 
Scaling/dryness Score 
Assessment 
0 
None 
1 
Minimal - barely perceptible desquamation 
2 
Mild - limited areas of fine desquamation in up to 1/3 of the 
treatment area 
3 
Moderate - fine desquamation involving 1/3 to 2/3 of the 
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Scaling/dryness Score 
Assessment 
4 
Severe - coarser scaling involving more than 2/3 of the 
treatment area or limited areas of very coarse scaling 
 
In addition, subjects were asked to rate the severity of the following LSRs that occurred in the 
treatment areas (face and trunk, separately) since the last visit, using the four-point ordinal 
scales described below: 
 
7. 
Stinging/burning 
 
8. 
Pruritus 
 
Stinging/burning Score 
Assessment 
0 
None 
1 
Minimal, barely perceptible - tolerable and little discomfort 
2 
Moderate - tolerable, but causes some discomfort 
3 
Severe - very uncomfortable or intolerable 
 
Pruritus (itching) Score 
Assessment 
0 
None - no evidence of itching 
1 
Mild - only aware of itching at times, only present when 
relaxing, not present when focused on other activities 
2 
Moderate - often aware of itching, annoying, sometimes 
disturbs sleep and daytime activities 
3 
Severe - constant itching, distressing; frequent sleep 
disturbance, interferes with activities 
 
These LSRs were collected independently of AEs. Only LSRs that require medical 
intervention (e.g., prescription medication) or require withholding the application of the test 
articles will be documented as AEs. Any LSRs that are not listed above will be recorded as 
AEs. 
 
3.3 
Truncal Body Surface Area (BSA) 
 
Treatment of truncal acne was discussed by the investigator and subject. If the subject desired, 
the truncal treatment area was defined and agreed upon by the investigator and the subject 
with the percent BSA to be treated recorded. Percent BSA to be treated was estimated using 
the assumption that 1% BSA is equivalent to the area of the subject’s hand with fingers held 
together. Once this truncal treatment area had been defined, the subject had to continue to 
treat this area for the remainder of the study until the area was clear (an IGA of grade 0 or 
“minimal” grade 1) as determined by the investigator and then re-initiate treatment (as/if 
required) per protocol for worsening. See section 6.2 of the study protocol (3) for further 
details. 
 


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4. 
PHOTOGRAPHY 
 
Photography documentation was not required in this study. However, the investigator might 
elect to photograph the subject to document the effects of treatment, AEs or other findings 
during the trial. All photographs taken as part of this study are for informational purposes 
only and are not to assist in grading or for any other assessment. 
 
5. 
LABORATORY TESTS 
 
5.1 
Urine Pregnancy Tests (UPTs) 
 
The UPT was performed at the study site if the site met local country requirements to perform 
the testing (e.g., United States sites 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 was performed at Visit 4-LTF (or Visit 4-Pivotal, if the visits occur on the 
same day) (i.e., Baseline), Visit 8 (LTF-Month 6), and Visit 10 (EOS) on all WOCBP (see 
Section 5.1 for definition). The investigator reported 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 had to have a minimum sensitivity of 25 mIU of β-HCG/mL of urine.  
 
 


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6. 
STATISTICAL CONSIDERATIONS 
 
6.1 
Study Endpoints 
 
6.1.1 
Safety Endpoints 
 
Safety endpoints will include: 
 
• 
Incidence of any local and systemic treatment emergent AEs (TEAEs). 
• 
Number of subjects with presence (and severity) of each individual LSR (telangiectasia, 
skin atrophy, striae rubrae, erythema, edema, scaling/dryness, stinging/burning, and 
pruritus) for each treatment area, as applicable, at each time point collected (Baseline, 
and LTF-Months 1, 3, 6 and 9, and any Unscheduled Visits). 
• 
UPT results in all WOCBP at Baseline, LTF-Month 6 and EOS. 
 
6.1.2 
Efficacy Endpoints 
 
Efficacy Endpoints will include: 
 
• 
Number of subjects with each IGA severity score for each treatment area, as applicable, 
at each time point collected (Baseline and LTF-Months 1, 3, 6 and 9). 
 
6.2 
Hypothesis Tests 
 
No formal hypothesis test will be performed. 
 
6.3 
Sample Size Calculations 
 
For large samples, the two-sided confidence interval for a single proportion extends a distance 
 
𝜔= 𝑧1−𝛼
2
ඨ𝜋(1 −𝜋)
𝑛
 
 
from the observed proportion in both directions. 
 
An incidence no greater than 1% of important AEs out of 100 subjects will provide the 
estimate of no greater than a 3% prevalence of important AEs at the 95% confidence level 
with a much larger number of subjects exposed for the same duration (i.e., 12 months). 
Applying the same approach, an incidence no greater than 1% of important AEs out of 300 
subjects will provide the estimate of no greater than a 2.1% prevalence of important AEs at 
the 95% confidence level with a much larger number of subjects exposed for the same 
duration (i.e., 6 months). 
 
