Conditions: Congenital Ichthyosis
Keywords: X-linked, lamellar
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 19
Healthy volunteers: no

Brief summary:
Congenital ichthyosis (CI) is a large, heterogeneous family of inherited skin disorders of cornification resulting from an abnormality of skin keratinization, such as scaling and thickening of the skin. Treatment options include keratolytic agents, which can abruptly lead to extensive shedding or peeling of scales. PAT-001 primarily acts as a keratolytic agent; thus, making it a potential drug candidate for the treatment of skin disorders associated with hyperkeratinization, such as CI. The current study intends to evaluate the safety and tolerability of PAT-001 in patients with CI of either the Lamellar or X-Linked subtypes.

Detailed description:
The management of CI is a life-long endeavor, which remains largely symptomatic (i.e., emollients with or without keratolytics agents) and commonly focused on reducing scaling and/or skin lubrication with both systemic and topical treatments. A first-line therapy includes hydration and lubrication accomplished by creams and ointments containing low concentrations of salt, urea, or glycerol, which increase the water-binding capacity of the horny layer. Addition of keratolytics agents are used to decrease corneocyte cohesiveness, to promote desquamation, and to dissolve keratins and lipids (e.g., α-hydroxy acids, salicylic acid, high dose urea, propylene glycol, N-acetylcysteine, and retinoids). Systemic retinoid treatment is reserved for those patients refractory to topical agents because of long-term adverse effects and teratogenicity.

This is a two part, Phase 2, multicenter, proof-of-concept (POC) study of the safety and tolerability of PAT-001 for the treatment of Congenital ichthyosis (CI) in patients ages 12 years of age and older. Part 1 will be a double-blind, randomized, vehicle controlled, bilateral comparison of two treatments (PAT-001 \[0.1% or 0.2%\] vs. vehicle) for eight (8) weeks.

Part 2 will be a double-blind, active only treatment comparison of the two PAT-001 concentrations (0.1% or 0.2%) for an additional four (4) weeks. Subjects will have the option to participate in the pharmacokinetics (PK) portion of the study.

Arms:
arm 1: Part 1: Bilateral comparison. Patients will have two comparable Treatment Areas: PAT-001, 0.1% (e.g., left side) and Vehicle, 0.0% (e.g., right side). This comparison lasts from Weeks 0-8 Part 2: Patients will apply only PAT-001, 0.1% to both Treatment Areas from Weeks 8-12. arm 2: Part 1: Bilateral comparison. Patients will have two comparable Treatment Areas: PAT-001, 0.2% (e.g., left side) and Vehicle, 0.0% (e.g., right side). This comparison lasts from Weeks 0-8 Part 2: Patients will apply PAT-001, 0.2% to both Treatment Areas. arm 3: Part 1: Bilateral comparison. Patients will have two comparable Treatment Areas: PAT-001, 0.1% (e.g., left side) and Vehicle, 0.0% (e.g., right side). The application of vehicle only lasts from Weeks 0-8. arm 4: Part 1: Bilateral comparison. Patients will have two comparable Treatment Areas: PAT-001, 0.2% (e.g., left side) and Vehicle, 0.0% (e.g., right side). The application of vehicle only lasts from Weeks 0-8.

Interventions: intervention 1: PAT-001, 0.1% intervention 2: PAT-001, 0.2% intervention 3: Vehicle for PAT-001 0.1% intervention 4: Vehicle for PAT-001 0.2%
Intervention descriptions: intervention 1: PAT-001 is a topical ointment. PAT-001, 0.1% contains 0.1% of active drug. intervention 2: PAT-001 is a topical ointment. PAT-001, 0.2% contains 0.2% of active drug. intervention 3: Vehicle topical ointment contains 0.0% of active drug and is color matched to the active test article, PAT-001 0.1%. intervention 4: Vehicle topical ointment contains 0.0% of active drug and is color matched to the active test article, PAT-001 0.2%.

Protocol document:
Prot_SAP_001.pdf: 
CONFIDENTIAL 
Page 1 of 89 
TI SOP 305-A Protocol Template, Version 06 
A RANDOMIZED, BILATERAL COMPARISON, VEHICLE-CONTROLLED, 
SAFETY AND TOLERABILITY STUDY OF TOPICAL PAT-001  
FOR THE TREATMENT OF CONGENITAL ICHTHYOSIS  
 
PROTOCOL NUMBER: 
205-9051-201 
TI PROJECT NUMBER: 
205-9051-201 
IND NUMBER: 
122,058 
ORIGINAL PROTOCOL:  
July 19, 2016 
AMENDMENT #1: 
September 30, 2016 
AMENDMENT #2: 
January 6, 2017 
FILENAME: 
205-9051-201_pro_06JAN2017_v3.0.docx 
SPONSOR: 
Patagonia Pharmaceuticals, LLC 
50 Tice Boulevard, Suite A26 
Woodcliff Lake, NJ 07677 
SPONSOR REPRESENTATIVE: 
Zachary Rome, B.S. 
Executive Vice President 
Patagonia Pharmaceuticals, LLC 
MEDICAL MONITOR: 
Daniel Piacquadio, M.D. 
Therapeutics, Inc. 
9025 Balboa Avenue, Suite 100 
San Diego, CA 92123 
858-571-1800, x107 (office) 
619-889-7058 (cell) 
858-571-1234 (fax) 
danp@therapeuticsinc.com (email) 
PROJECT MANAGER: 
Grace Liu, B.S., CCRA  
Therapeutics, Inc. 
9025 Balboa Avenue, Suite 100 
San Diego, CA 92123 
858-571-1800, ext. 129 (office) 
858-571-1234 (facsimile) 
gliu@therapeuticsinc.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 Patagonia Pharmaceuticals, LLC. 




Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 3 of 89 
TI SOP 305-A Protocol Template, Version 06 
STUDY ACKNOWLEDGEMENT 
I understand this protocol contains information that is confidential and proprietary to 
Patagonia Pharmaceuticals, LLC, the Sponsor. 
 
I have read this protocol, agree that it contains all the details necessary to conduct the 
study as described, and will conduct this study following this protocol. 
 
I will provide the contents of this protocol to study staff under my direct supervision that 
need to know the contents to conduct the study. I will discuss this information with the 
study staff to ensure they are fully informed about the study and the test articles. I will 
provide the contents of the protocol to the responsible Institutional Review Board(s). 
These disclosures may be made; providing the contents are not used in any other clinical 
study and they are not disclosed to any other person or entity without prior written 
consent from the Sponsor or designee. This condition does not apply to disclosure 
required by government regulations or laws; however, I agree to give prompt notice to 
the Sponsor or designee of any such disclosure. 
 
I understand the study may be terminated or enrollment suspended at any time by the 
Sponsor, 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 
the Sponsor and must be treated in the same manner as the contents of this protocol. 
 
____________________________________ 
Printed Name of Principal Investigator 
 
____________________________________ 
 
_____________________ 
Investigator Signature  
 
 
 
 
Date 
 
Protocol number: 205-9051-201 
 
 
 
Site number:              
 
Version: 3.0 
 
Date of original version (v1.0): July 19, 2016 
Date of Amendment #1 (v2.0): September 30, 2016 
Date of Amendment #2 (v3.0): January 6, 2017 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 4 of 89 
TI SOP 305-A Protocol Template, Version 06 
PROTOCOL SYNOPSIS 
Title 
A Randomized, Bilateral Comparison, Vehicle-Controlled, Safety And 
Tolerability Study Of Topical PAT-001 For The Treatment Of Congenital 
Ichthyosis 
Study Type 
Phase 2  
Test Articles 
The blinded test articles to be used in this study include: 
• 
PAT-001 (isotretinoin) Ointment (0.1% and 0.2%)  
• 
Vehicle Ointment (Control) 
Study Objectives 
Primary 
• 
To investigate the safety and tolerability of topically applied PAT-001 
as a treatment for congenital ichthyosis (CI) of either the Lamellar or 
X-Linked subtypes. 
 
Secondary  
• 
To explore evidence of a potential efficacy signal of the “active” test 
article(s) compared to vehicle. 
• 
To explore the plasma levels of isotretinoin and tretinoin from 
topically applied PAT-001 with comparison to background systemic 
retinoid levels pre- and post-treatment. 
Study Design 
Phase 2, proof-of-concept (POC), randomized, double-blind, vehicle-
controlled, bilateral comparison study with active only treatment follow-up. 
Treatment Groups 
There will be two parts to this study. In Part 1, subjects will be randomized 
to two treatment groups and treated bilaterally with active and vehicle test 
articles (as described below) for eight weeks. In Part 2, subjects will enter an 
active only follow-up period of four weeks in which both Treatment Areas 
identified in Part 1 will be treated with the active test article of their assigned 
Treatment Group. 
 
After enrollment in the study, each subject will be randomized (1:1) to one 
of two Treatment Groups. Randomization will be stratified by CI subtype. 
Each subject will have two comparable Treatment Areas defined per 
protocol. One Treatment Area shall be randomly designated to be treated 
with one “active” test article with the contralateral Treatment Area assigned 
to the second test article (i.e., vehicle) within the assigned Treatment Group 
for Part 1. In Part 2, both Treatment Areas will be treated with the “active” 
test article within the assigned Treatment Group. 
 
Treatment Groups Blinded Test Articles:   
• 
Group 1: PAT-001, 0.1% vs vehicle 
• 
Group 2: PAT-001, 0.2% vs vehicle 
 
Treatments will be applied twice daily to all disease affected skin in the 
Treatment Area. Dosing may be adjusted by the investigator if there are 
concerns with tolerability as detailed in the protocol. 
 
Subjects will have the option of participating in the pharmacokinetic (PK) 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 5 of 89 
TI SOP 305-A Protocol Template, Version 06 
portion of the study per the Schedule of Events. 
Duration of Treatment 
Twice a day application for 12 weeks: eight weeks in Part 1 and an additional 
four weeks in Part 2. 
Duration of Study 
Each subject will participate in the study for approximately 18 weeks 
(including up to 45-day screening period). 
Study Population 
Male and/or female subjects, 12 years of age and older with confirmed 
diagnosis of protocol specified subtypes of CI. 
Total Number of 
Subjects 
Approximately 18 subjects will be enrolled in the study, with approximately 
nine subjects randomized to each Treatment Group. 
Number of Sites 
Approximately three sites will participate in the study. 
Inclusion Criteria 
To enter the study, a subject must meet the following criteria:  
 
1. Subject is male or non-pregnant female, 12 years of age and older. 
Females must be post-menopausal1, surgically sterile2, or use two forms 
of birth control3,4. Women of childbearing potential (WOCBP) must 
have a negative urine pregnancy test (UPT)5 at Visit 1/Screening and 
Visit 2/Baseline.  
2. Subject has provided written informed consent/assent. A subject under 
18 years of age must provide written informed assent and be 
accompanied by the parent or legal guardian at the time of 
assent/consent signing. The parent or legal guardian must provide 
informed consent for the subject. If a subject becomes 18 years of age 
during the study the subject must provide written informed consent at 
that time to continue study participation. 
3. Subject is willing and able to apply the test article(s) as directed, comply 
with study instructions, and commit to all follow-up visits for the 
duration of the study. 
4. Subject has a clinical 
diagnosis of either 
Lamellar (e.g., 
transglutaminase 1-deficient) or X-Linked (e.g., deletion of steroid 
                                                 
1 Defined as amenorrhea greater than 12 consecutive months in women 50 years of age and older. 
2 Hysterectomy, bilateral tubal ligation (at least six months prior to initiation of treatment), or bilateral 
oophorectomy. 
3 Methods of acceptable contraception include A) total abstinence OR B) two forms of birth control including:  
1) oral, patch, injected, or implanted hormonal methods of contraception, AND  
2) a) partner vasectomy (performed at least six months prior to study entry) OR b) barrier methods of 
contraception [barrier methods include male condom with or without spermicide, diaphragm or 
cervical cap – both of which are to be used with spermicide] OR c) a vaginal contraceptive sponge 
containing a spermicide.  
Subjects who become sexually active or begin to have relations with a partner during the study must agree to 
use two forms of birth control for 30 days prior to having relations and to continue such forms for the duration 
of the study.  
4 WOCBP taking hormonal therapy must be on treatment for (1) oral or patch: one complete cycle (e.g., four 
to eight weeks) or (2) injectable or implanted: at least one week prior to study entry, continued per label, and 
must not change their dosing regimen during the study.  
5 UPTs must have a minimum sensitivity of 25 mIU ß-hCG/mL. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 6 of 89 
TI SOP 305-A Protocol Template, Version 06 
sulfatase gene) subtypes of CI and agrees to genetic testing6 to confirm 
such clinical diagnosis during the study. 
5. Subject must have two contralateral comparable Treatment Areas, as 
defined per protocol. Each Treatment Area must have a minimum of 
150 cm2 of affected diseased skin as identified by the investigator. 
[Note: each Treatment Area shall be contained within a discrete 
anatomic unit as defined in the protocol and shall not exceed 6% body 
surface area (BSA), excluding palms and soles.] 
6. Both Treatment Area(s) must be of comparable size per protocol and 
have an identical Investigator’s Global Assessment (IGA) score, with a 
score of either 3 (moderate) or 4 (severe) at Visit 2/Baseline.  
7. Subject is either naïve to oral retinoid treatments; or, if subject is 
currently taking retinoids, has completed at least a 12-week washout of 
oral retinoids or a 2-week washout of topical retinoids prior to 
Visit 2/Baseline.  
8. All protocol specified hematology, chemistry, and urinalysis 
assessments are considered not clinically significant with respect to the 
subject’s participation in the study and typically are ≤2.5 times upper 
limit of normal (ULN) at Visit 1/Screening. 
9. Subject has not donated blood within 30 days of Visit 2/Baseline and 
agrees to not donate blood during study drug treatment and for one 
month following discontinuation of treatment. 
10. Subject is in good general health and free of any disease state or physical 
condition that might impair evaluation of the Treatment Areas or which, 
in the investigator’s opinion, exposes the subject to an unacceptable risk 
by study participation.  
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 inflammatory skin disease unrelated to ichthyosis. 
3. Subject has previously failed on topical / oral retinoid therapy for 
treatment of CI. 
4. Subject has used topical retinoid-containing therapies to treat Treatment 
Areas (except emollients) within two weeks prior to Visit 2/Baseline or 
topical corticosteroids within five days prior to Visit 2/Baseline. Non-
Treatment Areas can be treated with topical therapies including 
emollients, keratolytics, or sunscreen. 
5. Subject has used ultraviolet (UV) treatment for ichthyosis within four 
weeks prior to Visit 2/Baseline. 
6. Subject has undergone systemic therapies using Vitamin A supplements 
or St. John’s Wort within four weeks prior to Visit 2/Baseline. Note: Use 
of systemic retinoids is prohibited within 12 weeks of Visit 2/Baseline 
per inclusion criterion #7. 
7. Subject is immunosuppressed (e.g., HIV, systemic malignancy, graft 
host disease, etc.). 
8. Subject is currently taking concomitant immunosuppressive drugs, 
                                                 
6 Fluorescence in situ hybridization (FISH) positive confirmation of steroid sulfatase gene deletion is also 
acceptable to diagnose X-Linked subtype of CI. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 7 of 89 
TI SOP 305-A Protocol Template, Version 06 
including 
systemic 
corticosteroids, 
within 
two 
weeks 
of 
Visit 2/Baseline. 
9. Subject has untreated secondary infections; however, subject may 
become eligible after successful treatment of his/her infections at the 
investigator’s discretion. 
10. Subject has clinically significant metabolic, pulmonary, cardiac, 
hematologic, renal, hepatic, immune, neurologic, psychiatric, infectious, 
neoplastic, or malignant disease (other than non-melanoma skin cancer) 
that would preclude his/her participation in the study. 
11. [For PK Subjects Only] Subject has chronic gastrointestinal disease such 
as Crohn’s disease, irritable bowel syndrome, colitis, inflammatory 
bowel disease, or chronic diarrhea. 
12. Subject with a history of drug or alcohol abuse within the past six 
months. 
13. Subject is currently enrolled in an investigational drug or device study. 
14. Subject has used an investigational drug or investigational device 
treatment within 30 days prior to Visit 2/Baseline. 
15. Subject has a history of allergy to any of the ingredients in the test 
articles (see Section 6.1). 
16. Subject has lesions suspicious for skin cancer (skin cancer not ruled out 
by biopsy) or untreated skin cancers within the Treatment Areas (the 
contralateral treatment and control areas of CI). 
17. Subject is unable to communicate or cooperate with the investigator due 
to language problems, impaired cerebral function, or physical 
limitations. 
18. Subject is known to be noncompliant or is unlikely to comply with the 
requirements of the study protocol (e.g., due to alcoholism, drug 
dependency, mental incapacity) in the opinion of the investigator.  
Study Procedures 
The study will consist of two parts. There will be one Screening Visit, five 
scheduled clinic visits, and two phone calls in Part 1 and one additional clinic 
visit in Part 2. Subjects will have the option to participate in the PK portion 
of the study. Note: Subjects that elect to participate in the PK portion of the 
study should do so with the intent of completing all PK samplings required 
in the study, per protocol. 
 
Visit 1: Screening (Day -45 to -7):  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. 
Demographics, 
inclusion/exclusion 
(I/E) 
criteria, 
medical/ichthyosis 
history, 
and 
prior/concomitant medications and therapies will be reviewed to determine 
subject eligibility. Subjects that require a “washout” period prior to 
enrollment into the treatment phase to meet I/E criteria requirements will be 
required to return to the clinic within 45 days to complete the remaining 
activities. Subjects who require “washout” for longer than 45 days will be 
re-consented. A brief physical examination including vital signs, UPT (if 
applicable), Fitzpatrick Skin Type assessment, and clinical laboratory testing 
will be performed at this visit. For those subjects who do not have 
confirmation of their clinical diagnosis of X-linked or lamellar ichthyosis, 
blood or buccal samples will be collected for genetic testing. Qualified 
subjects must have two comparable in size (≥150 cm2), contralateral 
Treatment Areas (per protocol) identified with equal IGA scores (i.e., 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 8 of 89 
TI SOP 305-A Protocol Template, Version 06 
IGA = 3 or 4) at Baseline, where an individual Treatment Area shall not 
exceed 6% BSA. Clinical evaluations (IGA) for both Treatment Areas will 
be performed. 
 
Prior to Visit 2/Baseline, after clinical laboratory results have been received 
and reviewed, and the investigator has confirmed the subject’s eligibility, the 
site will contact the subject to confirm their willingness to participate in the 
study. Assuming the qualified subject is willing to participate, then the site 
will: 
• 
Make a randomization request to order test article for the subject to 
be delivered to the site prior to the subject’s Baseline visit; 
• 
Schedule the subject’s Baseline visit at a mutually convenient time 
when the designated subject’s test article will be at the site; 
• 
NOTE: the ordered test article is specific to each subject and shall 
not be used for any other subject. In the event that the subject elects 
not to participate after receipt of their designated test article, the site 
should contact the monitor to discuss management of the test article 
received. 
 
Visit 2: Baseline (Day 1):  At Visit 2, study staff will reaffirm informed 
consent/assent and re-review laboratory results prior to the initiation of any 
study-related procedures. Medical history, I/E criteria, and concomitant 
medications and therapies will be reviewed to confirm subject eligibility. A 
UPT (if applicable) will be performed. Treatment Areas will be defined as a 
region contained within a discrete anatomic unit (e.g., upper arm, forearm, 
upper leg, lower leg) with bilateral involvement and a minimum of 150 cm2 
in area of diseased skin. Qualified subjects must have two contralateral 
Treatment Areas (per protocol) identified with equal IGA scores (i.e., 
IGA = 3 or 4) of comparable size where an individual Treatment Area 
shall not exceed 6% BSA. Clinical evaluations (IGA, CI Signs/Symptoms, 
as well as Baseline local skin reactions [LSRs] pre-application) for both 
Treatment Areas and photographs will be performed at this visit; 
photographs will be taken of lesions only, without sharing subject identity. 
Copy(s) of the Baseline photos may be provided to the subject at the 
discretion of the investigator to help the subject consistently identify the two 
Treatment Areas. For those subjects participating in the PK portion of the 
study, prior to test article application, a PK blood sample will be taken. 
Subjects will be randomized using the designated test article specific for that 
subject that was ordered by the site after completion of Visit 1. Test article 
accountability will be documented and test article and Subject Diary will be 
dispensed. Subjects and parent/guardian (if applicable) will be instructed on 
how to apply the test articles and to record applications in the Subject Diary. 
The first dose will be applied at the site under supervision of the investigator. 
Adverse events (AEs) and LSRs post-application will be assessed. For those 
subjects participating in the PK portion of the study, the subject will have 
additional serial blood samples taken at 1, 2, 3, and 4 hours post-test article 
application. The subject will be scheduled for the first follow-up visit. 
 
Note: If the subject experiences issues with medication tolerability or other 
complications arise, ideally the subject will be seen by the investigator at one 
of the scheduled clinic visits or via an Unscheduled Visit to document the 
reactions and modifications to the dosing regimen prescribed by the 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 9 of 89 
TI SOP 305-A Protocol Template, Version 06 
investigator. In the event that a clinic visit is not possible or not warranted in 
the opinion of the investigator, the change in the subject’s management will 
be clearly documented in the source documents and case report forms 
(CRFs) with corresponding changes noted in the Subject Diary regarding test 
article usage and/or concomitant medications/therapies (e.g., moisturizer 
use).  
 
Modifications to the dosing regimen and/or concomitant medication/therapy 
use may be prescribed by the investigator to manage intense LSRs and must 
be documented in the CRFs. Any dosing modifications will be made 
bilaterally (e.g., if dosing is decreased to once a day given tolerability 
issues, both sides will be treated once daily, even if only one side is having 
the tolerability issue). Frequency of dosing may be reduced to once per day 
(QD) or rest periods of up to several days may be allowed. Treatment per 
protocol should resume as soon as possible after any notable LSRs have 
materially subsided as determined by the investigator or designee (if possible 
via one of the scheduled clinic visits or via an Unscheduled Visit) such that 
dosing may resume. Additionally, use of provided bland emollient7 in the 
Treatment Area as an aid to managing LSRs may be prescribed with the 
approval of the investigator and must be documented in the CRFs. In the 
event that additional moisturizer use is needed (i.e., greater than QD or BID 
or in lieu of the test articles) in the opinion of the investigator, such therapy 
may be used, must be documented in the CRFs, and the investigator must 
notify the Medical Monitor promptly. Note: Bland emollients should not be 
applied within four hours of application of the test articles. No other topical 
therapy within the Treatment Area or in the surrounding skin within one inch 
of the Treatment Area is permitted. 
 
