Clinical trial NCT02720627
Conditions: Acne Vulgaris
Keywords: acne cortexolone anti-androgen
Sponsor: Cassiopea SpA
Start date: 2016-10-28; Completion date: 2018-03-21
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is designed to determine the hypothalamic-pituitary-adrenal (HPA) axis suppression potential and pharmacokinetic (PK) properties of CB-03-01 Cream, 1%, applied every twelve hours for two weeks, in pediatric patients 9 to less than 12 years of age with acne vulgaris. Adrenal suppression effects and systemic safety are an important safety concern. The current study is designed to investigate these potential concerns under maximal use conditions.

Detailed description:

Arms: arm 1: Topical CB-03-01 (cortexolone 17α-propionate) cream containing 1% active drug applied to the face and trunk twice daily for 14 days
Interventions: intervention 1: cortexolone 17α-propionate
Intervention descriptions: intervention 1: CB-03-01 cream is a topical steroidal antiandrogen that is being developed for the potential treatment of acne vulgaris, an androgen-dependent skin disorder.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
Page 1 of 66 
TI SOP 305-A Protocol Template, Version 06 
AN OPEN LABEL EVALUATION OF THE ADRENAL SUPPRESSION 
POTENTIAL AND TROUGH PLASMA CONCENTRATIONS OF 
CORTEXOLONE 17α-PROPIONATE (CB-03-01) CREAM  
APPLIED EVERY 12 HOURS FOR TWO WEEKS  
IN SUBJECTS 9 TO <12 YEARS OF AGE WITH ACNE VULGARIS 
 
PROTOCOL NUMBER: 
CB-03-01/28 
TI PROJECT NUMBER: 
171-7151-208 
REGULATORY FILING NUMBER: 
IND #112,137 
ORIGINAL PROTOCOL:  
February 18, 2016 
FILENAME: 
171-7151-208_pro_18Feb2016_v1.0.docx 
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 MONITOR: 
Daniel Piacquadio, M.D. (Therapeutics, Inc.) 
9025 Balboa Avenue, Suite 100 
San Diego, CA 92123 
858-571-1800, ext. 107 (office) 
858-571-1234 (facsimile) 
619-889-7058 (cell) 
danp@therapeuticsinc.com (email) 
PROJECT MANAGERS: 
Stephanie Magajna (Therapeutics, Inc.) 
9025 Balboa Ave, Ste 100, San Diego, CA 92123 
858-571-1800, ext. 128 (office) 
858-571-1234 (facsimile) 
smagajna@therapeuticsinc.com (email) 
Beata Kosak (Ergomed PLC) 
ul. Kolowa 8, 30-134 Krakow, Poland 
+48 12 622 44 67 (office) 
+48 12 622 44 60 (facsimile) 
beata.kosak@ergomedplc.com (email) 
 
24 Hour Emergency Telephone Number 
619-889-7058 
 
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: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
CONFIDENTIAL 
Page 3 of 66 
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. 
 
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) or 
Ethics Committee(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-03-01/28  
 
 
Site number:              
 
Version: 1.0 
 
Date of final version: February 18, 2016 
 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
CONFIDENTIAL 
Page 4 of 66 
TI SOP 305-A Protocol Template, Version 06 
PROTOCOL SYNOPSIS 
Title 
An Open Label Evaluation of the Adrenal Suppression Potential and Trough 
Plasma Concentrations of Cortexolone 17α-Propionate (CB-03-01) Cream 
Applied Every 12 Hours for Two Weeks in Subjects 9 to <12 Years of Age 
with Acne Vulgaris 
Protocol Number 
CB-03-01/28 
Study Type 
Phase 2 
Test Article(s) 
CB-03-01 cream containing 1% cortexolone 17α-propionate 
Study Objective 
The primary objectives of this study are to determine: a) the adrenal 
suppression potential and b) the trough plasma concentrations associated 
with topical application of CB-03-01 cream, 1% in subjects with acne 
vulgaris. 
Study Design 
An open label, multicenter study in children 9 to <12 years of age. 
Treatment Groups 
Eligible subjects will be dispensed CB-03-01 cream, 1% and will be 
instructed how and where to apply the test article to the face and trunk (see 
Section 6.2 for definition of the “Treatment Area”) every 12 hours for two 
(2) weeks. Subjects will apply 2 grams of the test article. The test article will 
be applied by the subject or subject’s parent/guardian in the clinic under 
supervision on Day 1 and Day 7 and at home for all other applications. 
Duration of Treatment 
Approximately 2 weeks 
Duration of Study 
Approximately 4-6 weeks  
Study Population 
Male and female subjects 9 to <12 years of age with moderate to severe facial 
acne vulgaris (Grade 3 or 4 on the Investigator’s Global Assessment [IGA]) 
and obvious acne on the trunk (i.e., shoulder, upper chest, and/or back). 
Total Number of 
Subjects 
At least twenty (20) evaluable subjects. This may require the enrollment of 
approximately 24 subjects. 
Number of Sites 
Approximately six sites in the United States and Poland. 
Inclusion Criteria 
To enter the study, a subject must meet the following criteria:  
 
1. Subject is male or female, 9 to <12 years of age at the time of 
consent/assent. 
2. Subject 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 written informed consent for the 
subject.  


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
CONFIDENTIAL 
Page 5 of 66 
TI SOP 305-A Protocol Template, Version 06 
3. Females of childbearing potential1 must be using highly effective birth 
control methods2,3 with a negative urine pregnancy test (UPT) at the 
Screening and Baseline Visits. 
4. Subject has moderate to severe facial acne vulgaris (Grade 3 or 4) as 
determined by the Investigator’s Global Assessment (IGA) [0 (clear) to 
4 (severe) scale] and obvious acne on the trunk (i.e., shoulders, upper 
chest, and/or back) at the Screening Visit. 
5. Subject has facial acne vulgaris with a minimum of 15 inflammatory 
lesions (papules, pustules, and nodules/cysts) and a minimum of 15 non-
inflammatory lesions (open and closed comedones) at the Screening 
Visit. 
6. Subject must be in general good health in the opinion of the investigator, 
with normal renal function as defined per protocol4 and no clinically 
relevant abnormalities present at the screening physical examination, in 
the subject’s medical history, or from safety laboratory tests 
(hematology, serum chemistry, and urinalysis). 
7. Subject has normal adrenal function measured with a Cosyntropin 
Stimulation Test (CST) at Screening, defined as a normal pre-
stimulation cortisol level and a 30-minute post-stimulation cortisol level 
of >18 μg/dL. 
8. Subject and parent/guardian are able to communicate with the staff and 
are willing to comply with study instructions, reside at and/or 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 a Body Mass Index (BMI) for age percentile >95% (see 
Appendix 5). 
3. Except for the use of contraceptives, subject reported use of any 
prescription drug or herbal product within two (2) weeks of Visit 2 
(Baseline), any non-prescription drug or vitamin or mineral supplements 
within one (1) week of Visit 2 (Baseline); any known enzyme-inducer, 
                                                 
1 Females of childbearing potential are defined as subjects who have experienced menarche or are 10 years 
of age or older. Note: If a female becomes 10 years of age during the study, she must have a negative UPT 
at that time to continue study participation. 
2 Highly effective contraception includes: a) an intrauterine device (IUD) for at least one week prior to Visit 
2 (Baseline); b) hormonal contraceptives (injections, implants, transdermal patch, vaginal ring); c) partner 
vasectomy (performed at least six months prior to Visit 2 [Baseline]); d) oral contraceptives WITH a barrier 
method: i) Male or female condom; diaphragm with spermicides; cervical cap with spermicides; 
contraceptive sponge; e) two barrier forms of contraception: i) male or female condom; ii) diaphragm with 
spermicides; iii) cervical cap with spermicides; iv) contraceptive sponge; OR f) total abstinence. 
3 Females taking hormonal therapy for any reason exclusive for the treatment of acne (e.g., as contraception, 
etc.) must be on treatment for at least 12 weeks prior to study entry and must not change their dosing regimen 
during the study. Those who have used hormonal therapy prior to study entry must have discontinued use at 
least eight weeks prior to the start of the study.   
4 Normal renal function (per the requirement of inclusion criterion #6) is defined as a creatinine clearance of 
80 mL/min or greater based on serum creatinine and the Cockcroft and Gault equation [1]. 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
CONFIDENTIAL 
Page 6 of 66 
TI SOP 305-A Protocol Template, Version 06 
enzyme-inhibitor, or reported chronic exposure to enzyme-inducers 
such as paint solvents or pesticides within 30 days of Visit 2 (Baseline). 
4. Subject has used topical anti-acne medications containing retinoids such 
as tazarotene, adapalene, or tretinoin within four (4) weeks of Visit 2 
(Baseline). 
5. Subject has used the following systemic anti-acne medications: 
antibiotics within two (2) weeks of Visit 2 (Baseline), spironolactone 
within four (4) weeks of Visit 2 (Baseline), or retinoid therapy within 
three (3) months of Visit 2 (Baseline). 
6. Subject has used topical corticosteroids (including inhaled and intranasal 
corticosteroids) within two (2) weeks of the CST at Visit 1 (Screening) 
and/or between Visit 1 (Screening) CST and Visit 2 (Baseline). 
7. Subject has used systemic corticosteroids (including intramuscular and 
intralesional injections) within four (4) weeks of the CST at Visit 1 
(Screening) and/or between the Visit 1 (Screening) CST and Visit 2 
(Baseline). 
8. Subject has used light treatments, microdermabrasion or chemical peels 
to the face, chest, and/or back within eight (8) weeks of Visit 2 
(Baseline). 
9. Subject has any skin or medical condition, including facial hair that 
could interfere with the evaluation of the test article or requires the use 
of interfering topical or systemic therapy. 
10. Subject has any condition which, in the investigator’s opinion, would 
make it unsafe for the subject to participate in this research study. 
11. Subject has the need or plans to be exposed to artificial tanning devices 
or excessive sunlight during the study. 
12. Subject cannot avoid any type of strenuous exercise (swimming, 
running, team sports, etc.) or the use of hot tubs/saunas from Visit 2 
(Baseline) to the end of the study (Visit 4). 
13. Subject has any clinically significant medical abnormality or chronic 
disease of the cardiovascular, gastrointestinal, respiratory, hepatic, or 
renal systems. This includes conditions (e.g., gastrointestinal surgery) 
that may interfere with metabolism or excretion. 
14. Subject has a history of alcohol and/or drug abuse in the investigator's 
judgment or has a positive urine drug screen result at Visit 1 (Screening). 
15. Subject is unable to communicate or cooperate with the investigator due 
to language problems, poor mental development, or impaired cerebral 
function. 
16. Subject is known to be hypersensitive to the test article or any 
components in the test article (see Section 6.1). 
17. Subject has received an investigational drug or been treated with an 
investigational device within 30 days prior to Visit 2 (Baseline). 
18. Subject is currently enrolled in an investigational drug or device study. 
19. Subject has an irregular sleep schedule (cortisol levels exhibit 
physiological diurnal variation) as judged by the investigator. 
20. Subject has experienced significant blood loss, as judged by the 
investigator, within 60 days or has donated plasma within 72 hours prior 
to Visit 2 (Baseline). 
21. Subject tests positive at screening for human immunodeficiency virus 
(HIV) or is known to be seropositive for HIV. 
22. Subject tests positive at Visit 1 (Screening) for hepatitis B surface 
antigen, hepatitis C antibody, or has a history of a positive result. 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
CONFIDENTIAL 
Page 7 of 66 
TI SOP 305-A Protocol Template, Version 06 
23. Subject had major surgery within 30 days prior to Visit 2 (Baseline) or 
plans to have surgery during the study. 
24. Subject has participated in a prior CB-03-01 clinical trial. 
Study Procedures 
The study will include a Screening Visit, a Baseline Visit, and two (2) 
scheduled follow-up visits.   
 
DLT and Stopping Rules: A Dose Limiting Toxicity (DLT) is defined as a 
systemic Grade 2 or higher (CTCAE, Version 4.0)5 adverse event (AE) for 
which there is no clear alternative explanation of the cause of the AE. Non-
systemic (local) AEs Grade 3 or higher for which there is no clear alternative 
explanation of the cause of the AE will also be considered DLTs. If more 
than 3 subjects within the study exhibit a DLT, enrollment will be stopped. 
Any subject who experiences a DLT, as described above, must discontinue 
treatment and be scheduled for a final visit. Any DLTs that are Grade 2 or 
greater systemic AEs with documented worsening from Baseline must be 
reported by the investigator immediately. 
 
1. Visit 1 (Days -45 to -14) – Screening Visit: This visit will be scheduled 
such that the CST occurs between 7 AM and 9 AM. Screening labs will 
be collected with the subject fasting; if fasting laboratory tests are not 
possible, samples should still be collected, noting the protocol deviation. 
At Visit 1, study staff will explain the study procedures and an informed 
consent/assent must be signed prior to the initiation of any study-related 
procedures. At this visit, consenting subjects will be assigned a 
sequential subject screening number and begin screening procedures. 
Demographics, medical/dermatological history, and prior and 
concomitant medications and procedures will be reviewed with the 
subject. If a subject requires a “washout” period to meet 
inclusion/exclusion (I/E) criteria requirements, the subject will be 
required to return to the clinic to complete the remaining screening 
activities. Subjects not requiring a wash-out period from prohibited 
medications and procedures will undergo screening activities at this 
visit. Screening activities to determine subject eligibility include a 
review of the I/E criteria, a dermatologic exam, a physical examination 
(including vital signs, height, and weight), a UPT (if applicable), an 
electrocardiogram (ECG), routine safety laboratory tests (hematology, 
clinical chemistry, and urinalysis), drug and virus screens, clinical 
evaluations (including lesion counts and IGA [face only]), 
pharmacokinetic (PK) blood draw (for screening levels of plasma 
cortexolone 17α-propionate and cortexolone concentrations), and a CST 
performed between 7 AM and 9 AM to determine adrenal system 
response (i.e., Screening CST). Mild soap will be dispensed to the 
subject to use during the study and the subject will be instructed, to the 
extent possible, to wash or shower with the provided mild soap in the 
morning prior to the next visit. Note: Subjects who were consented for 
longer than 45 days prior to Baseline will be re-consented prior to 
enrolling into the treatment phase of the trial. 
 
                                                 
5 NCI Common Terminology Criteria for Adverse Events, Version 4.0. 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
CONFIDENTIAL 
Page 8 of 66 
TI SOP 305-A Protocol Template, Version 06 
2. Visit 2 (Day 1) – Baseline Visit: The Baseline Visit must be 
conducted at least 14 days and not more than 45 days after the 
Screening CST. On Day 1, subjects with a normal response to CST 
(30-minute post-stimulation serum cortisol >18 µg/dL) who continue 
to meet all the other I/E criteria will be enrolled in the study. Facial 
lesion counts, IGA, and UPT (if applicable) will be performed prior to 
test article application. The severity of local skin reactions (LSRs) 
(telangiectasia, skin atrophy, striae rubrae, erythema, edema, 
scaling/dryness, stinging/burning, and pruritus) will be documented for 
the face and trunk, separately, prior to test article application. 
Concomitant medications/procedures will be reviewed. 
 
Subjects will be assigned to the next available (lowest) subject number 
in ascending order. A PK blood draw will be performed before the 
initial application of the test article for baseline concentrations of 
cortexolone 17α-propionate and cortexolone in plasma. 
 