Approximately six hundred (600) subjects had to be enrolled in order to have 300 subjects on-
study at 6 months and 100 subjects on-study at 12 months. These treatment durations include 
the 0 or 3 months of active treatment in the Phase 3 pivotal studies (CB-03-01/25 and CB-03-
01/26). 


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7. 
STATISTICAL METHODS 
 
All statistical processing will be performed using SAS for Windows Version 9.3 (TS1M1) (5) 
(or higher ) 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. 
 
7.1 
Tables, Listings and Figures layout 
 
Tables and Listings will be provided according to the following settings:  
 
 
Background: White 
 
Foreground: Black 
 
Font face: Times 
 
Font style: Roman 
 
Font size: 10 pt 
 
Font weight: Medium (data, footers and notes), Bold (titles and headers) 
 
Font width: Normal 
 
Layout: Landscape 
 
Top Margin: 0.8 cm 
 
Bottom Margin: 0.8 cm 
 
Left Margin: 0.8 cm 
 
Right Margin: 0.8 cm 
 
Test label: CB-03-01 
 
Date format: ddMMMyyyy 
 
Means, standard deviations, percent coefficient of variations, medians, lower confidence 
limits and upper confidence limits will be rounded to one digit more than the original 
data 
 
Minima and maxima will keep the same number of decimal digits as the source values 
 
7.2 
Analysis sets 
 
Subjects who completed 6 months or 12 months on-study without material non-compliance 
with test article (CB-03-01 cream, 1%) dosing per protocol will count towards the desired 300 
subjects at 6 months and 100 subjects at 12 months. 
 
The following analysis sets will be defined: 
 
1. 
Intent-to-Treat Set (ITT): all enrolled subjects. This analysis set will be used for 
efficacy analyses. 
 
2. 
Per Protocol Set (PP): all enrolled subjects who completed the study without any 
significant protocol deviations. This analysis set will be used for efficacy analyses. 
 
3. 
Safety Set: all subjects who received at least one application of the test article. This 
analysis set will be used for safety analyses. 
 


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7.2.1 
Exclusion from the Per Protocol Set 
 
Reasons for the exclusion from the Per Protocol Set include the following: 
 
1. 
failure to satisfy any inclusion/exclusion criteria (eligibility violations); 
2. 
intake of prohibited medications. 
 
The precise reasons for excluding subjects from the per protocol set will be fully defined and 
documented in the data review meeting/conference report. 
 
7.3 
Evaluation of Treatment Compliance 
 
Compliance to the test article will be evaluated at each visit and overall according to the 
following formula: 
𝐂𝐨𝐦𝐩𝐥𝐢𝐚𝐧𝐜𝐞= 𝟏𝟎𝟎×
𝐍𝐮𝐦𝐛𝐞𝐫 𝐨𝐟 𝐚𝐜𝐭𝐮𝐚𝐥 𝐚𝐩𝐩𝐥𝐢𝐜𝐚𝐭𝐢𝐨𝐧𝐬
𝐍𝐮𝐦𝐛𝐞𝐫 𝐨𝐟 𝐬𝐜𝐡𝐞𝐝𝐮𝐥𝐞𝐝 𝐚𝐩𝐩𝐥𝐢𝐜𝐚𝐭𝐢𝐨𝐧𝐬 
 
Non-compliance will be defined as a compliance value less than 80%. 
 
7.4 
Handling of missing data 
 
Missing data will not be replaced. 
 
7.5 
Demographic, baseline and background characteristics and other study 
information 
 
Demographic, baseline and background characteristics will be reported for all the enrolled 
subjects and analyses will be performed according to the treatment the subjects actually 
received. 
 
7.5.1 
Subjects’ disposition 
 
The disposition of all subjects enrolled in the study will be listed and summarised. The 
number and percentage of subjects completing the study, the number and percentage of 
withdrawals and the reasons for withdrawal will be presented (Listing 16.2.4.1, Table 
14.1.1.1). 
 
7.5.2 
Analysis sets 
 
The subjects included in each analysis sets will be listed and summarised (Listing 16.2.4.2, 
Table 14.1.1.2). 
 
7.5.3 
Subjects on-study 
 
The number and percentage of subjects who were on-study at 3, 6, 9 and 12 months will be 
presented (Table 14.1.1.3, Table 14.1.1.4, Table 14.1.1.5). 
 


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7.5.4 
Subjects excluded from efficacy and/or safety analysis 
 
All subjects excluded from the efficacy and/or safety analysis will be listed and the reasons 
for exclusion will be reported (Listing 16.2.3.1). 
 