Visits 3 and 7: Phone Call (Day 2 and Day 43±3): The site staff will contact 
the subject (or parent/guardian as applicable) by telephone to review the 
Subject Diary, test article compliance, changes in concomitant medications 
and therapies, query the subject about AEs, and confirm the next visit 
appointment. The site staff will remind the subject (and parent/legal 
guardian, if applicable) to continue to apply test article twice daily until the 
next clinic visit. Subjects with tolerability issues will ideally be scheduled 
for an in-office follow-up visit, but at the discretion of the investigator, as an 
Unscheduled Visit to stop/re-start/modify the dosing regimen. 
 
Visits 4 and 5 (Days 8+1 and 15±2): Subjects will return to the clinic and 
will be queried for any changes in health status and concomitant medications 
and therapies. Clinical evaluations (IGA, CI Signs/Symptoms, and LSRs) for 
both Treatment Areas will be performed and photographs (optional) may be 
taken. For those subjects participating in the PK portion of the study, a PK 
blood sample will be collected. Note: this sample will be collected 12 hours 
± 30 minutes after the dose on the previous day. Test article accountability 
will be documented and compliance will be reviewed (based on review of 
Subject Diary and weights of test articles) with the subject and 
                                                 
7 DML Lotion will be provided to subjects. Other bland emollients (e.g., Lubriderm [without alpha hydroxy 
acid], or other moisturizers that do not contain any “active” ingredients [e.g., salicylic acid, lactic acid, 
pyruvic acid, urea, or any other ingredient that could irritate or cause a keratolytic effect]) may be used with 
approval from the investigator, but must be documented as a concomitant medication/therapy. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 10 of 89 
TI SOP 305-A Protocol Template, Version 06 
parent/guardian (if applicable). Test articles and Subject Diary will be 
dispensed/returned (as required). If possible, at each clinic visit, the subject 
will apply one of the daily doses in the clinic under staff supervision to 
reinforce proper use. The subject will be scheduled for the next follow-up 
visit. 
 
Visit 6 (Day 29±3): Subjects will return to the clinic and will be queried for 
any changes in health status and concomitant medications and therapies. A 
brief physical examination including vital signs, UPT (if applicable), and 
clinical laboratory testing will be performed at this visit. Prior to test article 
application, clinical evaluations (IGA, CI Signs/Symptoms, and LSRs) for 
both Treatment Areas will be performed and photographs will be taken. For 
those subjects participating in the PK portion of the study, a PK blood sample 
will be collected. Note: this sample will be collected 12 hours ± 30 minutes 
after the dose on the previous day. Test article accountability will be 
documented and compliance will be reviewed (based on review of Subject 
Diary and weights of test articles) with the subject and parent/guardian (if 
applicable). Test articles and Subject Diary will be dispensed/returned (as 
required). If possible, at each clinic visit, the subject will apply one of the 
daily doses in the clinic under staff supervision to reinforce proper use. The 
subject will be scheduled for Visit 8/End of Part 1. 
 
Visit 8: End of Part 1 (Day 57±4): Subjects will return to the clinic for the 
final visit in Part 1 and will be queried for any changes in health status and 
concomitant medications/procedures. A brief physical examination 
including vital signs, UPT (if applicable), and clinical laboratory testing will 
be performed at this visit. Prior to test article applications, clinical 
evaluations (IGA, CI Signs/Symptoms, and LSRs) for both Treatment Areas 
will be performed and photographs will be taken. For those subjects 
participating in the PK portion of the study, a PK blood sample will be 
collected. Note: this sample will be collected 12 hours ± 30 minutes after the 
dose on the previous day. Test article accountability will be documented and 
compliance will be reviewed (based on review of Subject Diary and weights 
of test articles) with the subject and parent/guardian (if applicable); all test 
articles from Part 1 will be collected and test articles will be dispensed for 
Part 2. Subjects and parent/guardian (if applicable) will be instructed to 
apply the assigned test article to both Treatment Areas twice per day until 
the next study visit and to record applications in the Subject Diary. Subject 
Diaries will be dispensed/returned (as required). Application of the test 
article will be performed under staff supervision in the clinic. AEs and LSRs 
post-application will be assessed. The subject will be scheduled for 
Visit 9/End of Treatment (EOT). 
 
Visit 9: EOT & Early Termination (Day 84±4): Subjects will return to the 
clinic for the final visit of the study and will be queried for any changes in 
health status and concomitant medications/procedures. A brief physical 
examination including vital signs, UPT (if applicable), and clinical 
laboratory testing will be performed at this visit. Clinical evaluations (IGA, 
CI Signs/Symptoms, and LSRs) for both Treatment Areas will be performed 
and photographs will be taken. For those subjects participating in the PK 
portion of the study, a PK blood sample will be collected. Note: this sample 
will be collected 12 hours ± 30 minutes after the dose on the previous day. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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Test article accountability will be documented; all test articles and Subject 
Diaries will be returned. The subject will exit the study. 
Study Measurements 
The following assessments will be performed for each Treatment Area in a 
given subject. 
 
Efficacy 
Efficacy will be assessed by the investigator as follows for the Treatment 
Areas: 
• Investigator’s Global Assessment: Overall severity of ichthyosis 
using a five-point scale from 0=clear to 4=severe will be conducted 
at each clinic visit. This is a static morphological scale that refers to 
a point in time and not a comparison to Baseline. 
• Individual Clinical Signs/Symptoms: Overall severity of erythema, 
scaling, fissuring, and papulation/lichenification will be graded using 
a five-point scale from 0=clear to 4=severe at each clinic visit (except 
Screening). This is a static morphological scale that refers to a point 
in time and not a comparison to Baseline. 
 
Safety 
Physical examinations, vital signs, clinical laboratory tests, UPTs (if 
applicable), and AEs will be assessed by the investigator per the Schedule of 
Events.  
 
LSRs including burning/stinging, pain, and pruritus will be assessed in each 
Treatment Area using a four-point ordinal scale where 0=none, 1=mild, 
2=moderate, and 3=severe at Visits 2, 4-6 , and 8-9 to allow a comparison 
between Treatment Groups and Test Articles. These LSRs will be collected 
independently of AEs. Only LSRs that require medical intervention (e.g., 
prescription medication) or require the withholding of the application of the 
test article will be documented as AEs. Any LSRs that are not listed above 
will be recorded as AEs. 
 
Pharmacokinetics 
Note: Subjects that elect to participate in the PK portion of the study should 
do so with the intent of completing all PK samplings required in the study, 
per protocol. 
 
At Visit 2, for those subjects that have elected to participate in the optional 
PK portion of the study, serial PK blood samples will be collected pre-test 
article application (time 0) and at 1, 2, 3, and 4 hours post-test article 
application for the determination of isotretinoin and tretinoin levels. At 
Visits 4-6 and 8-9, a single PK blood sample will be collected pre-test article 
application (approximately 12 hours after the last dose on the previous day) 
for assessment of “trough” isotretinoin and tretinoin levels. 
Study Endpoints 
Safety Endpoints: 
• 
Incidence (severity and causality) of any local and systemic AEs. 
• 
Number of subjects with presence (and severity) of the following 
LSRs: stinging/burning, pain, and pruritus at each time point for 
each Treatment Area collected (summarized by Test Article). 
• 
Changes from Screening in vital signs at Days 29, 57, and 84 (or 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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EOT) (summarized by Treatment Group). 
• 
Changes from Screening in clinical laboratory tests (hematology, 
chemistry, and urinalysis) at Days 29, 57, and 84 (or EOT) 
(summarized by Treatment Group). 
• 
UPT results in all WOCBP at Screening, Baseline, Day 29, Day 57, 
and Day 84 (or EOT). 
 
Efficacy Endpoints: 
Part 1 (P1) and Part 2 (P2) efficacy data will be analyzed separately. For 
Part 1, efficacy endpoints will be summarized by Test Article (PAT-001, 
0.1%; PAT-001, 0.2%; and Vehicle [pooled across Treatment Groups]) 
and/or by Part 1 Treatment Group (Group 1: PAT-001, 0.1%/Vehicle; and 
Group 2: PAT-001, 0.2%/Vehicle) as described below. For Part 2, efficacy 
endpoints will be summarized by Part 2 Summary Group, which consists of 
four groups: 
• 
Group A: PAT-001, 0.1%-P2 Active/P1 Active; 
• 
Group B: PAT-001, 0.1%-P2 Active/P1 Vehicle; 
• 
Group C: PAT-001, 0.2%-P2 Active/P1 Active; and 
• 
Group D: PAT-001, 0.2%-P2 Active/P1 Vehicle. 
 
In Part 1, the following exploratory endpoints will be evaluated:  
• 
Frequency distribution of IGA and CI Signs/Symptoms at Baseline, 
and Days 8, 15, 29, and 57 summarized by Test Article. 
• 
Absolute change from Baseline in IGA and the CI Signs/Symptoms 
at Days 8, 15, 29, and 57 summarized by Test Article. 
• 
Within-subject difference in IGA and the CI Signs/Symptoms at 
Baseline, Days 8, 15, 29, and 57 summarized by Part 1 Treatment 
Group. 
• 
Within-subject difference in absolute change from Baseline in IGA 
and the CI Signs/Symptoms at Days 8, 15, 29, and 57 summarized 
by Part 1 Treatment Group. 
 
In Part 2, the following exploratory endpoints will be evaluated: 
• 
Frequency distribution of IGA and CI Signs/Symptoms at Day 84 
summarized by Part 2 Summary Group (Group A-D). 
• 
Absolute change from Baseline in IGA and CI Signs/Symptoms at 
Day 84 summarized by Part 2 Summary Group (Group A-D). 
• 
Absolute change from Day 57 in IGA and CI Signs/Symptoms at 
Day 84 summarized by Part 2 Summary Group (Group A-D). 
• 
Within subject difference in IGA and CI Signs/Symptoms at Day 
84 summarized by Part 2 Treatment Group (0.1% and 0.2%). 
• 
Within-subject difference in absolute change from Baseline in IGA 
and the CI Signs/Symptoms at Day 84 summarized by Part 2 
Treatment Group (0.1% and 0.2%). 
• 
Within subject difference in absolute change from Day 57 in IGA 
and CI Signs/Symptoms at Day 84 summarized by Part 2 Treatment 
Group (0.1% and 0.2%). 
 
PK Endpoints: 
• 
Concentration of isotretinoin and tretinoin pre-dose and at 1, 2, 3, 
and 4 hours after the first dose on Day 1. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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• 
Trough plasma concentrations of isotretinoin and tretinoin (C12h) on 
Days 8, 15, 29, 57, and 84. 
Sample Size 
Calculations 
As a first-in-man POC study, no formal power calculations were used to 
determine the sample size. 
Statistical Methods 
Summary tables (descriptive statistics and/or frequency tables) will be 
provided for screening variables, baseline variables, efficacy variables, and 
safety variables. Continuous variables will be described by descriptive 
statistics (n, mean, median, standard deviation, minimum, and maximum). 
Frequency counts and percentage of subjects within each category will be 
provided for categorical data. 
 
Study Populations: 
The Safety population will include all randomized subjects who applied the 
test article. The intent-to-treat (ITT) population will include all randomized 
subjects who were dispensed the test article. The PK population will include 
those subjects in the Safety population who participated in the PK portion of 
the study with no evidence of material dosing noncompliance. 
 
Safety Analyses: 
The analysis of safety will be conducted on the Safety population. 
 
Extent of Exposure 
Extent of exposure will be calculated separately for Part 1 and Part 2 and 
overall. The total amount of each 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 number of days dosed) will be calculated for each 
treatment group and test article. Descriptive statistics will be used to 
summarize the total amount and mean daily amount of test article applied. 
 
Adverse Events 
All AEs reported during the study will be listed, documenting onset, severity, 
whether therapy was required, any change in test article dosing, investigator 
assessment of the relationship to the test article, and outcome. AEs will be 
coded using MedDRA using preferred terms (PTs) and system organ class 
(SOC). The PTs and SOC will then be tabulated. All treatment emergent AEs 
(TEAEs) will be summarized by the number of subjects reporting AEs, SOC, 
PT, severity, and relationship to test article. 
 
Local Skin Reactions 
Severity of LSRs (stinging/burning, pain, and pruritus) will be recorded for 
each Treatment Area (i.e., Test Article). LSRs will be summarized by 
frequency and severity of each individual LSR at each visit. 
 
Physical Examinations 
Findings from the brief physical examinations will be recorded in medical 
history (from assessment at Screening) or as AEs (from assessment at Days 
29, 57, and 84). 
 
Vital Signs 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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Vital signs (heart rate, respiration rate, blood pressure (systolic and 
diastolic), and temperature) will be recorded at Screening, and Days 29, 57, 
and 84. Descriptive statistics will be used to summarize vital signs. Clinically 
significant changes from Screening in vital signs at Days 29, 57, and 84 will 
be summarized. 
 
Clinical Laboratory Tests 
Clinical laboratory data (hematology, chemistry, and urinalysis) will be 
tabulated at Screening and Days 29, 57, and 84. Changes from Screening in 
laboratory data at Days 29, 57, and 84 will also be summarized. All 
laboratory data will be listed and reported in the units received by the central 
laboratory. Shift tables by analyte and by out of range flag will be presented 
to facilitate the evaluation of change from Screening to Days 29, 57, and 84. 
 
Urine Pregnancy Tests 
UPT results (if applicable) at Screening, Baseline, and Days 29, 57, and 84 
will be provided in a subject listing. 
 
Concomitant Medications and Therapies 
Concomitant medications and therapies will be provided in subject listings. 
 
Efficacy Analyses: 
The analysis of efficacy will be conducted on the ITT population. Given the 
small sample size, no formal hypothesis testing will be done. 
 
Dosing Compliance 
Dosing compliance will be evaluated separately for Part 1 and Part 2 and 
overall. Measures of test article compliance will include the duration of 
treatment (in number of days) and the total number of applications. 
Descriptive statistics will be used to summarize test article compliance. 
Subjects who applied at least 80% of the expected applications will be 
considered to be compliant with test article dosing. 
 
Investigator’s Global Assessment 
Part 1. Frequency distributions of IGA score will be tabulated at Baseline, 
and Days 8, 15, 29, and 57 by Test Article. Absolute change from Baseline 
in IGA at Days 8, 15, 29, and 57 will also be summarized by Test Article. 
Within-subject difference (Active-Vehicle) in IGA score at Baseline, and 
Days 8, 15, 29, and 57 and absolute change from Baseline at Days 8, 15, 29, 
and 57 will be summarized by Part 1 Treatment Group. 
 
Part 2. Frequency distributions of IGA score will be tabulated at Day 84 by 
Part 2 Summary Group. Absolute change from Baseline and absolute change 
from Day 57 in IGA at Day 84 will also be summarized by Part 2 Summary 
Group. Within-subject difference (Active-Vehicle) in IGA score, absolute 
change from Baseline, and absolute change from Day 57 at Day 84 will be 
summarized by Part 2 Treatment Group. 
 
Individual Clinical Signs/Symptoms 
Part 1. Frequency distributions of erythema, scaling, fissuring, and 
papulation/lichenification will be tabulated at Baseline, and Days 8, 15, 29, 
and 57 by Test Article. Absolute change from Baseline in each of the 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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Signs/Symptoms at Days 8, 15, 29, and 57 will also be summarized by Test 
Article. Within-subject difference (Active-Vehicle) for each of the 
Signs/Symptoms scores at Baseline, and Days 8, 15, 29, and 57 and absolute 
change from Baseline at Days 8, 15, 29, and 57 will be summarized by Part 1 
Treatment Group. 
 
Part 2. Frequency distributions for each of the Signs/Symptoms will be 
tabulated at Day 84 by Part 2 Summary Group. Absolute change from 
Baseline and absolute change from Day 57 for each of the Signs/Symptoms 
at Day 84 will also be summarized by Part 2 Summary Group. Within-
subject difference (Active-Vehicle) for each of the Signs/Symptoms scores, 
absolute change from Baseline, and absolute change from Day 57 at Day 84 
will be summarized by Part 2 Treatment Group. 
 
Pharmacokinetic Analyses: 
A PK analysis will be conducted on the PK population. 
 
Concentrations After Single Dose 
Concentrations of isotretinoin and tretinoin will be summarized pre-test 
article application (time 0) and 1, 2, 3, and 4 hours post-test article 
application for each subject and compared among Treatment Groups. 
 
Trough Concentrations 
Trough plasma concentrations of isotretinoin and tretinoin at Days 8, 15, 29, 
57, and 84 will be compared between Treatment Groups. 
Interim Analysis 
No interim analysis is planned. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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SCHEDULE OF EVENTS 
 
Screening8 
Part 1 
Part 2 
Visit Number 
1 
2 
39 
4 
5 
6 
79
8 
9 
Visit Type 
Clinic 
Clinic 
Phone 
Clinic 
Clinic  
Clinic 
Phone 
Clinic 
Clinic 
Day 
-45 to -7 
1 
2 
8+1 
15±2 
29±3 
43±3 
57±4 
84±4 
Informed Consent/Assent 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
X10 
 
 
 
 
 
 
 
Medical/Ichthyosis History11 
X 
X 
 
 
 
 
 
 
 
Brief Physical Examination 
X 
 
 
 
 
X 
 
X 
X 
Vital Signs12 
X 
 
 
 
 
X 
 
X 
X 
UPT for WOCBP 
X 
X 
 
 
 
X 
 
X 
X 
Fitzpatrick Skin Type 
X 
 
 
 
 
 
 
 
 
Clinical Laboratory Tests 
X 
 
 
 
 
X 
 
X 
X 
Genetic Testing 
X13 
 
 
 
 
 
 
 
 
Selection of Treatment Areas14 
 
X 
 
 
 
 
 
 
 
IGA Scores  
X 
X 
 
X 
X 
X 
 
X 
X 
CI Sign / Symptoms 
 
X 
 
X 
X 
X 
 
X 
X 
                                                 
8 Screening window at -7 days allows clinical lab tests to be finalized and test article to be shipped prior to Visit 2/Baseline. 
9 Unscheduled Visits may be performed in the clinic at the investigator’s discretion, if there is a concern regarding tolerability or other AE. 
10 Subjects who do not meet the I/E criteria at Visit 2 will be classified as screen failures. 
11 Any change in Medical History from Visit 1/Screening to Visit 2/Baseline is not considered an AE, but will be captured as baseline Medical History. Ichthyosis 
history will only be captured at Visit 1/Screening. 
12 Vital signs will include weight and height at Visit 1/Screening. 
13 For those subjects who do not have genetic test confirmation of their clinical diagnosis of X-linked or lamellar ichthyosis, blood or buccal samples will be 
collected. 
14 Each contralateral Treatment Area must be comparable in size (≥150cm2) and have the same IGA score of 3 (moderate) or 4 (severe) at Baseline and be contained 
within a discrete anatomic unit that shall not exceed 6% BSA. Location by body region and percent BSA of disease affected skin in each Treatment Area will be 
documented. Percent BSA will be estimated using the assumption that 1% BSA is equivalent to the area of the subject’s hand with fingers held together. [Note: 
Palms and soles are not eligible; the treatment of scalp and skin folds/intertriginous regions should be avoided]. Additionally, for treatment on the arms in subjects 
participating in the PK portion, the antecubital fossa (e.g., approximately 10-15 cm2) will be excluded to minimize contamination of PK blood draws. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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Screening8 
Part 1 
Part 2 
Visit Number 
1 
2 
39 
4 
5 
6 
79
8 
9 
Visit Type 
Clinic 
Clinic 
Phone 
Clinic 
Clinic  
Clinic 
Phone 
Clinic 
Clinic 
Day 
-45 to -7 
1 
2 
8+1 
15±2 
29±3 
43±3 
57±4 
84±4 
LSR 
 
X15 
Pre&Post 
 
X 
X 
X 
 
X15 
Pre&Post 
X 
Photography 
 
X 
 
optional 
optional 
X 
 
X 
X 
PK Blood Draws (optional) 
 
X16  
Pre, 1, 2, 
3, & 4 hr 
 
X17 
X17 
X17 
 
X17 
X17 
Randomization 
X18 
X 
 
 
 
 
 
 
 
Part 1: Dosing at the Clinic 
 
X 
 
X19 
X19
X19
 
 
 
Part 2 Dosing & Per Protocol Instructions 
 
 
 
 
 
 
 
X20 
 
Test Articles Accountability: 
Dispense/Collect/Weigh –Part 1 Dosing 
 
X 
 
X 
X 
X 
 
X 
 
Test Articles Accountability: 
Dispense/Collect/Weigh – Part 2 Dosing 
 
 
 
 
 
 
 
X 
X 
Compliance / Diary Review21 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications and Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
                                                 