The subject and parent/guardian will be instructed on how to apply the 
test article to the face and trunk (see Section 6.2 for definition of the 
“Treatment Area”). The percent body surface area (BSA)6 to be treated 
(face + trunk) will be recorded. The test article will be weighed prior 
to dispensing and the first dose will be applied in the clinic under 
supervision of the investigator or study staff. Subjects should not wash 
the Treatment Area for at least eight (8) hours after test article 
application and not apply any make-up or skin care products to the 
Treatment Area for at least four (4) hours after test article application. 
Subjects will also be instructed not to swim or participate in any other 
activities which could potentially remove the product from the 
Treatment Area for the duration of the study.  
 
Approximately 15 minutes after application of the test article, AEs and 
LSRs (face and trunk, separately) post-application will be assessed. 
Subjects including the parent/guardian will be instructed to apply the 
test article to the Treatment Area every 12 hours at approximately the 
same time each morning and evening until the next scheduled follow-
up visit. The subject will be scheduled for the first follow-up visit; the 
timing of this visit (Visit 3) will occur so that the trough PK blood draw 
on Day 7 occurs 12 hours (± 30 minutes) after the evening application 
on Day 6. 
 
3. Visit 3 (Day 7±1) – Follow-Up Visit: Subjects will return to the clinic 
for clinical evaluations (AEs and LSRs [face and trunk, separately]) and 
review of concomitant medications/procedures. Prior to the visit, 
subjects will be requested to i) apply the test article to the Treatment 
Area in the evening prior to the scheduled clinic visit and record the time 
(treatment to occur 12 hours (± 30 minutes) prior to the PK blood draw); 
ii) to the extent possible, wash or shower with the provided mild soap 
prior to arriving at the clinic; iii) withhold application of the test article 
on the morning of the visit; and iv) bring all tubes of test article to the 
                                                 
6 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. 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
CONFIDENTIAL 
Page 9 of 66 
TI SOP 305-A Protocol Template, Version 06 
clinic for weighing. Subjects will have a trough PK blood draw in the 
clinic prior to the morning application of CB-03-01 cream, 1% for 
determination of plasma cortexolone 17α-propionate and cortexolone 
concentrations. Test article application will be reviewed with the subject 
and parent/guardian and additional test article will be dispensed, if 
necessary. Subjects will apply the test article to the Treatment Area in 
the clinic under staff supervision (and with assistance from 
parent/guardian, if necessary) and will be scheduled for the next follow-
up visit; the timing of this visit (Visit 4) will occur so that the trough PK 
blood draw on Day 14 occurs 12 hours (± 30 minutes) after the evening 
application on Day 13. 
 
4. Visit 4 (Day 14±2) – Final or End of Study (EOS) Visit: This visit will 
be scheduled such that the CST occurs between 7 AM and 9 AM and 
within one hour (±1) of the Screening CST. EOS safety laboratory test 
results will indicate if the subject was fasting (preferred) or not. Subjects 
will return early in the morning for clinical evaluations (IGA [face only], 
AEs, and LSRs [face and trunk, separately]), review of concomitant 
medications/procedures, and physical examination/vital signs. Prior to 
the visit, subjects will be requested to i) apply the test article to the 
Treatment Area in the evening prior to the scheduled clinic visit and 
record the time (treatment to occur 12 hours (± 30 minutes) prior to the 
PK blood draw); ii) withhold application of the test article on the 
morning of the visit; and iii) bring all tubes of test article to the clinic 
for weighing. Prior to the final application of the test article in the clinic, 
a CST will be performed within an hour (±1) of the Screening CST, 
ideally between 7 AM and 9 AM, to determine changes in the adrenal 
system response. Subjects will have a UPT (if applicable), an ECG, 
blood and urine collected for routine safety laboratory tests 
(hematology, clinical chemistry, and urinalysis), and a trough PK blood 
draw for determination of plasma cortexolone 17α-propionate and 
cortexolone concentrations. All tubes of test article will be collected. All 
subjects will be discharged from the study at this visit unless there is 
evidence of adrenal suppression. 
 
5. Post-Treatment Follow-up Visits (Suppressed Subjects Only): Any 
subject who has evidence of adrenal suppression (30-minute post-
stimulation serum cortisol level of ≤18 µg/dL) at Visit 4 (Day 14) or 
EOS will return for CST approximately every four (4) weeks BUT no 
sooner than four (4) weeks (28 days) after Visit 4, and subsequently 
about every four (4) weeks BUT no earlier than every four (4) weeks 
(>28 days) thereafter until the adrenal response returns to normal (30-
minute post-stimulation serum cortisol >18 µg/dL). During this period, 
the subject shall not use the test article or any steroid medication (topical 
or systemic). 
Study Measurements 
Acne severity will be assessed by the investigator as follows: 
• Investigator’s Global Assessment (IGA): Overall severity of facial 
acne using a five-point scale from 0 = clear to 4 = severe will be 
evaluated at Screening, Baseline, and Day 14 (or EOS). This is a 
static morphological scale that refers to a point in time and not a 
comparison to Baseline. 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
CONFIDENTIAL 
Page 10 of 66 
TI SOP 305-A Protocol Template, Version 06 
• Acne Lesion Counts: Inflammatory lesions (papules, pustules and 
nodules/cysts) and non-inflammatory lesions (open and closed 
comedones) on the entire face will be counted and recorded 
separately at Screening and Baseline. Lesions on the trunk (i.e., 
shoulders, upper chest, and/or back) will not be counted. 
 
Safety will be assessed by the investigator via the following: 
• 
Physical examination/vital signs at Screening and Day 14 (or EOS); 
• 
Safety laboratory tests (hematology, clinical chemistry, and 
urinalysis) at Screening and Day 14 (or EOS); 
• 
UPTs (for all females of childbearing potential) at Screening, 
Baseline, and Day 14 (or EOS); and 
• 
ECGs at Screening and Day 14 (or EOS). 
 
The following additional safety parameters will be assessed. 
 
Local Skin Reactions (LSRs): LSRs will be assessed by the investigator and 
the subject at Baseline (before and after the first test article application), Day 
7, and Day 14 for the face and trunk, separately. Telangiectasia, skin atrophy, 
and striae rubrae will be assessed by the investigator using a five-point 
ordinal scale (0 = none, 1 = trace, 2 = mild, 3 = moderate, and 4 = severe). 
Erythema, edema, and scaling/dryness will also be assessed by the 
investigator using a five-point ordinal scale (0 = none, 1 = minimal, 2 = mild, 
3 = moderate, and 4 = severe). Subjects will be asked to rate the severity of 
stinging/burning using a four-point ordinal scale (0 = none, 1 = minimal, 2 
= moderate, and 3 = severe) and pruritus using a four-point ordinal scale (0 
= none, 1 = mild, 2 = moderate, and 3 = severe). Only LSRs that require 
medical intervention (e.g., prescription medication) or require withholding 
the application of the test article will be documented as AEs. In addition, any 
LSRs that are not listed above will be recorded as AEs. 
 
Adverse Events (AEs): All local and systemic AEs will be recorded. At each 
visit, subjects will also be questioned specifically about the status of any new 
or ongoing AEs. 
 
Cosyntropin Stimulation Test (CST): At Visit 1 (Screening), a CST will be 
performed for each subject between 7 AM and 9 AM. The Visit 4 
(Day 14/EOS) CST will also be performed within one hour (±1) of the 
Screening CST and ideally also between 7 AM and 9 AM. Any subject who 
has an abnormal CST result (serum cortisol level <18 µg/dL) at Day 14 or 
EOS will return approximately every four (4) weeks thereafter for CST until 
the serum cortisol returns to normal. 
 
PK Assessment: Eligible subjects will have a PK blood draw at Screening, 
Baseline, Day 7, and Day 14. For Day 7 and Day 14, all subjects will have 
blood drawn 12 hours (± 30 minutes) after the evening application on the 
prior day for assessment of “trough” cortexolone 17α-propionate and 
cortexolone concentrations in plasma. 
 
Test Article Compliance: Test article applications on Day 1 and Day 7 will 
occur in the clinic under study staff supervision. The other test article doses 
will be applied by the subject or the subject’s parent/guardian at home. The 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
CONFIDENTIAL 
Page 11 of 66 
TI SOP 305-A Protocol Template, Version 06 
subject will be instructed to record the date and time of application on a 
diary. Subject diaries will be reviewed at follow-up visits to determine the 
doses of test article applied since the last visit and the subject will be 
counseled regarding compliance, if necessary. All dispensed tubes of CB-
03-01 cream, 1% will be weighed at each visit and the amount of test article 
used will be recorded.   
Study Endpoints 
Safety Endpoints: 
Primary Safety Endpoints 
• 
Hypothalamic-Pituitary-Adrenal 
(HPA) 
Axis 
Response 
to 
Cosyntropin: Measurement of serum cortisol concentrations after 
stimulation of the adrenal cortex with Cosyntropin (CST) at 
Screening and Day 14 (or EOS). HPA axis suppression is defined 
as a post-stimulation serum cortisol level <18 µg/dL at Day 14 (or 
EOS). 
• 
Trough Plasma Concentrations: Trough measurements of 
cortexolone 17α-propionate and cortexolone concentration in 
plasma at Screening, Baseline, Day 7 and Day 14. 
 
Secondary Safety Endpoints  
• 
Safety laboratory testing (hematology, clinical chemistry, and 
urinalysis) at Screening and Day 14 (or EOS). 
• 
Local and systemic AEs at every visit (Baseline, Days 7 and 14).  
• 
The severity of the following LSRs [for face and trunk, separately]: 
telangiectasia, skin atrophy, striae rubrae, erythema, edema, 
scaling/dryness, stinging/burning, and pruritus at Baseline (pre- and 
post-test article application), Day 7, and Day 14. 
• 
Physical examination/vital signs at Screening and Day 14 (or EOS). 
• 
UPTs (for all females of childbearing potential) at Screening, 
Baseline, and Day 14 (or EOS). 
• 
ECG at Screening and Day 14 (or EOS). 
 
Efficacy Endpoints: 
Due to the short duration of this PK study, no efficacy assessments/endpoints 
are planned. However, the overall severity of each subject’s facial acne at 
the end of the study will be documented by the investigator or designee using 
the IGA score. 
Sample Size 
Calculations 
No formal power calculations were performed to establish the sample size. 
The number of evaluable subjects is historically consistent with other 
HPA/PK studies. 
Statistical Methods 
All statistical processing will be performed using SAS® unless otherwise 
stated. Excel or SAS® will be used for the analysis of trough plasma 
concentrations data. 
 
All subjects enrolled in the study who were dispensed and applied test article 
at least once will be included in the analysis of safety and will be considered 
the Safety population. Subjects who were discontinued from the study at 
Visit 2 (Baseline) due to abnormal screening laboratory test results or failure 
to meet any other eligibility criteria will be classified as screen failures and 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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excluded from the HPA axis suppression summaries. Subjects with both 
Screening and Day 14 (or EOS) serum cortisol data (pre- and post-
cosyntropin stimulation) who completed the study without significant 
protocol violations will be considered evaluable (Evaluable population). 
Subjects included in the PK analysis (PK population) must not have any 
significant protocol deviations, must have at least an 80% dose compliance 
based on number of applications, and must apply the final three doses as 
prescribed prior to the EOS PK assessment. 
 
Demographic and baseline characteristics will be summarized for the Safety, 
Evaluable, and PK populations. In addition, demographic variables, AEs, 
and primary reason for screen failure will be summarized separately for 
screen fail subjects. Frequency counts and percentages will be reported for 
categorical data and sample size, mean, standard deviation, median, 
minimum, and maximum will be reported for the continuous variables. 
 
Safety Analyses: 
Primary Safety Analyses 
HPA Axis Suppression 
Serum cortisol results will be summarized for evaluable subjects. HPA axis 
responses to CST will be dichotomized to normal and abnormal. An 
abnormal HPA axis response (HPA suppression) is defined as a 30-minute 
post-stimulation serum cortisol level of <18 µg/dL at Day 14. The proportion 
of subjects manifesting laboratory based evidence of adrenal suppression at 
Day 14 will be summarized and 95% confidence intervals for the proportion 
of abnormal responses will be derived. The changes in serum cortisol levels 
after stimulation at Screening and Day 14 (or EOS) will also be summarized. 
 
Pharmacokinetic Analysis 
Morning trough concentrations (C12) of cortexolone 17α-propionate and 
cortexolone in plasma at Day 7 and Day 14 (prior to the morning test article 
application, where applicable) will be determined using validated methods. 
Descriptive statistics of the plasma concentrations will be provided at 
Screening, Baseline, Day 7 and Day 14 for each analyte. 
 
Secondary Safety Analyses 
Extent of Exposure to Test Article 
The total amount of CB-03-01 cream, 1% used (grams applied) will be 
calculated from the weights of the returned test articles. Descriptive statistics 
(mean, standard deviation, median, minimum, and maximum) will be 
determined for the total amount of test article (grams) used by each subject 
in the Safety, PK, and evaluable populations. 
 
Dosing Compliance 
Descriptive statistics will be used to summarize test article compliance for 
the Safety, PK, and evaluable populations. Measures of test article 
compliance will include the duration of treatment, the total number of 
applications (determined from the actual number of applications reported by 
the subject), and the percent of expected doses applied. A subject will be 
considered compliant with the dosing regimen if the subject applies at least 
80% of the expected number of applications prior to the HPA assessment. 
Subjects included in the PK analysis (PK population) must not have any 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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significant protocol deviations, must have at least an 80% dose compliance 
based on number of applications, and must apply the final three doses as 
prescribed prior to the end of study PK assessment. 
 
Safety Laboratory Tests  
Laboratory data collected at Screening and Day 14 (or EOS), including 
clinical chemistry, hematology, and urinalysis, will be tabulated for each 
visit and changes from Screening to Day 14 (or EOS) will also be tabulated 
for the Safety population. All laboratory data will also be listed. Data will be 
reported in units received from the central laboratory. Shift tables by analyte 
and by out of range flag will also be presented to facilitate the evaluation of 
change from Screening at Day 14 (or EOS). 
 
Local Skin Reactions (LSRs) 
The frequency distributions of the severity of LSRs associated with the 
topical application of corticosteroids and/or acne including telangiectasia, 
skin 
atrophy, 
striae 
rubrae, 
erythema, 
edema, 
scaling/dryness, 
stinging/burning, and pruritus will be summarized with frequency counts and 
percentages at Baseline, Day 7, and Day 14 for face and trunk, separately. 
 
Adverse Events (AEs) 
All AEs reported during the study will be listed, documenting onset, whether 
therapy was required, any change in test article dosing, severity, possible 
relationship to test article, and outcome for the Safety population. Verbatim 
terms on the case report forms (CRFs) will be linked to preferred terms (PTs) 
and system organ class (SOC) using the MedDRA mapping system. All 
reported AEs will be summarized by the number of subjects reporting AEs, 
SOC, PT, severity, and relationship to test article. 
 
Urine Pregnancy Tests (UPTs) 
A listing of UPT results at Screening, Baseline, and Day 14 (or EOS) will 
also be prepared. 
 
Physical Examination/Vital Signs 
Physical examination findings at Screening and Day 14 will be recorded in 
medical history or as AEs. Vital signs will be recorded at Screening and Day 
14. 
 
