Clinical trial NCT03738800
Conditions: Lamellar Ichthyosis
Sponsor: Mayne Pharma International Pty Ltd
Start date: 2019-05-01; Completion date: 2021-09-03
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 2 randomized, multi-center, double-blind, vehicle controlled, 90 day, safety, efficacy, and systemic exposure study followed by a 90 day open-label extension of trifarotene cream in adults and adolescents with autosomal recessive ichthyosis with lamellar scale.

Detailed description:
This is a 2-cohort, multicenter study in subjects with moderate to severe LI. Adults (Cohort A) and adults and adolescents (Cohort B) will be randomized in a double-blind fashion to 1 of 2 doses of active or vehicle and treated twice weekly for 90 days. Subjects who complete the randomized, double-blind portion of the study will be eligible to enter a 90 day, open-label extension study.

Approximately 15 adults (≥18 years old) will be randomized into the first cohort of subjects (Cohort A) in a 1:1:1 ratio and treated twice weekly for up to 90 days. If no safety issues are identified, both adults and adolescents (ages 12-17 years, inclusive) will be allowed to enroll in Cohort B. Subjects in Cohort B will be randomized 1:1:1 and treated twice weekly for up to 90 days in the same manner as subjects in Cohort A.

All subjects who complete 90 days of double-blind study treatment will be eligible to enroll in a 90 open-label extension. Subjects in the open-label extension will receive active twice weekly for up to 90 days.

Arms: arm 1: CD5789 200 µg/g, topical, 50g arm 2: CD5789 100 µg/g, topical, 50g arm 3: CD5789 Cream Vehicle, topical, 50g
Interventions: intervention 1: CD5789 Cream 200 µg/g intervention 2: CD5789 Cream 100 µg/g intervention 3: CD5789 Cream Vehicle
Intervention descriptions: intervention 1: A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA intervention 2: A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA intervention 3: A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA

Protocol documents:
Prot_000.pdf: 
Mayne Pharma, LLC 
16.1 Study Information 
Abbreviated Clinical Study Report 18-ICH-001 
AD-MW-36.04 18-Jun-2019 
CONFIDENTIAL 
16.1.1 
Protocol and Protocol Amendments 
18-ICH-001 Protocol Amendment 3, Final Protocol Version 4.0 (Ukraine), dated 19-Nov-2020
18-ICH-001 Protocol Amendment 2, Final Protocol Version 3.0, dated 28-Oct-2020
18-ICH-001 Protocol Amendment 2, Final Protocol Version 3.0 (Ukraine), dated 21-Nov-2019 
18-ICH-001 Protocol Amendment 1, Final Protocol Version 2.0 (Ukraine), dated 21-Oct-2019 
18-ICH-001 Protocol Amendment 1, Final Protocol Version 2.0, dated 10-Jul-2019
18-ICH-001 Protocol, Final Protocol Version 1.0, dated 28-Nov-2018
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PROTOCOL/CLINICAL INVESTIGATION PLAN AMENDMENT 
PRODUCT NAME/NUMBER: 
Trifarotene (CD5789) Cream HE1 
PROTOCOL NUMBER: 
18-ICH-001
IND NUMBER: 
140538 
NCT NUMBER:  
NCT03738800 
EUDRACT NUMBER: 
2018-003272-12 
DEVELOPMENT PHASE: 
2 
PROTOCOL TITLE: 
A Phase 2 Randomized, Multicenter, Double-blind, 
Vehicle-controlled, 90-Day, Safety, Efficacy, and 
Systemic Exposure Study followed by a 90-Day 
Open-label Extension of Trifarotene (CD5789) Cream 
HE1 in Subjects with Autosomal Recessive Ichthyosis 
with Lamellar Scale  
PROTOCOL DATE: 
Original: 28-Nov-2018 
AMENDMENT 1 DATE: 
Final v2.0, 21-Oct-2019 
AMENDMENT 2 DATE: 
Final v3.0 for Ukraine, 21-Nov-2019 
AMENDMENT 3 DATE: 
Final 4.0 for Ukraine, 19-Nov-2020 
COORDINATING/PRINCIPAL 
INVESTIGATOR: 
Keith A. Choate, MD 
Department of Dermatology, Yale University School of 
Medicine,  
PO Box 208059 
333 Cedar Street 
New Haven, CT 06520, USA 
+1 203 789 1249
SPONSORED BY: 
Mayne Pharma LLC 
1240 Sugg Parkway   
Greenville, NC 27834, USA 
+1 984 242 1400
CONTRACT RESEARCH 
ORGANIZATION: 
Premier Research  
One Park Drive, Suite 150 
Durham, NC 27709, USA 
+1 919 627 9100
· pharma 
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This study will be performed in compliance with ICH Good Clinical Practices and applicable 
regulatory requirements, including the archiving of essential documents. Information contained in 
this protocol is confidential in nature and may not be used, divulged, published, or otherwise 
disclosed to others except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. Persons to whom this information 
is disclosed should be informed that it is confidential and may not be further disclosed without the 
express permission of Mayne Pharma LLC. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.