15 LSRs will be evaluated pre- and post-test article application on Day 1 and Day 57. 
16 On Day 1, PK blood samples will be collected for isotretinoin and tretinoin pre-test article application (time 0) and at 1, 2, 3, and 4 hours post-application. 
17 On Days 8, 15, 29, 57, and 84, a PK blood sample will be collected for isotretinoin and tretinoin pre-test article application (approximately 12 hours ± 30 minutes 
after the last test article application on the previous day). 
18 Prior to Visit 2/Baseline, after laboratory results have been received and reviewed, a randomization request will be placed by the site in order for the test article 
to be provided to the site prior to baseline. Note: the ordered test article is specific to each subject and shall not be used for any other subject. 
19 If possible, the subject will apply one of the daily doses in the clinic under staff supervision to reinforce proper use. 
20 In Part 2, subjects will enter an active only treatment follow-up period of four weeks in which both Treatment Areas identified in Part 1 will be treated with the 
active test article of their assigned treatment group. 
21 Subject Diary will be reviewed; compliance will be discussed based on review of Subject Diary and Test Article Accountability, as applicable. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
β-HCG 
Beta-Human Chorionic Gonadotropin 
BID 
Twice per day 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
C12h 
Trough plasma concentrations 
CFR 
Code of Federal Regulations 
CI 
Congenital Ichthyosis 
CLIA 
Clinical Laboratory Improvement Amendments 
CRF 
Case Report Form 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FISH 
Fluorescence In Situ Hybridization 
GGT 
Gamma-Glutamyl Transpeptidase 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator Brochure 
I/E 
Inclusion/Exclusion 
IGA 
Investigator’s Global Assessment 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
LDH 
Lactate Dehydrogenase 
LI 
Lamellar Ichthyosis 
LSR 
Local Skin Reaction 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
OTC 
Over-the-Counter 
P1 
Part 1 
P2 
Part 2 
PEG 
Polyethylene Glycol 
PK 
Pharmacokinetic 
POC 
Proof-of-Concept 
PT 
Preferred Term 
QD 
Once per day 
RA 
Retinoic Acid 
RBC 
Red Blood Cells 
RDW 
Red Blood Cell Distribution Width 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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TI SOP 305-A Protocol Template, Version 06 
SAE 
Serious Adverse Event 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SOC 
System Organ Class 
STS 
Steroid Sulfatase 
TA 
Treatment Area 
TEAE 
Treatment Emergent Adverse Event 
TGM1 
Transglutaminase Type 1 
TI 
Therapeutics, Incorporated 
ULN 
Upper Limit of Normal 
UPT 
Urine Pregnancy Test 
USP 
United States Pharmacopeia 
UV 
Ultraviolet 
WBC 
White Blood Cells 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 
XRI 
X-Linked Recessive Ichthyosis 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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TABLE OF CONTENTS 
Protocol Approval ............................................................................................................... 2 
Study Acknowledgement .................................................................................................... 3 
Protocol Synopsis................................................................................................................ 4 
Schedule of Events ............................................................................................................ 16 
Abbreviations .................................................................................................................... 18 
Table of Contents .............................................................................................................. 20 
1. 
Background ....................................................................................................... 23 
2. 
Rationale ........................................................................................................... 24 
3. 
Objective ........................................................................................................... 25 
4. 
Study Design ..................................................................................................... 25 
5. 
Study Population ............................................................................................... 26 
5.1 
Subject Eligibility ............................................................................................. 26 
5.1.1 
Inclusion Criteria ....................................................................................... 26 
5.1.2 
Exclusion Criteria ...................................................................................... 27 
5.1.3 
Subject Withdrawal Criteria ...................................................................... 28 
6. 
Test Articles and Regimen ................................................................................ 28 
6.1 
Description ........................................................................................................ 28 
6.2 
Instructions for Use and Application ................................................................ 29 
6.3 
Warnings, Precautions and Contraindications .................................................. 31 
7. 
Randomization Assignment .............................................................................. 32 
8. 
Prior and Concomitant Therapies ..................................................................... 32 
8.1 
Prohibited Medications or Therapies ................................................................ 32 
8.2 
Allowed Medications or Therapies ................................................................... 33 
9. 
Study Procedures .............................................................................................. 33 
9.1 
Visit 1 (Day -45 to -7): Screening..................................................................... 34 
9.2 
Visit 2 (Day 1): Baseline................................................................................... 35 
9.3 
Visit 3 (Day 2) and Visit 7 (Day 43±3): Phone Calls ....................................... 36 
9.4 
Visit 4 (Day 8+1) and Visit 5 (Day 15±1): Follow-Up .................................... 37 
9.5 
Visit 6 (Day 29±3): Follow-Up......................................................................... 37 
9.6 
Visit 8 (Day 57±4): End of Part 1 ..................................................................... 38 
9.7 
Visit 9 (Day 84±4): End of Study and Early Termination ................................ 39 
10. 
Clinical Evaluations .......................................................................................... 39 
10.1 
Investigator’s Global Assessment ..................................................................... 39 
10.2 
Individual Clinical Signs/Symptoms ................................................................ 41 
10.3 
Fitzpatrick Skin Type Assessment .................................................................... 42 
10.4 
Local Skin Reactions ........................................................................................ 42 
11. 
Photography ...................................................................................................... 43 
12. 
Laboratory Tests ............................................................................................... 43 
12.1 
Blood Chemistries, Hematology and Urinalysis ............................................... 43 
12.2 
Urine Pregnancy Tests ...................................................................................... 44 
12.3 
Pharmacokinetic Sample Collection, Storage, and Assay ................................ 45 
12.4 
Genetic Testing ................................................................................................. 45 


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Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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13. 
End of Study Criteria ........................................................................................ 46 
13.1 
Completion of the Study ................................................................................... 46 
13.2 
Subject Discontinuation .................................................................................... 46 
13.3 
Study Termination ............................................................................................ 46 
14. 
Adverse Event Reporting .................................................................................. 47 
14.1 
Adverse Event ................................................................................................... 48 
14.2 
Serious Adverse Event ...................................................................................... 50 
14.3 
Laboratory Test Abnormalities ......................................................................... 52 
14.4 
Pregnancy .......................................................................................................... 52 
15. 
Blinding/Unblinding ......................................................................................... 53 
16. 
Clinical Supplies ............................................................................................... 54 
16.1 
Test Article Information ................................................................................... 54 
16.2 
Supplies Provided by Therapeutics, Inc............................................................ 54 
16.3 
Supplies Provided by Investigator .................................................................... 54 
16.4 
Supplies Provided by the Clinical Laboratory .................................................. 54 
17. 
Statistical Considerations .................................................................................. 55 
17.1 
Sample Size ....................................................................................................... 55 
17.2 
Endpoints .......................................................................................................... 55 
17.2.1 
Safety Endpoints ........................................................................................ 55 
17.2.2 
Pharmacokinetic Endpoints ....................................................................... 55 
17.2.3 
Efficacy Endpoints .................................................................................... 55 
17.3 
Statistical Methods ............................................................................................ 56 
17.3.1 
Safety Analyses ......................................................................................... 56 
17.3.2 
Efficacy Analyses ...................................................................................... 58 
17.3.3 
Pharmacokinetics Analyses ....................................................................... 58 
17.4 
Subgroup Analyses ........................................................................................... 59 
17.5 
Interim Analyses ............................................................................................... 59 
18. 
Ethical and Regulatory Considerations ............................................................. 59 
18.1 
Compliance with Good Clinical Practice .......................................................... 59 
18.2 
Institutional Review Board and Informed Consent/Assent .............................. 59 
18.3 
Protocol Compliance ......................................................................................... 60 
18.4 
Protocol Revisions ............................................................................................ 60 
18.5 
Study Monitoring .............................................................................................. 60 
18.6 
Case Report Form Requirements ...................................................................... 60 
18.7 
Reports to Institutional Review Board .............................................................. 61 
18.8 
Quality Assurance Audits ................................................................................. 61 
18.9 
Records Retention ............................................................................................. 61 
18.10 Record Confidentiality ...................................................................................... 62 
19. 
References ......................................................................................................... 62 
Appendix 1 
Sample Subject and Parent/Guardian Instruction Sheet ............................ 64 
Appendix 2 
Sample Subject Diary ................................................................................ 69 
Appendix 3 
Test Article Information ............................................................................ 71 
A 3.1 Test Article Packaging and Labeling ................................................................ 71 
A 3.2 Test Article Storage and Preparation ................................................................ 71 
A 3.3 Dispensing Test Article..................................................................................... 71 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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TI SOP 305-A Protocol Template, Version 06 
A 3.4 Test Article Supply Records at Study Sites ...................................................... 72 
A 3.5 Dose Modifications ........................................................................................... 72 
A 3.6 Documentation of Application and Compliance............................................... 73 
A 3.7 Return and Destruction of Test Article Supplies .............................................. 73 
Appendix 4 
Protocol Amendments ............................................................................... 74 
A 4.1 Protocol Amendment #1: v2.0 .......................................................................... 74 
A 4.2 Protocol Amendment #2: v3.0 .......................................................................... 85 
 
 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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1. 
BACKGROUND 
Congenital ichthyosis (CI) is a large, heterogeneous family of inherited skin disorders of 
cornification resulting from an abnormality of skin keratinization [1]. The classification of 
ichthyosis is complex and CI presents in a multitude of forms and phenotypes; however, 
the main features are scaling and often thickening of the skin. The presentation and severity 
of symptoms can differ greatly by patient and by the form of ichthyoses, but generally 
include skin inflammation and fragility, pruritus, fissuring and cracking of thickened skin, 
ectropion, anhidrosis, and in some severe cases, an increased susceptibility to infection. 
X-linked recessive ichthyosis (XRI), which occurs at a frequency of about one in/2500 (in 
males), shows no distinguishing features other than a thick horny layer [1] and diagnosis 
can be confirmed using genetic testing identifying a complete deletion of the gene encoding 
steroid sulfatase (STS) that is located at the terminus of the X chromosome [2]. Lamellar 
ichthyosis (LI), which occurs at a frequency of about one in 100,000-300,000, is a member 
of the nonsyndromic autosomal recessive CI group which manifests itself clinically as 
hyperkeratosis and dry, scaling skin across the entire body [3]; pathogenesis is related to a 
severely disturbed barrier function due either to abnormal corneocytes or to a defective 
deposition of stratum corneum lipids and is typically caused by truncation or missense 
mutations in the gene encoding keratinocyte transglutaminase type 1 (TGM1) [1, 3]. 
 
The management of the disease is a life-long endeavor, which remains largely symptomatic 
(i.e., emollients with or without keratolytics agents) and commonly focused on reducing 
scaling and/or skin lubrication with both systemic and topical treatments [1]. A first-line 
therapy includes hydration and lubrication accomplished by creams and ointments 
containing low concentrations of salt, urea, or glycerol, which increase the water-binding 
capacity of the horny layer. Addition of keratolytics agents are used to decrease corneocyte 
cohesiveness, to promote desquamation, and to dissolve keratins and lipids (e.g., α-hydroxy 
acids, salicylic acid, high dose urea, propylene glycol, N-acetylcysteine, and retinoids). 
Systemic retinoid treatment is reserved for those patients refractory to topical agents 
because of long-term adverse effects and teratogenicity [4]. 
 
Isotretinoin, a ‘natural’ retinoid (13-cis isomer of naturally occurring tretinoin [all-trans-
retinoic acid]), was initially developed as a synthetic retinoid, but is also present in cells as 
a naturally occurring metabolite. Oral isotretinoin was first approved by the FDA as 
treatment for severe acne in 1982 [5]. Additionally, oral isotretinoin has demonstrated 
remarkable efficacy for the treatment of ichthyoses and other skin disorders associated with 
hyperkeratinization as one of isotretinoin mechanisms of action produces a significant 
reduction in comedogenesis by decreasing hyperkeratinization [6]. Teratogenicity is 
regarded as one of the most serious potential adverse effects, while common 
mucocutaneous side effects are dose dependent and can be managed by modification of the 
dose (e.g., reductions and/or drug holidays) and additional symptomatic therapy (e.g., 
moisturizers). 
 
Patagonia Pharmaceuticals, LLC is developing a topical ointment (0.1% and 0.2%) 
formulation of isotretinoin, called PAT-001 (isotretinoin) Ointment, for the treatment of 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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CI (XRI and LI subtypes) in subjects 12 years of age and older. Development of a topical 
isotretinoin therapy for the treatment of ichthyosis would be advantageous as it would 
provide a product which encompasses the three main objectives of treatment: hydration, 
lubrication, and removal of thick scales (keratolysis) [4], while likely exhibiting a more 
favorable side effect profile than systemic retinoid treatment. 
2. 
RATIONALE 
Vitamin A, the parent molecule of the retinoid family, is important in maintaining general 
growth, in regulating proliferation and differentiation of epithelial tissues, and in 
maintaining visual and reproductive functions [7]; however, it is inactive and can be 
metabolized to its active form, all-trans-retinoic acid (RA) [8]. Retinoids cause a 
generalized keratolytic effect, which can abruptly lead to extensive shedding or peeling of 
scales [4]; thus making this class of molecules an attractive candidate to develop for the 
treatment of skin disorders associated with hyperkeratinization, such as CI. However, the 
side effects associated with systemic bioavailability constrain the use of the retinoid class 
of products.  
 
Isotretinoin (13-cis-RA), a naturally occurring retinoid (derivative of Vitamin A), is an 
isomer of all-trans-RA [9] and offers several advantages over other synthetic retinoids and 
the naturally occurring tretinoin. The fact that isotretinoin can be considered a pro-drug, in 
which it converts into the naturally occurring tretinoin (or one of the other metabolites) as 
the intracellular moiety [6] suggests that isotretinoin could be used to selectively enhance 
the efficacy of pharmacologically active drug, while dampening any undesirable properties 
of the parent molecule. While some of isotretinoin’s activity may be mediated by tretinoin, 
the isomerization of isotretinoin (13-cis-RA) into tretinoin (all-trans-RA) does not account 
for all the pharmacological effects observed upon use of this retinoid [9]; thus, 
isotretinoin’s broader range of activity compared to other retinoids makes it advantageous 
for clinical development. Additionally, the shorter elimination half-life of isotretinoin (i.e., 
between 10 to 20 hours) compared to other synthetic retinoids (e.g., acitretin with an 
elimination half-life of two days [4]) provides practical considerations in clinical use 
simplifying dose changes, drug holidays, and family planning. 
 
Nonclinical models can be used to evaluate the toxicity profile considering 
hypervitaminosis A and adverse effects on fertility and reproductive performance as 
metrics for comparison. In a mouse papilloma model, the substantially (5-fold) lower dose 
of tretinoin that causes hypervitaminosis A (80 mg/kg) compared to isotretinoin (400 
mg/kg) suggests that the toxicity profile of tretinoin is more severe compared to 
isotretinoin. Additionally, isotretinoin may have a lower risk of teratogenicity given that 
adverse effects on fertility and reproductive performance in rats was observed at oral doses 
of 2 mg/kg/day of tretinoin [10] and no adverse effects were observed at oral doses of 
32 mg/kg/day of isotretinoin [5]. Thus, these findings suggest that isotretinoin has a more 
favorable efficacy to toxicity ratio than tretinoin and supports its classification as a pro-
drug. 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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For the treatment of CI, it would be desirable to have a topical formulation of isotretinoin 
as it would afford targeted delivery of the keratolytics agent at the disease tissue site, while 
minimizing systemic exposure compared to that of systemic retinoid treatment and also 
providing a topical formulation that would provide hydration and lubrication to the 
diseased skin. 
3. 
OBJECTIVE 
The primary objective is to investigate the safety and tolerability of topically applied 
PAT-001 as a treatment for CI of either the Lamellar or X-Linked subtypes. 
 
The secondary objectives are (1) to explore evidence of a potential efficacy signal of the 
“active” test article (i.e., PAT-001, 0.1% and 0.2%) compared to vehicle and (2) to explore 
the plasma levels of isotretinoin and tretinoin from topically applied PAT-001 with 
comparison to background systemic retinoid levels pre- and post-treatment. 
4. 
STUDY DESIGN 
This is a two part, Phase 2, multicenter, proof-of-concept (POC) study of the safety and 
tolerability of PAT-001 for the treatment of CI in subjects 12 years of age and older. Part 
1 will be a double-blind, randomized, vehicle controlled, bilateral comparison, and Part 2 
will be a double-blind, active only treatment comparison of the two PAT-001 
concentrations. Subjects will have the option to participate in the PK portion of the study. 
Approximately 18 subjects will be enrolled at three study sites. 
 
Subjects will be randomized (1:1) to one of two Treatment Groups: 
• Group 1: PAT-001, 0.1% vs. vehicle 
• Group 2: PAT-001, 0.2% vs. vehicle 
 
Subjects will have two comparable Treatment Areas defined per protocol. Each Treatment 
Area must be comparable in size, with a minimum of 150 cm2 of affected diseased skin 
with an identical Investigator’s Global Association (IGA) score, with a score of either 3 
(moderate) or 4 (severe) at Baseline; each Treatment Area shall be contained within a 
discrete anatomic unit as defined in the protocol and shall not exceed 6% body surface area 
(BSA), excluding palms and soles. In Part 1, one Treatment Area (e.g., right side) will be 
randomly designated to be treated with one “active” test article (i.e., PAT-001, 0.1%, or 
0.2%) and the other Treatment Area (e.g., left side) will be assigned the second test article 
(i.e., vehicle). Treatments will be applied twice daily for eight weeks to all disease affected 
skin in the Treatment Area. In Part 2, both Treatment Areas (i.e., right and left sides) will 
be treated with the “active” test article (i.e., PAT-001, 0.1% or 0.2%) of the assigned 
Treatment Group twice daily for an additional four weeks. 
 
Subjects will have seven clinic visits and two phone calls. Safety, tolerability, and efficacy 
measures will be evaluated by Test Article, Treatment Group, within subjects, and by 
Summary Group as applicable (see Section 17). Pharmacokinetic (PK) measures of 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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isotretinoin and tretinoin will be compared to background systemic retinoid levels pre- and 
post-treatment for each Treatment Group in an optional PK portion of the study. 
5. 
STUDY POPULATION 
Approximately 18 male or female subjects, 12 years of age and older with confirmed 
diagnosis of Lamellar or X-Linked subtypes of CI will be enrolled in the study. 
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 non-pregnant female, 12 years of age and older. Females must be 
post-menopausal22, surgically sterile23, or use two forms of birth control24,25. Women 
of childbearing potential (WOCBP) must have a negative urine pregnancy test (UPT)26 
at Visit 1/Screening and Visit 2/Baseline.  
2. Subject has provided written informed consent/assent. A subject under 18 years of age 
must provide written informed assent and be accompanied by the parent or legal 
guardian at the time of assent/consent signing. The parent or legal guardian must 
provide informed consent for the subject. If a subject becomes 18 years of age during 
the study the subject must provide written informed consent at that time to continue 
study participation. 
3. Subject is willing and able to apply the test article(s) as directed, comply with study 
instructions, and commit to all follow-up visits for the duration of the study. 
4. Subject has a clinical diagnosis of either Lamellar (e.g., transglutaminase 1-deficient) 
or X-Linked (e.g., deletion of steroid sulfatase gene) subtypes of CI and agrees to 
                                                 
22 Defined as amenorrhea greater than 12 consecutive months in women 50 years of age and older. 
23 Hysterectomy, bilateral tubal ligation (at least six months prior to initiation of treatment), or bilateral 
oophorectomy. 
24 Methods of acceptable contraception include A) total abstinence OR B) two forms of birth control 
including:  
1) oral, patch, injected, or implanted hormonal methods of contraception, AND  
2) a) partner vasectomy (performed at least six months prior to study entry) OR b) barrier methods of 
contraception [barrier methods include male condom with or without spermicide, diaphragm or 
cervical cap – both of which are to be used with spermicide] OR c) a vaginal contraceptive sponge 
containing a spermicide.  
Subjects who become sexually active or begin to have relations with a partner during the study must agree to 
use two forms of birth control for 30 days prior to having relations and to continue such forms for the duration 
of the study.  
25 WOCBP taking hormonal therapy must be on treatment for (1) oral or patch: one complete cycle (e.g., four 
to eight weeks) or (2) injectable or implanted: at least one week prior to study entry, continued per label, and 
must not change their dosing regimen during the study.  
26 UPTs must have a minimum sensitivity of 25 mIU ß-hCG/mL. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 27 of 89 
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genetic27 testing to confirm such diagnosis during the study. 
5. Subject must have two contralateral comparable Treatment Areas, as defined per 
protocol. Each Treatment Area must have a minimum of 150 cm2 of affected diseased 
skin as identified by the investigator. [Note: each Treatment Area shall be contained 
within a discrete anatomic unit as defined in the protocol and shall not exceed 6% BSA, 
excluding palms and soles.] 
6. Both Treatment Area(s) must be of comparable size per protocol and have an identical 
IGA score, with a score of either 3 (moderate) or 4 (severe) at Visit 2/Baseline.  
7. Subject is either naïve to oral retinoid treatments; or, if subject is currently taking 
retinoids, has completed at-least a 12-week washout of oral retinoids or a 2-week 
washout of topical retinoids prior to Visit 2/Baseline.  
8. All protocol specified hematology, chemistry, and urinalysis assessments are 
considered not clinically significant with respect to the subject’s participation in the 
study and typically are ≤2.5 times upper limit of normal (ULN) at Visit 1/Screening. 
9. Subject has not donated blood within 30 days of Visit 2/Baseline and agrees to not 
donate blood during study drug treatment and for one month following discontinuation 
of treatment. 
10. Subject is in good general health and free of any disease state or physical condition that 
might impair evaluation of the Treatment Areas or which, in the investigator’s opinion, 
exposes the subject to an unacceptable risk by study participation.  
5.1.2 Exclusion Criteria 
1. Subject is pregnant, lactating, or is planning to become pregnant during the study. 
2. Subject has inflammatory skin disease unrelated to ichthyosis. 
3. Subject has previously failed on topical / oral retinoid therapy for treatment of CI. 
4. Subject has used topical retinoid-containing therapies to treat Treatment Areas (except 
emollients) within two weeks prior to Visit 2/Baseline or topical corticosteroids within 
five days prior to Visit 2/Baseline. Non-Treatment Areas can be treated with topical 
therapies including emollients, keratolytics, or sunscreen. 
5. Subject has used ultraviolet (UV) treatment for ichthyosis within four weeks prior to 
Visit 2/Baseline. 
6. Subject has undergone systemic therapies using Vitamin A supplements or St. John’s 
Wort within four weeks prior to Visit 2/Baseline. Note: Use of systemic retinoids is 
prohibited within 12 weeks of Visit 2/Baseline per inclusion criterion #7. 
7. Subject is immunosuppressed (e.g., HIV, systemic malignancy, graft host disease, etc.). 
8. Subject is currently taking concomitant immunosuppressive drugs, including systemic 
corticosteroids within two weeks of Visit 2/Baseline. 
9. Subject has untreated secondary infections; however, subject may become eligible after 
successful treatment of his/her infections at the investigator’s discretion. 
10. Subject has clinically significant metabolic, pulmonary, cardiac, hematologic, renal, 
hepatic, immune, neurologic, psychiatric, infectious, neoplastic, or malignant disease 
                                                 
27 Fluorescence in situ hybridization (FISH) positive confirmation of steroid sulfatase gene deletion is also 
acceptable to diagnose X-Linked subtype of CI. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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(other than non-melanoma skin cancer) that would preclude his/her participation in the 
study. 
11. [For PK Subjects Only] Subject has chronic gastrointestinal disease such as Crohn’s 
disease, irritable bowel syndrome, colitis, inflammatory bowel disease, or chronic 
diarrhea. 
12. Subject with a history of drug or alcohol abuse within the past six months. 
13. Subject is currently enrolled in an investigational drug or device study. 
14. Subject has used an investigational drug or investigational device treatment within 30 
days prior to Visit 2/Baseline. 
15. Subject has a history of allergy to any of the ingredients in the test articles (see 
Section 6.1). 
16. Subject has lesions suspicious for skin cancer (skin cancer not ruled out by biopsy) or 
untreated skin cancers within the Treatment Areas (the contralateral treatment and 
control areas of CI). 
17. Subject is unable to communicate or cooperate with the investigator due to language 
problems, impaired cerebral function, or physical limitations. 
18. Subject is known to be noncompliant or is unlikely to comply with the requirements of 
the study protocol (e.g., due to alcoholism, drug dependency, mental incapacity) in the 
opinion of the investigator.  
5.1.3 Subject Withdrawal Criteria 
Procedures for handling subjects who are discontinued from the study are described in 
Section 13.2. Subjects who are discontinued will not be replaced. 
6. 
TEST ARTICLES AND REGIMEN 
6.1 
Description 
PAT-001 is a pale yellow, viscous ointment. Vehicle ointment is color matched to the 
active test article. In Part 1, each subject shall receive two test articles: a vehicle ointment 
and an active ointment product (either 0.1% or 0.2% PAT-001) for treatment to the left and 
right Treatment Areas. The test articles will be blinded using color coded labeling as 
detailed in Section 6.2 and Appendix 1 to facilitate proper use during the study period. In 
Part 2, each subject will receive the active ointment product assigned in Part 1 for both 
Treatment Areas. 
 