Electrocardiogram (ECG) 
ECGs will be evaluated at Screening and Day 14 (or EOS) for any material 
changes. 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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SCHEDULE OF EVENTS 
PROCEDURES 
Visit 1 
Screening 
(Days -45 to -14) 
Visit 2 
Baseline 
Day 1 
Visit 3 
 
Day 7 ± 1 
Visit 4 
EOS7 
Day 14 ± 2 
Informed Consent/Assent 
X 
X8 
 
 
Demographics 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
Reconfirm eligibility 
 
 
Medical/Dermatological History 
X 
 
 
 
Dermatologic Exam 
X 
 
 
 
Physical Exam 
X 
 
 
X 
Vital Signs, Height, and Weight9 
X 
 
 
X 
UPT10 (females of childbearing 
potential) 
X 
X 
 
X 
ECG 
X 
 
 
X 
Safety Labs (Hematology, 
Chemistry and Urinalysis)11 
X 
 
 
X 
Urine Drug Screen 
X 
 
 
 
Virus Screen (HIV, HCV, HBV) 
X 
 
 
 
Investigator’s Global Assessment 
Confirm eligibility 
X 
 
X 
Lesion Counts 
Confirm eligibility 
X 
 
 
LSR Assessment 
 
X 
(pre- & post-
application) 
X 
X 
PK Blood Draws12 
X 
X 
X 
X 
Cosyntropin Stimulation Test 
(CST)13 
X 
Confirm eligibility 
 
X 
Study Medication Dispensed & 
Collected14 
 
X 
X 
X 
Study Treatment (q. 12 hours) 
 
X 
X15 
 
Percent BSA to be treated 
 
X 
 
 
Weigh Test Article/Verify 
Compliance 
 
X 
X 
X 
AEs Evaluation 
X 
X 
X 
X 
Review of Concomitant 
Medications & Procedures 
X 
X 
X 
X 
                                                 
7 Subjects who terminate early shall complete all final visit activities designated at Day 14 with the exception 
of the PK blood draws. 
8 Subjects who were consented for longer than 45 days prior to the Baseline Visit will be re-consented prior 
to enrolling into the treatment phase of the trial. 
9 Height and weight at Visit 1 only. 
10 Testing will be conducted on all females of childbearing potential. UPT minimal sensitivity is 25 mIU/mL. 
11 Laboratory test results will indicate if the subject was fasting. Screening laboratory tests will be conducted 
with the subject fasting and EOS laboratory tests are preferred to be in a fasting state. 
12 PK blood draws at Visit 3 and Visit 4 will occur 12 hours (± 30 minutes) after the evening application on 
the prior day. 
13 CST will be performed at Visits 1 and 4 as indicated. If results at the Day 14 visit show an abnormal CST 
response, testing will be performed at 4-week intervals until CST response has been documented to return to 
normal. 
14 Instruct subject on test article application and provide instruction sheet. 
15 Withhold morning application until after trough PK blood draw. 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
β-HCG 
Beta-Human Chorionic Gonadotropin 
b.i.d. 
Twice a day 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CLIA 
Clinical Laboratory Improvement Amendments 
CFR 
Code of Federal Regulations 
CK 
Creatine Kinase 
CO2 
Bicarbonate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CST 
Cosyntropin Stimulation Test 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCF 
Data Clarification Form 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOS 
End of Study 
EU 
European Union 
FDA 
Food and Drug Administration 
GGT 
Gamma-Glutamyl Transferase 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HPA 
Hypothalamic-Pituitary-Adrenal 
I/E 
Inclusion/Exclusion 
IEC 
Institutional Ethics Committee 
IGA 
Investigator’s Global Assessment 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
LDH 
Lactate Dehydrogenase 
LSR 
Local Skin Reaction 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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mIU 
Milli International Units 
µg/dL 
Micrograms/deciliter 
NCI 
National Cancer Institute 
OTC 
Over-the-Counter 
PK 
Pharmacokinetics 
PT 
Preferred Term 
QA 
Quality Assurance 
RBC 
Red Blood Cells 
RDW 
Red Blood Cell Distribution Width 
SAE 
Serious Adverse Event 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SOC 
System Organ Class 
TI 
Therapeutics, Incorporated 
UPT 
Urine Pregnancy Test 
US 
United States 
USP 
United States Pharmacopeia 
WBC 
White Blood Cells 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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TABLE OF CONTENTS 
Protocol Approval ............................................................................................................... 2 
Study Acknowledgement .................................................................................................... 3 
Protocol Synopsis................................................................................................................ 4 
Schedule of Events ............................................................................................................ 14 
Abbreviations .................................................................................................................... 15 
Table of Contents .............................................................................................................. 17 
1. 
Background ....................................................................................................... 20 
2. 
Rationale ........................................................................................................... 21 
3. 
Objective ........................................................................................................... 21 
4. 
Study Design ..................................................................................................... 21 
5. 
Study Population ............................................................................................... 21 
5.1 
Subject Eligibility ............................................................................................. 22 
5.1.1 
Inclusion Criteria ....................................................................................... 22 
5.1.2 
Exclusion Criteria ...................................................................................... 23 
5.1.3 
Subject Withdrawal Criteria ...................................................................... 24 
6. 
Test Articles and Regimen ................................................................................ 24 
6.1 
Description ........................................................................................................ 24 
6.2 
Instructions for Use and Application ................................................................ 24 
6.3 
Warnings, Precautions and Contraindications .................................................. 26 
7. 
Randomization Assignment .............................................................................. 26 
8. 
Dose Limiting Toxicity (DLT) And “Stopping Rules” .................................... 27 
9. 
Prior and Concomitant Therapies ..................................................................... 27 
9.1 
Prohibited Medications or Therapies ................................................................ 27 
9.2 
Allowed Medications or Therapies ................................................................... 27 
10. 
Study Procedures .............................................................................................. 28 
10.1 
Visit 1 (Days -45 to -14): Screening Visit ........................................................ 28 
10.2 
Visit 2 (Day 1): Baseline Visit .......................................................................... 29 
10.3 
Visit 3 (Day 7±1): Follow-Up Visit .................................................................. 30 
10.4 
Visit 4 (Day 14±2): Final or End of Study Visit ............................................... 31 
10.5 
Post-Treatment Follow-Up Visits ..................................................................... 32 
11. 
Clinical Evaluations .......................................................................................... 32 
11.1 
Investigator’s Global Assessment (IGA) .......................................................... 32 
11.2 
Acne Lesion Counting ...................................................................................... 33 
11.3 
Local Skin Reactions ........................................................................................ 33 
12. 
Photography ...................................................................................................... 35 
13. 
Laboratory Tests ............................................................................................... 35 
13.1 
Blood Chemistries, Hematology, and Urinalysis .............................................. 35 
13.2 
Drug and Virus Screening ................................................................................. 37 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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13.3 
Urine Pregnancy Tests ...................................................................................... 37 
13.4 
Plasma Sample Collection ................................................................................ 37 
13.4.1 
Plasma Sample Collection ......................................................................... 37 
13.4.2 
Plasma Storage .......................................................................................... 38 
13.4.3 
Specimen Shipment ................................................................................... 38 
13.4.4 
Analytical Methodology ............................................................................ 38 
13.5 
Cosyntropin Stimulation Test ........................................................................... 38 
14. 
End of Study Criteria ........................................................................................ 39 
14.1 
Completion of the Study ................................................................................... 40 
14.2 
Subject Discontinuation .................................................................................... 40 
14.3 
Study Termination ............................................................................................ 40 
14.4 
Screen Failures .................................................................................................. 41 
15. 
Adverse Event Reporting .................................................................................. 41 
15.1 
Adverse Event (AE) .......................................................................................... 42 
15.2 
Serious Adverse Event (SAE) ........................................................................... 44 
15.3 
Laboratory Test Abnormalities ......................................................................... 46 
15.4 
Pregnancy .......................................................................................................... 46 
16. 
Blinding/Unblinding ......................................................................................... 47 
17. 
Clinical Supplies ............................................................................................... 48 
17.1 
Test Article Information ................................................................................... 48 
17.2 
Supplies Provided by Sponsor or Sponsor’s CRO ............................................ 48 
17.3 
Supplies Provided by Investigator .................................................................... 48 
17.4 
Supplies Provided by the Clinical Laboratory .................................................. 48 
18. 
Statistical Considerations .................................................................................. 48 
18.1 
Sample Size ....................................................................................................... 48 
18.2 
Endpoints .......................................................................................................... 48 
18.2.1 
Efficacy Endpoints .................................................................................... 48 
18.2.2 
Safety Endpoints ........................................................................................ 49 
18.3 
Statistical Methods ............................................................................................ 49 
18.3.1 
Efficacy Analyses ...................................................................................... 50 
18.3.2 
Safety Analyses ......................................................................................... 50 
18.3.2.1 
HPA Axis Suppression ........................................................................ 50 
18.3.2.2 
Pharmacokinetic Analysis ................................................................... 50 
18.3.3 
Secondary Safety Analysis ........................................................................ 50 
18.3.3.1 
Extent of Exposure to Test Article ...................................................... 50 
18.3.3.2 
Dosing Compliance ............................................................................. 50 
18.3.3.3 
Safety Laboratory Tests ....................................................................... 51 
18.3.3.4 
Local Skin Reactions ........................................................................... 51 
18.3.3.5 
Adverse Events .................................................................................... 51 
18.3.3.6 
Urine Pregnancy Tests ......................................................................... 51 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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18.3.3.7 
Physical Examination / Vital Signs ..................................................... 51 
18.3.3.8 
Electrocardiogram ............................................................................... 51 
18.4 
Subgroup Analyses ........................................................................................... 51 
18.5 
Interim Analyses ............................................................................................... 51 
19. 
Ethical and Regulatory Considerations ............................................................. 52 
19.1 
Compliance with Good Clinical Research Practice .......................................... 52 
19.2 
Institutional Review Board / Ethics Committee and Informed Consent/Assent52 
19.3 
Protocol Compliance ......................................................................................... 52 
19.4 
Protocol Revisions ............................................................................................ 53 
19.5 
Study Monitoring .............................................................................................. 53 
19.6 
Case Report Form Requirements ...................................................................... 53 
19.7 
Reports to Institutional Review Board / Ethics Committee .............................. 54 
19.8 
Quality Assurance Audits ................................................................................. 54 
19.9 
Records Retention ............................................................................................. 54 
18.10 Record Confidentiality ...................................................................................... 54 
20. 
References ......................................................................................................... 56 
Appendix 1 
Sample Subject Instruction Sheet .............................................................. 57 
Appendix 2 
Sample Subject Diary ................................................................................ 59 
Appendix 3 
Test Article Information ............................................................................ 61 
A 3.1 Test Article Packaging and Labeling ................................................................ 61 
A 3.2 Test Article Storage and Preparation ................................................................ 61 
A 3.3 Dispensing Test Article..................................................................................... 61 
A 3.4 Test Article Supply Records at Study Sites ...................................................... 62 
A 3.5 Dose Modifications ........................................................................................... 62 
A 3.6 Documentation of Application and Compliance............................................... 63 
A 3.7 Return and Destruction of Test Article Supplies .............................................. 63 
Appendix 4 
Cosyntropin Stimulation Test Package Insert ........................................... 64 
Appendix 5 
Body Mass Index for Age .......................................................................... 65 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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1. 
BACKGROUND 
CB-03-01 (cortexolone 17α-propionate) is a steroidal antiandrogen that is being developed 
as a 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 [2_References]. 
 
To date, four Phase 1 and three Phase 2 clinical studies have been completed with CB-03-
01 cream in Europe and the United States, with over 500 subjects exposed to CB-03-01 
creams. All studies were conducted using CB-03-01 cream, 1%; additional concentrations 
of CB-03-01 cream (0.1% and 0.5%) were also used in the most-recent Phase 2 Dose-
Escalating study. The studies included: 
 
1. A Phase 1 Single Dose Pharmacokinetics (PK) Study in 24 healthy volunteers 
[randomized, double-blind, vehicle-controlled, single-ascending dose], 
2. A Phase 1 Repeat Dose PK Study in 24 healthy volunteers [randomized, vehicle-
controlled, 14-day repeat-dose], 
3. A Phase 1 Steady State PK Study in 8 subjects with acne vulgaris [single center, 
open-label, pilot, 6-week repeat-dose] 
4. A Phase 1 Three-week Cumulative Skin Irritation Study in 36 healthy volunteers, 
5. A Phase 2 HPA/PK study in 42 subjects with acne vulgaris [open-label, 14-day 
repeat-dose] 
6. A Phase 2 Comparator Proof of Concept Study in 72 adult subjects with facial acne 
vulgaris [randomized, double-blind, vehicle-controlled, active-comparator (Retin-
A® [tretinoin] 0.05% cream), 8-week repeat-dose], and 
7. A Phase 2 Dose-Escalating Study in 363 subjects with facial acne vulgaris [multi-
center, randomized, double-blind, vehicle controlled, 12-week repeat-dose] 
 
Overall, the data that resulted from the completion of the aforementioned studies has 
demonstrated that CB-03-01 creams selected for clinical development (a) are well tolerated 
locally, (b) result in minimal systemic exposure when applied topically, (c) have a clinical 
safety profile without any concern and similar to the vehicle, and (d) at 1% concentration 
applied b.i.d. are significantly more effective than its vehicle at reducing inflammatory and 
non-inflammatory lesions counts in adolescent and adult subjects. 
 
Two Phase 3, randomized (1:1), double-blind, vehicle-controlled studies have been 
initiated in subjects 9 years of age and older with moderate to severe acne vulgaris. In each 
study, approximately seven hundreds subjects will be treated twice daily for 12 weeks with 
either CB-03-01 cream, 1% or vehicle cream. 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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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 
This study was designed to investigate the safety (adrenal suppression effects and systemic 
concentrations of the drug product) of CB-03-01 cream, 1% in subjects 9 to <12 years of 
age with facial acne vulgaris. Adrenal suppression effects and systemic safety are an 
important safety concern. The current study was designed to investigate these concerns. 
Based on the results of Study 171-7151-202, a Phase 2, open label, maximal use HPA/PK 
study that was conducted in 42 subjects [twenty-two (22) adolescents (12 to <18 years of 
age) and twenty (20) adults (≥18 years of age)] with moderate to severe acne vulgaris of 
the face and chest/back (the “Treatment Area”), few subjects (1/20 adults [5.0%] and 2/22 
[9.1%] adolescents) demonstrated laboratory evidence of adrenal suppression and no 
subjects demonstrated any clinical evidence of adrenal suppression [3_References]. 
Additionally, systemic exposure to CB-03-01 was low per the PK evaluation.  
3. 
OBJECTIVE 
The primary objectives of this study are to determine a) the adrenal suppression potential 
and b) the trough plasma concentrations associated with topical application of CB-03-01 
cream, 1% in subjects with acne vulgaris. 
4. 
STUDY DESIGN 
This is an open-label, multicenter study in approximately 20 subjects 9 to <12 years of age 
with moderate to severe facial acne vulgaris (IGA score of 3 or 4) and obvious acne on the 
trunk (i.e., shoulders, upper chest, and/or back). The study will include a Screening Visit, 
a Baseline Visit, and two (2) scheduled follow-up visits. Eligible subjects will be dispensed 
CB-03-01 cream, 1% and will be instructed how and where to apply the test article to the 
face and trunk (see Section 6.2 for definition of the “Treatment Area”) every 12 hours for 
two (2) weeks. Subjects will apply 2 grams of the test article per application. The test article 
will be applied by the subject or subject’s parent/guardian in the clinic under supervision 
on Day 1 and Day 7 and at home for all other applications. The Medical Monitor will 
consider Dose Limiting Toxicity (DLT) when reviewing the safety data (see Section 8). 
5. 
STUDY POPULATION 
Male and female subjects 9 to <12 years of age with moderate to severe facial acne vulgaris 
(IGA of Grade 3 or 4) and obvious acne on the trunk (i.e., shoulder, upper chest, and/or 
back will be enrolled into the study. Subjects will be enrolled at approximately six sites in 
the United States and Poland.  