APPROVAL SIGNATURES
PROTOCOL NUMBER: 
18-ICH-001 
PROTOCOL TITLE: 
A Phase 2 Randomized, Multicenter, Double-blind, 
Vehicle-controlled, 90-Day, Safety, Efficacy, and Systemic 
Exposure Study followed by a 90-Day Open-label Extension of 
Trifarotene (CD5789) Cream HE1 in Subjects with Autosomal 
Recessive Ichthyosis with Lamellar Scale 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge, it 
accurately describes the planned conduct of the study. 
SIGNATURE 
DATE: 
Phoevos Hughes, JD 
Head of Medical and Clinical Affairs 
Mayne Pharma LLC 
Marlis Sarkany, MD 
Senior Medical Director 
Premier Research 
Valerie H. Smith 
Manager, Biostatistics 
Premier Research 
23-Nov-2020 | 03:54:30 EST
20-Nov-2020 | 06:28:08 PST
20-Nov-2020 | 09:21:52 EST
r
DocuSigned by: 
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Signer Name: Phoevos Hughes 
I 
Signing Reason: I approve this document 
Signing Time: 20-Nov-2020 I 06:28:06 PST 
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DocuSigned by: 
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Signer Name: Marlis Sarkany 
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Signing Reason: I have reviewed this document 
_ 
Signing Time: 23-Nov-2020 I 03:54:26 EST 
16E1CBAEDC854CDC86688C1FD466E26F 
(
DocuSigned by: 
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Signer Name: Valerie Smith 
L= Signing Reason: I approve this document 
Signing Time 20-Nov 2020 I 09 21 50 EST 
882C53F2B5164EEAA9FA446FC310O506 
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2. PROTOCOL SUMMARY 
2.1. Synopsis 
PRODUCT 
NAME/NUMBER 
Trifarotene (CD5789) Cream HE1 
PROTOCOL 
NUMBER 
18-ICH-001 
EUDRACT 
NUMBER 
2018-003272-12 
DEVELOPMENT 
PHASE 
2 
PROTOCOL TITLE 
A Phase 2 Randomized, Multicenter, Double-blind, Vehicle-controlled, 90-Day, Safety, 
and Efficacy, and Systemic Exposure Study followed by a 90-Day Open-label Extension 
of Trifarotene (CD5789) Cream HE1 in Subjects with Autosomal Recessive Ichthyosis 
with Lamellar Scale  
INDICATION 
Lamellar ichthyosis 
OBJECTIVES 
Primary: To compare the safety and efficacy of 2 concentrations of trifarotene cream HE1 
versus vehicle in subjects with moderate to severe autosomal recessive ichthyosis with 
lamellar scale, also known as lamellar ichthyosis (LI) after 90 days of treatment. 
Secondary:  
• 
To assess systemic exposure to trifarotene and its major metabolites after topical 
application of the investigational product (IP) on up to 90% body surface area (BSA) 
twice weekly. 
• 
To assess safety for up to 180 days of dosing with open-label trifarotene cream HE1 
200 µg/g. 