Test Article Name: 
PAT-001 (isotretinoin) Ointment, 0.1% 
Active ingredient: 
isotretinoin, USP 
Other ingredients: 
super refined polyethylene glycol (PEG) 400, PEG 1450, PEG 3350, 
methylparaben, 
butylated 
hydroxytoluene, 
and 
propyl 
4-
hydroxybenzoate, propylparaben 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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Test Article Name: 
PAT-001 (isotretinoin) Ointment, 0.2% 
Active ingredient: 
isotretinoin, USP 
Other ingredients: 
super refined PEG 400, PEG 1450, PEG 3350, methylparaben, 
butylated 
hydroxytoluene, 
and 
propyl 
4-hydroxybenzoate, 
propylparaben 
 
Test Article Name: 
Vehicle Ointment 
Other ingredients: 
super refined PEG 400, PEG 1450, PEG 3350, methylparaben, 
butylated 
hydroxytoluene, 
and 
propyl 
4-hydroxybenzoate, 
propylparaben; color additive28 
6.2 
Instructions for Use and Application 
At Visit 2/Baseline, the investigator will designate two comparable Treatment Areas. Each 
Treatment Area shall be contained within a discrete anatomic unit (e.g., upper arm, 
forearm, upper leg, lower leg) with bilateral involvement and a minimum of 150 cm2 in 
area of diseased skin that shall not exceed 6% BSA; these Treatment Areas will be selected 
for treatment and designated by right and left sides. Both Treatment Areas must have 
comparable area of disease involvement and have the same IGA score of 3 (moderate) or 
4 (severe) at Visit 2/Baseline. Note: Palms and soles are not eligible; the treatment of scalp 
and skin folds/intertriginous regions should be avoided. Additionally, for those subjects 
participating in the PK portion of the study, treatment on the arms, the antecubital fossa 
(e.g., approximately 10-15 cm2) will be excluded to minimize contamination of PK blood 
draws. Location by body region and percent BSA29 of disease affected skin in each 
Treatment Area at Baseline will be documented. 
 
Subjects will be provided with an instruction sheet detailing how to apply the test articles 
(see Appendix 1) and a study staff member will demonstrate how to dispense and apply 
the test articles. If the subject is a minor, the parent/legal guardian will be given the Subject 
Instructions with their child and instructed to apply or supervise application on the subject; 
the level of involvement (i.e., application vs. supervision) by the parent/legal guardian will 
be determined by the investigator. Note: For Part 1, the test articles will be blinded using 
color coded labels to designate which test article to apply to each Treatment Area: RED = 
Right and LEMON YELLOW = Left. 
 
Subjects (and parent/legal guardians, if applicable) will be instructed to wash their hands 
before and after each test article application. Subjects (and parent/legal guardians, if 
applicable) will be instructed to wash the Treatment Areas with a mild non-medicated 
cleanser and water and then to dry the area gently. Subjects (with parent/legal guardian 
supervision, as required) will be instructed to apply a sufficient amount of the test article 
to provide a thin uniform film over the disease affected skin within the Treatment Area 
                                                 
28 FD&C Yellow #3 and FD&C Blue #2. 
29 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: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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(Note: the volume of test article applied will vary with disease severity). For Part 1, the 
subject (and parent/legal guardians, if applicable) will be instructed to take great care to 
use the assigned test article to the right Treatment Area (on the subject’s right side) and the 
other test article to the left Treatment Area (on the subject’s left side). Subjects (with 
parental supervision, as required) will apply a thin uniform film of the assigned test article 
twice daily to the designated Treatment Area for eight weeks. Subjects (and parent/legal 
guardians, if applicable) will wash their hands after application with the first test article 
and prior to applying the second test article. For Part 2, the subject (and parent/legal 
guardians, if applicable) will be instructed to apply the assigned test article to both 
Treatment Areas by applying a thin uniform film twice daily for an additional four weeks. 
The test article will be applied at approximately the same time every day and at least eight 
hours apart. Note: for those subjects who are participating in the optional PK portion of the 
study, the application before a scheduled clinic visit with PK time point (i.e., on Days 7, 
14, 28, 56, and 83) must be approximately 12 hours ± 30 minutes prior to the blood draw. 
 
Subjects (with parent/legal guardian supervision, as required) will be instructed to record 
the date and time of each application in a Subject Diary (see Appendix 2). Subjects (and 
parent/legal guardians, if applicable) will be instructed to bring all containers of the test 
articles (used and unused) and the completed Subject Diary to each visit. If the subject is a 
minor, the parent/legal guardian will be given the Subject Diary and instructed to complete 
or supervise the completion of the Subject Diary; the level of involvement (i.e., completion 
vs. supervision) by the parent/legal guardian will be determined by the investigator.  
 
At each visit, the study staff will review the application instructions with the subject 
and/or parent/legal guardian, if applicable (see Appendix 1) paying particular 
attention to proper use of the labeled test article for the Left and Right Treatment 
Areas (Part 1 only). If possible, at each clinic visit, the subject will apply one of the 
daily doses in the clinic under staff supervision to reinforce proper use. 
 
Subjects (and parent/legal guardian, if applicable) will be instructed not to wash the treated 
area for at least four hours following test article application. Subject should not apply the 
test articles within four hours prior to clinic visits. For those subjects who are participating 
in the PK portion of the study, subjects must NOT apply the test articles prior to visits that 
require PK sample collection (i.e., Visit 4/Day 8, Visit 5/Day 15, Visit 6/Day 29, 
Visit 8/Day 57, and Visit 9/Day 84). 
 
If the subject experiences issues with medication tolerability or other complications arise, 
ideally the subject will be seen by the investigator at one of the scheduled clinic visits or 
via an Unscheduled Visit to document the reactions and modifications to the dosing 
regimen prescribed by the investigator. In the event that a clinic visit is not possible or not 
warranted in the opinion of the investigator, the change in the subject’s management will 
be clearly documented in the source documents and case report forms (CRFs) with 
corresponding changes noted in the Subject Diary regarding test article usage and/or 
concomitant medications/therapies (e.g., moisturizer use).  
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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Modifications to the dosing regimen and/or concomitant medication/therapy use may be 
prescribed by the investigator to manage intense LSRs and must be documented in the 
CRFs. Any dosing modifications or changes to concomitant medications/therapies will 
be made bilaterally (e.g., if dosing is decreased to once a day given tolerability issues, 
both sides will be treated once daily, even if only one side is having the tolerability 
issue). Frequency of dosing may be reduced to once per day (QD) or rest periods of up to 
several days may be allowed. Treatment per protocol should resume as soon as possible 
after any notable LSRs have materially subsided as determined by the investigator or 
designee (if possible via one of the scheduled clinic visits or via an Unscheduled Visit) 
such that dosing may resume. Additionally, use of provided bland emollient30 in the 
Treatment Areas as an aid to managing LSRs may be prescribed with the approval of the 
investigator and must be documented in the CRFs. In the event that additional moisturizer 
use is needed (i.e., greater than QD or twice a day (BID) or in lieu of the test articles) in 
the opinion of the investigator, such therapy may be used, must be documented in the 
CRFs, and the investigator must notify the Medical Monitor promptly. Note: Bland 
emollients should not be applied within four hours of application of the test articles. No 
other topical therapy within the Treatment Area or in the surrounding skin within one inch 
of the Treatment Area is permitted. 
6.3 
Warnings, Precautions and Contraindications 
These test articles are for topical use only. Care should be taken to avoid contact with eyes 
and all mucous membranes. If contact with eyes occurs, rinse thoroughly with water. 
 
Subjects with a known allergy to any of the ingredients in the test articles should not 
participate in this study. 
 
Should severe skin irritation or rash develop, the subject should contact the investigator 
immediately to discuss the possibility of dose modifications or moisturizer use as detailed 
in Section 6.2). 
 
In case of accidental ingestion, subjects should contact the investigator immediately. 
 
The effects of the test article in nursing mothers, pregnant women and their unborn children 
are unknown. WOCBP must not be pregnant, lactating, or planning a pregnancy during the 
study period. 
 
Exposure to sunlight, including UV sunlamps, may provoke additional irritation. 
Therefore, exposure should be avoided or minimized during the use of the test articles. In 
cases where significant exposure to sunlight cannot be avoided, use of sun protection 
                                                 
30 DML Lotion will be provided to subjects. Other bland emollients (e.g., Lubriderm [without alpha hydroxy 
acid], or other moisturizers that do not contain any “active” ingredients [e.g., salicylic acid, lactic acid, 
pyruvic acid, urea, or any other ingredient that could irritate or cause a keratolytic effect]) may be used with 
approval from the investigator, but must be documented as a concomitant medication/therapy. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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measures such as sunscreen products (for areas outside of the Treatment Area) and/or 
protective clothing over the Treatment Areas is recommended. 
7. 
RANDOMIZATION ASSIGNMENT 
Prior to Visit 2/Baseline, after laboratory results have been received and reviewed, a 
randomization request will be placed by the site in order for the test article to be provided 
to the site prior to baseline. 
 
Subjects will be randomized to one of the two Treatment Groups on a 1:1 basis (PAT-001, 
0.1%/Vehicle and PAT-001, 0.2%/Vehicle) using a central randomization scheme, which 
is stratified by disease subtype. Subjects with XRI and LI subtypes will be enrolled such 
that at least two thirds of the total number of subjects (i.e., 12 subjects) will be in the XRI 
subtype group and so that the proportion of subjects with XRI and LI subtypes will be 
similar across the two Treatment Groups. 
8. 
PRIOR AND CONCOMITANT THERAPIES 
Current medications and any medications taken within 30 days prior to the start of the study 
(Visit 1/Screening) will be recorded as prior/concomitant medications with the dose and 
corresponding indication. The medications to be recorded include prescription and over-
the-counter (OTC) medications and vitamins, minerals, and dietary supplements. All 
medications taken on a regular basis should be recorded on the CRFs prior to commencing 
the use of the test article. All concomitant medications will be coded with the current 
version of the WHO Drug Dictionary. 
 
Therapies (medication and non-medication therapies) not restricted by the protocol may be 
used during the study for the treatment or prevention of disease or to maintain good health. 
Vitamin and mineral supplements are permitted at dosages considered by the investigator 
as reasonable for maintaining good health. Non-prohibited chronic therapies being used at 
Visit 1/Screening may be continued, but must be recorded. 
 
Any changes to concomitant medications or therapies during the study must be recorded. 
The reason for any change in concomitant medications and/or therapies will be evaluated 
and, if appropriate, reported as, or in conjunction with, an AE. 
8.1 
Prohibited Medications or Therapies 
Prohibited medications or therapies during the study include: 
• No topical therapy within the Treatment Area or in the surrounding skin within one 
inch of the Treatment Area other than the designated test article or provided bland 
emollient (e.g., DML Lotion)31, if needed to manage LSRs (see Section 8.2); 
                                                 
31 Other bland emollients (e.g., Lubriderm [without alpha hydroxy acid], or other moisturizers that do not 
contain any “active” ingredients [e.g., salicylic acid, lactic acid, pyruvic acid, urea, or any other ingredient 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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• Topical retinoid-containing therapies in the Treatment Areas or in the surrounding 
skin within one inch of the Treatment Area within two weeks of Visit 2/Baseline 
or any topical retinoid use during the study; 
• Topical corticosteroids in the Treatment Areas or in the surrounding skin within 
one inch of the Treatment Area within five days of Visit 2/Baseline; 
• UV treatment within four weeks of Visit 2/Baseline; 
• Systemic retinoids within 12 weeks of Visit 2/Baseline; 
• Other systemic therapies using vitamin A supplements or St. John’s Wort within 
four weeks of Visit 2/Baseline; 
• Immunosuppressive systemic drugs, including systemic corticosteroids, within two 
weeks of Visit 2/Baseline; 
• Any other investigational drugs or devices within 30 days of Visit 2/Baseline. 
8.2 
Allowed Medications or Therapies 
Allowed medication or therapies during the study must be documented and include: 
• Bland emollients, keratolytics, or sunscreen to treat diseased areas that are NOT in 
the Treatment Area (but not in the surrounding skin within one inch of the 
Treatment Area); 
• Topical steroids to treat cutaneous diseased areas that are NOT in the Treatment 
Area (but not in the surrounding skin within one inch of the Treatment Area); 
• Inhaled, intranasal, and ophthalmic steroid dosage forms. 
 
Additionally, use of provided bland emollients (e.g., DML Lotion)32 in the Treatment 
Areas as an aid to managing LSRs may be prescribed by the investigator as detailed in 
Section 6.2 and must be documented in the CRFs. Application of such bland emollients 
should not be applied within four hours of application of the test articles. 
9. 
STUDY PROCEDURES 
The study will consist of seven clinic visits and two phone calls (see Schedule of Events). 
Specific activities for each study visit are listed below. 
 
Note: If the subject experiences issues with medication tolerability or other complications 
arise, ideally the subject will be seen by the investigator at one of the scheduled clinic visits 
or via an Unscheduled Visit to document the reactions and modifications to the dosing 
regimen prescribed by the investigator. In the event that a clinic visit is not possible or not 
warranted in the opinion of the investigator, the change in the subject’s management will 
                                                 
that could irritate or cause a keratolytic effect]) may be used with approval from the investigator, but must 
be documented as a concomitant medication/therapy. 
32 Other bland emollients (e.g., Lubriderm [without alpha hydroxy acid], or other moisturizers that do not 
contain any “active” ingredients [e.g., salicylic acid, lactic acid, pyruvic acid, urea, or any other ingredient 
that could irritate or cause a keratolytic effect]) may be used with approval from the investigator, but must 
be documented as a concomitant medication/therapy. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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be clearly documented in the source documents and CRF with corresponding changes 
noted in the Subject Diary regarding test article usage and/or concomitant 
medications/therapies (e.g., moisturizer use).  
 
Any dosing modifications and/or changes to concomitant medications/therapies will 
be made bilaterally (e.g., if dosing is decreased to once a day given tolerability issues, 
both sides will be treated once daily even if only one side is having the tolerability 
issue) (see Section 6.2). Treatment per protocol should resume as soon as possible after 
any notable LSRs have materially subsided as determined by the investigator or designee 
(if possible via one of the scheduled clinic visits or via an Unscheduled Visit) such that 
dosing may resume.  
9.1 
Visit 1 (Day -45 to -7): Screening 
Subjects can be screened for the study up to 45 days before Visit 2. If applicable, qualified 
subjects can washout from prohibited medications or treatments prior to Visit 2 (after 
obtaining consent/assent). Subjects that require washout for longer than 45 days will be re-
consented. Clinical laboratory tests will be performed after the subject has fasted (for 
approximately eight hours). 
 
At Screening, the investigator or designee will: 
• Obtain a signed, written informed consent (unless the subject signed a consent 
within the past 45 days). Note: Subjects under 18 years of age must provide written 
informed assent and be accompanied by the parent and legal guardian at the time 
of assent/consent signing. The parent or legal guardian must provide informed 
consent for the subject. If a subject becomes 18 years of age during the study, the 
subject must provide written informed consent at the time to continue study 
participation. 
• Record demographics. 
• Confirm I/E criteria. 
• Confirm the subject has qualified analogous right and left Treatment Areas, with 
adequate disease (≥150 cm2) and identical IGA scores (≥ 3) consistent with the I/E 
criteria (see Section 5.1) that will likely meet protocol requirements and Baseline, 
in the opinion of the investigator. 
• Record medical/ichthyosis history. 
• For those subjects who do not have confirmation of their clinical diagnosis of X-
linked or lamellar ichthyosis, collect blood or buccal samples for genetic testing 
(see Section 12.4). 
• Record prior and/or concomitant medications and therapies. 
• Perform brief physical exam. Record any findings in the medical history. 
• Perform vital signs (heart rate, respiration rate, blood pressure, and temperature), 
and height/weight. 
• Perform UPT for WOCBP. Results must be negative for the subject to be enrolled 
in the study. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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• Perform Fitzpatrick Skin Type assessment. 
• Collect urine and blood samples for clinical laboratory tests. 
 
QUALIFIED SUBJECT DETERMINATION AND TEST ARTICLE REQUEST: Prior to 
Visit 2/Baseline, after clinical laboratory results have been received and reviewed, and the 
investigator has confirmed the subject’s eligibility, the site will contact the subject to 
confirm their willingness to participate in the treatment phase of the study. Assuming the 
qualified subject is willing to participate, then the site will: 
 
a) Make a randomization request to order test article for the subject to be delivered to the 
site prior to the subject’s Baseline visit; 
b) Schedule the subject’s Baseline visit at a mutually convenient time when the 
designated subject’s test article will be at the site; 
c) NOTE: the ordered test article is specific to each subject and shall not be used for 
any other subject.  In the event a subject elects not to participate after receipt of their 
designated test article, the site should contact your monitor to discuss management of 
the test article received. 
9.2 
Visit 2 (Day 1): Baseline 
At Baseline, the investigator or designee will: 
• Query the subject about any changes in health status since the previous visit, 
including concomitant medications and therapies, and document the findings. 
• Re-confirm eligibility and re-review laboratory results. Patients who do not meet 
I/E criteria at Visit 2 will be classified as screen failures. 
• Update medical history, as required. Any changes in health status from Visit 1 to 
Visit 2 are not considered an AE, and will be captured as baseline medical history. 
• Perform UPT for WOCBP. Results must be negative for the subject to be enrolled 
in the study. 
• Select the Treatment Areas (see Section 6.2); record location by body region and 
percent BSA of disease affected skin in each Treatment Area. Estimate BSA using 
the assumption that 1% BSA is equivalent to the area of the subject’s hand with 
fingers held together. Note: Palms and soles are not eligible; the treatment of skin 
scalp and folds/intertriginous regions should be avoided. Additionally for treatment 
on the arms in subjects participating in the PK portion of the study, the antecubital 
fossa (e.g., approximately 10-15 cm2) will be excluded to minimize contamination 
of PK blood draws. 
• Perform IGA for each Treatment Area. 
• Assess CI Signs/Symptoms for each Treatment Area. 
• Document LSRs for each Treatment Area PRIOR to test article application for each 
Treatment Area. 
• Take Baseline photographs. Note: Copy(s) may be provided to the subject at the 
discretion of the investigator to help the subject consistently identify the two 
Treatment Areas. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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• For those subjects participating in the PK portion of the study, collect PK blood 
sample pre-application. Note: Subjects that elect to participate in the PK portion of 
the study should do so with the intent of completing all PK samplings required in 
the study, per protocol. 
• Randomize the subject using the designated test article specific for that subject that 
was ordered by the site after completion of Visit 1. Note: the ordered test article 
is specific to each subject and shall not be used for any other subject.   
• Dispense the Subject Instruction Sheet to the subject (and parent/legal guardian, if 
applicable). Instruct the subject (and parent/legal guardian, if applicable) where and 
how to apply the test articles to the designated Treatment Areas. 
• Document test article accountability; weigh the tubes and dispense the test articles 
to the subject. 
• Dispense the Subject Diary to the subject (and parent/legal guardian, if applicable) 
and provide completion instructions. 
• Supervise the first application of the test articles. The test article with the RED label 
should be applied to the RIGHT Treatment Area and the test article with the 
LEMON YELLOW label should be applied to the LEFT Treatment Area. 
• Record any AEs. 
• Assess LSRs approximately 10 minutes post-application for each Treatment Area. 
• For those subjects participating in the PK portion of the study, collect additional 
PK blood samples at 1, 2, 3, and 4 hours post-application. 
• Instruct the subject (and parent/legal guardian, if applicable) to apply the test 
articles to the designated Treatment Areas twice per day, once in the morning and 
once in the evening with at least eight hours between applications, and to hold the 
application of the test articles on days of clinic visits. Note: For those subjects 
participating in the PK portion of the study, the application before a scheduled 
clinic visit with PK time point (i.e., on Days 7, 14, 28, 56, and 83) must be 
approximately 12 hours ± 30 minutes prior to the blood draw. 
• Schedule Visit 3 (Phone Call) and Visit 4 (Clinic Visit). 
9.3 
Visit 3 (Day 2) and Visit 7 (Day 43±3): Phone Calls 
The investigator or designee will contact the subject or parent/guardian (as appropriate) 
by telephone to: 
• Review any change in health status since the previous visit, including concomitant 
medications and therapies to assure the subject is not using any prohibited 
medications, and document the findings. Note: concomitant mediations and 
therapies are not formally updated at these phone call visits in the CRF just in the 
subject’s source documentation. 
• Review compliance with the test articles. 
• Emphasize the need to maintain the Subject Diary daily with each application. 
• If there are any concerns regarding tolerability or other AE, schedule a clinic visit 
(i.e., Unscheduled Visit) at the discretion of the investigator. 
• Confirm the next scheduled visit and remind the subject (and parent/legal guardian, 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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if applicable) to hold the morning application of the test articles on days of clinic 
visits. Note: For those subjects participating in the PK portion of the study, the 
application before a scheduled clinic visit with PK time point (i.e., on Day 56) must 
be approximately 12 hours ± 30 minutes prior to the blood draw. 
9.4 
Visit 4 (Day 8+1) and Visit 5 (Day 15±1): Follow-Up 
At this visit the investigator or designee will: 
• Query the subject about any changes in health status since the previous visit, 
including concomitant medications and therapies, and document the findings. 
Ensure any changes concomitant medications and therapies identified during phone 
visits are reviewed and documented in the CRFs. 
• Perform IGA for each Treatment Area. 
• Assess CI Signs/Symptoms for each Treatment Area. 
• Document LSRs for each Treatment Area. 
• Update Concomitant Medications and Therapies, as applicable. 
• Take photographs (optional). 
• For those subjects participating in the PK portion of the study, collect PK blood 
sample PRIOR to application of the test articles. Note: This sample will be collected 
12 hours ± 30 minutes after the dose on the previous day. 
• Document test article accountability; weigh the tubes and return/dispense the test 
articles, as applicable. 
• Review compliance and collect/dispense Subject Diary, as applicable. 
• Review proper test article use and application guidelines with the subject (and 
parent/legal guardian, if applicable), stressing the importance that care should 
be taken so that the correct test article is applied to the two Treatment Area(s) 
on the subjects RIGHT and LEFT side.  
• If possible, supervise the application of the test articles. The test article with the 
RED label should be applied to the RIGHT Treatment Area and the test article with 
the LEMON YELLOW label should be applied to the LEFT Treatment Area. 
• Document any AEs. 
• Remind the subject (and parent/legal guardian, if applicable) to hold the application 
of the test articles on days of clinic visits. Note: For those subjects participating in 
the PK portion of the study, the application before a scheduled clinic visit with PK 
time point (i.e., on Day 28) must be approximately 12 hours ± 30 minutes prior to 
the blood draw. 
• Schedule follow-up visit. 
9.5 
Visit 6 (Day 29±3): Follow-Up 
At this visit the investigator or designee will: 
• Query the subject about any changes in health status since the previous visit, 
including concomitant medications and therapies, and document the findings. 
• Perform brief physical exam. Record any new or worsening findings as AEs. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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• Perform vital signs (heart rate, respiration rate, blood pressure, and temperature). 
• Perform UPT for WOCBP. Results must be negative for the subject to continue in 
the study. 
• Collect urine and blood samples for clinical laboratory tests. If possible, subject 
will have fasted for approximately eight hours or more prior to these laboratory 
tests. 
• Perform IGA for each Treatment Area. 
• Assess CI Signs/Symptoms for each Treatment Area. 
• Document LSRs for each Treatment Area. 
• Update Concomitant Medications and Therapies, as applicable. 
• Take photographs. 
• For those subjects participating in the PK portion of the study, collect PK blood 
sample PRIOR to application of the test articles. Note: This sample will be collected 
12 hours ± 30 minutes after the dose on the previous day. 
• Document test article accountability; weigh the tubes and return/dispense the test 
articles, as applicable. 
• Review compliance and collect/dispense Subject Diary, as applicable. 
• Review proper test article use and application guidelines with the subject (and 
parent/legal guardian, if applicable), stressing the importance that care should 
be taken that the correct test article is applied to the two Treatment Area(s) 
on the subjects RIGHT and LEFT side.  
• If possible, supervise the application of the test articles. The test article with the 
RED label should be applied to the RIGHT Treatment Area and the test article with 
the LEMON YELLOW label should be applied to the LEFT Treatment Area. 
• Document any AEs. 
• Schedule Visit 7 (Phone Call; see Section 9.3) and Visit 8 (Clinic Visit). 
9.6 
Visit 8 (Day 57±4): End of Part 1 
At this visit the investigator or designee will: 
• Query the subject about any changes in health status since the previous visit, 
including concomitant medications and therapies, and document the findings. 
• Perform brief physical exam. Record any new or worsening findings as AEs. 
• Perform vital signs (heart rate, respiration rate, blood pressure, and temperature). 
• Perform UPT for WOCBP. Results must be negative for the subject to continue in 
the study. 
• Collect urine and blood samples for clinical laboratory tests. If possible, subject 
will have fasted for approximately eight hours or more prior to these laboratory 
tests. 
• Perform IGA for each Treatment Area. 
• Assess CI Signs/Symptoms for each Treatment Area. 
• Document LSRs for each Treatment Area. 
• Take photographs. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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• For those subjects participating in the PK portion of the study, collect PK blood 
sample PRIOR to the application of the test articles. Note: This sample will be 
collected 12 hours ± 30 minutes after the dose on the previous day. 
• Document test article accountability; weigh the tubes and return the test articles 
from Part 1. Dispense the test article for Part 2 to the subject. 
• Re-educate the subject (and parent/legal guardian, if applicable) with respect to 
dosing and related activities for Part 2.  
o Review compliance and collect/dispense Subject Diary, as applicable. 
o Supervise the application of the test article to both Treatment Areas. 
• Record any AEs. 
• Assess LSRs approximately 10 minutes post-application for each Treatment Area. 
• Schedule Visit 9. 
9.7 
Visit 9 (Day 84±4): End of Study and Early Termination 
At this visit the investigator or designee will: 
• Query the subject about any changes in health status since the previous visit, 
including concomitant medications and therapies, and document the findings. 
• Perform brief physical exam. Record any new or worsening findings as AEs. 
• Perform vital signs (heart rate, respiration rate, blood pressure, and temperature). 
• Perform UPT for WOCBP. 
• Collect urine and blood samples for clinical laboratory tests. If possible, subject 
will have fasted for approximately eight hours or more prior to these laboratory 
tests. 
• Perform IGA for each Treatment Area. 
• Assess CI Signs/Symptoms for each Treatment Area. 
• Document LSRs for each Treatment Area. 
• Take photographs. 
• Document test article accountability; weigh the tubes and collect all test articles. 
• Collect Subject Diary. 
• Exit the subject from the study. 
10. 
CLINICAL EVALUATIONS 
The following clinical evaluations will be performed according to the schedules indicated 
during the study. The same investigator should complete the evaluations for a given subject 
throughout the study. If this becomes impossible a sub-investigator with overlapping 
experience with the subject and the study should complete the evaluations. 
10.1 
Investigator’s Global Assessment 
At each clinic visit, overall severity of ichthyosis will be assessed using a five-point IGA 
scale where 0=clear, 1=almost clear, 2=mild, 3=moderate, and 4=severe. This is a static 
morphological scale that refers to a point in time and not a comparison to Baseline. Subjects 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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must have an IGA score of 3 (moderate) or 4 (severe) at Baseline AND the IGA score must 
be identical in each Treatment Area. 
 