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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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 is male or female 9 to <12 years of age at the time of consent/assent. 
2. Subject 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 written informed consent for the subject.  
3. Females of childbearing potential16 must be using highly effective birth control 
methods17,18 with a negative urine pregnancy test (UPT) at the Screening and Baseline 
Visits. 
4. Subject has moderate to severe facial acne vulgaris (Grade 3 or 4) as determined by the 
Investigator’s Global Assessment (IGA) [0 (clear) to 4 (severe) scale] and obvious acne 
on the trunk (i.e., shoulders, upper chest, and/or back) at the Screening Visit. 
5. Subject has facial acne vulgaris with a minimum of 15 inflammatory lesions (papules, 
pustules, and nodules/cysts) and a minimum of 15 non-inflammatory lesions (open and 
closed comedones) at the Screening Visit. 
6. Subject must be in general good health in the opinion of the investigator, with normal 
renal function as defined per protocol19 and no clinically relevant abnormalities present 
at the screening physical examination, in the subject’s medical history, or from safety 
laboratory tests (hematology, serum chemistry, and urinalysis). 
7. Subject has normal adrenal function with a Cosyntropin Stimulation Test (CST) at 
Screening, defined as a normal pre-stimulation cortisol level and a 30-minute post-
stimulation cortisol level of >18 μg/dL. 
8. Subject and parent/guardian are able to communicate with the staff and are willing to 
comply with study instructions, reside at and/or return to the clinic for required visits.  
                                                 
16 Females of childbearing potential are defined as subjects who have experienced menarche or are 10 years 
of age or older.  Note: If a female becomes 10 years of age during the study, she must have a negative UPT 
at that time to continue study participation. 
17 Highly effective contraception includes: a) intrauterine device (IUD) for at least one week prior to Visit 2 
(Baseline); b) hormonal contraceptives (injections, implants, transdermal patch, vaginal ring); c) partner 
vasectomy (performed at least six months prior to Visit 2 [Baseline]); d) oral contraceptives WITH a barrier 
method: i) Male or female condom; diaphragm with spermicides; cervical cap with spermicides; 
contraceptive sponge e) two barrier forms of contraception: i) male or female condom; ii) diaphragm with 
spermicides; iii) cervical cap with spermicides; iv) contraceptive sponge; OR f) total abstinence. 
18 Females taking hormonal therapy for any reason exclusive for the treatment of acne (e.g., as contraception, 
etc.) must be on treatment for at least 12 weeks prior to study entry and must not change their dosing regimen 
during the study.  Those who have used hormonal therapy prior to study entry must have discontinued use at 
least eight weeks prior to the start of the study.   
19 Normal renal function (per the requirement of inclusion criterion #6) is defined as a creatinine clearance 
of 80 mL/min or greater based on serum creatinine and the Cockcroft and Gault equation [1]. 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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5.1.2 Exclusion Criteria 
1. Subject is pregnant, lactating, or is planning to become pregnant during the study. 
2. Subject has a Body Mass Index (BMI) for age percentile >95% (see Appendix 5). 
3. Except for the use of contraceptives, subject reported use of any prescription drug or 
herbal product within two (2) weeks of Visit 2 (Baseline), any non-prescription drug or 
vitamin or mineral supplements within one (1) week of Visit 2 (Baseline); any known 
enzyme-inducer, enzyme-inhibitor, or reported chronic exposure to enzyme-inducers 
such as paint solvents or pesticides within 30 days of Visit 2 (Baseline). 
4. Subject has used topical anti-acne medications containing retinoids such as tazarotene, 
adapalene, or tretinoin within four (4) weeks of Visit 2 (Baseline). 
5. Subject has used the following systemic anti-acne medications: antibiotics within two 
(2) weeks of Visit 2 (Baseline), spironolactone within four (4) weeks of Visit 2 
(Baseline), or retinoid therapy within three (3) months of Visit 2 (Baseline). 
6. Subject has used topical corticosteroids (including inhaled and intranasal 
corticosteroids) within two (2) weeks of the CST at Visit 1 (Screening) and/or between 
Visit 1 (Screening) CST and Visit 2 (Baseline). 
7. Subject has used systemic corticosteroids (including intramuscular and intralesional 
injections) within four (4) weeks of the CST at Visit 1 (Screening) and/or between the 
Visit 1 (Screening) CST and Visit 2 (Baseline). 
8. Subject has used light treatments, microdermabrasion or chemical peels to the face, 
chest, and/or back within eight (8) weeks of Visit 2 (Baseline). 
9. Subject has any skin or medical condition, including facial hair that could interfere with 
the evaluation of the test article or requires the use of interfering topical or systemic 
therapy. 
10. Subject has any condition which, in the investigator’s opinion, would make it unsafe 
for the subject to participate in this research study. 
11. Subject has the need or plans to be exposed to artificial tanning devices or excessive 
sunlight during the study. 
12. Subject cannot avoid any type of strenuous exercise (swimming, running, team sports, 
etc.) or the use of hot tubs/saunas from Visit 2 (Baseline) to the end of the study (Visit 
4). 
13. Subject has any clinically significant medical abnormality or chronic disease of the 
cardiovascular, gastrointestinal, respiratory, hepatic, or renal systems. This includes 
conditions (e.g., gastrointestinal surgery) that may interfere with metabolism or 
excretion. 
14. Subject has a history of alcohol and/or drug abuse in the investigator's judgment or has 
a positive urine drug screen result at Visit 1 (Screening). 
15. Subject is unable to communicate or cooperate with the investigator due to language 
problems, poor mental development, or impaired cerebral function. 
16. Subject is known to be hypersensitive to the test article or any components in the test 
article (see Section 6.1). 
17. Subject has received an investigational drug or been treated with an investigational 
device within 30 days prior to Visit 2 (Baseline). 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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18. Subject is currently enrolled in an investigational drug or device study. 
19. Subject has an irregular sleep schedule (cortisol levels exhibit physiological diurnal 
variation) as judged by the investigator. 
20. Subject has experienced significant blood loss, as judged by the investigator, within 60 
days or has donated plasma within 72 hours prior to Visit 2 (Baseline). 
21. Subject tests positive at screening for human immunodeficiency virus (HIV) or is 
known to be seropositive for HIV. 
22. Subject tests positive at Visit 1 (Screening) for hepatitis B surface antigen, hepatitis C 
antibody, or has a history of a positive result. 
23. Subject had major surgery within 30 days prior to Visit 2 (Baseline) or plans to have 
surgery during the study. 
24. Subject has participated in a prior CB-03-01 clinical trial 
5.1.3 Subject Withdrawal Criteria 
Procedures for handling subjects who are discontinued from the study are described in 
Section 14.2. Subjects who are discontinued will not be replaced; however, enrollment will 
continue until at least 20 evaluable subjects are achieved. 
6. 
TEST ARTICLES AND REGIMEN 
6.1 
Description 
CB-03-01 (cortexolone 17 α -propionate) Cream, 1% is an opaque topical formulation. 
 
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, α-tocopherol, sodium edetate, polysorbate 80, citric acid 
monohydrate, purified water.  
 
For test article labeling information refer to Appendix 3. 
6.2 
Instructions for Use and Application 
Mild soap will be dispensed to the subject at Visit 1/Screening, which must be used for 
washing the Treatment Area and other areas of the body throughout the study; the subject 
must, at a minimum, begin using the provided mild soap in the morning prior to the clinic 
visit on Day 1 (i.e., Visit 2).  
 
The subject and parent/guardian will be instructed to wash the area(s) to be treated (i.e., 
face and trunk) in the morning prior to clinic visits with the mild soap and water and then 
dry the area gently. At the clinic, the study staff will then instruct the subject and 
parent/guardian on how to dispense the test article and where to apply the test article. The 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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“Treatment Area” will be defined at Visit 2/Baseline by the investigator as the area to 
which the test article is applied and will include the face and trunk. The test article will be 
applied to the entire face and areas of the trunk (i.e., shoulders, upper chest, and/or upper 
back) where acne is present. The entire 2 grams of the test article must be applied; thus, if 
there is still test article remaining after the affected area of the trunk is treated, the test 
article will be applied to the adjacent skin. The subject will be instructed to apply the test 
article to this same Treatment Area with each application, regardless of whether acne is 
still present. The percent BSA20 of the Treatment Area will be recorded at Baseline. 
 
The first application of test article will be applied in the clinic under supervision of the 
study staff. The staff will dispense 2 grams of the test article; the subject will then be 
instructed (with assistance from parent/guardian, if necessary) to apply the test article to 
the defined Treatment Area using the “Dab, Spread, Pat” method of application. Subjects 
will be instructed to dab small amounts of the test article using a fingertip gently on the 
areas to be treated, then spread the test article to provide a thin, uniform layer over the 
entire Treatment Area, and finally to gently pat the skin until the test article has been 
absorbed into the skin. The study staff must assure that the subject (or with assistance from 
parent/guardian) is able to apply the test article to the entire Treatment Area (including the 
back).  
 
Reminders for Each Application: The subject should wash the Treatment Area with the 
provided mild soap and water and then dry gently prior to application of the test article. 
The subject should not wash the Treatment Area for at least eight (8) hours after test article 
application and not apply any make-up or skin care products to the Treatment Area for at 
least four (4) hours after test article application. The subject will also be instructed not to 
swim or participate in any other activities which potentially could remove the product from 
the treated areas for the duration of the study. 
 
The subject and parent/guardian will be provided with a Subject Instruction Sheet and a 
Subject Diary to record the dates and times of test article application on non-clinic days. 
Note: The dispensing, recording, and application of test article by the subject may 
require adult supervision by the subject’s parent/guardian. The subject will be 
instructed to apply the test article only to the Treatment Area as instructed by the 
investigator or designated study personnel and to ask his/her parent/guardian for assistance, 
if needed. It should be emphasized to the subject that with each application of CB-03-01 
cream, 1% the entire dosage must be applied for the entire study period, even if his/her 
acne begins to clear. The subject will be instructed to dispense 2 grams of the test article 
using the scale provided and apply the entire amount of the test article at home to the 
designated Treatment Area every 12 hours for two (2) weeks per the instructions from 
study staff on Day 1. The test article should be applied in the mornings and evenings at 
approximately the same time each day. The evening applications that will occur prior to a 
                                                 
20 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. 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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clinic visit (e.g., on Day 6 prior to Visit 3 and on Day 13 prior to Visit 4) must be applied 
12 hours (± 30 minutes) prior to the PK blood draw; the study staff should instruct the 
subject what time to apply the test article on those days. The test article should be spread 
uniformly to cover the Treatment Area until all the test article is applied (regardless of 
whether acne is still present). 
 
The subject will also be provided with instructions on how to store the test article at home 
during the study period. The subject will be instructed to bring all the containers of the test 
article (used and unused) and his/her completed diary to each visit. The study staff will 
weigh all the returned containers and will record the weights on the appropriate study 
medication accountability logs and CRFs. 
 
Subjects who are not compliant with applying the test article as instructed by study staff 
(determined from subject diaries and/or the weight of test article used) may be discontinued 
from the study.  
6.3 
Warnings, Precautions and Contraindications 
This test article is for topical use only on the skin. 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. Females must not be pregnant or planning a pregnancy during the study 
period. If the subject’s mother is pregnant or nursing a glove should be worn when assisting 
the subject with test article application. 
7. 
RANDOMIZATION ASSIGNMENT 
There is no randomization assignment in this study. This is an open-label study in which 
all eligible subjects will be dispensed the test article at the Baseline Visit and provided with 
additional labeled test article during the study period. Subjects who are eligible for 
enrollment into the study will be assigned a three digit subject number by the study staff in 
ascending order beginning with the lowest available number. Subject numbers will be 
included on the kits and the tubes for each subject. Enrollment will continue until 20 
evaluable subjects are achieved. 


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Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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8. 
DOSE LIMITING TOXICITY (DLT) AND “STOPPING RULES” 
The Medical Monitor will consider Dose Limiting Toxicity (DLT) when reviewing the 
safety data. A DLT is defined as a systemic Grade 2 or higher (CTCAE, Version 4.0)21 
adverse event (AE) for which there is no clear alternative explanation of the cause of the 
AE. Non-systemic (local) AEs Grade 3 or higher for which there is no clear alternative 
explanation of the cause of the AE will also be considered DLTs. If more than 3 subjects 
within the study exhibit a DLT, enrollment will be stopped. Any subject who experiences 
a DLT, as described above, must discontinue treatment and be scheduled for a final visit. 
Any DLTs that are Grade 2 or greater systemic AEs with documented worsening from 
Baseline must be reported by the investigator immediately. 
9. 
PRIOR AND CONCOMITANT THERAPIES 
Any medications taken or therapies performed in the 90 days prior to the start of the study 
(Screening, Visit 1) will be recorded on the appropriate CRFs with the corresponding 
indication. The medications to be recorded include prescription and over-the-counter 
(OTC) medications (including vitamins, herbs, and dietary supplements). Any changes in 
concomitant medications and/or therapies/procedures during the study must be recorded on 
the appropriate CRFs. The reason for any changes in concomitant medications or 
therapies/procedures should be reported and should reflect either a baseline medical 
condition documented in the medical history of the CRF or an AE. 
9.1 
Prohibited Medications or Therapies 
Medications or therapies that are prohibited during the duration of the study are as follows: 
 
Prior to entry into the study, subjects must not use the medications and/or 
therapies/procedures as specified in Section 5.1.2. 
 
During the study, subjects must not use any prescription or non-prescription drugs 
(including OTC acne treatments), vitamins, herbal products, and mineral supplements 
except for contraceptives. 
9.2 
Allowed Medications or Therapies 
Subjects will be provided with a mild soap (Cetaphil® Gentle Skin Cleanser or equivalent), 
which must be used for washing the Treatment Area and other areas of the body throughout 
the study; the subject must, at a minimum, begin using the provided mild soap in the 
morning prior to the clinic visit on Day 1 (i.e., Visit 2). Skin care products (including make-
up) must not be applied within four (4) hours of test article application. 
 
                                                 
21 NCI Common Terminology Criteria for Adverse Events, Version 4.0. 


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Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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No medications, including prescription drugs, herbal products, non-prescription drugs, 
mineral supplements, and vitamins are permitted during the study period as described in 
Section 5.1.2 without the knowledge and, if possible, permission of the investigator.  
10. 
STUDY PROCEDURES 
The study will consist of a Screening Visit, a Baseline Visit, and two (2) scheduled follow-
up visits at Day 7 and Day 14. Specific activities for each study visit are listed below. 
10.1 
Visit 1 (Days -45 to -14): Screening Visit 
Subjects can be screened for the study up to 45 days before Baseline. During Screening, 
the study requirements will be reviewed, written informed consent/assent obtained and 
eligibility confirmed. Screening labs will be collected with the subject fasting; if fasting 
laboratory tests are not possible, samples should still be collected, recording the protocol 
deviation. If applicable, the washout from prohibited medications or treatments will be 
determined and implemented. This visit will be scheduled such that the CST occurs 
between 7 AM and 9 AM. 
 
At Screening, the investigator or designee will: 
 
• Obtain a signed, written informed consent/assent. Subjects 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. 
• Assign a sequential subject screening number. 
• Complete demographics. 
• Review eligibility criteria. 
• Review and document medical/dermatological history. 
• Record any prior or concomitant medications and therapies. 
• Have subject complete washout from any prohibited medications, if necessary. The 
subject should return to the clinic to complete the remaining screening activities, if 
applicable. If the subject does not require a wash-out from prohibited medications 
and procedures, perform additional screening activities at this visit. 
• Perform a dermatologic exam. 
• Perform a physical exam (including vital signs, height, and weight). 
• Perform a UPT for all females of childbearing potential22 (Section 13.3). The 
results must be negative for the subject to be enrolled into the study. 
• Perform a 12-lead ECG. 
• Collect urine and blood samples for drug and virus screens and routine safety 
laboratory tests (see Sections 13.1 and 13.2). Laboratory tests will be collected with 
                                                 
22 Females of childbearing potential are defined as subjects who have experienced menarche or are 10 years 
of age or older. 