STUDY DESIGN 
 
This is a 2-cohort, multicenter study in subjects with moderate to severe LI (i.e., 3–4 on 
a 5-point Investigator’s Global Assessment [IGA] where 0 = clear; 1 = almost clear; 
2 = mild; 3 = moderate; and 4 = severe). Adults will be randomized in a double-blind 
fashion to 1 of 2 doses of trifarotene cream HE1 or vehicle and treated twice weekly for 
90 days. Subjects who complete the randomized, Double-blind Period of the study will 
be eligible to enter a 90-day, Open-label Extension (OLE) in which additional PK, safety, 
and efficacy data will be collected. 
Subjects will be randomized into the first cohort of subjects (Cohort A) in a 1:1:1 ratio to 
trifarotene cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle and treated 
twice weekly for up to 90 days. After the initial 15 subjects complete at least 28 days of 
treatment, an independent data safety monitoring board (DSMB) will review aggregate 
safety and tolerability data (including PK and electrocardiogram [ECG] data). If no safety 
issues are identified, an additional group of approximately 105 subjects will be allowed 
to enroll in Cohort B. Subjects in Cohort B will be randomized 1:1:1 to trifarotene cream 
HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle and treated twice weekly for 
up to 90 days in the same manner as subjects in Cohort A.  
All subjects (Cohort A and Cohort B) who complete the 90-day Double-blind Treatment 
Period will be eligible to enroll in the 12-week OLE. Subjects in the OLE will receive 
open-label trifarotene cream HE1 200 µg/g twice weekly for up to 12 weeks.  
Upon signing informed consent and entering the Screening Period, a Washout Period of 
90 days. Participants will stop using physical and medical treatments for LI, including 
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balneotherapy, as well as the following prohibited medications, as applicable. The 
following list applies to both prescription and over-the-counter medications:  
a. 
Topical treatments 
Medication 
Washout  
Corticosteroids (except inhaled and ophthalmic corticoids) 
2 weeks 
Retinoids (e.g., tretinoin, tazarotene) 
4 weeks 
Vitamin D analogues 
2 weeks 
Immunosuppressants (e.g., tacrolimus) 
2 weeks 
Antracen derivatives, tar and salicylic preparations 
2 weeks 
Keratolytics (such as urea, lactic acid, propylene glycol, 
salicylic acid) except keratolytic shampoo 
2 weeks 
b. Systemic treatments 
Medication 
Washout  
Retinoids 
8 weeks 
Oral Vitamin A supplementation more than 3500 IU per day 
2 weeks 
Medication interfering with bone activity, e.g., corticosteroids, 
thyroid hormones unless the dose is stable and 
thyroid-stimulating hormone (TSH) is normal, cytotoxics, 
bisphosphonates, selective estrogen receptor modulators 
(SERM), teriparatide, calcitonins, tetracyclines, quinolones, 
thiazides, long-term use of salicylates, heparin, theophylline, 
barbiturates, colchicines. Vitamin D analogs taken at stable dose 
for at least 30 days are allowed) 
8 weeks 
QT-prolonging drugs 
5 half lives 
CYP enzymatic inducers (such as rifampicine, phenytoin, 
carbamazepine, phenobarbital, St. John’s Wort) 
3 months 
CYP2C9 and 2C8 inhibitors (including, but not limited to the 
following: gemfibrozil, fluconazole, fluvoxamine, 
sulfaphenazole, miconazole, amiodarone, sertraline, 
sulfamethoxazole, valproic acid, voriconazole, trimethoprim, 
rosiglitazone, pioglitazone) 
5 half lives 
Monoclonal antibodies 
5 half lives 
Before asking a subject to washout of their prescription and over-the-counter prohibited 
treatments, investigators should confirm the subject meets all study eligibility criteria 
except for LI severity (inclusion criterion #3). After completing the necessary washout 
period, subjects will return to the site to have their LI severity assessed and to complete 
study eligibility requirements. 
During washout, subjects may continue their standard of care of visible skin (face and 
scalp) for cosmetic reasons and of extremities (palms/soles) to avoid functional 
consequences on walking or moving their fingers. In the US/EU, this may include 
compounded emollients with keratolytics (alpha or beta hydroxyl acids) and/or urea. The 
investigator should approve and document these standard of care treatments in the 
electronic case report form (eCRF). If the standard of care treatments of the face and/or 
palms/soles contain prohibited medications, they must be stopped at the Baseline Visit. 