The investigator should NOT refer to any other assessments to assist with this evaluation. 
The following scale will be used to assess the “average” degree of severity within each 
Treatment Area (TA), taking into consideration the four lead individual characteristics of 
ichthyosis: 
 
Clear (0) 
Erythema 
No erythema (hyperpigmentation may be present). 
Scaling 
No evidence of scaling. 
Fissuring 
No evidence of fissuring. 
Papulation, and/or 
lichenification  
No evidence of papulation and/or lichenification. 
 
Almost Clear (1) 
Erythema 
No more than faint red coloration predominates over the TA. 
Scaling 
No more than a limited amount of very fine scales predominate, 
little of the TA is affected. 
Fissuring 
No or extremely rare fissuring predominates, little of the TA is 
affected. 
Papulation, and/or 
lichenification 
No more than a very slight papulation and/or lichenification 
predominates, often easier felt than seen, little of the TA is affected. 
 
Mild (2) 
Erythema 
No more than light red coloration predominates over the TA. 
Scaling 
No more than mainly fine scales predominate, with less than half 
of the TA is affected. 
Fissuring 
No more than mild fissuring, with less than half of the TA is 
affected. 
Papulation, and/or 
lichenification 
No more than a slight (≤ 1mm), but definite elevation of focal skin 
areas due to papulation and/or lichenification predominates, with 
less than half of the TA is affected. 
 
Moderate (3) 
Erythema 
No more than moderate red coloration predominates over the TA. 
Scaling 
No more than somewhat coarser scales predominate; greater than 
half the TA is affected. 
Fissuring 
No more than moderate fissuring; greater than half the TA is 
affected. 
Papulation, and/or 
lichenification 
No more than a moderate (1.1 to ≤ 2 mm) elevation of focal skin 
areas due to papulation and/or lichenification predominates; greater 
than half the TA is affected. 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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Severe (4) 
Erythema 
Dusky to deep red coloration predominates over the TA. 
Scaling 
Coarse, thick tenacious scales predominate; virtually all of the TA 
is affected. 
Fissuring 
Severe fissuring predominates; virtually all of the TA is affected. 
Papulation, and/or 
lichenification 
Marked elevation (> 2mm) of papulation and/or lichenification 
predominates; virtually all of the TA is affected. 
10.2 
Individual Clinical Signs/Symptoms 
At each clinic visit (except Visit 1/Screening), overall severity of erythema, scaling, 
fissuring, and papulation/lichenification will be graded for each TA using a five-point scale 
where 0=clear, 1=almost clear, 2=mild, 3=moderate, and 4=severe. This is a static 
morphological scale that refers to a point in time and not a comparison to Baseline. 
 
ERYTHEMA 
0 
Clear 
No redness 
1 
Almost Clear 
Faint red coloration predominates 
2 
Mild 
Light red coloration predominates 
3 
Moderate 
Moderate red coloration predominates 
4 
Severe 
Dusky to deep red coloration predominates 
 
SCALING 
0 
Clear 
No evidence of scaling 
1 
Almost Clear 
Limited amount of very fine scales, little of the TA is affected 
2 
Mild 
Mainly fine scales predominate, less than half of TA is 
affected 
3 
Moderate 
Somewhat coarser scales predominate, greater than half of the 
TA is affected 
4 
Severe 
Coarse, thick, tenacious scales predominate, virtually all of 
the TA is affected 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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FISSURING 
0 
Clear 
No evidence of fissuring 
1 
Almost Clear 
No more than a very slight fissuring predominates, often easier 
felt than seen, little of the TA is affected 
2 
Mild 
Mainly mild fissuring predominate, less than half of TA is 
affected 
3 
Moderate 
Mainly moderate fissuring predominate, greater than half of 
the TA is affected 
4 
Severe 
Mainly severe fissuring predominate, virtually all of the TA is 
affected 
 
PAPULATION AND/OR LICHENIFICATION 
0 
Clear 
No evidence of plaque elevation above normal skin level. 
1 
Almost Clear 
Very slight elevation above normal skin level predominates, 
easier felt than seen, little of the TA is affected. 
2 
Mild 
No more than a slight (≤1 mm) but definite elevation of focal 
skin 
areas 
due 
to 
papulation 
and/or 
lichenification 
predominates; less than half of the TA is affected 
3 
Moderate 
No more than a moderate (≤2 mm) elevation of focal skin areas 
due to papulation and/or lichenification predominates; greater 
than half the TA is affected 
4 
Severe 
Marked elevation (>2 mm) of papulation and/or lichenification 
predominates; virtually all of the TA is affected. 
10.3 
Fitzpatrick Skin Type Assessment 
At Visit 1, the investigator or designee will document the subject’s skin phototype (I-VI) 
using the Fitzpatrick Skin Type Assessment. 
 
Fitzpatrick Skin Type Assessment 
Phototype Typical Features 
Tanning Ability 
I 
Pale white skin, blue/hazel eyes, Always burns, does not tan 
II 
Fair skin, blue eyes 
Burns easily, tans poorly 
III 
Darker white skin 
Tans after initial burn 
IV 
Light brown skin 
Burns minimally, tans easily 
V 
Brown skin 
Rarely burns, tans darkly easily 
VI 
Dark brown or black skin 
Never burns, always tans darkly 
10.4 
Local Skin Reactions 
At each clinic visit (except Visit 1/Screening), LSRs including burning/stinging, pain, and 
pruritus will be documented in each Treatment Area using a four-point ordinal scale where 
0=none, 1=mild, 2=moderate, and 3=severe. These LSRs will be collected independently 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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of AEs. Only LSRs that require medical intervention (e.g., prescription medication) or 
require withholding or reduction in dosing frequency of the test articles will be documented 
as AEs. Any LSRs that are not listed above will be recorded as AEs. 
11. 
PHOTOGRAPHY 
Photography documentation is required in this study at Visit 2/Baseline/Day 1, 
Visit 6/Day 29, Visit 8/Day 57, and Visit 9/Day 84. Copy(s) of the Baseline photos may be 
provided to the subject, at the discretion of the investigator, to help the subject consistently 
identify the two Treatment Areas. Photographs may also be taken at other visits at the 
discretion of the investigator. Photographs taken as part of this study will be used to 
document the effects of treatment, AEs, or other findings during the study. The site will be 
provided with suggested guidelines to assist them in taking standardized photographs. 
Photographs will be taken of lesions only, without including subject identity (i.e., facial 
photos). All photographs taken as part of this study are for informational purposes only and 
are not to be used in grading or for any other assessment. 
 
Note: Subjects may decline to have photographs taken during the conduct of the study. If 
a subject initially consents to photographs, then declines further photography, the Sponsor 
may use the photographs taken under consent for the purposes noted above. 
12. 
LABORATORY TESTS 
12.1 
Blood Chemistries, Hematology and Urinalysis 
Blood and urine specimens will be collected at Visit 1/Screening, Visit 6/Day 29, 
Visit 8/Day 57 (End of Part 1), and Visit 9/Day 84 (EOT or early termination) for 
chemistry, hematology, and urinalysis. Subjects must be fasting (approximately 8 hours) 
for screening laboratory tests and, if possible, for laboratory tests at Visit 6/Day 29, 
Visit 8/Day 57, and Visit 9/Day 84; however, if a subject arrives at the clinic for Visit 6, 
Visit 8, or Visit 9 without fasting for at least eight hours, laboratory specimens may be 
collected as non-fasting, at the discretion of the investigator, and with the appropriate 
fasting status documented on the lab requisition form. 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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The following tests will be performed 
Chemistries 
Hematology 
Urinalysis 
Albumin 
Hemoglobin 
Blood 
Alkaline Phosphatase 
Hematocrit 
Glucose 
ALT (SGPT) 
MCV 
Ketone 
AST (SGOT) 
MCH 
pH 
Bicarbonate 
MCHC 
Specific Gravity 
Bilirubin, total 
RBC (Erythrocytes) 
Microscopic Analysis 
Calcium 
WBC (Leucocytes) 
   WBC 
Chloride 
RDW 
   RBC 
Cholesterol 
Differential count 
   Casts 
Creatinine 
   Basophils 
 
GGT 
   Eosinophils 
 
Glucose (fasting) 
   Lymphocytes 
 
LDH 
   Monocytes 
 
Potassium 
   Neutrophils 
 
Phosphate 
Platelets 
 
Protein, total 
 
 
Sodium 
 
 
Triglycerides 
 
 
Urea (BUN) 
 
 
Uric Acid 
 
 
 
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 include: 
• Pain 
• Bruising 
• Bleeding at the puncture site 
• Fainting 
• Inflammation of the vein 
12.2 
Urine Pregnancy Tests 
UPTs must be performed on all WOCBP at Visit 1/Screening, Visit 2/Day 1 (prior to 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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randomization), Visit 6/Day 29, Visit 8/Day 57, and Visit 9/Day 84 (EOT or early 
termination); UPTs must be negative for the subject to be eligible for and to continue in 
the study. 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. 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. 
12.3 
Pharmacokinetic Sample Collection, Storage, and Assay 
At Visit 2/Day 1, PK blood samples will be collected for isotretinoin and tretinoin pre-test 
article application (time 0) and at 1, 2, 3, and 4 hours post-test article application. At 
Visit 4/Day 8, Visit 5/Day 15, Visit 6/Day 29, Visit 8/Day 57, and Visit 9/Day 84, a PK 
blood sample will be collected for isotretinoin and tretinoin pre-test article application 
(approximately 12 hours after the last test article application on the previous day). 
Sampling times will be recorded on the appropriate CRFs. Site (e.g., right versus left arm) 
of PK blood draws will be recorded. 
 
The method of sample collection for PK analysis is detailed in the laboratory manual to be 
provided by the laboratory vendor. Each PK blood sample will be processed and stored as 
detailed in the laboratory manual. Samples will be prepared in duplicate; one of the samples 
will be shipped to the analytical laboratory using an authorized courier and the other sample 
will be stored at the site as back-up samples until confirmation that the initial shipment has 
been safely received by the analytical laboratory. Details and specific instructions on 
labeling and management of these specimens are provided in the laboratory manual. 
 
Plasma will be analyzed for levels of isotretinoin and tretinoin and compared to background 
systemic retinoid levels pre- and post-treatment. 
12.4 
Genetic Testing 
At Visit 1/Screening, for those subjects who do not have confirmation of their clinical 
diagnosis of X-linked or lamellar ichthyosis, blood or buccal samples will be collected for 
genetic testing. As/if required, this test may be repeated during the study as determined by 
the investigator (e.g., specimen quality, loss or handling concerns, indeterminate outcome). 
The subject may be enrolled based upon their clinical diagnosis only, with genetic testing 
to follow, such that the results are available at or before the conclusion of the study. 
Specifics regarding the testing options for these two ichthyosis subtypes, specimen 
handling, and related matters will be determined by the company used for genetic testing. 
In the event the genetic testing results do not concur with the clinical diagnosis the subject 
may complete the study as the inclusion criteria are based upon the clinical assessment of 
their skin disease by the Investigator at Baseline. 


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13. 
END OF STUDY CRITERIA 
At the end of each subject’s participation in the study, the investigator will complete an 
End of Study form for all completed and discontinued subjects.  
13.1 
Completion of the Study 
Subjects who complete the 12 week course of treatment as specified in this protocol and 
all of the Visit 9/Day 84 evaluations will have completed the study. 
13.2 
Subject Discontinuation 
A subject may be withdrawn from the study prior to completion for any of the following 
reasons: 
• AE 
• Death 
• Lack of efficacy 
• Lost to follow-up 
• Noncompliance with study drug 
• Physician decision 
• Pregnancy 
• Progressive disease 
• Protocol deviation 
• Study terminated by Sponsor 
• Withdrawal by subject; 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. 
• Other (e.g., any other reason that may affect the outcome of the study or the safety 
of subjects) 
 
If a subject withdraws from the study prematurely for any reason, the site should make 
every effort to have the subject return for the next scheduled visit to complete the final visit 
procedures. When a subject is withdrawn from the study for a test article related AE (i.e., 
possibly, probably or definitely related as defined in Section 14), when possible, the subject 
should be followed until resolution or stabilization of the AE. If the subject is discontinued 
from the study due to pregnancy, the pregnancy and its outcome should be followed. 
 
Subjects who are prematurely withdrawn or discontinued from the study will not be 
replaced. 
13.3 
Study Termination 
The study may be terminated by the investigator or the Sponsor. If, in the opinion of the 
investigator, clinical observations made during the study suggest that it may be unwise to 
continue, he or she may stop the study. A study termination by the investigator will be 
reported to the Sponsor. 


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In addition, a written statement fully documenting the reasons for this action will be 
submitted to the Sponsor by the investigator within five working days. 
 
In the event that the Sponsor chooses to discontinue or terminate the study, appropriate 
notification will be given to the investigator. 
14. 
ADVERSE EVENT REPORTING 
An adverse event 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 informed 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) 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; 
therefore AE data should be collected from the date of the first dose of test article until the 
date of the final study visit. These data are considered TEAEs.  
 
Timely and complete reporting of all AEs assists the Sponsor or designee in identifying 
any untoward medical occurrence, thereby allowing:  
1) protection of the safety of study subjects;  
2) a greater understanding of the overall safety profile of the test article;  
3) recognition of dose-related test article toxicity; 
4) appropriate modification of study protocols;  
5) improvements in study design or procedures; and  
6) adherence to worldwide regulatory requirements.  
 
Test article is defined as a pharmaceutical form of an active ingredient (or “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 


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that are present at the end of their participation in the study should receive follow-up as 
appropriate. If possible, report the outcome of any AE that caused permanent 
discontinuation or that was present at the end of the study particularly if the AE is 
considered by the investigator to be treatment-related (i.e., definitely, probably, or possibly 
related to test article). 
14.1 
Adverse Event 
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. 
 
No human studies have been conducted with PAT-001 (isotretinoin) Ointment. The most 
common adverse reactions associated with other topical retinoid formulations include 
application site erythema, skin exfoliation, pain of skin, application site pruritus, skin 
irritation, skin tenderness, skin burning sensation, application site stinging, dry skin/lips, 
skin hyperpigmentation, skin hypopigmentation, and photosensitivity. The most notable or 
common adverse reactions with oral isotretinoin are: dry lips , dry skin, back pain, dry eye, 
arthralgia, epistaxis, headache, nasopharyngitis, chapped lips, dermatitis, renal or 
hepatotoxicity, musculoskeletal discomfort, teratogenicity, and visual acuity reduced. 
Although systemic exposure is expected to be low given the route of topical administration 
and therefore many of these risks are unlikely, these, as well as other unknown risks, are 
considered potential risks pending clinical experience with this new dosage form. 
 
The investigator will instruct the subject to report any AEs that may occur during the study. 
At each visit, the investigator should ask the subject, in non-directive fashion, about any 
change in the subject’s overall condition since the previous visit. 
 
The severity of each AE, as judged by the investigator, will be recorded on the appropriate 
AE CRF and will be graded according to the following scale: 
 
Mild – The AE is transient and easily tolerated by the subject. 
 
Moderate – The AE causes the subject discomfort and interrupts the subject’s usual 
activities. 
 
Severe – The AE causes considerable interference with the subject’s usual 
activities, and may be incapacitating or life-threatening. 
 
The investigator must determine the relationship of the AE to the test article according to 
the following categories: 
 
Definite – An event that follows a reasonable temporal sequence from 
administration of the test article; that follows a known or expected response pattern 
to the test article; and that is confirmed by improvement on stopping or reducing 


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Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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the dosage, and reappearance of the event on repeated exposure (re-challenge). 
 
Probable – An event that follows a reasonable temporal sequence from 
administration of the test article; that follows a known or expected response pattern 
to the test article; and that is confirmed by improvement on stopping or reducing 
the dosage of the test article; and that is unlikely to have been caused by 
concurrent/underlying illness or other drugs, procedures, or other causes. 
 
Possible – An event that follows a reasonable temporal sequence from 
administration of the test article; that follows a known or expected response pattern 
to the test article; but may have been caused by concurrent/underlying illness, other 
drug, procedure, or other causes. 
 
Unlikely – An event that does not follow a reasonable temporal sequence from 
administration of the test article; that does not follow a known or expected response 
pattern to the test article, or most likely was caused by concurrent/underlying 
illness, other drug, procedure, or other causes, because of their known effects.  
 
Not Related – An event almost certainly caused by concurrent/underlying illness, 
other drug, procedure, or other causes. 
 
The investigator should categorize the outcome of the AE according to the following 
categories: 
 
 
Fatal – Termination of life as a result of an AE. 
 
 
Not Recovered/Not Resolved – AE has not improved or the subject has not 
recuperated. 
 
 
Recovered/Resolved – AE has improved or the subject has recuperated. 
 
 
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 


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Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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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 (IB) or is not listed at the specificity or severity that has been 
observed; or, if an IB 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 IB referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the IB listed only cerebral vascular accidents. “Unexpected,” as used in this 
definition, also refers to AEs or suspected adverse reactions that are mentioned in the IB 
as occurring with a class of drugs or as anticipated from the pharmacological properties of 
the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 
14.2 
Serious Adverse Event 
An event that is serious must be recorded on the AE CRF and on the TI SAE Report Form, 
and requires expeditious handling to comply with regulatory requirements. 
 
An AE or suspected adverse reaction is considered “serious” if, in the opinion of either the 
investigator or Sponsor, it results in any of the following outcomes: 
• Death. 
• Life-threatening event. 
• Inpatient hospitalization or prolongation of existing hospitalization. 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• Congenital anomaly/birth defect. 
• Is an important medical event – defined as a medical event(s) that may not result in 
death, be life-threatening, or require hospitalization but, based upon appropriate 
medical judgment, may jeopardize the patient/subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in the definition above. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.  
• Although not defined as an AE, pregnancy shall be considered as a serious 
event and 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 


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the first page of the protocol.  
 