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Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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the subject fasting; if fasting laboratory tests are not possible, samples should still 
be collected, recording the protocol deviation. 
• Perform clinical evaluations (IGA and acne lesion counts [face only]) to determine 
subject eligibility (see Section 11). 
• Collect PK blood draw for screening levels of plasma cortexolone 17α-propionate 
and cortexolone concentrations (see Section 13.4). 
• Perform a CST (see Section 13.5). CST will be performed between 7 AM and 9 
AM at this visit. 
• Inform the subject that if the CST results are not within the normal range, he/she 
will not be eligible for the study. 
• Confirm the subject meets the inclusion/exclusion criteria (pending drug screen, 
laboratory test results, and CST results). 
• Dispense mild soap to the subject and instruct the subject and parent/guardian to 
wash the face and trunk with the provided soap in the morning prior to the next 
clinic visit. 
 
Once the Screening procedures have been completed, the investigator or designee will 
schedule a Baseline Visit. Note: Subjects who were consented for longer than 45 days will 
need to be re-consented prior to enrolling into the treatment phase of the trial. 
10.2 
Visit 2 (Day 1): Baseline Visit 
The Baseline Visit must be conducted at least 14 days and not more than 45 days after the 
Screening CST. 
 
At this visit, the investigator or designee will: 
• Obtain a new signed, written informed consent/assent (if this visit is more than 45 
days from Screening Visit). 
• Query the subject and record any changes in concomitant medications and 
therapies. 
• Review laboratory test and CST results and reconfirm that the subject meets the 
inclusion/exclusion criteria. 
• Perform Baseline clinical evaluations (IGA and acne lesion counts [face only]) (see 
Section 11). 
• Perform a UPT for all females of childbearing potential22 (see Section 13.3). The 
results must be negative for the subject to be enrolled into the study. 
• Assign the subject to the next available (lowest) subject number. 
• Record any baseline LSRs, for the face and trunk separately, prior to application of 
the test article (see Section 11.3). 
• Collect PK blood draw for baseline levels of plasma cortexolone 17α-propionate 
and cortexolone concentrations (see Section 13.4). 
• Weigh and dispense initial tube(s) of test article and complete the Study Medication 
Accountability Log. 


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Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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• Dispense the Subject Instruction Sheet to the subject (Appendix 1). 
• Dispense the Subject Diary (Appendix 2) to the subject and provide completion 
instructions. 
• Dispense and weigh 2 grams of the test article into a disposable container and 
provide to subject for application. 
• Instruct the subject where and how to apply the initial dose of test article and define 
the “Treatment Area” (entire face and affected areas of the trunk including adjacent 
areas, as needed; see Section 6.2). 
• Record the areas of the trunk that were treated and the total percent BSA (face + 
trunk) that was treated. Estimate BSA based on the assumption that 1% BSA is 
equivalent to the area of the subject’s hand with fingers held together. 
• Approximately 15 minutes after application, record any AEs and LSRs (for face 
and trunk, separately) after the initial application of the test article. 
• Instruct the subject to apply the test article to the Treatment Area every 12 hours 
(i.e., in the morning and evening) at approximately the same time each day until 
the next scheduled follow-up visit. 
• Schedule Visit 3 (Day 7). The timing of this visit will occur so that the trough PK 
blood draw on Day 7 occurs 12 hours (± 30 minutes) after the evening application 
on Day 6. 
10.3 
Visit 3 (Day 7±1): Follow-Up Visit 
Subjects should, to the extent possible, shower or wash the treated areas with the provided 
mild soap in the morning prior to the visit and should not apply the test article at home on 
the day of the visit. 
 
At this visit, the investigator or designee will: 
• Query the subject and record any changes in health status (i.e., AEs) or concomitant 
medications and therapies. 
• Record any LSRs (for face and trunk, separately). 
• Collect trough PK blood draw for levels of plasma cortexolone 17α-propionate and 
cortexolone concentrations (see Section 13.4). PK blood draw will occur 12 hours 
(± 30 minutes) after the evening application on the prior day. 
• Collect, dispense, and weight tube(s) of test article, as needed, and complete the 
Study Medication Accountability Log. 
• Dispense the Subject Instruction Sheet to the subject, if needed (Appendix 1). 
• Dispense (new) Subject Diary (Appendix 2), if necessary, to the subject. 
• Dispense and weigh 2 grams of the test article into a disposable container and 
provide to subject for application. 
• Apply test article to the “Treatment Area” under study staff supervision (see 
Section 6.2). 


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Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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• Instruct the subject to apply the test article to the Treatment Area every 12 hours 
(i.e., in the morning and evening) at approximately the same time each day until 
the next scheduled follow-up visit. 
• Schedule Visit 4 (Day 14). The timing of this visit will occur so that the trough PK 
blood draw on Day 7 occurs 12 hours (± 30 minutes) after the evening application 
on Day 13. 
10.4 
Visit 4 (Day 14±2): Final or End of Study Visit 
This visit will be scheduled such that the CST occurs between 7 AM and 9 AM and within 
one hour (±1) of the Screening CST. Laboratory test results will indicate if the subject was 
fasting (preferred) or not.  
 
At this visit, the investigator or designee will: 
• Query the subject and record any changes in health status (i.e., AEs) or concomitant 
medications and therapies. 
• Record any LSRs (for face and trunk, separately). 
• Perform clinical evaluation (IGA) (see Section 11.1). 
• Perform a physical exam (including vital signs). 
• Perform a CST (see Section 13.5). CST will be performed between 7 AM and 9 
AM and within one hour (±1) of Screening. 
• Perform routine laboratory tests (see Section 13.1). 
• Collect trough PK blood draw for levels of plasma cortexolone 17α-propionate and 
cortexolone concentrations (see Section 13.4). PK blood draw will occur 12 hours 
(± 30 minutes) after the evening application on the prior day. 
• Perform a 12-lead ECG. 
• Perform a UPT for all females of childbearing potential23 (Section 13.3).  
• Collect and weight tube(s) of test article, as needed, and complete the Study 
Medication Accountability Log. 
• Discharge the subject from the study, unless there is evidence of adrenal 
suppression. 
• Note: Medication restrictions as outlined in Section 9.1 are no longer required, with 
the exception of those medications that may affect adrenal function. Remind 
subjects not to use any medication that may affect adrenal axis function including 
topical corticosteroids (including inhaled and intranasal corticosteroids) or 
systemic corticosteroids (including intramuscular and intralesional injections) until 
the CST results are known. For those subjects with laboratory evidence of adrenal 
suppression, they must continue off such therapy and follow-up as designated in 
Section 10.5. 
                                                 
23 Females of childbearing potential are defined as subjects who have experienced menarche or are 10 years 
of age or older. 


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Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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• Review safety laboratory test results including serum cortisol levels, and complete 
the End of Study Form, unless the subject has an abnormal HPA axis response or 
any laboratory tests that need to be repeated, then follow the procedures in Section 
10.5. 
10.5 
Post-Treatment Follow-Up Visits 
These visits are only required for subjects who have demonstrated abnormal CST results 
at the end of study and are returning for the follow-up CST per Section 13.5. This visit 
should take place every four (4) weeks BUT no sooner than four (4) weeks (28 days) after 
Visit 4, and subsequently about every four (4) weeks BUT no earlier than every four (4) 
weeks (28 days) thereafter until the adrenal response returns to normal (30-minute post-
stimulation serum cortisol >18 μg/dL). 
 
At this visit, the investigator or designee will: 
• Observe/query the subject about any changes in health status (AEs, concomitant 
medications, etc.) since previous visit. Document the findings on the appropriate 
AE or Concomitant Medication forms, as required. 
• Perform the CST. If possible, the CST should be initiated between 7AM and 9 AM 
and within one hour (±1) of the Screening CST (see Section 13.5). 
• If the subject has a normal HPA axis response, complete the End of Study Form. 
• If the subject has an abnormal HPA axis response, notify the subject that he/she 
will need to return to the clinic in approximately four (4) weeks. Remind the subject 
that he/she is prohibited from using any medication that may affect adrenal axis 
function including topical, inhaled, intranasal, or systemic (including intramuscular 
and intralesional) corticosteroids. 
• Repeat the CST every approximately four (4) weeks until HPA axis response has 
returned to normal and is documented as such. 
11. 
CLINICAL EVALUATIONS 
IGA and acne lesion counts will be performed to document the severity of acne on the face 
at the Screening and Baseline visits as part of the I/E criteria. IGA will be performed again 
at the Final Visit (EOS). The same investigator should complete the evaluations for all 
subjects screened and enrolled into the study. If this becomes impossible a sub-investigator 
with overlapping experience with the study should complete the IGA evaluations. 
11.1 
Investigator’s Global Assessment (IGA) 
Overall severity of acne on the face using a five-point scale from 0 = clear to 4 = severe 
will be conducted at the Screening, Baseline, and EOS visits. This is a static morphological 
scale that refers to a point in time and not a comparison to Baseline. Eligible subjects should 
also have obvious acne on the trunk (i.e., shoulder, upper chest and/or back), but these 
areas will not be included in the IGA. 
 


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Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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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. 
11.2 
Acne Lesion Counting 
The number of inflammatory lesions (papules, pustules and nodules/cysts) and non-
inflammatory lesions (open and closed comedones) on the face vertically from the hairline 
to mandible rim and horizontally from ear to ear, including those on the nose, will be 
counted at the Screening and Baseline visits. Eligible subjects must have obvious acne on 
the trunk (i.e., shoulder, upper chest and/or back), but the number and type of lesions on 
the trunk will not be counted.  
 
Lesions are defined as follows: 
• Comedones- open (blackheads) and closed (whiteheads).  
• Papules- raised inflammatory lesions with no visible purulent material. 
• Pustules- raised inflammatory lesions with visible purulent material. 
• Nodules/cysts- Any circumscribed, inflammatory masses greater or equal to 5mm 
in diameter with or without cystic changes. 
11.3 
Local Skin Reactions 
LSRs will be collected separately for the face and trunk. At Days 1 (before and after first 
application), 7, and 14, the investigator or designee will document the presence of the 
following LSRs known to be associated with application of topical steroids:  
• Telangiectasia 
• Skin atrophy 
• Striae rubrae 
 
A five-point ordinal scale will be used to assess the severity of these reactions (0 = none, 
1= trace, 2 = mild, 3 = moderate, and 4 = severe). 
 
The investigator or designee will also evaluate the severity of erythema, edema, and 
scaling/dryness using the five-point ordinal scales described below.  
 


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Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
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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 
 
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 
 
At Days 1 (before and after first application), 7, and 14, the subject will be asked to rate 
the severity of any stinging/burning and pruritus that occurred in the Treatment Area using 
the four-point scales described below. 
 


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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 article will be documented as AEs. Any LSRs that are not listed above will be recorded 
as AEs. 
12. 
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.  
13. 
LABORATORY TESTS 
13.1 
Blood Chemistries, Hematology, and Urinalysis 
Blood and urine specimens for chemistry, hematology, and urinalysis will be collected at 
the Screening Visit (Days -45 to -14) and Day 14 (or at EOS / early termination) for all 
subjects. Laboratory test results will indicate if the subject was fasting. Screening 
laboratory tests will be collected with the subject fasting and EOS laboratory tests are 
preferred to be in a fasting state. 
 


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The following tests will be performed: 
SAFETY LABORATORY TESTS 
Chemistries 
Hematology 
Urinalysis  
Albumin 
WBC 
Specific gravity 
Alkaline phosphatase 
RBC 
pH 
ALT (SGPT) 
Hemoglobin 
Glucose 
AST (SGOT) 
Hematocrit 
Blood 
Bilirubin, total 
MCV 
Ketones 
BUN 
MCH 
Microscopic analysis 
CO2 (bicarbonate) 
MCHC 
 
WBCs 
Chloride 
Platelet count 
 
RBCs 
Cholesterol, total 
RDW 
 
Casts 
Creatinine 
Differential 
 
Glucose 
 
Neutrophils 
 
LDH 
 
Lymphocytes 
 
Potassium 
 
Eosinophils 
 
Sodium 
 
Monocytes 
 
Total protein 
 
Basophils 
 
Triglycerides 
 
 
Uric acid 
 
 
GGT 
 
 
CK 
 
 
 
Sample collection, handling, labeling, and shipping should be done following the 
instructions provided by the relevant certified laboratory and the applicable local 
regulations. 
 
The investigator must review all the subject’s laboratory reports in a timely manner. Note: 
The investigator will initial and date each laboratory report to indicate his/her review. The 
investigator will note, directly on the laboratory report, whether or not any abnormal test 
results are clinically significant. The investigator must complete an appropriate AE form 
for any new or worsening abnormal test results that are identified as clinically significant 
after Baseline.  
 
AEs that may be associated with venipuncture and that must be included in the informed 
consent/assent include: 
• Pain 


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• Bruising 
• Bleeding at the puncture site 
• Fainting 
• Inflammation of the vein 
13.2 
Drug and Virus Screening 
At the Screening Visit, the urine and blood samples will be taken for: 
 
Standard Drug Panel:  Urine drug screen for barbiturates, benzodiazepines, opioids, 
cocaine, cannabinoids, and amphetamines. Result must be negative at Screening. 
 
Virus Screen:  Serology screen in blood for the detection of antivirus antibodies for human 
immunodeficiency virus (HIV), hepatitis C virus (HCV) and hepatitis B virus (HBV) 
surface antigen. Result must be negative at Screening for inclusion into the study. 
 
Sample collection, handling, labeling and shipping should be done following the 
instructions provided by the relevant certified laboratory and the applicable local 
regulations. 
13.3 
Urine Pregnancy Tests 
The UPTs will be performed at the study site, if the site is registered and conforms to CLIA 
regulations for such testing (possesses a current valid CLIA Certificate of Waiver), or at 
an appropriately registered reference laboratory. A UPT will be performed on all females 
of childbearing potential24 at Screening, Baseline, and Day 14 (or EOS). The investigator 
will report the UPT results on the CRFs, in the subject’s medical records, and in 
independent records maintained at the study site. The UPT used must have a minimum 
sensitivity of 25 mIU of β-HCG/mL. 
13.4 
Plasma Sample Collection 
One of the objectives of the study is to determine the trough plasma concentrations of 
cortexolone 17α-propionate and cortexolone associated with the topical application of CB-
03-01 cream, 1% in subjects with acne vulgaris. 
13.4.1 Plasma Sample Collection 
Blood will be collected at each visit (Screening, Baseline, Day 7, and Day 14) immediately 
prior to the application of the test article (if applicable). Concentrations of cortexolone 17α-
propionate and cortexolone will be determined. The method of blood sample collection for 
                                                 
24 Females of childbearing potential are defined as subjects who have experienced menarche or are 10 years 
of age or older. 


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trough PK analysis is detailed in the laboratory manual to be provided by the bioanalytical 
laboratory. 
13.4.2 Plasma Storage 
Each plasma sample will be divided into two pre-labeled and pre-cooled polypropylene 
tubes and placed on dry ice and acetone until final storage in an ultra-low freezer as 
specified in the laboratory manual. 
 
Each sample tube will be identified with a label resistant to storage temperature. Please 
refer to the laboratory manual for specific instructions related to the labeling and 
management of these specimens. 
13.4.3 Specimen Shipment 
On request, site staff personnel shall ship one of the duplicate samples of plasma frozen 
under dry ice. The secondary plasma sample will be retained in an ultra-low freezer as 
specified in the laboratory manual as back-up samples until confirmation that the initial 
shipment has been received safely by the analytical laboratory. 
 