Subjects may shower, but not bathe or swim during the Screening Period.  
Study drug will be packaged in 50-g tubes from which up to 36 g of IP may be dispensed 
per application, i.e., the maximum dose per application. Study staff will choose 1 tube 
from the kit dispensed to the subject at that visit, and apply the first dose of study drug to 
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each subject in the clinic on Day 1 after Baseline measurements; they will weigh the study 
tube before and after application to determine the amount used. If the product will be 
applied at home by someone other than the study subject, it is recommended that this 
person assist with application at the first visit to learn how the IP is applied. 
The kit dispensed at Baseline must be weighed before the first tube is chosen for 
application by the study staff. Weight of the kits dispensed and returned by the subject 
during the study includes both tubes and cartons, but not leaflets, which need to be 
removed before weighing. The subject must be reminded to return the kits with tubes and 
cartons, whether used or not, when returning to the next visit. 
Thereafter, each subject will apply up to 36 g of study drug as for the first dose on up to 
90% of BSA twice weekly, 3 to 4 days apart, sparing the scalp, inguinal, and axillary 
areas. Subjects with heavy facial hair should not apply IP to hair-bearing areas. Subjects 
will receive an adequate number of tubes to use 1 tube per application and will use a new 
tube for each treatment day. Subjects may use less than the full amount of product in a 
tube. Subjects will record the date and time of study treatment administration in the 
subject diary. 
The study protocol limits application of IP to 36 g maximum; no additional tubes can be 
given, whether during the randomization period or the OLE period. If the study staff and 
subject note that there is insufficient volume for full body application, the subject should 
apply trifarotene cream sparingly twice weekly to the most affected areas, and always to 
the same skin areas. Study cream should be very sparingly applied. Trifarotene cream 
100 or 200 µg/g is a highly potent topical retinoid, and it is not necessary to apply much 
for efficacy; application of more will increase the risk of irritation and systemic 
penetration. 
Local tolerability may differ in subjects with LI compared to healthy subjects, as their 
skin is drier and may be more sensitive. Local tolerability will be followed very carefully 
during the study. Subjects will receive information on study drug use and stopping rules 
and will be instructed to contact the site with any safety/tolerability issues. Study 
personnel will telephone subjects in between scheduled visits (i.e., at Day 7 and Day 45 
in the Double-blind Period; at Day 97 and 134 in the OLE) to assess safety; an 
unscheduled clinic visit may be performed, if necessary. If the treatment causes 
application site reactions, the frequency of application will be reduced or interrupted only 
on the area of concern, as indicated herein. During all clinic visits, the investigator will 
assess local tolerability (stinging/burning, pruritus, or erythema on 0-3 scales [none, mild, 
moderate, severe]) for each body area (chest/abdomen, back, arms, legs, and face/neck), 
and the following procedures will be followed: 
- 
If a score of 2 (moderate) is recorded for any of the local tolerability assessment 
scales (stinging/burning, pruritus, or erythema) on any treated area, the study drug 
will be applied on that area only once weekly, until the score is back to <2. 
Continue to treat all other areas twice weekly provided the score is <2 on those 
areas. 
- 
If a score of 3 (severe) is recorded for any of the local tolerability assessment scale 
(stinging/burning, pruritus, or erythema) on any treated area, the study drug will not 
be applied on that area until the score is back to <3 (i.e., “drug holiday”). Continue 
to treat all other areas twice weekly provided the score is <2 on those areas. 
Stopping rules and treatment modification will be defined at the subject level based on 
local tolerability, selected laboratory parameters, and adverse events (AEs). Any changes 
in dosing must be documented in the subject diary and the electronic case report form. 
All subjects will be provided with diaries in which to record study drug application 
(days/times and any areas of skin not treated [e.g., due to local reactions]) and any AEs, 
including application site reactions and concomitant medications used. Subjects will also 
be advised on permitted emollient(s) use on nontreatment days during the study; use of 
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emollient(s) and/or sunscreen(s) on study drug treatment days within 4 hours before or 
after study drug application is prohibited. 