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 TI to comply with regulatory requirements. All SAEs, whether 
related or unrelated to test article, must be immediately reported by telephone to the 
Medical Monitor (619-889-7058) and, in the event that he/she is unavailable, to the 
Project Manager (858-571-1800, ext. 129) [additional contact information 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 IB and must include an assessment of whether there is a reasonable 
possibility that the drug caused the event.  
 
Study endpoints that are SAEs (e.g., all-cause mortality) must be reported in accordance 
with the protocol unless there is evidence suggesting a causal relationship between the drug 
and the event (e.g., death from anaphylaxis). In this case, the investigator must immediately 
report the event to the Sponsor. In addition, such information should also be provided to 
the site’s respective IRB per their governing guidelines for SAE reporting.  
 
If only limited information is initially available, follow-up reports are required. Should the 
investigator become aware of 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 TI, if available. 
 
As required, TI 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 


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Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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adverse reactions. 
v) Confirmed pregnancy at any time during the study or within one month 
from discontinuing from the study.  
 
Upon receiving such notices, the investigator must review and retain the notice with the IB 
and immediately submit a copy of this information to the responsible IRB according to 
local regulations. The investigator and IRB will determine if the informed consent/assent 
requires revision. The investigator should also comply with the IRB procedures for 
reporting any other safety information. Where required, submission of safety updates by 
the investigator to Health Authorities should be handled according to local regulations. 
14.3 
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 14) or SAE (see Section 14.2) must 
also be recorded on the AE CRF. SAEs must be reported to the Sponsor and IRB as per 
Section 14.2. In these cases, TI 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. 
14.4 
Pregnancy 
WOCBP include any female who has experienced menarche or is 10 years of age or older 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea >12 
consecutive months in women 50 years of age and older]. Even women who are using 
hormonal methods of contraception and/or barrier methods to prevent pregnancy, 
practicing abstinence, or who have a monogamous partner that is sterile (e.g., vasectomy) 
should be considered to be of childbearing potential. Surgical means of sterilization (e.g., 
vasectomy, tubal ligation) must be a minimum of six months post-procedure to be 
considered effective birth control. 
 
WOCBP must have a negative pregnancy test prior to study enrollment and must use the 
methods of contraception outlined in the protocol during the course of the study, in a 
manner such that risk of failure is minimized. Methods of acceptable contraception include 
A) total abstinence OR B) two forms of birth control including: 
• Oral, patch, injected, or implanted hormonal methods of contraception33 AND 
• Partner vasectomy (performed at least six months prior to study entry) OR barrier 
                                                 
33 WOCBP taking hormonal therapy must be on treatment for (1) oral or patch: one complete cycle (e.g., four 
to eight weeks) or (2) injectable or implanted: at least one week prior to study entry, continued per label, and 
must not change their dosing regimen during the study. 


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methods of contraception (barrier methods include male condom with or without 
spermicide, diaphragm with spermicide, or cervical cap with spermicide) OR 
vaginal contraceptive sponge containing a spermicide. 
 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent/assent form documenting this 
discussion. 
 
WOCBP 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. The investigator must immediately notify the Medical 
Monitor of the pregnancy and record the pregnancy on the appropriate pregnancy 
surveillance form.  
 
If following initiation of study treatment, it is subsequently discovered that a study 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 TI. The investigator 
must notify the IRB of any pregnancy associated with the study therapy and keep careful 
source documentation of the event. 
 
Protocol-required procedures for those subjects that are discontinued from the study must 
be performed on the subject unless contraindicated by pregnancy (e.g., x-ray studies). 
Other appropriate pregnancy follow-up procedures should be considered if indicated, 
including counseling of the subject by the investigator and her managing physician or 
health care provider (e.g., obstetrician). In addition, the investigator must report to TI, on 
the appropriate TI 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. 
15. 
BLINDING/UNBLINDING 
Blinding is important for the integrity of this clinical study. However, the blind may be 
broken in the event of a medical emergency in a subject, in which knowledge of the test 
article identity is critical to the subject’s management. Before breaking the blind for a 
subject, the investigator should determine that the information is necessary (i.e., that it will 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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alter the subject’s immediate management). In many cases, particularly when the 
emergency is clearly not test article related, the problem may be effectively managed by 
assuming that the subject is receiving active product without the need for unblinding. The 
need to break the blind should first be discussed with the responsible Medical Monitor and 
the best method to do this will be determined. 
 
In Part 1, the test articles will be blinded using color coded labels to designate which test 
article to apply to each Treatment Area. 
16. 
CLINICAL SUPPLIES 
16.1 
Test Article Information 
Test articles will be packaged and labeled by the Sponsor or designee. Detailed information 
on the packaging/labeling, blinding/unblinding, storage and preparation, dispensing, 
accountability etc. is included in Appendix 3. 
16.2 
Supplies Provided by Therapeutics, Inc. 
• CRFs 
• Source document draft templates 
• Site regulatory binder 
• UPT kits 
• Digital camera 
• Bland emollient (e.g., DML Lotion) 
16.3 
Supplies Provided by Investigator 
• Personal computer to store and view study images 
• Urine collection containers for UPTs 
• Centrifuge to process blood samples per specifications in laboratory manual (if 
participating in PK portion of the study) 
• Ultra-low freezer for storage of PK blood samples (if participating in PK portion of 
the study) 
16.4 
Supplies Provided by the Clinical Laboratory 
• Supplies to collect and transport urine and blood samples to the clinical laboratory 
• Tubes and labels for plasma aliquots for PK analysis (for sites participating in the 
PK portion of the study) 
• Urine collection containers for urinalysis 


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17. 
STATISTICAL CONSIDERATIONS 
17.1 
Sample Size 
As a first-in-man POC study, no formal power calculations were used to determine the 
sample size. 
17.2 
Endpoints 
17.2.1 Safety Endpoints 
Safety endpoints will include: 
• Incidence (severity and causality) of any local and systemic AEs 
• Number of subjects with presence (and severity) of the following LSRs: 
stinging/burning, pain, and pruritus at each time point for each Treatment Area 
collected (summarized by Test Article). 
• Changes from Screening in vital signs at Days 29, 57, and 84 (or EOT) 
(summarized by Treatment Group). 
• Changes from Screening in clinical laboratory tests (hematology, chemistry, and 
urinalysis) at Days 29, 57, and 84 (or EOT) (summarized by Treatment Group). 
• UPT results in all WOCBP at Screening, Baseline, Day 29, Day 57, and Day 84 (or 
EOT). 
17.2.2 Pharmacokinetic Endpoints 
PK endpoints with include: 
• Concentration of isotretinoin and tretinoin pre-dose and at 1, 2, 3, and 4 hours after 
the first dose on Day 1. 
• Trough plasma concentrations (C12h) on Days 8, 15, 29, 57, and 84. 
17.2.3 Efficacy Endpoints 
Part 1 (P1) and Part 2 (P2) efficacy data will be analyzed separately. For Part 1, efficacy 
endpoints will be summarized by Test Article (PAT-001, 1%; PAT-001, 0.2%; and Vehicle 
[pooled across Treatment Groups]) and/or by Part 1 Treatment Group (Group 1: PAT-001, 
0.1%/Vehicle; and Group 2: PAT-001, 0.2%/Vehicle) as described below. For Part 2, 
efficacy endpoints will be summarized by Part 2 Summary Group, which consists of four 
groups: 
• Group A: PAT-001, 0.1%-P2 Active/P1 Active 
• Group B: PAT-001, 0.1%-P2 Active/P1 Vehicle;  
• Group C: PAT-001, 0.2%-P2 Active/P1 Active; and  
• Group D: PAT-001, 0.2%-P2 Active/P1 Vehicle. 
 
In Part 1, the following exploratory endpoints will be evaluated:  
• Frequency distribution of IGA and CI Signs/Symptoms at Baseline, and Days 8, 


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15, 29, and 57 summarized by Test Article. 
• Absolute change from Baseline in IGA and the CI Signs/Symptoms at Days 8, 15, 
29, and 57 summarized by Test Article. 
• Within subject difference in IGA and CI Signs/Symptoms at Baseline and Days 8, 
15, 29, and 57 summarized by Part 1 Treatment Group. 
• Within subject difference in change from Baseline in IGA and CI Signs/Symptoms 
at Baseline and Days 8, 15, 29, and 57 summarized by Part 1 Treatment Group. 
 
In Part 2, the following exploratory endpoints will be evaluated: 
• Frequency distribution of IGA and CI Signs/Symptoms at Day 84 summarized by 
Part 2 Summary Group (Group A-D). 
• Absolute change from Baseline in IGA and CI Signs/Symptoms at Day 84 
summarized by Part 2 Summary Group (Group A-D). 
• Absolute change from Day 57 in IGA and CI Signs/Symptoms at Day 84 
summarized by Part 2 Summary Group (Group A-D). 
• Within subject difference in IGA and CI Signs/Symptoms at Day 84 summarized 
by Part 2 Treatment Group (0.1% and 0.2%). 
• Within subject difference in absolute change from Baseline in IGA and CI 
Signs/Symptoms at Day 84 summarized by Part 2 Treatment Group (0.1% and 
0.2%). 
• Within subject difference in absolute change from Day 57 in IGA and CI 
Signs/Symptoms at Day 84 summarized by Part 2 Treatment Group (0.1% and 
0.2%). 
17.3 
Statistical Methods 
Summary tables (descriptive statistics and/or frequency tables) will be provided for screening 
variables, baseline variables, efficacy variables, and safety variables. Continuous variables 
will be described by descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum). Frequency counts and percentage of subjects within each category will be 
provided for categorical data. 
 
Study Populations: 
The Safety population will include all enrolled subjects who applied the test article. The 
intent-to-treat (ITT) population will include all randomized subjects who were dispensed the 
test article. The PK population will include those subjects in the Safety population who 
participated in the PK portion of the study with no evidence of material dosing 
noncompliance. 
17.3.1 Safety Analyses 
The analysis of safety will be conducted on the Safety population. 
 


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Extent of Exposure 
Extent of exposure will be calculated separately for Part 1 and Part 2 and overall. The total 
amount of each 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 number of days dosed) will be 
calculated for each Treatment Group and Test Article. Descriptive statistics will be used to 
summarize the total amount and mean daily amount of test article applied. 
 
Adverse Events 
All AEs reported during the study will be listed, documenting onset, severity, whether 
therapy was required, any change in test article dosing, investigator assessment of the 
relationship to the test article, and outcome. AEs will be coded using MedDRA using 
preferred terms (PTs) and system organ class (SOC). The PTs and SOC will then be 
tabulated. All treatment emergent AEs (TEAEs) will be summarized by the number of 
subjects reporting AEs, SOC, PT, severity, and relationship to test article. 
 
Local Skin Reactions 
Severity of LSRs (stinging/burning, pain, and pruritus) will be recorded for each Treatment 
Area (i.e., Test Article). LSRs will be summarized by frequency and severity of each 
individual LSR at each visit. 
 
Physical Examinations 
Findings from the brief physical examinations will be recorded in medical history (from 
assessment at Screening) or as AEs (from assessment at Days 29, 57, and 84). 
 
Vital Signs 
Vital signs (heart rate, respiration rate, blood pressure (systolic and diastolic), and 
temperature) will be recorded at Screening, and Days 29, 57, and 84. Descriptive statistics 
will be used to summarize vital signs. Clinically significant changes from Screening in 
vital signs at Days 29, 57, and 84 will be summarized. 
 
Clinical Laboratory Tests 
Clinical laboratory data (hematology, chemistry, and urinalysis) will be tabulated at 
Screening and Days 29, 57, and 84. Changes from Screening in laboratory data at Days 29, 
57, and 84 will also be summarized. All laboratory data will be listed and reported in the 
units received by the central laboratory. Shift tables by analyte and by out of range flag 
will be presented to facilitate the evaluation of change from Screening to Days 29, 57, and 
84. 
 
Urine Pregnancy Tests 
UPT results (if applicable) at Screening, Baseline, and Days 29, 57, and 84 will be provided 
in a subject listing. 
 
Concomitant Medications and Therapies 
Concomitant medications and therapies will be provided in subject listings. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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17.3.2 Efficacy Analyses 
The analysis of efficacy will be conducted on the ITT population. Given the small sample 
size, no formal hypothesis testing will be done. 
 
Dosing Compliance 
Dosing compliance will be evaluated separately for Part 1 and Part 2 and overall. Measures 
of test article compliance will include the duration of treatment (in number of days) and 
the total number of applications. Descriptive statistics will be used to summarize test article 
compliance. Subjects who applied at least 80% of the expected applications will be 
considered to be compliant with test article dosing. 
 
Investigator’s Global Assessment 
Part 1. Frequency distributions of IGA score will be tabulated at Baseline and Days 8, 15, 
29, and 57 by Test Article. Absolute change from Baseline in IGA at Days 8, 15, 29, and 
57 will also be summarized by Test Article. Within-subject difference (Active-Vehicle) in 
IGA score at Baseline, and Days 8, 15, 29, and 57 and absolute change from Baseline at 
Days 8, 15, 29, and 57 will be summarized by Part 1 Treatment Group. 
 
Part 2. Frequency distributions of IGA score will be tabulated at Day 84 by Part 2 
Summary Group. Absolute change from Baseline and absolute change from Day 57 in IGA 
at Day 84 will also be summarized by Part 2 Summary Group. Within-subject difference 
(Active-Vehicle) in IGA score, absolute change from Baseline, and absolute change from 
Day 57 at Day 84 will be summarized by Part 2 Treatment Group. 
 
Individual Clinical Signs/Symptoms 
Part 
1. 
Frequency 
distributions 
of 
erythema, 
scaling, 
fissuring, 
and 
papulation/lichenification will be tabulated at Baseline, and Days 8, 15, 29, and 57 by Test 
Article. Absolute change from Baseline in each of the Signs/Symptoms at Days 8, 15, 29, 
and 57 will also be summarized by Test Article. Within-subject difference (Active-
Vehicle) for each of the Signs/Symptoms scores at Baseline, and Days 8, 15, 29, and 57 
and absolute change from Baseline at Days 8, 15, 29, and 57 will be summarized by Part 1 
Treatment Group. 
 
Part 2. Frequency distributions for each of the Signs/Symptoms will be tabulated at Day 
84 by Part 2 Summary Group. Absolute change from Baseline and absolute change from 
Day 57 for each of the Signs/Symptoms at Day 84 will also be summarized by Part 2 
Summary Group. Within-subject difference (Active-Vehicle) for each of the 
Signs/Symptoms scores, absolute change from Baseline, and absolute change from Day 57 
at Day 84 will be summarized by Part 2 Treatment Group. 
17.3.3 Pharmacokinetics Analyses 
A PK analysis will be conducted on the PK population. 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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Concentrations After Single Dose 
Concentrations of isotretinoin and tretinoin will be summarized pre-test article application 
(time 0) and 1, 2, 3, and 4 hours post-test article application for each subject and compared 
among Treatment Groups. 
 
Trough Concentrations 
Trough plasma concentrations of isotretinoin and tretinoin at Days 8, 15, 29, 57, and 84 
will be compared between Treatment Groups. 
17.4 
Subgroup Analyses 
No formal subgroup analyses are planned; however, potential differences between the two 
types of CI may be evaluated depending on the availability of subjects in both groups. 
17.5 
Interim Analyses 
No interim analyses are planned. 
18. 
ETHICAL AND REGULATORY CONSIDERATIONS 
18.1 
Compliance with Good Clinical 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 approval prior to study 
initiation. Voluntary informed consent/assent will be given by every subject prior to the 
initiation of any study-related procedures. The rights, safety and well-being of the study 
subjects are the most important considerations and prevail over the interests of science and 
society. All personnel involved in the conduct of this study must be qualified by education, 
training, and experience to perform their assigned responsibilities. 
18.2 
Institutional Review Board and Informed Consent/Assent 
Before study initiation, the investigator must have written and dated approval from the IRB 
for the protocol, consent/assent form, subject recruitment materials/process (e.g., 
advertisements), and any other written information to be provided to subjects and 
parent/guardian (if applicable). The investigator should also provide the IRB with a copy 
of the product labeling, information to be provided to subjects and parent/guardian (if 
applicable) and any updates. The investigator will submit documentation of the IRB 
approval to TI.  
 
The IRB approved consent/assent form must include all elements required by FDA, state, 
and local regulations, and may include appropriate additional elements. 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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The investigator/designee will explain the study to each potential subject and 
parent/guardian (if applicable) and the subject must indicate voluntary consent/assent by 
signing and dating the approved informed consent/assent form. The investigator must 
provide the subject with a copy of the consent form, in a language the subject understands. 
If the subject is under 18 years of age, the 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 informed consent for the subject. If a subject 
becomes 18 years of age during the study the subject must provide written informed 
consent at that time to continue study participation. 
 
The investigator will maintain documentation that informed consent/assent was obtained 
prior to the initiation of any study-specific procedures. 
18.3 
Protocol Compliance 
The IRB approved protocol must be followed except in the case of a change that is intended 
to eliminate an immediate risk to subjects. All protocol deviations must be documented.  
18.4 
Protocol Revisions 
TI must prepare all protocol revisions. All protocol amendments must receive IRB approval 
prior to implementation. All administrative letters must be submitted to the IRB for their 
information. Copies of all correspondence with the IRB regarding this study must be sent 
to TI. 
 
New or altered consent/assent forms required by the IRB due to a protocol change must be 
signed by all subjects and parent/guardian (if applicable) currently enrolled in the study 
and must be used for any subsequent subject enrollment. 
18.5 
Study Monitoring 
Representatives of TI 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 TI of any audits of this study by any regulatory 
agency, and must promptly provide copies of any audit reports. 
18.6 
Case Report Form Requirements 
The study will utilize electronic CRFs (eCRFs) with a validated 21CFR Part 11 compliant 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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TI SOP 305-A Protocol Template, Version 06 
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 after completion of EDC 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. 
18.7 
Reports to Institutional Review Board 
The investigator should provide the IRB with reports, updates, and other information (e.g., 
safety updates, protocol amendments, and administrative letters) according to regulatory 
requirements or Institution procedures. 
18.8 
Quality Assurance Audits 
Representatives from TI and/or the Sponsor or a third party selected by the Sponsor may 
conduct a quality assurance 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 TI in the event of a FDA site audit. 
18.9 
Records Retention 
The investigator must maintain all study records (including test article disposition, 
informed consents/assents, eCRFs, source documents, correspondence, regulatory 
documents, contracts etc.) for the maximum period required by TI or the institution where 
the study is conducted, whichever is longer. The original Test Article Accountability Logs 
will be kept at the sites. Copies of the Test Article Accountability Logs will be returned to 
the Sponsor. 
 
The investigator must contact TI 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 TI. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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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 guardian (if appropriate), except as 
necessary for monitoring by TI or the Sponsor, the FDA or other regulatory authority, or 
the IRB. 
 
The investigator and all employees and coworkers involved with this study shall not 
disclose or use for any purpose other than performance of the study, any data, records, or 
other unpublished, confidential information disclosed to those individuals for the purpose 
of the study. Prior written agreement from TI or the Sponsor must be obtained for the 
disclosure of any said confidential information to other parties. 
19. 
REFERENCES 
1. 
Vahlquist A, Ganemo A, Virtanen M. Congenital ichthyosis: an overview of current 
and emerging therapies. Acta Derm Venereol. 2008;88:4-14. 
2. 
Nomura K, Nakano H, Umeki K, Harada K, Kon A, Tamai K, et al. A study of the 
steroid sulfatase gene in families with X-linked ichthyosis using polymerase chain reaction. 
Acta Derm Venereol. 1995;75:340-2. 
3. 
Vahlquist A, Blockhuys S, Steijlen P, van Rossem K, Didona B, Blanco D, et al. 
Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results 
of a randomized, double-blind, multinational, placebo-controlled phase II/III trial. Br J 
Dermatol. 2014;170:173-81. 
4. 
Digiovanna JJ, Mauro T, Milstone LM, Schmuth M, Toro JR. Systemic retinoids 
in the management of ichthyoses and related skin types. Dermatol Ther. 2013;26:26-38. 
5. 
ACCUTANE® (isotretinoin) capsules, 10-mg, 20-mg, 40-mg (US Package Insert). 
Nutley, NJ: Roche Laboratories Inc.; 1982. 
6. 
Layton A. The use of isotretinoin in acne. Dermatoendocrinol. 2009;1:162-9. 
7. 
Lucek RW, Colburn WA. Clinical pharmacokinetics of the retinoids. Clin 
Pharmacokinet. 1985;10:38-62. 
8. 
Napoli JL. Retinoic acid biosynthesis and metabolism. FASEB J. 1996;10:993-
1001. 
9. 
Blaner WS. Cellular metabolism and actions of 13-cis-retinoic acid. J Am Acad 
Dermatol. 2001;45:S129-35. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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TI SOP 305-A Protocol Template, Version 06 
10. 
RETIN-A® (tretinoin) Liquid, 0.05% (US Package Insert). Skillman, NJ: Ortho 
Dermatological; 2002. 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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TI SOP 305-A Protocol Template, Version 06 
APPENDIX 1 
SAMPLE 
SUBJECT 
AND 
PARENT/GUARDIAN 
INSTRUCTION SHEET 
A copy of the Subject and Parent/Guardian Instruction Sheet will be provided to each site. 
 
The investigator or designee should provide a copy of the Part 1 Subject and 
Parent/Guardian Instruction Sheet to each subject and parent/guardian (if applicable) at 
Visit 2 prior to dispensing containers of the test articles and a copy of the Part 2 Subject 
and Parent/Guardian Instructions Sheet at Visit 8. 
 