7.5.5 
Discontinued subjects 
 
All subjects who discontinued the clinical trial will be listed. Sex, age, last visit performed 
before discontinuation, type of discontinuation, date of premature discontinuation and primary 
reason for subject premature discontinuation will be reported (Listing 16.2.1.1). 
 
7.5.6 
Demography 
 
Demographic data will be listed and summarised. The number and percentage of subjects in 
each category of categorical variables (e.g. sex) and the descriptive statistics (mean, standard 
deviation, CV%, minimum, median and maximum) of continous variables (e.g. age) will be 
presented (Listing 16.2.4.3, Table 14.1.1.6, Table 14.1.1.7, Table 14.1.1.8). 
 
7.5.7 
Inclusion/Exclusion criteria 
 
All the unmet inclusion/exclusion criteria will be listed and summarised. The number and 
percentage of subjects for each skin type will be reported (Listing 16.2.4.4, Table 14.1.1.9, 
Table 14.1.1.10).  
 
7.5.8 
Protocol deviations 
 
All the protocol deviations reported during the clinical trial will be listed by subject and 
summarised; the number and percentage of subjects for each deviation will be reported 
(Listing 16.2.2.1, Table 14.1.1.11, Table 14.1.1.12). 
 
7.5.9 
Medical and dermatological history 
 
All the findings of medical history of all subjects enrolled in the study will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) and listed  (Listing 16.2.10.1). The 
version of the dictionary used for coding will be reported in the clinical study report. 
 
The findings of medical history will be summarised. The number and percentage of subjects 
with any findings will be presented by PT and SOC (Table 14.1.1.13). 
 
7.5.10 
Brief physical examination 
 
Whether the physical examination was performed or not and, if performed, the date of 
examination will be listed  (Listing 16.2.10.2). 
 
7.5.11 
Prior and concomitant medications 
 
All prior and concomitant medications will be coded using the World Health Organization 
Drug Dictionary Enhanced (WHO DDE) and listed (Listing 16.2.10.3). The version of the 
dictionary used for coding will be reported in the clinical study report. 


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Prior and concomitant medications will be listed and summarized. The number and 
percentage of subjects with any concomitant medication will be presented by and ATC 4th 
level (or the higher available ATC level if 4th level is missing) and standardised drug name 
(Table 14.1.1.14, Table 14.1.1.15). 
 
7.5.12 
Concurrent Therapies and Procedures 
 
Non medication concurrent therapies and procedures will be listed (Listing 16.2.10.4). 
 
7.5.13 
Subjects study visits 
 
The dates of all subjects study visits will be listed (Listing 16.2.10.5). 
 
7.6 
Efficacy analysis 
 
The investigator's global assessment scores for face and trunk will be listed (Listing 16.2.6.1) 
and summarised using contingency tables for the ITT and PP sets (Table 14.2.1.1, Table 
14.2.1.2, Table 14.2.1.3, Table 14.2.1.4). 
 
7.7 
Subgroup Analyses 
 
No subgroup analysis is planned. 
 
7.8 
Treatment compliance and extent of exposure analyses 
 
7.8.1 
Treatment compliance 
 
The dispensation date, the weight of the dispensed article, the return date, the weight of the 
returned article, the number of applied doses, the number of expected doses and compliance 
rate will be listed separately for face and trunk (Listing 16.2.5.1, Listing 16.2.5.2). 
 
Descriptive statistics will be used to summarize the test article compliance at each visit and 
overall for the ITT and PP sets separately for face and trunk. The proportion of compliant (i.e. 
with a compliance ≥ 80%) and non-compliant (i.e. with a compliance < 80%) subjects will be 
summarized by table of frequencies at each visit and overall for the ITT and PP sets 
separately for face and trunk (Table 14.2.2.1, Table 14.2.2.2, Table 14.2.2.3, Table 14.2.2.4). 
 
7.8.2 
Extent of exposure 
 
The date/time of first and last application, the total amount of test article used (calculated as 
number of grams applied for each subject from the weights of the returned test articles) and 
the mean daily amount of test article applied (calculated as the total amount of test article 
used divided by the number of days of treatment) will be listed (Listing 16.2.5.3). 
 
Descriptive statistics will be used to summarize exposure to the test article at each visit and 
overall for the ITT, PP and Safety sets (Table 14.2.2.5, Table 14.2.2.6, Table 14.2.2.7). 
 


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7.8.3 
Treated areas and dose adjustments 
 
The treated areas and any dose adjustments will be listed (Listing 16.2.5.4). 
 
7.8.4 
Dosing 
 
The date/time of facial application and truncal application, the trunk areas to be treated and 
the percent BSA of truncal acne to be treated wil be listed at each visit (Listing 16.2.5.5). 
 