At all sites with photographic capability, photographs will be taken as source data to 
support scoring at Baseline, Day 30, and Day 90. A central reader who will not be an 
investigator in the study will review the photographs to assess consistency of investigator 
scoring of LI severity as a quality check. Photographs may also be used for scientific 
publication purposes. Subjects will sign a separate, optional photographic informed 
consent form (ICF). 
Samples for pharmacokinetic (PK) analysis will be drawn from all subjects at Baseline 
and at each clinic visit. Visits for PK must occur at least 24 hours after the last application 
of the IP to avoid contamination of the blood samples with any IP that may have remained 
on the skin after the last application. Subjects should not apply IP on visit days until after 
the visit. 
In addition, a PK substudy will be conducted on Days 1 and 30 at sites with the capability 
to conduct it. Participation in the PK substudy will be optional and will include at least 
30 subjects. Subjects who participate in the PK substudy will come from both study 
cohorts and will undergo serial blood sampling predose and at 1, 2, 4, 8, 12, and 24 hours 
postdose on Day 1 and Day 30. Trough levels will be drawn for these subjects at each of 
the other clinic visits. For the subjects in the PK substudy, postdose ECGs will be 
performed at each serial blood draw on Day 1 and Day 30. 
Subjects who complete the Double-blind Treatment Period will have the option to 
continue into the OLE to assess safety for an additional 90 days with trifarotene cream 
HE1 200 µg/g twice weekly, on up to 90% of BSA, sparing the scalp, inguinal, and 
axillary areas. During the study, subjects with heavy facial hair should not apply IP to 
hair-bearing areas. During the OLE, subjects will return to the site at Days 104, 120, 150, 
180, and 194 for safety, tolerability, and efficacy assessments. Blood samples will be 
drawn for clinical laboratory safety tests and PK at Days 120 and 180. Study personnel 
will telephone subjects in between scheduled visits (i.e., at Day 97 and Day 134) to assess 
safety; an unscheduled clinic visit may be performed, if necessary.  
The coronavirus disease 2019 (COVID-19) global pandemic has impacted the free 
movement of the world’s population, which has been restricted in order to control the 
spread of the disease. It is recommended that all sites and subjects comply with the 
applicable local and federal guidelines regarding the necessary and proper precautions 
regarding COVID-19. 
Although it is preferable to conduct all necessary study assessments in person (onsite 
visits), this may not be possible as a result of COVID-19-related travel restrictions. To 
ensure the safety of subjects, investigators, and site staff, Visits 3-6 (Double-blind Period; 
Table 2-1), Visits 7-11 (OLE Period; Table 2-2) and unscheduled visits may be conducted 
remotely. Screening and Baseline Visits must be performed on site only. These visits must 
be postponed or scheduled for when onsite visits can be safely conducted. The following 
assessments may occur remotely: 
• Safety Assessments 
o Concomitant medications and concomitant therapies 
o Adverse Events and related information reported by the patient in the diary 
o General health status of the subject 
• Tolerability Assessments 
• Pregnancy Tests: Urine pregnancy tests along with the instructions on proper use will 
be sent to the subject’s home for women of childbearing potential (WOCBP). Study 
staff will instruct patient to perform the urine pregnancy at the applicable remote visit. 
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• Study Medication Supply: As necessary and according to applicable local regulations, 
study medication will be sent to subjects. 
• DLQI and EQ-5D Questionnaires: Quality of Life questionnaires should be completed 
on the day of the remote visit and prior to applying treatment (if the remote visit falls 
on a treatment day). Questionnaires may be sent to subjects electronically or via postal 
service, and completed questionnaires may be returned to the site in the same manner. 
If subjects are unable to send completed questionnaires to the site, investigators should 
ask and record the subject’s responses during the remote visit. 
• Subject Diary: Subject diaries may be sent to subjects electronically or via postal 
service. Completed diaries may be returned to the site in the same manner. 