Samples will be shipped by an authorized courier to: 
MicroConstants Inc. 
9050 Camino Santa Fe, San Diego, CA 92121 USA 
Phone: (866) 232-9497; FAX: (858) 652-4699 
 
The study site shall retain copies of the shipping documents generated at the time of 
shipment. Refer to the laboratory manual for additional detailed instructions related to the 
labeling and management of these specimens. 
13.4.4 Analytical Methodology 
The concentrations of cortexolone 17α-propionate (CB-03-01) and cortexolone will be 
determined in the plasma samples using validated analytical methods for each analyte [4, 
5]. 
13.5 
Cosyntropin Stimulation Test 
At Visit 1 (Screening), a CST will be performed for each subject between 7 AM and 9 AM. 
 
At Visit 4 (or EOS), a CST (and any follow-up CSTs) will be performed within ± one hour 
of the screening CST and ideally between 7 AM and 9 AM. 
 
Perform the CST as follows (see Appendix 4): 
• Collect a pre-stimulation blood sample as specified in the Laboratory Manual. 


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• Reconstitute one vial of cosyntropin (0.25mg) in sodium chloride for injection USP 
(the volume of sodium chloride in the package insert for Cortrosyn® is 2 to 5mL). 
• Inject the cosyntropin intravenously (the length of time during which the 
cosyntropin should be injected is 2 minutes). 
• Thirty (30) minutes after completing the cosyntropin injection, collect a post-
stimulation blood sample as specified in the Laboratory Manual. 
 
If the results of the Visit 1 (Screening) CST indicate the subject has an abnormal HPA axis 
response (defined as a post-stimulation serum cortisol level of ≤18µg/dL), the subject will 
be classified as a screen failure and withdrawn from the study following the procedures in 
Section 14.4. In addition, direct the subject to consult with their physician concerning the 
abnormality unless the investigator believes it is not medically indicated. The conversation 
with the subject must be documented in the source documents. 
 
If a subject’s EOS laboratory results show an abnormal HPA axis response (defined as a 
post-stimulation serum cortisol level of ≤18 µg/dL), the test article will be considered to 
have caused the abnormal CST result in the subject. Report this abnormality as an AE. 
Instruct the subject not to use ANY topical or systemic steroids; however, other therapies 
that will not affect their adrenal function may be used to treat their acne. The subject should 
be scheduled to return for a follow-up visit no less than four (4) weeks after the EOS 
laboratory samples are collected. In the event the subject is still found to have laboratory 
evidence of adrenal suppression, the subject will be required to return for additional follow-
up visits, no less than every four (4) weeks, until the HPA axis response has been 
documented to return to normal. 
 
AEs that may be associated with the CST and that must be included in the informed 
consent/assent include: 
• Rare hypersensitivity reactions 
• Bradycardia 
• Tachycardia 
• Hypertension 
• Peripheral edema 
• Rash 
 
AEs associated with venipuncture and that must also be included in the informed 
consent/assent include those listed in Section 13.1. 
14. 
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. 


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14.1 
Completion of the Study 
Each subject who completes the course of treatment as specified in this protocol will have 
completed the study. 
14.2 
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 withdraw. NOTE: if the subject 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 
• Progressive disease 
• Noncompliance with study drug 
• Protocol deviation 
• Pregnancy (if applicable) 
• Lost to follow-up 
• Study terminated by Sponsor 
• Death 
 
If a subject withdraws from the study prematurely for any reason, every attempt should be 
made to complete the EOS procedures prior to discharging the subject from the study. If a 
subject withdraws prematurely during the treatment period for any reason, the Visit 4 
procedures (minus the PK blood draw) will be completed. Subjects who withdraw 
prematurely will be replaced until at least 20 subjects with both Screening and Day 14 
serum cortisol data (pre- and post-cosyntropin stimulation) have completed the study 
without any significant protocol violations (i.e., evaluable subjects). When a subject is 
withdrawn from the study for a treatment-related AE (i.e., possibly, probably or definitely 
related as defined in Section 15.1), when possible, the subject should be followed until 
resolution of the AE. 
14.3 
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. 
 


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In the event that the Sponsor chooses to discontinue or terminate the study, appropriate 
notification will be given to the investigator. 
14.4 
Screen Failures 
A subject will be considered a screen failure if Visit 1/Screening laboratory results indicate 
(1) an abnormal pre-CST serum cortisol level, (2) abnormal HPA axis function (a low post-
CST serum cortisol level), or (3) other clinically significant out-of-range laboratory test 
results, in the opinion of the investigator. If these conditions apply, the subject should be 
excluded from study participation, and the Screen Failure CRF should be completed. No 
clinical evaluation or follow-up CST will be performed in these subjects.  
 
If a subject withdraws prematurely during the treatment period for another reason, 
complete the CRF for the appropriate visit, then complete the End of Study CRFs including 
scheduling appropriately to obtain the End of Study CST. 
 
Subject enrollment will continue until at least 20 evaluable subjects with both Screening 
and Day 14 serum cortisol data (pre- and post-cosyntropin stimulation) have completed the 
study without any significant protocol violations (evaluable subjects). This may require the 
enrollment of approximately 24 subjects. 
15. 
ADVERSE EVENT REPORTING 
An adverse event (AE) is any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  
 
An AE (also referred to as an adverse experience) can be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a drug, without any judgment about causality. An AE can arise from any use of 
the drug (e.g., off-label use, use in combination with any drug) and from any route of 
administration, formulation or dose, including an overdose. 
 
Information on the medical condition of subjects should begin following the subject’s 
written consent/assent to participate in the study and a medical history should be taken at 
screening. During any wash out and baseline periods, any changes in the health of subjects 
should be recorded as changes in medical history unless an event occurred as a result of a 
study-related procedure and is unanticipated; in such cases, the event should be recorded 
as an AE and reported to the Institutional Review Board (IRB) or Institutional Ethics 
Committee (IEC) as an “unanticipated problem” in accordance with local procedures. 
Other changes in subject health information becomes AE data when the subject begins 
dosing with the test article and therefore AE data should be collected from the date of the 
first dose 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:  


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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 “primary 
operational component” for devices) 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). 
15.1 
Adverse Event (AE) 
All AEs must be recorded on the AE CRF. AEs should be followed to resolution or 
stabilization (if possible), and reported as serious adverse events (SAEs) if they become 
serious. 
 
LSRs that have been reported in subjects treated with CB-03-01 creams (0.1%-1% 
concentration) include (with decreasing frequency) erythema, pruritus, scaling/dryness, 
skin atrophy, striae rubrae, stinging/burning, edema, and telangiectasia; however most 
LSRs were typically of minimal to mild severity. No subjects discontinued treatment due 
to these LSRs. 
 
AEs that have been reported in subjects treated with CB-03-01 creams (0.1-1% 
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. 


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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. 
 
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. 
 


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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. 
 
An adverse reaction is any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the 
event. For the purposes of prescription drug labeling, the term adverse reaction means an 
undesirable effect, reasonably associated with the use of a drug that may occur as part of 
its pharmacological action or may be unpredictable in its occurrence.  
 
A suspected adverse reaction is any AE for which there is a reasonable possibility that 
the drug caused the event.  
 
For the purposes of IND safety reporting, “reasonable possibility” means there is evidence 
to suggest a causal relationship between the drug and the AE. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which means any 
AE caused by a drug.  
 
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. 
15.2 
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. 
 


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An AE or suspected adverse reaction is considered “serious” if, in the opinion of either the 
investigator or Sponsor, it results in any of the following outcomes: 
• Death. 
• Life-threatening event. 
• Inpatient hospitalization or prolongation of existing hospitalization. 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• Congenital anomaly/birth defect. 
• Is an important medical event - defined as a medical event(s) that may not result in 
death, be life-threatening, or require hospitalization but, based upon appropriate 
medical judgment, may jeopardize the patient/subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in the definition above. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.  
 
Events NOT considered to be serious AEs 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/IEC 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 a 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. 
 


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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 
safety report of potential serious risks as soon as possible but no later than 15 calendar days 
after the Sponsor determines that the information is “reportable” according to the criteria 
listed in 21 CFR Section 312.32. These are: 
 
i) Serious and unexpected suspected adverse reactions, 
ii) Findings from other studies including epidemiological studies, pooled 
analyses or other clinical studies that suggest a significant risk in humans 
exposed to the test articles, 
iii) Findings from animal or in vitro tests that suggest a significant risk to 
humans exposed to the test articles, or reports of significant organ toxicity 
at or near the expected human exposure, and 
iv) Clinically important increases in the rate of occurrence of serious suspected 
adverse reactions. 
 
Upon receiving such notices, the investigator must review and retain the notice with the 
Investigator Brochure and immediately submit a copy of this information to the responsible 
IRB/IEC according to local regulations. The investigator and IRB/IEC will determine if 
the informed consent/assent requires revision. The investigator should also comply with 
the IRB/IEC 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. 
15.3 
Laboratory Test Abnormalities 
In addition to being recorded on the appropriate laboratory test results CRF, or being 
electronically submitted from a central laboratory, any clinically significant laboratory test 
result that meets the criteria for an AE (see Section 15) or SAE (see Section 15.2) must 
also be recorded on the AE CRF. SAEs must be reported to the Sponsor and IRB/IEC as 
per Section 15.2. In these cases, the CRO will typically require additional information 
about the clinically significant abnormality, including information regarding relationship 
to test article or other causes, any action taken, and resolution. Other laboratory test 
abnormalities will be addressed by the investigator on the actual laboratory test reports, 
and on the associated laboratory test results CRF. 
15.4 
Pregnancy 
Females of childbearing potential will be defined as subjects who have experienced 
menarche or are 10 years of age or older. All females of childbearing potential must have 
a negative pregnancy test prior to study enrollment, and must use a highly effective25 
                                                 
25 Highly effective contraception includes a) total abstinence, b) oral, injected, or implanted hormonal 
methods of contraception, c) IUD, d) partner vasectomy (performed at least six (6) months prior to study 
entry), e) oral contraceptive WITH a barrier method, or f) double barrier methods of contraception [barrier 


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method of contraception during the course of the study, in a manner such that risk of failure 
is minimized. Note: If a female becomes 10 years of age during the study, she must have a 
negative UPT at that time to continue study participation. Prior to study enrollment, 
females 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. 
 
Females should be instructed to contact the investigator immediately if they suspect they 
might be pregnant (e.g., missed or late menstrual period). 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 receive or 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 
investigator must notify the IRB/IEC 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). 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 a SAE and details documented in the pregnancy 
surveillance form. Abortion, whether accidental, therapeutic or spontaneous should be 
reported as a SAE. 
16. 
BLINDING/UNBLINDING 
This study is an open label study. There is no blinding of the test article. 
                                                 
methods include male or female condom, diaphragm with spermicidal foam/gel/film/vaginal suppository, 
cervical cap with spermicides, or contraceptive sponge]. 


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17. 
CLINICAL SUPPLIES 
17.1 
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 3. 
17.2 
Supplies Provided by Sponsor or Sponsor’s CRO 
• eCRFs 
• Subject Diaries 
• Source document draft templates 
• Site regulatory binder 
• UPT kits (for US sites) 
• CST kits or equivalent (see Appendix 4) 
• Weighing scales (if necessary) 
• Mild soap cleanser or equivalent 
17.3 
Supplies Provided by Investigator 
• Urine collection containers for UPTs 
• Refrigerated centrifuge to process blood samples  
• Ultra-low freezer for storage of plasma samples 
17.4 
Supplies Provided by the Clinical Laboratory 
• Supplies to collect and transport urine and blood samples to the clinical laboratory 
• Polypropylene tubes and labels for plasma aliquots for PK analysis 
• Urine collection containers 
• UPT kits (for EU sites) 
18. 
STATISTICAL CONSIDERATIONS 
18.1 
Sample Size 
No formal power calculations were performed to establish the sample size. The number of 
evaluable subjects is historically consistent with other HPA/PK studies in this age range. 
18.2 
Endpoints 
18.2.1 Efficacy Endpoints 
Efficacy will not be assessed in this study. 


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18.2.2 Safety Endpoints 
Primary Safety Endpoints 
• HPA Axis Response to Cosyntropin: Measurement of serum cortisol concentrations 
after stimulation of the adrenal cortex with cosyntropin (CST) at Screening, and 
Day 14 (or EOS). HPA axis suppression is defined as a post-stimulation serum 
cortisol level <18 µg/dL at Day 14 (or EOS). 
• Trough Plasma Concentrations: Trough measurements of cortexolone 17α-
propionate and cortexolone in plasma at Screening, Baseline, Day 7 and Day 14. 
 
Secondary Safety Endpoints  
• Safety laboratory testing (hematology, clinical chemistry, and urinalysis) at 
Screening and Day 14 (or EOS). 
• Local and systemic AEs at every visit (Baseline, Days 7 and 14).  
• The severity of the following LSRs [for face and trunk, separately]: telangiectasia, 
skin atrophy, striae rubrae, erythema, edema, scaling/dryness, stinging/burning and 
pruritus will be documented at Baseline (pre- and post-test article application), Day 
7, and Day 14. 
• Physical examination/vital signs at Screening and Day 14 (or EOS). 
• UPTs (for all females of childbearing potential) at Screening, Baseline, and Day 14 
(or EOS). 
• ECG at Screening and Day 14 (or EOS). 
18.3 
Statistical Methods 
All statistical processing will be performed using SAS® unless otherwise stated. Excel or 
SAS® will be used for the analysis of trough plasma concentrations data. 
 
All subjects enrolled in the study who were dispensed and applied test article at least once 
will be included in the analysis of safety and will be considered the Safety population. 
Subjects who were discontinued from the study at Visit 2 (Baseline) due to abnormal 
screening laboratory test results or failure to meet any other eligibility criteria will be 
classified as screen failures and excluded from the HPA axis suppression summaries. 
Subjects with both Screening and Day 14 (or EOS) serum cortisol data (pre- and post-
cosyntropin stimulation) who completed the study without significant protocol violations 
will be considered evaluable (Evaluable population). Subjects included in the PK analysis 
(PK population) must not have any significant protocol deviations, must have at least an 
80% dose compliance based on number of applications, and must apply the final three 
doses as prescribed prior to the EOS PK assessment. 
 
Demographic and baseline characteristics will be summarized for the Safety, Evaluable, 
and PK populations. In addition, demographic variables, AEs, and primary reason for 
screen failure will be summarized separately for screen fail subjects. Frequency counts and 


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percentages will be reported for categorical data and sample size, mean, standard deviation, 
median, minimum, and maximum will be reported for the continuous variables. 
18.3.1 Efficacy Analyses 
There will be no efficacy analyses. 
18.3.2 Safety Analyses 
18.3.2.1 
HPA Axis Suppression 
Serum cortisol results will be summarized for the evaluable subjects. HPA axis responses 
to CST will be dichotomized to normal and abnormal. An abnormal HPA axis response 
(HPA suppression) is defined as a 30-minute post-stimulation serum cortisol level of 
<18 µg/dL at Day 14. The proportion of subjects manifesting laboratory based evidence of 
adrenal suppression at Day 14 will be summarized and 95% confidence intervals for the 
proportion of abnormal responses will be derived. The changes in serum cortisol levels 
after stimulation at Screening and Day 14 (or EOS) will also be summarized. 
18.3.2.2 
Pharmacokinetic Analysis 
Morning trough concentrations (C12) of cortexolone 17α-propionate and cortexolone in 
plasma at Day 7 and Day 14 (prior to the morning test article application, where applicable) 
will be determined using validated methods. Descriptive statistics of the plasma 
concentrations will be provided at Screening, Baseline, Day 7, and Day 14 for each analyte. 
18.3.3 Secondary Safety Analysis 
18.3.3.1 
Extent of Exposure to Test Article 
The total amount of CB-03-01 cream, 1% used (grams applied) will be calculated from the 
weights of the returned test articles. Descriptive statistics (mean, standard deviation, 
median, minimum, and maximum) will be determined for the total amount of test article 
(grams) used by each subject in the Safety, PK, and evaluable populations. 
18.3.3.2 
Dosing Compliance 
Descriptive statistics will be used to summarize test article compliance for the Safety, PK, 
and evaluable populations. Measures of test article compliance will include the duration of 
treatment, the total number of applications (determined from the actual number of 
applications reported by the subject), and the percent of expected doses applied. A subject 
will be considered compliant with the dosing regimen if the subject applies at least 80% of 
the expected number of applications prior to the HPA assessment. Subjects included in the 
PK analysis (PK population) must not have any significant protocol deviations, must have 
at least an 80% dose compliance based on number of applications, and must apply the final 
three doses as prescribed prior to the end of study PK assessment. 