7.9 
Safety analysis 
 
All safety analyses will be performed on subjects of the Safety set. Subjects will be analysed 
according to the treatment they actually received. 
 
7.9.1 
Local Skin Reactions (LSRs) 
 
LSRs (telangiectasia, skin atrophy, striae rubrae, erythema, edema, scaling/dryness, 
stinging/burning, and pruritus) will be listed separately for face and trunk (Listing 16.2.9.1, 
Listing 16.2.9.2) and summarized separately for face and trunk by the frequency of each 
individual LSR and severity at each visit (Table 14.3.5.1, Table 14.3.5.2).  
 
7.9.2 
Adverse events 
 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
listed. The version of the dictionary used for coding will be reported in the clinical study 
report. 
 
Individual TEAEs (i.e. all the all AEs occurring or worsening after the first dose of the test 
article) will be listed (Listing 16.2.7.1). 
 
TEAEs will be summarised as follows: 
 
• 
The number and percentage of subjects with any TEAE and the number of TEAEs will 
be presented overall (Table 14.3.1.1) and by SOC and PT (Table 14.3.1.2); 
• 
The number and percentage of subjects with any TEAE by relationship and the number 
of TEAEs by relationship will be presented (Table 14.3.1.1); 
• 
The number and percentage of subjects with any TEAE related to the IMP and the 
number of TEAEs related to the IMP will be presented by SOC and PT (Table 
14.3.1.3); 
• 
The number and percentage of subjects with any TEAE by severity and the number of 
TEAEs by severity will be presented overall (Table 14.3.1.1) and by SOC and PT 
(Table 14.3.1.4); 
• 
The number and percentage of subjects with any TEAE leading to discontinuation and 
the number of TEAEs leading to discontinuation will be presented (Table 14.3.1.1). 
 


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Serious TEAEs will be summarised as follows: 
 
• 
The number and percentage of subjects with any Serious TEAE and the number of 
Serious TEAEs will be presented overall (Table 14.3.1.1) and by SOC and PT (Table 
14.3.1.5); 
• 
The number and percentage of subjects with any Serious TEAE by relationship and the 
number of Serious TEAEs by relationship will be presented (Table 14.3.1.1); 
• 
The number and percentage of subjects with any Serious TEAE related to the IMP and 
the number of Serious TEAEs related to the IMP will be presented by SOC and PT 
(Table 14.3.1.6); 
• 
The number and percentage of subjects with any Serious TEAE leading to 
discontinuation and the number of Serious TEAEs leading to discontinuation will be 
presented (Table 14.3.1.1). 
• 
The number and percentage of subjects with any Serious TEAE leading to death and the 
number of Serious TEAEs leading to death will be presented (Table 14.3.1.1). 
 
All Serious TEAEs will be listed and all TEAEs leading to discontinuation will be listed 
(Table 14.3.2.1). 
 
7.9.3 
Vital signs 
 
Vital signs will be listed (Listing 16.2.9.3) and summarised. Descriptive statistics (mean, 
standard deviation, CV%, minimum, median and maximum) will be presented (Table 
14.3.5.3). 
 
7.9.4 
Pregnancy tests 
 
The results of pregnancy at Baseline, LTF-Month 6 and EOS test will be listed (Listing 
16.2.8.1). 
 
7.10 
Interim Analyses 
 
No interim statistical analysis is planned. 
 
8. 
ANALYSIS DATASETS 
 
Analysis datasets will be created according to the ADaM model of CDISC (6). 
 


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9. 
REFERENCES 
 
1. 
ICH Topic E9: Statistical principles for clinical trials. CPMP/ICH/363/96 
2. 
Guidance for Industry - Acne Vulgaris: Developing Drugs Treatment - Draft version, 
September 2005 
3. 
CB-03-01/27. A Phase 3, An Open-Label, Long-Term Extension Study To Evaluate 
The Safety Of Cortexolone 17Α-Propionate (Cb-03-01) Cream, 1% Applied Twice 
Daily In Subjects With Acne Vulgaris. Cassiopea SpA, September 9, 2015 
4. 
Celasco G, Moro, L, Bozzella R, Ferraboschi P, Bartorelli L, Quattrocchi C, Nicoletti F. 
Biological profile of cortexolone 17α-propionate (CB-03-01), a new topical and 
peripherally selective androgen antagonist.  Arzneim.-Forsch. 2004; 54, 881-886 
5. 
SAS/STAT® 9.3 User’s Guide 
6. 
Analysis Data Model (ADaM) - Implementation Guide - Final version 1.0, December 
17, 2009 
 
 


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10. 
APPENDICES 
 
Appendix 1. Section 14 - Tables Shells 
Appendix 2. Section 16.2 - Individual Subject Data Listings Shells