PLANNED 
NUMBER OF 
SUBJECTS 
Approximately 120 total subjects; 15 subjects in Cohort A and 105 subjects in Cohort B. 
STUDY ENTRY 
CRITERIA 
Inclusion criteria:  
1. Subject is ≥18 years old.  
2. Subject has known diagnosis of LI.  
3. Subject has moderate to severe (IGA 3-4) LI on the IGA of LI severity.  
4. Subject has signed an ICF at Screening before any investigational procedures.  
5. Subject who is participating in photography has signed a photography ICF. 
6. Subject who is participating in the optional PK substudy has signed a PK ICF. 
7. Subject is not of childbearing potential, who is postmenopausal (absence of 
menstrual bleeding for 1 year before Baseline, without any other medical reason), 
or has documented hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy. For individuals with permanent infertility due to an alternate 
medical cause other than the above, (e.g., Mullerian agenesis, androgen 
insensitivity), investigator discretion should be applied to determining study entry. 
OR  
Subject is a woman of childbearing potential (WOCBP) or a male subject with sexual 
partners capable of reproduction who agrees to use 2 effective forms of contraception 
during the study and for at least 1 month after the last study drug application. The 
2 authorized forms of contraception are condom used with 1 of the following 
methods of contraception: 
• bilateral tubal ligation 
• combined oral contraceptives (estrogens and progesterone), vaginal ring, or 
implanted or injectable hormonal contraceptives with a stable dose for at least 
1 month before Baseline; hormonal contraceptives must inhibit ovulation 
• intrauterine device (IUD) inserted at least 1 month before Baseline 
OR 
Agrees to abstain from heterosexual intercourse during study participation and for 
1 month after the last application of study drug and to use a highly effective 
contraceptive as backup if he or she becomes sexually active during the study. 
Abstinence is only acceptable if this is the subject’s usual lifestyle. Periodic 
abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception. 
AND 
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Male subjects may not donate sperm during the study and for at least 1 month after 
the last study drug application. 
8. Women of childbearing potential must be nonlactating and have negative pregnancy 
test results at Screening (serum) and on Day 1 before study drug administration 
(urine). 
9. Subject is reliable and capable of adhering to the protocol and visit schedule, in the 
investigator’s judgment, and has signed informed consent. 
10. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin). 
 
Exclusion criteria: 
1. Subject has any variant of ichthyosis other than LI or another disorder of 
keratinization, including syndromic ichthyoses.  
2. Subject has current moderate or severe stinging/burning at Screening. 
3. Subject has an ongoing cutaneous infection or any other significant concomitant skin 
disease (other than the LI) which, in the investigator’s opinion, may interfere with 
the study assessments. 
4. Subject with fasting triglycerides >200 mg/dL or >2.25 mmol/L and/or total 
cholesterol >250 mg/dL or >6.5 mmol/L. Subjects whose triglycerides and/or total 
cholesterol are within normal limits with a stable dose of lipid-lowering agents for at 
least 6 months may be included. 
5. Subject was previously treated with trifarotene/CD5789 in an acne or ichthyosis 
study.  
6. Subject has any other significant concomitant disease, or poorly controlled medical 
condition other than LI that in the investigator’s opinion may put him or her at risk if 
he or she takes part in the study, and/or that may interfere with the study assessments. 
7. Subject has a medical condition that potentially alters bone metabolism 
(e.g., osteoporosis, thyroid dysfunction, Cushing syndrome, Crohn’s disease, or 
ulcerative colitis). Subjects with hypothyroidism who are on a stable dose of thyroid 
hormone replacement therapy and whose TSH is normal may be included. 
8. Subject is being treated for major depression disorder and/or has a history of major 
depression or suicide attempt requiring hospitalization, medications, and close 
psychiatric surveillance to prevent suicide attempts.  
9. Subject with positive serology for hepatitis B surface antigen, hepatitis C, or are 
known to be HIV positive or to have AIDS at Screening. 
10. Subject with any of the following laboratory values at Screening: 
a. 
Aspartate aminotransferase or alanine aminotransferase >1.5 × upper limit 
of normal (ULN) defined by the laboratory 
b. Total bilirubin >1.25 × ULN at Screening. Subjects with known Gilbert’s 
syndrome may be included with total bilirubin >1.25 × ULN  
c. 
Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women 
d. Platelets <150 × 109/L or >400 × 109/L 
11. Subject has any clinically other significant abnormal laboratory value (hematology, 
chemistry, or urinalysis) at Screening that, in the investigator’s opinion, may put the 
subject at risk if he or she takes part in the study, and/or that may interfere with the 
study assessments. 
12. Subject has had recent systemic malignancy (e.g., within 5 years) with exception of 
nonmelanoma skin cancer or cervical intraepithelial neoplasia of Grade 1 who are 
>6 months post-treatment. 
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13. Subject has a history of long QT syndrome or has clinically significant 
electrocardiogram (ECG) abnormalities, including clinically significant conduction 
disorders or significant arrhythmias, or QTcF interval >450 ms. 
14. Subject has a known allergy or sensitivity to any of the components of the 
investigational products.  
15. Subject has been exposed to excessive ultraviolet (UV) radiations on the treated 
zones within 1 month before Baseline visit or is planning intensive UV exposure 
during the study (e.g., occupational exposure to the sun, sunbathing, phototherapy, 
etc.). 
16. Subject is inherently sensitive to sunlight. 
17. Subject is unable or unwilling to stop use of topical or systemic retinoids. 
18. Subject is presumed to be abusing drugs or alcohol at Screening or Baseline Visits 
based on medical history or current clinical symptoms. 
19. Subject is participating in another interventional clinical trial. 
20. Subject is institutionalized. 
21. Subject is in any way related to the sponsor, investigator, or site personnel. 
INVESTIGATIONAL 
PRODUCT 
Name: Trifarotene (CD5789) cream HE1  
Double-blind Period dose, route, frequency: Up to 36 g per dose of 100 µg/g or 200 µg/g 
applied topically twice weekly on up to 90% BSA  
Open-label Extension dose, route, frequency: Up to 36 g per dose of 200 µg/g applied 
topically twice weekly on up to 90% BSA 
REFERENCE 
PRODUCT 
Name: Vehicle cream 
Double-blind Period dose, route, frequency: A fixed dose (up to 36 g per dose, determined 
at Visit 2) applied topically twice weekly on up to 90% BSA  
TREATMENT 
REGIMENS 
Topical application twice weekly to all affected skin except the scalp, axillae, and inguinal 
area.   
COORDINATING/ 
PRINCIPAL 
INVESTIGATOR 
Keith A. Choate, MD 
Department of Dermatology, Yale University School of Medicine 
New Haven, CT 06520, USA 
PLANNED STUDY 
SITES 
Approximately 40 sites across North America, Europe, Israel, and Australia 
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CRITERIA FOR 
EVALUATION 
Primary efficacy endpoint: The proportion of subjects in each treatment group who 
experience successful resolution of LI where “success” is defined as clear/almost clear on 
treated areas and at least a 2-grade change from Baseline at Day 90/end-of-treatment 
(EOT) in the Double-blind Period on the 5-point IGA full body scale.  
Secondary endpoints: 
−
The difference in mean scores between the active trifarotene cream HE1 and vehicle 
groups in the following assessment indices from Baseline through Day 90:
−
5-point Visual Index for Ichthyosis Severity (VIIS) for scaling (overall 16 
points for scaling, i.e., 0-4 points for 4 body areas: chest/abdomen, back, 
arms, and legs)
−
Individual score for roughness (Scale: 0–4)
−
Palm/sole Assessment (Scale: 0–4)
−
Quality of life per Dermatology Life Quality Index (DLQI)
−
The difference in proportion of subjects with presence of fissures on palms/soles
(presence/absence, number of fissures, and pain associated with fissures on a
0-3 scale) at Day 90 between the active trifarotene cream HE1 and vehicle groups
Exploratory endpoints: 
−
The difference in mean ectropion (Ectropion Severity Score [ESS] of 0–8) scores
between the active trifarotene cream HE1 and vehicle groups from Baseline through
Day 90
−
The difference in quality of life per EQ-5D-5L score between the active trifarotene
cream HE1 and vehicle groups from Baseline through Day 90
Safety endpoints: 
−
Reported serious adverse events (SAEs), treatment-emergent AEs (TEAEs), and
changes in clinical laboratory tests, vital signs, physical examinations, and 12-lead
ECGs
−
Local tolerability (stinging/burning, pruritus, or erythema on: 0-3 scales [none,
mild, moderate, severe]) for each body area (chest/abdomen, back, legs, arms, and
face/neck)
Pharmacokinetic endpoints: Plasma concentrations of CD5789 and its major metabolites 
will be measured. 