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18.3.3.3 
Safety Laboratory Tests 
Laboratory data collected at Screening and Day 14 (or EOS), including clinical chemistry, 
hematology, and urinalysis, will be tabulated for each visit and changes from Screening to 
Day 14 (or EOS) will also be tabulated for the Safety population. All laboratory data will 
also be listed. Data will be reported in units received from the central laboratory. Shift 
tables by analyte and by out of range flag will also be presented to facilitate the evaluation 
of change from Screening at Day 14 (or EOS). 
18.3.3.4 
Local Skin Reactions 
The frequency distributions of the severity of LSRs associated with the topical application 
of corticosteroids and/or acne including telangiectasia, skin atrophy, striae rubrae, 
erythema, edema, scaling/dryness, stinging/burning, and pruritus will be summarized with 
frequency counts and percentages at Baseline, Day 7, and Day 14 for face and trunk, 
separately. 
18.3.3.5 
Adverse Events 
All AEs reported during the study will be listed, documenting onset, whether therapy was 
required, any change in test article dosing, severity, possible relationship to test article, and 
outcome for the Safety population. Verbatim terms on the case report forms (CRFs) will 
be linked to preferred terms (PTs) and system organ class (SOC) using the MedDRA 
mapping system. All reported AEs will be summarized by the number of subjects reporting 
AEs, SOC, PT, severity, and relationship to test article. 
18.3.3.6 
Urine Pregnancy Tests 
A listing of UPT results at Screening, Baseline, and Day 14 (or EOS) will also be prepared. 
18.3.3.7 
Physical Examination / Vital Signs 
Physical examination findings at Screening and Day 14 will be recorded in medical history 
or as AEs. Vital signs will be recorded at Screening and Day 14. 
18.3.3.8 
Electrocardiogram 
ECGs will be evaluated at Screening and Day 14 (or EOS) for any material changes. 
18.4 
Subgroup Analyses 
No subgroup analyses are planned. 
18.5 
Interim Analyses 
No interim analyses are planned. 


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19. 
ETHICAL AND REGULATORY CONSIDERATIONS 
19.1 
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 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/IEC 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. 
19.2 
Institutional Review Board / Ethics Committee and Informed Consent/Assent 
Before study initiation, the investigator must have written and dated approval from the 
IRB/IEC 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/IEC with a copy 
of the product labeling, information to be provided to subjects and their parent/guardian 
and any updates. The investigator will submit documentation of the IRB/IEC approval to 
the CRO. 
 
The IRB/IEC approved consent/assent form must include all elements required by FDA (or 
other Health Authority), state, and local regulations, and may include appropriate 
additional elements. 
 
The investigator/designee will explain the study to each potential subject and the subject’s 
parent/guardian. The subject must indicate voluntary assent by signing and dating the 
approved informed 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. 
19.3 
Protocol Compliance 
The IRB/IEC 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.  


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19.4 
Protocol Revisions 
TI must prepare all protocol revisions. All protocol amendments must receive IRB/IEC 
approval prior to implementation. All administrative letters must be submitted to the 
IRB/IEC for their information. Copies of all correspondence with the IRB/IEC regarding 
this study must be sent to the CRO. 
 
New or altered consent/assent forms required by the IRB/IEC 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. 
19.5 
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. 
19.6 
Case Report Form Requirements 
The study will utilize validated 21CFR Part 11 compliant electronic data capture (EDC) 
software to collect data; all requested information must be entered on the eCRFs in the 
areas provided in a timely manner. When changes or corrections are made in the eCRF, 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 eCRF completion may make 
entries on the eCRFs. 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 eCRF. 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. 


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19.7 
Reports to Institutional Review Board / Ethics Committee 
The investigator should provide the IRB/IEC with reports, updates, and other information 
(e.g., safety updates, protocol amendments, and administrative letters) according to 
regulatory requirements or Institution procedures. 
19.8 
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 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 
regulatory authority) site audit. 
19.9 
Records Retention 
The investigator must maintain all study records (including test article disposition, 
informed consents/assents, CRFs/DCFs (data clarification forms), 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 original 
Study Medication Accountability Logs will be kept at the sites and copies will be returned 
to the Sponsor. 
 
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 regulatory 
authority, or the IRB/IEC. 
 
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 


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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. 
 
 


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20. 
REFERENCES 
1. 
Cockcroft DW and Gault MH. Prediction of Creatinine Clearance from Serum 
Creatinine. Nephron 16:31-41, 1976. 
 
2. 
Celasco G, Moro L, Bozzella R, Ferraboshi P, Bartorelli L, Quattrochhi C, Nicoletti 
F. Biological profile of cortexolone 17α-propionate (CB-03-01), a new topical and 
peripherally selective androgen antagonist. Arzneim Forsch 54:881-6, 2004. 
 
3. 
Study 171-7151-202. An Open Label Evaluation of the Adrenal Suppression 
Potential and Pharmacokinetic Properties of Cortexolone 17α-Propionate (CB-03-
01) Cream Applied Every Twelve Hours for Two Weeks in Subjects with Acne 
Vulgaris. Intrepid Therapeutics, 2014. 
 
4. 
Method No. MN12059. Method for the Determination of Cortexolone-17-Alpha-
Propionate and Cortexolone in Human Plasma using High-Performance Liquid 
Chromatography with Mass Spectrometric Detection. MicroConstants, 2012. 
 
5. 
Study No. PF12B-0163. Validation of a Method for the Determination of 
Cortexolone-17-Alpha-Propionate and Cortexolone in Human Plasma using High-
Performance Liquid Chromatography with MS/MS Detection. MicroConstants, 
2012. 
 


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APPENDIX 1 
SAMPLE SUBJECT INSTRUCTION SHEET 
Copies of the Subject Instruction Sheet will be provided to the study site. The investigator 
should provide this sheet to the subject and the subject’s parent/guardian at Visit 2 / 
Baseline / Day 1. Any modifications to the sample provided must be approved by the 
IRB/IEC. 
 
 


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SAMPLE SUBJECT/PARENT INSTRUCTION SHEET 
Please follow these instructions carefully. If you do not understand anything in these instructions, 
ask your parent or guardian for help. 
Contact/ask your parent or guardian to contact the study staff at the telephone number noted below 
if you have any questions about the study: 
Contact: 
 
 
 
 
 
 
At: 
 
 
 
 
STUDY MEDICATION APPLICATION: 
• 
You will be shown how and where to apply the study medication in the clinic. 
• 
Wash the area to be treated (your face and trunk) with mild soap and water. Gently dry the area. 
• 
Wash your hands before applying the study medication. 
• 
Dispense 2 grams of study medication using the scale provided by the study doctor. 
• 
Use the “Dab, Spread, Pat” method of application:  
O With one of your fingertips, DAB small amounts of the study medication onto all areas of 
your face (forehead, cheeks, nose, and chin), avoiding application on eyes. 
O SPREAD the study medication evenly with your fingertip to cover your entire face with a 
very thin even coat of the study medication.  
O Then, gently PAT the skin until the study medication has absorbed into the skin. 
• 
Apply the remaining amount of the study medication to the areas of your trunk as instructed by 
the study staff using the “Dab, Spread, Pat” method until all of the study medication has been 
applied. This may include your shoulders, upper chest, and/or upper back (get assistance if you 
are not able to apply the study medication to your back on your own).  
• 
Record date and time of study medication application in your subject diary. 
• 
Wash your hands after applying the study medication. 
• 
Do not wash the treated areas for at least 8 hours after application of the study medication. 
• 
Do not cover or wrap areas where study medication was applied. Loose fitting clothing is 
recommended after application of study medication. 
• 
Do not apply skin care products for at least 4 hours after application of the study medication. 
• 
At home, apply the study medication every 12 hours as directed by the study doctor. 
BEFORE EACH STUDY VISIT: 
• 
Please shower or wash the areas to be treated before each clinic visit. 
• 
DO NOT APPLY THE STUDY MEDICATION ON THE DAY OF YOUR SCHEDULED 
STUDY VISITS. 
ADDITIONAL REMINDERS: 
• 
Store the study medication 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 other children and pets. 
• 
Discontinue use if skin irritation or rash develop and contact the study site. 
• 
Do not swim or participate in any other activities which could potentially remove the product 
from the Treatment Area for the duration of the study 
STUDY VISIT SCHEDULE:  
VISIT 3: Date:                   Time:                        VISIT 4: Date:                  Time:                        


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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 at Visit 2 / Baseline / Day 1 and all 
follow-up visits as necessary. 
 
 


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SAMPLE SUBJECT DIARY for PROTOCOL CB-03-01/28 
 
Apply the study medication as instructed by the study doctor. After dosing every 12 hours 
(each morning and evening), at approximately the same time each day, record the date and 
time that the dose was applied. If you miss a dose, write MISSED where the time is 
recorded. PARENT/GUARDIAN SHOULD ASSIST IN RECORDING THE 
SUBJECT DIARY. DO NOT APPLY THE STUDY MEDICATION ON THE DAY 
OF YOUR SCHEDULED STUDY VISITS. 
 
Date 
(dd/MMM/yy)__ 
Dose 
(time of day) 
____/_____/____ 
___ ___ : ___ ___  am 
___ ___ : ___ ___  pm 
____/_____/____ 
___ ___ : ___ ___ am 
___ ___ : ___ ___ pm 
____/_____/____ 
___ __ : __ ___  am 
___ __ : __ ___ pm 
____/_____/____ 
___ ___ : ___ ___ am 
___ ___ : ___ ___ pm 
____/_____/____ 
___ ___ : ___ ___ am 
___ ___ : ___ ___ pm 
____/_____/____ 
___ ___ : ___ ___ am 
___ ___ : ___ ___ pm 
____/_____/____ 
___ ___ : ___ ___ am 
___ ___ : ___ ___ pm 
____/_____/____ 
___ ___ : ___ ___ am 
___ ___ : ___ ___ pm 
____/_____/____ 
___ ___ : ___ ___ am 
___ ___ : ___ ___ pm 
 
Next appointment: _____________, ______/________/_____ at ________am 
Week Day               dd        MMM      yy 
Return this diary, your used AND unused medication tubes at each visit. 
 
If you have any questions,  
Contact: 
 
 
 
 
 
 
At: 
 
 
 
 
 
Site Use Only: 
Subject #: ___ ___ ___ Initials: ___ ___ ___ 
Diary dispensed at: 
Date Returned 
Visit 2 (Day 1) 
 
Visit 3 (Day 7) 
  


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APPENDIX 3 
TEST ARTICLE INFORMATION 
A 3.1 Test Article Packaging and Labeling 
The test articles will be packaged and labeled by Cassiopea S.p.A, Lainate Italy. CB-03-
01 cream, 1% will be packaged in epoxy lined aluminum tubes, with a polypropylene cap 
closure, containing 30 grams of test article. Each subject will be assigned a subject number 
according to the numerical order that they will be enrolled in. 
 
Over the duration of the study, the subjects will be dispensed the necessary amount of test 
article. Subjects should not have more than two tubes of test article in their possession at 
any one time. When the tubes are dispensed to subjects, the tube label should be completed 
entirely and the information documented on the Study Medication Accountability Log 
which is to be kept at the investigational site. 
 
Tube labels will, at a minimum, contain the following information: protocol number, 
subject identifiers (subject number and initials to be filled in), an investigational test article 
disclaimer (e.g., Caution: New Drug, Limited by United States law to investigational use 
or similar language as appropriate for the Health Authority governing the site), and the 
appropriate storage conditions for the study medication. 
A 3.2 Test Article Storage and Preparation 
Study medication will be stored under secure conditions until they are dispensed to the 
subjects. Test articles should be stored in accordance with the temperature specified on the 
tube labels. 
A 3.3 Dispensing Test Article 
Subjects who are eligible for enrollment in the study will be assigned a subject number. 
This number will consist of five digits, two digits for the site number, and three digits 
assigned by the study staff in ascending order beginning with the lowest available number. 
 
The test article must be dispensed only to study subjects and only at study sites specified 
on the form FDA 1572 (or corresponding form of another Health Authority for sites in the 
EU) by authorized personnel as required by applicable regulations and guidelines. 
 
On dispensing the test article for the first time at the Baseline Visit, each subject will be 
dispensed 2 tubes and the information will be recorded on the Study Medication 
Accountability Log. Each tube contains approximately 30 grams of test article and should 
last for approximately seven days with dosing every 12 hours. 
 
The subject will also be instructed to bring all the tubes (used and unused) to each clinic 
visit. When a subject returns each used tube of test article, the date of return and initials of 


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the individual accepting the return for each tube of test article will be documented on the 
same line of the Study Medication Accountability Log as the dispensing information. 
 
At Visit 3 (Day 7), all tubes will be collected and weighed. The amount of test article 
applied (2 grams per application) should be verified by reviewing the drug weights and 
diary entries. Additional tubes may be dispensed for the next visit interval, as applicable. 
If necessary, review the application instructions with the subject. 
 
At Visit 4 (Day 14 or EOS), all the tubes of test article that were dispensed to the subjects 
will be collected. Every effort should be made to obtain the return of all dispensed tubes of 
test article. If these efforts fail, make a detailed note of the reason for the failure in the 
source documents. 
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. 
• 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. Subjects should be instructed to discontinue use if skin irritation or rash 
develop and contact the study site. In the event that the investigator believes dose 
modification is necessary (e.g., problems with tolerance) the subject’s care should be 
discussed with the Medical Monitor prior to making any dose modifications. All dose 
modifications must be reported on the appropriate CRF. 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
CONFIDENTIAL 
Page 63 of 66 
TI SOP 305-A Protocol Template, Version 06 
A 3.6 Documentation of Application and Compliance 
The date and time of the first application of test article will be recorded on the appropriate 
CRF. A CRF will also be used to record any changes from the application specified in the 
protocol (e.g., missed applications, investigator directed reduction in application 
frequency). The date and time of the last application of the test article will be recorded on 
a CRF. 
 
A Subject Diary will be dispensed to subjects to record the dates and times of all application 
doses and to record any missed doses of the test article (Appendix 2). Subjects will be 
instructed to bring the diary with them to each study visit. 
A 3.7 Return and Destruction of Test Article Supplies 
At completion or termination of the study, all unused and/or partially used test article tubes 
must be returned to the CRO, if not authorized by the CRO to be destroyed at the site. All 
tubes of the test article should be accounted for and any missing tubes of test article must 
be explained on the completed Study Medication Accountability Log. All returned tubes 
will be weighed to the nearest tenth gram (0.1 gram) 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) provided to a sponsor-identified third party 
vendor for appropriate destruction according to applicable regulations with the provision 
of a certificate of destruction. 
 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
CONFIDENTIAL 
Page 64 of 66 
TI SOP 305-A Protocol Template, Version 06 
APPENDIX 4 
COSYNTROPIN STIMULATION TEST PACKAGE INSERT 
 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
CONFIDENTIAL 
Page 65 of 66 
TI SOP 305-A Protocol Template, Version 06 
APPENDIX 5 
BODY MASS INDEX FOR AGE 
 
 
 


Product Name: CB-03-01 cream, 1% 
 
Protocol: CB-03-01/28 
Sponsor Name: Cassiopea S.p.A. 
 