A body diagram will be given to the subject by the study staff to remind the subject where 
to apply the test articles. A sample body diagram is included on the back of the Subject 
Instruction Sheet. 
 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 65 of 89 
TI SOP 305-A Protocol Template, Version 06 
SAMPLE SUBJECT AND PARENT/GUARDIAN INSTRUCTION SHEET 
FOR PROTOCOL 205-9051-201 
Please follow these instructions carefully. Parents/guardians should apply or supervise 
each application on their child, as determined by the study doctor. Contact the study staff 
at the telephone number below, if you have any questions or concerns about the study. 
Subject Number:____________ Initials: _________  
Phone: _________________ 
PART 1 
You will be instructed how to apply the study medication. If you need help, ask your 
parent/guardian. Apply EACH study medication to the designated RIGHT and LEFT 
Treatment Areas twice daily, once in the morning and once in the evening at approximately 
the same time every day with at least 8 hours between doses.  **TAKE SPECIAL CARE 
TO USE THE CORRECT STUDY MEDICATION ON THE RIGHT AND LEFT 
TREATMENT AREAS.** 
1. Wash and dry your hands before and after applying each of the study medications. 
2. Wash the Treatment Areas with mild cleanser and water and gently dry the areas. 
3. Refer to the diagram on the back of this form for the Treatment Areas. In addition, if the study 
doctor instructs you to, you can refer to the photos that the study staff has taken to help you 
identify the two Treatment Areas. 
4. Dispense a sufficient amount of study medication #1 with the RED label and marked RIGHT 
to provide a thin uniform film over the diseased skin in the Treatment Area. 
5. Using your fingertip, gently apply the RED label study medication #1 to the diseased skin 
within the designated Treatment Area ON YOUR RIGHT SIDE and spread the study 
medication evenly in a thin even coat over the entire area. 
6. Wash your hands after applying study medication #1. Then, repeat Steps #3 and #4 for study 
medication #2 with the LEMON YELLOW label and marked LEFT, applying the study 
medication to the Treatment Area ON YOUR LEFT SIDE. 
7. Record the date and time of study medication application in your Subject Diary. 
8. Do not wash the treated area for at least 4 hours after application. 
9. Do not apply the study medication within 4 hours of clinic visits. 
If you are participating in the PK portion of the study, apply the study medication between  
 
_______________ (time) and ______________ (time) on ____________________ (date). 
 
 
STUDY VISIT SCHEDULE 
V4: Date:  
 
Time: 
V5: Date:  
 
Time: 
V6: Date:  
 
Time: 
V8: Date:  
 
Time: 
 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 66 of 89 
TI SOP 305-A Protocol Template, Version 06 
Your Treatment Areas are: 
(1) __________________________________ and (2) __________________________________ 
 
The study doctor or designee will indicate which areas are to be treated on the diagram below. 
 
 
ADDITIONAL REMINDERS 
• 
Store the study medication according to the instructions on the label. 
• 
Bring this sheet, the Subject Diary, and ALL containers (used and unused) of study 
medication with you to every study visit. 
• 
Do not allow anyone else to use the study medications, only apply the study medication 
to the designated Treatment Area, and keep the containers of study medication away from 
children/pets. 
• 
Discontinue use if severe skin irritation or rash develop and contact the study site. 
• 
Avoid significant sun exposure; use appropriate sun protection measures such as 
sunscreen (for areas outside of the Treatment Areas) and/or protective clothing over the 
Treatment Area is recommended. 
• 
Be extra careful not to use other topical products on the Treatment Area(s), no topical 
products should be applied within one inch of either Treatment Areas. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 67 of 89 
TI SOP 305-A Protocol Template, Version 06 
SAMPLE SUBJECT AND PARENT/GUARDIAN INSTRUCTION SHEET 
FOR PROTOCOL 205-9051-201 
Please follow these instructions carefully. Parents/guardians should apply or supervise 
each application on their child, as determined by the study doctor. Contact the study staff 
at the telephone number below, if you have any questions or concerns about the study. 
Subject Number:____________ Initials: _________  
Phone: _________________ 
PART 2 
You will be instructed how to apply the study medication. If you need help, ask your 
parent/guardian. Apply the study medication to BOTH Treatment Areas twice daily, once 
in the morning and once in the evening at approximately the same time every day with at 
least 8 hours between doses. 
1. Wash and dry your hands before and after applying the study medications. 
2. Wash the Treatment Areas with mild cleanser and water and gently dry the areas. 
3. Refer to the diagram on the back of this form for the Treatment Areas. In addition, if the study 
doctor instructs you to, you can refer to the photos that the study staff has taken to help you 
identify the two Treatment Areas. 
4. Dispense a sufficient amount of the study medication to provide a thin uniform film over the 
diseased skin in one of the Treatment Areas. 
5. Using your fingertip, gently apply the study medication to the diseased skin within that 
Treatment Area and spread it evenly in a thin even coat over the entire area. 
6. Repeat Steps #3 and #4 for the second Treatment Area. 
7. Record the date and time of study medication application in your Subject Diary. 
8. Do not wash the treated area for at least 4 hours after application. 
9. Do not apply the study medication within 4 hours prior to Visit 9. 
 
If you are participating in the PK portion of the study, apply the study medication between  
 
_______________ (time) and ______________ (time) on ____________________ (date). 
 
STUDY VISIT SCHEDULE 
V9: Date:  
 
Time: 
 
 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 68 of 89 
TI SOP 305-A Protocol Template, Version 06 
Your Treatment Areas are: 
(1) __________________________________ and (2) __________________________________ 
 
Please refer to the body diagram below, which indicates which areas are to be treated. 
 
ADDITIONAL REMINDERS 
• 
Store the study medication according to the instructions on the label. 
• 
Bring this sheet, the Subject Diary, and ALL containers (used and unused) of study 
medication with you to every study visit. 
• 
Do not allow anyone else to use the study medications, only apply the study medication 
to the designated Treatment Area, and keep the containers of study medication away from 
children/pets. 
• 
Discontinue use if severe skin irritation or rash develop and contact the study site. 
• 
Avoid significant sun exposure; use appropriate sun protection measures such as 
sunscreen (for areas outside of the Treatment Areas) and/or protective clothing over the 
Treatment Area is recommended. 
• 
Be extra careful not to use other topical products on the Treatment Area(s), no topical 
products should be applied within one inch of either Treatment Area.


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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TI SOP 305-A Protocol Template, Version 06 
APPENDIX 2 
SAMPLE SUBJECT DIARY 
A copy of the Subject Diary will be provided to each site. 
 
The investigator or designee should provide a copy of the Subject Diary to each subject 
and parent/guardian (if applicable) at Visit 2 and all follow-up visits as necessary. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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TI SOP 305-A Protocol Template, Version 06 
SAMPLE SUBJECT DIARY FOR PROTOCOL 205-9051-201 
Parents/legal guardians should complete or supervise the diary entry for their child, as determined 
by the study doctor. Apply the study medications as prescribed by the study doctor. After dosing, 
record the date and time of the dose applied. If you miss a dose, write MISSED where the time is 
recorded. Return this diary and all study medications (used and unused) at each visit. 
Next Appointment: _________________________________ at _______________ am/pm 
DATE 
(dd-MMM-yyyy) 
DOSE 1 TIME 
(HH:MM) 
AREAS 
DOSED 
DOSE 2 TIME 
(HH:MM) 
AREAS 
DOSED 
_____ / ________ / __________ ____ : ____ am  Right 
 Left 
____ : ____ pm  Right 
 Left 
_____ / ________ / __________ ____ : ____ am  Right 
 Left 
____ : ____ pm  Right 
 Left 
_____ / ________ / __________ ____ : ____ am  Right 
 Left 
____ : ____ pm  Right 
 Left 
_____ / ________ / __________ ____ : ____ am  Right 
 Left 
____ : ____ pm  Right 
 Left 
_____ / ________ / __________ ____ : ____ am  Right 
 Left 
____ : ____ pm  Right 
 Left 
_____ / ________ / __________ ____ : ____ am  Right 
 Left 
____ : ____ pm  Right 
 Left 
_____ / ________ / __________ ____ : ____ am  Right 
 Left 
____ : ____ pm  Right 
 Left 
_____ / ________ / __________ ____ : ____ am  Right 
 Left 
____ : ____ pm  Right 
 Left 
_____ / ________ / __________ ____ : ____ am  Right 
 Left 
____ : ____ pm  Right 
 Left 
_____ / ________ / __________ ____ : ____ am  Right 
 Left 
____ : ____ pm  Right 
 Left 
_____ / ________ / __________ ____ : ____ am  Right 
 Left 
____ : ____ pm  Right 
 Left 
_____ / ________ / __________ ____ : ____ am  Right 
 Left 
____ : ____ pm  Right 
 Left 
_____ / ________ / __________ ____ : ____ am  Right 
 Left 
____ : ____ pm  Right 
 Left 
_____ / ________ / __________ ____ : ____ am  Right 
 Left 
____ : ____ pm  Right 
 Left 
If you have any questions, call: 
Name: __________________________ 
 
Telephone: _______________________ 
Date Diary Dispensed: 
 
Date Diary Returned: 
Visit Dispensed:    Visit 2  Visit 4  
 Visit 5  Visit 6 ( x 2)  Visit 8 ( x 2) 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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TI SOP 305-A Protocol Template, Version 06 
APPENDIX 3 
TEST ARTICLE INFORMATION 
A 3.1 Test Article Packaging and Labeling 
The test articles will be packaged and labeled by the Sponsor or designee. PAT-001 
Ointment will be packaged in laminate tubes. Each subject will be assigned a subject 
number sequentially at Visit 1/Screening. At Visit 2/Baseline, the subject will be dispensed 
the necessary amount of each test article for the designated treatment period during the 
study based on the size of the Treatment Area; dispensing/return of all test articles will be 
documented in a Test Article Accountability Log, which is to be kept at the investigational 
site. 
 
Subject Kits, Cartons, and Labels 
Each Subject Kit will consist of two or more Subject Cartons for Part 1 and one or more 
Subject Cartons for Part 2. The number of Subject Cartons to be provided will be based on 
the BSA to be treated by each subject. Tubes of the test articles will be contained within 
Subject Cartons. Each Subject Carton label will, at a minimum, contain the following 
information: protocol number, subject identifiers (subject number and subject initials, to 
be filled in), the contents, the carton number, an investigational test article disclaimer (e.g., 
Caution: New Drug Limited by United States law to investigational use), and the 
appropriate storage conditions. In the event of an emergency, the contents of the carton can 
be unblinded using the proper procedures as outlined in the protocol and by instructions 
provided to the site. 
 
Tube Labels 
Each tube will contain, at a minimum, the following information: the protocol number, 
subject identifiers (subject number), the contents, the tube number, an investigational test 
article disclaimer (e.g., Caution: New Drug Limited by United States law to investigational 
use), and the appropriate storage conditions. 
 
Note: In Part 1, the test articles will be blinded using color coded labels to designate each 
test article to the correct Treatment Area. The RED label should be identified as RIGHT 
and the LEMON YELLOW label should be identified as LEFT. 
A 3.2 Test Article Storage and Preparation 
Test articles will be stored under secure conditions until they are dispensed to the subjects. 
Test articles should be stored in accordance with the temperature specified on the label. 
A 3.3 Dispensing Test Article 
Sites will receive shipments of Subject Cartons after a randomization request has been 
placed. At Visit 1/Screening, subjects will be assigned a three digit subject number by the 
study staff in ascending order beginning with the lowest available number. Prior to 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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Visit 2/Baseline, after laboratory results have been received and reviewed, a randomization 
request will be placed by the site in order for the Subject Carton to be provided to the site 
prior to Baseline, on a subject-by-subject basis. The test article will only be dispensed to 
the subjects who qualify for enrollment at Visit 2/Baseline. 
 
The test article must be dispensed only to study subjects and only at study sites specified 
on the form FDA 1572 by authorized personnel as required by applicable regulations and 
guidelines. 
 
The subject will be dispensed the necessary amount of each test article for the designated 
treatment period during the study. The subject will be instructed to bring all tubes (used 
and unused) to each clinic visit. All test articles will be weighed prior to dispensing to the 
subject and at return. At each post-Baseline visit, all tubes should be collected and 
accounted for; additional tubes may be dispensed to the subject to ensure each subject has 
sufficient test article for the designated treatment period. Test Article Accountability logs 
will be used to record dispensing information. Every effort should be made to obtain the 
return of all dispensed tubes of the test article. If these efforts fail, a detailed note of the 
reason for failure should be made 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. 
• Label ID number or batch number. 
• Dates and initials of the person responsible for each product inventory 
entry/movement. 
• Amount dispensed to and returned by each subject, including unique subject 
identifiers. 
• Amount transferred to another area for dispensing or storage. 
• Non-study disposition (e.g., lost, wasted, broken). 
• Amount returned to Sponsor. 
• Amount destroyed at study site, if applicable. 
 
TI 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. See Section 6.2 for details on managing intense LSRs. If skin irritation or 
rash develops, the subject should contact the study site immediately. All dose modifications 


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Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
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must be reported on the appropriate CRF. 
A 3.6 Documentation of Application and Compliance 
The date of the first and last application of the test articles will be recorded on the 
appropriate CRF for Part 1 and Part 2. A CRF will also be used to record any changes in 
Test article dosing from the application as specified in the protocol. A Subject Diary will 
be dispensed to the subjects and parent/guardian (if applicable) to record all dates and times 
of application doses and to record any missed doses of the test articles (Appendix 2). 
Subjects will be instructed to bring the Subject Diary with them to each study visit. 
A 3.7 Return and Destruction of Test Article Supplies 
Upon completion or termination of the study, all test articles must be accounted for and 
any missing tubes of the test articles must be explained on the completed Test Article 
Accountability Log. All returned test articles will be weighed to the nearest tenth gram 
(0.1 grams) in order to document extent of exposure. Unless instructed otherwise by the 
Sponsor, the study site will keep the original Test Article Accountability Log in the study 
file and a copy will be returned to the Sponsor. All tubes of the test articles will then either 
be a) returned to the study Sponsor or b) emptied and provided to a sponsor-identified third 
party vendor for appropriate destruction, according to applicable regulations with the 
provision of a certificate of destruction.


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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APPENDIX 4 
PROTOCOL AMENDMENTS 
A 4.1 Protocol Amendment #1: v2.0 
Summary: 
1. Each treatment area was limited to 6% BSA based on feedback from the FDA. 
2. Operational procedures were updated concerning randomization processes and test 
article dispensing. 
3. Section 12.4 was added to include genetic testing, for subjects who do not have 
confirmation of their clinical diagnosis of X-linked or lamellar ichthyosis prior to 
enrollment. 
 
SPECIFIC CHANGES: Added text has been bolded and deleted text has been redlined. 
Section # / Name 
Revised Text 
Title Page 
Amendment 1, Date of Amendment 1 and updated name of file 
Page Headers 
Updated to include protocol date and version number. 
Protocol Approval 
The following individuals approve version 12.0 of the 205-
9051-201 protocol dated September 30July 19, 2016 
… 
Garet Heintz, RAC 
Associate Director of Regulatory Affairs 
Study 
Acknowledgement 
Version: 12.0 
 
Date of original version (v1.0): July 19, 2016 
Date of Amendment #1 (v2.0): September 30, 2016 
Protocol Synopsis & 
Section 5.1, Inclusion 
Criteria 
4. Subject has a clinically and genetically6 confirmed diagnosis 
of either Lamellar (e.g., transglutaminase 1-deficient) or X-
Linked (e.g., deletion of steroid sulfatase gene) subtypes of CI. 
 
Footnote #6/26: Fluorescence in situ hybridization (FISH) 
positive confirmation of steroid sulfatase gene deletion is also 
acceptable to diagnose X-Linked subtype of CI. If the 
investigator is highly confident in the clinical diagnosis of X-
Linked or Lamellar CI without confirmatory genetic testing, 
the subject may be enrolled in the study pending the results of 
genetic testing as detailed in Section 12.4fter discussion with 
AND written permission from the Medical Monitor with the 
genetic testing being performed at Baseline. 
 
5. Subject must have two contralateral comparable Treatment 
Areas, as defined per protocol. TheEach Treatment Area must 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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have a minimum of 150 cm2 of affected disease as identified 
by the investigator. [Note: theeach Treatment Area shall be 
contained within a discrete anatomic unit as defined in the 
protocol thatand shall not exceed 6% body surface area 
(BSA), excluding palms and soles.] 
Protocol Synopsis & 
Section 5.2, Exclusion 
Criteria 
10. Subject has clinically significant metabolic, pulmonary, 
cardiac, hematological, renal, hepatic, immune, neurological, 
psychiatric, infectious, neoplastic, or malignant disease (other 
than non-melanoma skin cancer) that would preclude their 
participation in the study. 
11. [For PK Subjects Only] Subject has chronic 
gastrointestinal disease such as Crohn’s disease, irritable 
bowel syndrome, colitis, inflammatory bowel disease, or 
chronic diarrhea. 
Protocol Synopsis, 
Study Procedures 
Visit 1: Screening (Day -45 to -73): … Qualified subjects must 
have two comparable in size (≥150 cm2), contralateral 
Treatment Areas (per protocol) identified with equal IGA 
scores (i.e., IGA = 3 or 4) at Baseline, where an individual 
Treatment Area shall not exceed 6% BSA. Clinical 
evaluations (IGA) for both Treatment Areas will be performed. 
The subject will be scheduled for Visit 2/Baseline. 
 
Prior to Visit 2/Baseline, after laboratory results have been 
received and reviewed, and the investigator has confirmed 
the subject’s eligibility, the site will contact the subject to 
confirm their willingness to participate in the study. 
Assuming the qualified subject is willing to participate, 
then the site will: 
• Make a randomization request to order test article 
for the subject to be delivered to the site prior to the 
subject’s Baseline visit; 
• Schedule the subject’s Baseline visit at a mutually 
convenient time when the designated subject’s test 
article will be at the site; 
• NOTE: the ordered test article is specific to each 
subject and shall not be used for any other subject. 
In the event that the subject elects not to participate 
after receipt of their designated test article, the site 
should contact the monitor to discuss management 
of the test article received. 
 
Visit 2: Baseline (Day 1):  At Visit 2, study staff will reaffirm 
informed consent/assent and re-review laboratory results prior 
to the initiation of any study-related procedures. Medical 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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history, I/E criteria, and concomitant medications and 
therapies will be reviewed to confirm subject eligibility. A 
UPT (if applicable) will be performed. For those subjects who 
do not have confirmation of their clinical diagnosis of X-
linked or lamellar ichthyosis, blood or buccal samples will 
be collected for genetic testing. Treatment Areas will be 
defined as a region contained within a discrete anatomic 
unit (e.g., upper arm, forearm, upper leg, lower leg) with 
bilateral involvement and a minimum of 150 cm2 in area of 
diseased skin. Qualified subjects must have two contralateral 
Treatment Areas (per protocol) identified with equal IGA 
scores (i.e., IGA = 3 or 4) of comparable size where an 
individual Treatment Area shall not exceed 6% BSA. 
Clinical evaluations (IGA, CI Signs/Symptoms, as well as 
Baseline local skin reactions [LSRs] pre-application) for both 
Treatment Areas and photographs will be performed at this 
visit; photographs will be taken of lesions only, without 
sharing subject identity. Copy(s) of the Baseline photos may 
be provided to the subject at the discretion of the 
investigator to help the subject consistently identify the two 
Treatment Areas. For those subjects that do not have 
documented prior confirmatory genetic testing, blood samples 
will be collected for genetic testing. For those subjects 
participating in the PK portion of the study, prior to test article 
application, a PK blood sample will be taken. Subjects will be 
randomized using the designated test article specific for that 
subject that was ordered by the site after completion of 
Visit 1and assigned to the next available (lowest) subject 
number in ascending order. Test article accountability will be 
documented and test article and Subject Diary will be 
dispensed. Subjects and parent/guardian (if applicable) will be 
instructed on how to apply the test articles and to record 
applications in the Subject Diary.  
… 
Modifications to the dosing regimen and/or concomitant 
medication/therapy use may be prescribed by the 
investigator to manage intense LSRs and must be 
documented in the CRFs. Any dosing modifications will be 
made bilaterally (e.g., if dosing is decreased to once a day 
given tolerability issues, both sides will be treated once 
daily, even if only one side is having the tolerability issue). 
Frequency of dosing may be reduced to once per day (QD) 
or rest periods of up to several days may be allowed. 
Treatment per protocol should resume as soon as possible 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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after any notable LSRs have materially subsided as 
determined by the investigator or designee (if possible via 
one of the scheduled clinic visits or via an Unscheduled 
Visit) such that dosing may resume. Additionally, use of 
provided bland emollient7 in the Treatment Area as an aid 
to managing LSRs may be prescribed with the approval of 
the investigator and must be documented in the CRFs. In 
the event that additional moisturizer use is needed (i.e., 
greater than QD or BID or in lieu of the test articles) in the 
opinion of the investigator, such therapy may be used, must 
be documented in the CRFs, and the investigator must 
notify the Medical Monitor promptly. Note: Bland 
emollients should not be applied within four hours of 
application of the test articles. No other topical therapy 
within the Treatment Area or in the surrounding skin 
within one inch of the Treatment Area is permitted. 
 
Footnote #7: DML Lotion will be provided to subjects. 
Other bland emollients (e.g., Lubriderm [without alpha 
hydroxy acid], or other moisturizers that do not contain 
any “active” ingredients [e.g., salicylic acid, lactic acid, 
pyruvic acid, urea, or any other ingredient that could 
irritate or cause a keratolytic effect]) may be used with 
approval from the investigator, but must be documented as 
a concomitant medication/therapy. 
Schedule of Events 
Visit 1; Days -45 to -73, added X16 under Randomization 
Visit 2; Day 1, added X12 in a row for Genetic Testing 
 
Footnote #87: Screening window at -73 days allows clinical 
lab tests to be finalized and test article to be shipped prior to 
Visit 2/Baseline. 
 
Footnote #13: For those subjects who do not have genetic 
test confirmation of their clinical diagnosis of X-linked or 
lamellar ichthyosis, blood or buccal samples will be 
collected. 
 
Footnote #142: Each contralateral Treatment Area must be 
comparable in size (>150cm2) and have the same IGA score 
of 3 (moderate) or 4 (severe) at Baseline and be contained 
within a discrete anatomic unit that shall not exceed 6% 
body surface area (BSA). Location by body region and 
percent body surface area (BSA) of disease affected skin in 
each Treatment Area will be documented. Percent BSA will be 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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estimated using the assumption that 1% BSA is equivalent to 
the area of the subject’s hand with fingers held together. [Note: 
Palms and soles are not eligible; the treatment of skin scalp and 
folds/intertriginous regions should be avoided]. Additionally 
for treatment on the arms in subjects participating in the PK 
portion of the study, the antecubital fossa (e.g., approximately 
10-15 cm2) will be excluded to minimize contamination of PK 
blood draws. 
 
Footnote #176: Prior to Visit 2/Baseline, after laboratory 
results have been received and reviewed, a randomization 
request will be placed by the site in order for the test article 
to be provided to the site prior to baseline. Note: the 
ordered test article is specific to each subject and shall not 
be used for any other subject. 
Schedule of Events, 
Section 6.2, and 
Section 9.2 
Note: Palms and soles are not eligible; the treatment of scalp 
and skin folds/intertriginous regions should be avoided.  
Section 4, Study 
Design 
Subjects will have two comparable Treatment Areas defined 
per protocol.; Each Treatment Areas must be comparable in 
size, with a minimum of (≥150 cm2) of affected diseased 
skin with an identical Investigator’s Global Association (IGA) 
score, with a score of either 3 (moderate) or 4 (severe) at 
Baseline; each Treatment Area shall be contained within a 
discrete anatomic unit as defined in the protocol and shall 
not exceed 6% body surface area (BSA), excluding palms 
and soles.  
Section 6.2 Instructions 
for Use and 
Application 
At Visit 2/Baseline, the investigator will designate two 
comparable Treatment Areas. Each Treatment Area shall be 
contained within a Ddiscrete anatomic units (e.g., upper arm, 
forearm, upper leg, lower leg, etc.) with bilateral involvement 
with and a minimum of 150 cm2 in area of diseased skin that 
shall not exceed 6% BSA; these Treatment Areas will be 
selected for treatment and designated by right and left sides.  
… 
 Subjects will be instructed to wash their hands before and 
after each test article application.  
… 
Subjects will be instructed should not to wash the treated area 
for at least four hours following test article application.  
 