Protocol Date: February 18, 2016 
 
CONFIDENTIAL 
Page 66 of 66 
TI SOP 305-A Protocol Template, Version 06 
 

SAP_001.pdf: 


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TABLE OF CONTENTS 
 
GLOSSARY OF TERMS ................................................................................................... 4 
1 
INTRODUCTION ...................................................................................................... 5 
2 
PURPOSE OF THE ANALYSES .............................................................................. 5 
3 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 5 
3.1 
Objectives ............................................................................................................. 5 
3.2 
Safety Endpoints .................................................................................................. 5 
3.3 
Other Endpoint ..................................................................................................... 6 
4 
STUDY DESIGN........................................................................................................ 6 
5 
DEFINITIONS ............................................................................................................ 8 
6 
CLINICAL EVALUATIONS ..................................................................................... 8 
6.1 
Investigator’s Global Assessment ........................................................................ 8 
6.2 
Acne Lesion Counts ............................................................................................. 8 
6.3 
Adverse Events ..................................................................................................... 9 
6.4 
Local Skin Reactions ............................................................................................ 9 
6.5 
Cosyntropin Stimulation Test............................................................................. 10 
6.6 
Blood Draw for Morning Trough Concentrations.............................................. 10 
6.7 
Physical Examination, Vital Signs, ECGs and Safety Laboratory Tests ........... 10 
6.8 
Concomitant Medications and Concurrent Therapies/Procedures ..................... 10 
7 
STATISTICAL METHODS ..................................................................................... 10 
7.1 
General Considerations ...................................................................................... 10 
7.2 
Analysis Populations .......................................................................................... 10 
7.2.1 
Safety Population ........................................................................................ 11 
7.2.2 
Evaluable Population .................................................................................. 11 
7.2.3 
Pharmacokinetic Population ....................................................................... 11 
7.3 
Final Analyses and Reporting ............................................................................ 11 
7.4 
Methods for Handling Missing Data .................................................................. 11 
7.5 
Sample Size ........................................................................................................ 11 
7.6 
Subject Disposition ............................................................................................ 12 
7.7 
Screening and Baseline Assessments ................................................................. 12 
7.7.1 
Demographics ............................................................................................. 12 
7.7.2 
Medical History, Dermatological Examination and Physical Examination 12 
7.7.3 
Baseline Vital Signs, Height and Weight ................................................... 12 
7.7.4 
Baseline Clinical Evaluations ..................................................................... 12 
7.7.5 
Extent of Exposure ...................................................................................... 12 
7.7.6 
Dosing Compliance ..................................................................................... 12 
7.8 
Safety Analyses .................................................................................................. 13 
7.8.1 
Adverse Events ........................................................................................... 13 
7.8.2 
HPA Axis Suppression Analysis ................................................................ 13 
7.8.3 
Trough Concentrations................................................................................ 13 
7.8.4 
Local Skin Reactions .................................................................................. 13 
7.8.5 
Vital Signs and Electrocardiograms............................................................ 14 
7.8.6 
Safety Laboratory Tests .............................................................................. 14 
7.8.7 
Urine Pregnancy Tests ................................................................................ 14 
7.8.8 
Concomitant Medications and Concurrent Therapies/Procedures .............. 14 


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7.9 
Other Analysis: Investigator’s Global Assessment ............................................ 14 
7.10 
Subgroup Analyses ......................................................................................... 14 
7.11 
Interim Analysis and Study Stopping Rule .................................................... 14 
8 
Planned Listings, Tables and Figures ....................................................................... 14 
 
 
 




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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned statistical analyses to be 
performed for data from Protocol 171-7151-208, “An Open Label Evaluation of the 
Adrenal Suppression Potential and Trough Plasma Concentrations of Cortexolone 17α-
Propionate (CB-03-01) Cream Applied Every 12 Hours for Two Weeks in Subjects 9 to 
<12 Years of Age with Acne Vulgaris”. 
 
This SAP was created using clinical protocol 171-7151-208 dated February 18, 2016 with 
two administrative amendments (March 18 and May 19, 2016) and the Electronic Case 
Report Forms (eCRF) for protocol 171-7151-208 dated January 16, 2017 v2.0. 
 
 
2 
PURPOSE OF THE ANALYSES 
The purpose of this SAP is to outline the planned analyses to be completed to support the 
Clinical Study Report (CSR) for protocol 171-7151-208.  Any post-hoc or unplanned 
analyses not identified in this SAP will be clearly identified in the CSR. 
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
The study objective is to determine: a) the adrenal suppression potential and b) the trough 
plasma concentrations associated with topical application of CB-03-01 cream, 1% in 
subjects with acne vulgaris. 
 
3.2 
Safety Endpoints  
Safety endpoints include: 
 
• Hypothalamic-Pituitary-Adrenal (HPA) Axis Response to Cosyntropin by 
Cosyntropin Stimulation Test (CST): Measurement of serum cortisol 
concentrations after stimulation of the adrenal cortex with cosyntropin at 
Screening, and Day 14 (or End of Study (EOS)). HPA axis suppression is defined 
as a post-stimulation serum cortisol level ≤18 μg/dL at Day 14 (or EOS).  
• Trough Plasma Concentrations: Trough measurements of cortexolone 17α-
propionate and cortexolone in plasma at Screening, Day 1, Day 7 and Day 14.  
• Local and systemic Adverse Event (AEs).  
• The severity of the following Local Skin Reaction (LSRs) [for face and trunk, 
separately]: telangiectasia, skin atrophy, striae rubrae, erythema, edema, 
scaling/dryness, stinging/burning and pruritus at Day 1 (pre- and post-test article 
application), Day 7, and Day 14 (or EOS).  
• Safety laboratory testing (hematology, clinical chemistry, and urinalysis) at 
Screening and Day 14 (or EOS).  
• Physical examination/vital signs at Screening and Day 14 (or EOS).  
• ECG at Screening and Day 14 (or EOS).  
• UPTs (for all females of childbearing potential) at Screening, Day 1, and Day 14 
(or EOS).  
 


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3.3 
Other Endpoint 
The overall severity of each subject’s facial acne at Day 14 (EOS) will be assessed by the 
investigator or designee using the Investigator’s Global Assessment (IGA) score. 
4 
STUDY DESIGN 
This is an open-label, multicenter study in approximately 20 subjects 9 to <12 years of 
age with moderate to severe facial acne vulgaris (IGA score of 3 or 4) and obvious acne 
on the trunk (i.e., shoulders, upper chest, and/or back). The study will include a Screening 
Visit, a Baseline Visit (Day 1), and two (2) scheduled follow-up visits (Day 7 and Day 
14). Subjects will apply 2 grams of the test article per application every 12 hours for 2 
weeks. 
 
The study schedule of events and assessment is presented in Table 1.  Further details 
regarding the study may be found in the study protocol. 
 








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6.5 
Cosyntropin Stimulation Test  
CST will be performed at Screening and Day 14 (or EOS). If a subject’s laboratory 
results at Day 14 (or EOS) show an abnormal HPA axis response (defined as a post-
stimulation serum cortisol level of ≤18 µg/dL), the test article will be considered to have 
caused the abnormal CST result in the subject and the subject should return for follow-up 
visits until the HPA axis response has been documented to return to normal. 
6.6 
Blood Draw for Morning Trough Concentrations 
Blood samples will be collected for morning trough concentrations (C12) of cortexolone 
17α-propionate and cortexolone in plasma at Screening, Day 1 (pre-dose), Day 7 and Day 
14. 
6.7 
Physical Examination, Vital Signs, ECGs and Safety Laboratory Tests 
Findings from the physical examinations will be recorded in medical history (from 
assessment at Screening) or as AEs (from assessment at Day 14 (EOS)). 
 
Vital Signs, ECGs, and safety laboratory data are to be collected at Screening and Day 14 
(or EOS). Urine pregnancy test (UPT) for women of childbearing potential (WOCBP) 
will be performed at Screening, Days 1 and 14. 
6.8 
Concomitant Medications and Concurrent Therapies/Procedures 
Details of prior and concomitant medication use and concurrent therapies/procedures will 
be collected throughout the study. 
 
 
7 
STATISTICAL METHODS 
7.1 
General Considerations 
This section presents the statistical approaches that are anticipated for the analysis of the 
study data.  These approaches may at times require modifications due to unanticipated 
features of the data.  Deviations from analyses summarized in this document will be 
noted in the CSR. 
Version 9.4 (or higher) of the SAS statistical software package will be used to provide 
summary tables and data listings, unless otherwise stated.   
For continuous variables, descriptive statistics will include the number of subjects with 
non-missing data (n), mean, median, standard deviation, minimum and maximum values.  
For categorical variables, the number and percentage of subjects within each category 
will be presented. Subject data listings sorted by study site and subject number will be 
presented.  Summaries and analyses will be provided as specified below. 
 
7.2 
Analysis Populations 
All subjects will be classified into the Safety, Evaluable, and Pharmacokinetic (PK) 
populations according to the following definitions.   


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7.2.1 Safety Population 
The Safety population will include all enrolled subjects who were dispensed and applied 
at least one dose of the test article.  
7.2.2 Evaluable Population 
The evaluable population will include those subjects in the safety population who have 
both Screening and Day 14 serum cortisol data (pre- and post-cosyntropin stimulation) 
and meet the following criteria:-  
• Meets all inclusion/exclusion criteria, including normal response to cosyntropin 
stimulation defined as a Screening CST with a 30-minute post-stimulation cortisol 
level of > 18 μg/dL. 
• Screening and Day 14 CST were conducted between 7-9 AM. 
• Day 14 CST was conducted within ±1 hour of the Screening CST. 
• Applied at least 80% of expected applications and applied the final dose no more 
than 14 hours prior to the start of the CST test. 
• Has not taken or applied any medications that may interfere with HPA axis 
function. 
• Do not have any other significant protocol deviations. 
 
HPA axis suppression analysis will be conducted on the Evaluable population. 
7.2.3 Pharmacokinetic Population 
The PK population will include those subjects in the Safety population who have at least 
an 80% dose compliance based on number of applications, have at least one post-baseline 
PK blood draw within ±2 days of the scheduled visit at Days 7 and 14, and do not have 
any significant protocol deviations. For subjects who are in the PK population but did not 
apply the final three doses prior to the PK blood draw at Day 14, their Day 14 data will 
be excluded. For subjects in the PK population who discontinued from the study 
prematurely, their Screening, Day 1 and Day 7 data will be included as long as their dose 
compliance up to Day 7 is at least 80%.   
The morning trough concentrations of cortexolone 17α-propionate and cortexolone will 
be presented for the PK population. 
7.3 
Final Analyses and Reporting 
Final database lock will occur after all subjects have completed the study assessment 
period (or discontinued early) and all subject data has been monitored.  Analysis may not 
occur until after database lock, this SAP is approved, and analysis populations have been 
identified.  
7.4 
Methods for Handling Missing Data 
All summaries and analyses will use observed data only.   
7.5 
Sample Size 
No formal sample size calculations were performed. The number of evaluable subjects 
(20) is historically consistent with other HPA/PK studies. 


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7.6 
Subject Disposition 
The number and percentage of subjects who were enrolled in the study, who completed 
the study, who withdrew from the study and their reasons for discontinuation will be 
tabulated for each analysis population. 
Subject data listings of the protocol deviations, if any, and analysis population 
identification will be provided. 
7.7 
Screening and Baseline Assessments 
7.7.1 Demographics  
Demographic information including age, sex, ethnicity, race will be summarized for each 
analysis population. The demographic data for screen failures will be listed separately. 
7.7.2 Medical History, Dermatological Examination and Physical Examination  
Medical history, dermatological examination, and abnormalities noted during the 
physical examination at Screening will be presented in subject data listings for the Safety 
population. 
7.7.3 Baseline Vital Signs, Height and Weight 
Descriptive statistics will be provided for Baseline vital signs (blood pressure, pulse rate, 
temperature, and respiration rate), height, weight and BMI for the Safety population.  
7.7.4 Baseline Clinical Evaluations 
Baseline IGA and inflammatory and non-inflammatory lesion counts will be summarized 
for the Safety population.  
Baseline LSRs will be tabulated for the Safety population. 
7.7.5 Extent of Exposure 
The total amount of test article used by each subject (difference between the weight of the 
tubes dispensed and weight of the tubes returned) and the mean daily amount of test article 
applied (total amount of test article used divided by the treatment duration) will be 
calculated. The treatment duration is calculated by last dose date - first dose date +1. 
Descriptive statistics will be used to summarize the total amount and mean daily amount 
of test article applied for each analysis population. 
7.7.6 Dosing Compliance 
Dosing compliance (%) is derived by the following formula: 
 
Total number of applications
expected applications
x 100, 
 
where expected applications are 26 considering 13-day course of planned treatment for 
subjects who completed the study; and (study day of the last dose)x2 for subjects who 
discontinued from the study prematurely. 
 
 
 


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Descriptive statistics will be used to summarize test article dosing compliance. Subjects 
who applied at least 80% of the expected applications will be considered to be compliant 
with test article dosing. 
 
7.8 
Safety Analyses 
Summaries of the safety parameters will be provided as described below for the Safety 
population, unless otherwise specified. 
7.8.1 Adverse Events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 19.1. Verbatim terms will be mapped into a MedDRA 
system organ class (SOC) and preferred term (PT).  For all AE summaries, if a subject 
has more than one AE within a PT, the subject is counted once in that PT.  If a subject 
has more than one AE within a SOC, the subject is similarly counted once in that SOC. 
The number and percentage of unique subjects reporting any local and systemic treatment-
emergent AE will be summarized by SOC and PT. The number and percent of unique 
subjects reporting any local and systemic TEAE will also be summarized by SOC, PT, and 
maximum severity (mild, moderate, severe) and closest relationship to test article (not 
related, unlikely, possibly, probably related). 
Serious AEs and DLTs, if any, will be listed separately. 
7.8.2 HPA Axis Suppression Analysis  
HPA axis responses to cosyntropin will be dichotomized to normal and abnormal. An 
abnormal HPA axis response (HPA suppression) is defined as a 30-minute post-
stimulation serum cortisol level of ≤18 μg/dL at Day 14. The proportion of subjects 
manifesting laboratory based evidence of adrenal suppression at Day 14 will be presented 
along with 95% confidence intervals for the Evaluable population. The observed serum 
cortisol levels (pre- and post-cosyntropin stimulation) and the changes in serum cortisol 
levels after stimulation at Screening, Day 14, and, if any, at follow-up visits will also be 
summarized. 
7.8.3 Trough Concentrations 
Morning trough concentrations (C12) of cortexolone 17α-propionate and cortexolone in 
plasma at Screening, Day 1, Day 7 and Day 14 will be summarized for the PK population 
using geometric mean, coefficient of variation in addition to n, mean, median, standard 
deviation, minimum and maximum.  
Individual trough concentrations of cortexolone 17α-propionate and cortexolone in 
plasma across visits will be plotted. Individual average trough concentrations of 
cortexolone 17α-propionate and cortexolone will also be plotted by adrenal suppression 
status. 
7.8.4 Local Skin Reactions 
Severity of LSRs (telangiectasia, skin atrophy, striae rubrae, erythema, edema, and 
scaling/dryness, stinging/burning, and pruritus) will be tabulated by frequency and severity