(moved from below) If the subject experiences issues with 
medication tolerability or other complications arise, ideally 


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Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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the subject will be seen by the investigator at one of the 
scheduled clinic visits or via an Unscheduled Visit to document 
the reactions and modifications to the dosing regimen 
prescribed by the investigator. In the event that a clinic visit is 
not possible or not warranted in the opinion of the investigator, 
the change in the subject’s management will be clearly 
documented in the source documents and case report forms 
(CRFs) with corresponding changes noted in the Subject Diary 
regarding 
test 
article 
usage 
and/or 
concomitant 
medications/therapies (e.g., moisturizer use).  
 
Modifications to the dosing regimen and/or concomitant 
medication/therapy use may be prescribed by the investigator 
to manage intense LSRs and must be documented in the 
CRFs. Any dosing modifications or changes to concomitant 
medications/therapies will be made bilaterally (e.g., if dosing 
is decreased to once a day given tolerability issues, both sides 
will be treated once daily, even if only one side is having the 
tolerability issue). If the subject experiences issues with 
medication tolerability or other complications arise, ideally the 
subject will be seen by the investigator at one of the scheduled 
clinic visits or via an Unscheduled Visit to document the 
reactions and modifications to the dosing regimen prescribed 
by the investigator. In the event that a clinic visit is not possible 
or not warranted in the opinion of the investigator, the change 
in the subject’s management will be clearly documented in the 
source documents and case report forms (CRFs) with 
corresponding changes noted in the Subject Diary regarding 
test article usage and/or concomitant medications/therapies 
(e.g., moisturizer use). Frequency of dosing may be reduced to 
once per day (QD) or rest periods of up to several days may be 
allowed. Treatment per protocol should resume as soon as 
possible after any notable LSRs have materially subsided as 
determined by the investigator or designee (if possible via one 
of the scheduled clinic visits or via an Unscheduled Visit) such 
that dosing may resume. Dosing modifications prescribed by 
the investigator must be documented in the CRFs. 
Additionally, use of provided bland emollient  in the Treatment 
Areas as an aid to managing LSRs may be prescribed with the 
approval of the investigator and must be documented in the 
CRFs. In the event that additional moisturizer use is needed 
(i.e., greater than QD or BID or in lieu of the test articles) in 
the opinion of the investigator, such therapy may be used, with 
the approval of the Medical Monitor and must be documented 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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in the CRFs, and the investigator must notify the Medical 
Monitor promptly. Note: Bland emollients should not applied 
within four hours of application of the test articles. No other 
topical therapy within the Treatment Area or in the 
surrounding skin within one inch of the Treatment Area is 
permitted. 
Section 7, 
Randomization 
Assignment 
Prior to Visit 2/Baseline, after laboratory results have been 
received and reviewed, a randomization request will be 
placed by the site in order for the test article to be provided 
to the site prior to baseline. 
Section 8.1, Prohibited 
Medications or 
Therapies 
Prohibited medications or therapies during the study include: 
• No topical therapy within the Treatment Area or in the 
surrounding skin within one inch of the Treatment 
Area other than the designated test article or provided 
bland emollient (e.g., DML Lotion)31, if needed to 
manage LSRs (see Section 8.2); 
• Topical retinoid-containing therapies in the Treatment 
Areas or in the surrounding skin within one inch of 
the Treatment Area (except emollients) within two 
weeks of Visit 2/Baseline or any topical retinoid use 
during the study; 
• Topical corticosteroids in the Treatment Areas or in 
the surrounding skin within one inch of the Treatment 
Area within five days of Visit 2/Baseline; 
Section 8.2, Allowed 
Medications or 
Therapies 
Allowed medication or therapies during the study must be 
documented and include: 
• Bland emollients, keratolytics, or sunscreen to treat 
diseased areas that are NOT in the Treatment Area (but 
not in the surrounding skin within one inch of the 
Treatment Area); 
• Topical steroids to treat cutaneous diseased areas that 
are NOT in the Treatment Area (but not in the 
surrounding skin within one inch of the Treatment 
Area); 
• Inhaled, intranasal, and ophthalmic steroid dosage 
forms. 
 
Additionally, use of provided bland emollients (e.g., DML 
Lotion)32 in the Treatment Areas as an aid to managing LSRs 
may be prescribed by the investigator with the approval of the 
Medical Monitor as detailed in Section 6.2 and must be 
documented in the CRFs. Application of such bland emollients 
should not be applied within four hours of application of the 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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test articles. 
Section 9.1, Visit 1 
(Day -45 to -73): 
Screening 
• Confirm the subject has qualified analogous right and 
left Treatment Areas, with adequate disease (≥150 cm2) 
and identical IGA scores (≥ 3) consistent with the 
inclusion and exclusion criteria (see Section 5.1) that 
will likely meet protocol requirements and Baseline, 
in the opinion of the investigator. 
… 
QUALIFIED SUBJECT DETERMINATION AND TEST 
ARTICLE REQUEST: Prior to Visit 2/Baseline, after 
laboratory results have been received and reviewed, and the 
investigator has confirmed the subject’s eligibility, the site will 
contact the subject to confirm their willingness to participate 
in the treatment phase of the study. Assuming the qualified 
subject is willing to participate, then the site will: 
 
a) Make a randomization request to order test article for the 
subject to be delivered to the site prior to the subject’s 
Baseline visit; 
b) Schedule the subject’s Baseline visit at a mutually 
convenient time when the designated subject’s test article 
will be at the site; 
c) NOTE: the ordered test article is specific to each 
subject and shall not be used for any other subject.  In 
the event a subject elects not to participate after receipt of 
their designated test article, please contact your monitor to 
discuss management of the test article received. 
Section 9.2, Visit 2 
(Day 1): Baseline 
• Take Baseline photographs. Note: Copy(s) may be 
provided to the subject at the discretion of the 
investigator to help the subject consistently identify 
the two Treatment Areas. 
• For those subjects that do not have documented 
prior confirmatory genetic testing, collect blood 
samples and manage genetic testing as detailed in 
Section 12.4. 
• Randomize the subject using the designated test 
article specific for that subject that was ordered by 
the site after completion of Visit 1. Note: the ordered 
test article is specific to each subject and shall not 
be used for any other subject. 
Section 9.3, Visit 3 
(Day 2) and Visit 7 
• Confirm the next scheduled visit and remind the 
subject to hold the morning application of the test 


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Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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(Day 43±3): Phone Call 
articles on days of clinic visits. Note [for Visit 7]: For 
those subjects participating in the PK portion of the 
study, the application before a scheduled clinic visit 
with PK time point (i.e., on Day 56) must be 
approximately 12 hours ± 30 minutes prior to the blood 
draw. 
Section 9.4, visit 4 
(Day 8+1) and Visit 5 
(Day 15±1): Follow-Up 
• Remind the subject to hold the application of the test 
articles on days of clinic visits. Note [for Visit 5]: For 
those subjects participating in the PK portion of the 
study, the application before a scheduled clinic visit 
with PK time point (i.e., on Day 28) must be 
approximately 12 hours ± 30 minutes prior to the blood 
draw. 
Section 11, 
Photography 
Photography documentation is required in this study at 
Visit 2/Baseline/Day 1, Visit 6/Day 29, Visit 8/Day 57, and 
Visit 9/Day 84. Copy(s) of the Baseline photos may be 
provided to the subject, at the discretion of the investigator, 
to help the subject consistently identify the two Treatment 
Areas.  
Section 12.1, Blood 
Chemistries, 
Hematology and 
Urinalysis 
Blood and urine specimens will collected at Visit 1/Screening, 
Visit 6/Day 29, Visit 8/Day 57 (End of Part 1), and 
Visit 9/Day 84 (EOT or early termination) for chemistry, 
hematology, and urinalysis. Subjects must be fasting 
(approximately 8 hours) for screening laboratory tests 
Visit 1/Screening and, if possible, for laboratory tests at 
Visit 6/Day 29, Visit 8/Day 57, and Visit 9/Day 84; however, 
if a subject arrives at the clinic for Visit 6, Visit 8, or Visit 9 
without fasting for at least eight hours, laboratory specimens 
may be collected as non-fasting, at the discretion of the 
investigator, and with the appropriate fasting status 
documented on the lab requisition form. 
Section 12.4, Genetic 
Testing 
At Visit 2/Baseline, for those subjects who do not have 
confirmation of their clinical diagnosis of X-linked or 
lamellar ichthyosis, blood or buccal samples will be 
collected for genetic testing. The subject may be enrolled 
based upon their clinical diagnosis only, with genetic 
testing to follow, such that the results are available at or 
before the conclusion of the study. Specifics regarding the 
testing options for these two ichthyosis subtypes, specimen 
handling, and related matters are detailed in a separate 
Study Lab Manual provided by the Sponsor. 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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Section 13.2, Subject 
Discontinuation 
If the subject is discontinued from the study due to 
pregnancy, the pregnancy and its outcome should be 
followed. 
Section 14.2, Serious 
Adverse Event 
• Although not defined as an AE, pregnancy shall be 
considered as a serious event and 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.  
… 
All SAEs, whether related or unrelated to test article, must be 
immediately reported by telephone to the Medical Monitor 
(619-889-7058) and, in the event that he/she is unavailable, to 
the Project Manager (858-571-1800, ext. 129) [additional 
contact information listed on the first page of the protocol]. 
… 
v) Confirmed pregnancy at any time during the study or 
within one month from discontinuing from the study.  
… 
The investigator must immediately notify the Medical 
Monitor of the pregnancy and record the pregnancy on the 
appropriate pregnancy surveillance form.  
Appendix 1, Sample 
Subject and 
Parent/Guardian 
Instruction Sheet (for 
Both Part 1 and Part 2) 
A body diagram will be given to the subject by the study 
staff to remind the subject where to apply the test articles. 
A sample body diagram is included on the back of the 
Subject Instruction Sheet. 
… 
Subject 
Number:____________ 
InitialsName: 
________________ Phone: _________________ 
… 
3. Refer to the diagram on the back of this form for the 
Treatment Areas. In addition, if the study doctor instructs 
you to, you can refer to the photos that the study staff has 
taken to help you identify the two Treatment Areas. 
… 
Your Treatment Areas are: 
(1) ________________________ and (2) ________________ 
The study doctor or designee will indicate which areas are 
to be treated on the diagram below. 
… 
Under ‘ADDITIONAL REMINDERS’ 
• Be extra careful not to use other topical products on 
the Treatment Area(s), no topical products should 
be applied within one inch of either Treatment 


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Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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Areas. 
In Part 2 only: 
9. Do not apply the study medication within 4 hours prior to 
Visit 9. 
Appendix 3, A3.1, Test 
Article Packaging and 
Labeling 
The test articles will be packaged and labeled by the Sponsor 
or designee. PAT 001 Ointment will be packaged in laminate 
tubes. Each subject will be assigned a subject number 
sequentially in the order of enrollmentat Visit 1/Screening. At 
Visit 2/Baseline, Tthe subject will be dispensed the necessary 
amount of each test article for the designated treatment period 
during the study based on the size of the Treatment Area; 
dispensing/return of all test articles will be documented in a 
Test Article Accountability Log, which is to be kept at the 
investigational site. 
 
Subject Kits, Cartons, and Labels 
Each Subject Kit will consist of two or more Subject 
Cartons for Part 1 and one or more Subject Cartons for 
Part 2. The number of Subject Cartons to be provided will 
be based on the BSA to be treated by each subject. Tubes of 
the test articles will be contained within Subject KitsCartons. 
Each Subject KitCarton label will, at a minimum, contain the 
following information: protocol number, subject identifiers 
(subject number and subject initials, to be filled in), the 
contents, the kitcarton number, an investigational test article 
disclaimer (e.g., Caution: New Drug Limited by United States 
law to investigational use), and the appropriate storage 
conditions. In the event of an emergency, the contents of the 
kitcarton can be unblinded using the proper procedures as 
outlined in the protocol and by instructions provided to the site. 
Appendix 3, A3.3, 
Dispensing Test Article 
Sites will receive shipments of Subject CartonsKits as 
subjects qualify for the studyafter a randomization request 
has been placed. At Visit 1/Screening, Ssubjects 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. Prior to Visit 
2/Baseline, after laboratory results have been received and 
reviewed, a randomization request will be placed by the 
site in order for the Subject Carton to be provided to the 
site prior to Baseline, on a subject-by-subject basis. The 
test article will only be dispensed to the subjects who 
qualify for enrollment at Visit 2/Baseline. 
 
 
 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
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A 4.2 Protocol Amendment #2: v3.0 
Summary: 
1. Genetic testing will be performed at Visit 1/Screening instead of Visit 2/Baseline. 
2. Inclusion Criteria #4 was updated such that subjects will be enrolled based on 
clinical diagnosis, but must agree to genetic testing at Visit 1/Screening. 
3. Clarification of parent/legal guardian assistance with application and diary 
completion was included. 
4. Changes from Administrative Amendment #1 were incorporated. 
 
SPECIFIC CHANGES: Added text has been bolded and deleted text has been redlined. 
Section # / Name 
Revised Text 
Title Page 
Amendment 2, Date of Amendment 2 and updated name of file 
Headers 
Date of Protocol Amendment 2 updated and v3.0 
Protocol Approval 
The following individuals approve version 32.0 of the 205-
9051-201 protocol dated September 30, 2016January 6, 2017. 
Study 
Acknowledgement 
Version: 32.0 
 
Date of original version (v1.0): July 19, 2016 
Date of Amendment #1 (v2.0): September 30, 2016 
Date of Amendment #2 (v3.0): January 6, 2017 
Synopsis, Inclusion 
Criteria and Section 
5.1.1 
4. 
Subject has a clinically and genetically6 confirmed 
diagnosis of either Lamellar (e.g., transglutaminase 1-
deficient) or X-Linked (e.g., deletion of steroid sulfatase gene) 
subtypes of CI and agrees to genetic testing6 to confirm such 
clinical diagnosis during the study. 
 
6 Fluorescence in situ hybridization (FISH) positive 
confirmation of steroid sulfatase gene deletion is also 
acceptable to diagnose X-Linked subtype of CI. If the 
investigator is highly confident in the clinical diagnosis of X-
Linked or Lamellar CI without confirmatory genetic testing, 
the subject may be enrolled in the study as detailed in Section 
12.4 with the genetic testing being performed at Baseline. 
6 Fluorescence in situ hybridization (FISH) positive 
confirmation of steroid sulfatase gene deletion is also 
acceptable to diagnose X-Linked subtype of CI. 
Synopsis, Study 
Procedures, Visit 1 
For those subjects who do not have confirmation of their 
clinical diagnosis of X-linked or lamellar ichthyosis, blood 
or buccal samples will be collected for genetic testing.  
… 
Prior to Visit 2/Baseline, after clinical laboratory results have 
been received and reviewed, and the investigator has 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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confirmed the subject’s eligibility, the site will contact the 
subject to confirm their willingness to participate in the study. 
Synopsis, Study 
Procedures, Visit 2 
For those subjects who do not have confirmation of their 
clinical diagnosis of X-linked or lamellar ichthyosis, blood or 
buccal samples will be collected for genetic testing.  
Synopsis, Study 
Procedures, Visits 3 
and 7 
The site staff will remind the subject (and parent/legal 
guardian, if applicable) to continue to apply test article twice 
daily until the next clinic visit. 
Schedule of Events 
Genetic Testing at Screening (instead of Baseline) 
Section 6.2, 
Instructions for Use 
and Application 
If the subject is a minor, the parent/legal guardian will be 
given the Subject Instructions with their child and 
instructed to apply or supervise application on the subject; 
the level of involvement (i.e., application vs. supervision) by 
the parent/legal guardian will be determined by the 
investigator.  
… 
Subjects (and parent/legal guardians, if applicable) will be 
instructed to wash their hands before and after each test article 
application. Subjects (and parent/legal guardians, if 
applicable) will be instructed to wash the Treatment Areas 
with a mild non-medicated cleanser and water and then to dry 
the area gently. Subjects (with parent/legal guardian 
supervision, as required) will be instructed to apply a 
sufficient amount of the test article to provide a thin uniform 
film over the disease affected skin within the Treatment Area 
(Note: the volume of test article applied will vary with disease 
severity). For Part 1, the subject (and parent/legal guardians, 
if applicable) will be instructed to take great care to use the 
assigned test article to the right Treatment Area (on the 
subject’s right side) and the other test article to the left 
Treatment Area (on the subject’s left side). Subjects (with 
parental supervision, as required) will apply a thin uniform 
film of the assigned test article twice daily to the designated 
Treatment Area for eight weeks. Subjects (and parent/legal 
guardians, if applicable) will wash their hands after 
application with the first test article and prior to applying the 
second test article. For Part 2, the subject (and parent/legal 
guardians, if applicable) will be instructed to apply the 
assigned test article to both Treatment Areas by applying a thin 
uniform film twice daily for an additional four weeks. The test 
article will be applied at approximately the same time every 
day and at least eight hours apart. Note: for those subjects who 
are participating in the optional PK portion of the study, the 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 87 of 89 
TI SOP 305-A Protocol Template, Version 06 
application before a scheduled clinic visit with PK time point 
(i.e., on Days 7, 14, 28, 56, and 83) must be approximately 12 
hours ± 30 minutes prior to the blood draw. 
 
Subjects (with parent/legal guardian supervision, as 
required) will be instructed to record the date and time of each 
application in a Subject Diary (see Appendix 2). Subjects (and 
parent/legal guardians, if applicable) will be instructed to 
bring all containers of the test articles (used and unused) and 
the completed Subject Diary to each visit. If the subject is a 
minor, the parent/legal guardian will be given the Subject 
Diary and instructed to complete or supervise the 
completion of the Subject Diary; the level of involvement 
(i.e., completion vs. supervision) by the parent/legal 
guardian will be determined by the investigator.  
 
At each visit, the study staff will review the application 
instructions with the subject and/or parent/legal guardian, if 
applicable (see Appendix 1) paying particular attention to 
proper use of the labeled test article for the Left and Right 
Treatment Areas (Part 1 only). If possible, at each clinic visit, 
the subject will apply one of the daily doses in the clinic under 
staff supervision to reinforce proper use. 
 
Subjects (and parent/legal guardian, if applicable) will be 
instructed not to wash the treated area for at least four hours 
following test article application.  
Section 9.1, Visit 1 
• For those subjects who do not have confirmation of 
their clinical diagnosis of X-linked or lamellar 
ichthyosis, collect blood or buccal samples for 
genetic testing (see Section 12.4). 
… 
Visit 2/Baseline, after clinical laboratory results have been 
received and reviewed, and the investigator has confirmed the 
subject’s eligibility, the site will contact the subject to confirm 
their willingness to participate in the treatment phase of the 
study. 
Section 9.2, Visit 2 
• For those subjects who do not have confirmation of 
their clinical diagnosis of X-linked or lamellar 
ichthyosis, collect blood or buccal samples for genetic 
testing (see Section 12.4). 
… 
• Dispense the Subject Instruction Sheet to the subject 
(and parent/legal guardian, if applicable). Instruct 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
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TI SOP 305-A Protocol Template, Version 06 
the subject (and parent/legal guardian, if applicable) 
where and how to apply the test articles to the 
designated Treatment Areas. 
… 
• Dispense the Subject Diary to the subject (and 
parent/legal guardian, if applicable) and provide 
completion instructions. 
… 
• Instruct the subject (and parent/legal guardian, if 
applicable) to apply the test articles to the designated 
Treatment Areas twice per day, once in the morning 
and once in the evening with at least eight hours 
between applications, and to hold the application of the 
test articles on days of clinic visits. 
Section 9.3, Visit 3 and 
Visit 7 
• Confirm the next scheduled visit and remind the 
subject (and parent/legal guardian, if applicable) to 
hold the morning application of the test articles on days 
of clinic visits. 
Section 9.4, Visit 4 and 
Visit 5 
• Review proper test article use and application 
guidelines with the subject (and parent/legal 
guardian, if applicable), stressing the importance that 
care should be taken so that the correct test article is 
applied to the two Treatment Area(s) on the subjects 
RIGHT and LEFT side.  
… 
• Remind the subject (and parent/legal guardian, if 
applicable) to hold the application of the test articles 
on days of clinic visits.  
Section 9.5, Visit 6 
• Review proper test article use and application 
guidelines with the subject (and parent/legal 
guardian, if applicable), stressing the importance that 
care should be taken so that the correct test article is 
applied to the two Treatment Area(s) on the subjects 
RIGHT and LEFT side. 
Section 9.6, Visit 8 
• Re-educate the subject (and parent/legal guardian, if 
applicable) with respect to dosing and related activities 
for Part 2.  
Section 12.4, Genetic 
Testing 
At Visit 21/BaselineScreening, for those subjects who do not 
have confirmation of their clinical diagnosis of X-linked or 
lamellar ichthyosis, blood or buccal samples will be collected 
for genetic testing. As/if required, this test may be repeated 
during the study as determined by the investigator (e.g., 
specimen quality, loss or handling concerns, indeterminate 


Product Name: PAT-001 Ointment 
 
Protocol: 205-9051-201, v3.0 
Sponsor Name: Patagonia Pharmaceuticals, LLC 
Protocol Date: January 6, 2017 
 
CONFIDENTIAL 
Page 89 of 89 
TI SOP 305-A Protocol Template, Version 06 
outcome). The subject may be enrolled based upon their 
clinical diagnosis only, with genetic testing to follow, such that 
the results are available at or before the conclusion of the study. 
Specifics regarding the testing options for these two ichthyosis 
subtypes, specimen handling, and related matters are detailed 
in a separate Study Lab Manual provided by the Sponsor.will 
be determined by the company used for genetic testing. In 
the event the genetic testing results do not concur with the 
clinical diagnosis the subject may complete the study as the 
inclusion criteria are based upon the clinical assessment of 
their skin disease by the Investigator at Baseline. 
Appendix 1, Subject 
and Parent/Guardian 
Instruction Sheet: For 
Part 1 and Part 2 
Please follow these instructions carefully. Parents/guardians 
should apply or supervise each application on their child, 
as determined by the study doctor.  
… 
You will be instructed how to apply the study medication. If 
you need help, ask your parent/guardian.  
Appendix 2, Sample 
Subject Diary 
Parents/legal guardians should complete or supervise the 
diary entry for their child, as determined by the study 
doctor.