STATISTICAL 
METHODS 
Analysis Populations:  
The following are planned for the Double-blind Period of the study: 
The Safety population will be the primary population for analyses of safety and 
tolerability and will comprise all subjects who are randomized to treatment and receive at 
least 1 application of study drug.  
The intent-to-treat (ITT) population will comprise all randomized subjects. This 
population will be used as the primary population for the analysis of efficacy for the 
Double-blind Period of the study. 
The modified intent-to-treat (mITT) population comprises all subjects in the safety 
population with at least 1 postbaseline assessment of efficacy in the Double-blind Period. 
This population will be used as the primary population for the analysis of efficacy for the 
Double-blind Period of the study. 
The per protocol (PP) population will be defined prior to database lock and will comprise 
subjects in the mITT population who met all inclusion criteria and no exclusion criteria, 
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were compliant with study drug application, and who had no significant protocol 
deviations.  
The PK population includes all subjects in the Safety Population who have at least 
1 plasma sample with quantifiable concentration. The PK population will be used to 
summarize all PK endpoints. 
The following populations are planned for the OLE of this study: 
The OLE Safety population: all subjects who complete the 90-day Double-blind 
Treatment Period and receive at least 1 application of study drug in the OLE. 
OLE ITT population: all subjects who complete the 90-day Double-blind Period and who 
sign the OLE informed consent. 
The OLE mITT population: all subjects in the OLE safety population with at least 
1 assessment of efficacy after Visit 6. 
The OLE PP population: all subjects in the OLE mITT population who met all inclusion 
criteria and no exclusion criteria, were compliant with study drug application from 
baseline through EOT, and who had no significant protocol deviations throughout the 
study. 
Subject Characteristics and Disposition: Descriptive statistics will be used to summarize 
demographic characteristics (age, sex, ethnicity, and race) and baseline characteristics for 
all enrolled subjects. Medical history, physical examination findings, and vital sign 
measurements for all randomized subjects will be presented in listings. 
Efficacy Analyses: The number and proportion of subjects in each treatment group with 
successful resolution of LI by Day 90/EOT in the Double-blind Period will be presented. 
The primary efficacy endpoint will be analyzed using a logistic regression model with 
treatment and age group as factors. Other baseline characteristics and interactions may be 
included. The odds ratios and 95% CIs for the odds ratios will be presented. The difference 
in proportions between the active trifarotene cream HEI and vehicle cream groups, 
95% CIs for the differences, and P-values for the differences in treatment will also be 
presented. 
The IGA scores as well as secondary and exploratory efficacy endpoints will be analyzed 
by visit using descriptive statistics through Day 180 (end of OLE treatment period). 
Change from Baseline through Day 90 will be presented and analyzed using a mixed 
model for repeated measures (MMRM). The model will include the change from Baseline 
score as the dependent variable, treatment group as a fixed effect, subject as a random 
effect, and Baseline score value as a covariate. Frequencies of results and 95% confidence 
intervals will also be reported, and scores will be analyzed as categorical variables using 
the Cochran-Mantel-Haenszel test. For subjects who report having fissures, the number 
of fissures and pain related to fissures will also be presented on a scale of 0-3 (none, mild, 
moderate, severe). 
Clinical Pharmacology Analyses: Noncompartmental PK analysis will be performed for 
the PK subset of subjects, as data permit. Plasma concentrations of CD5789 and its major 
metabolites will be measured and will be listed by subject. 
Safety Analyses: Safety and tolerability will be assessed based on the incidence of 
reported TEAEs, and SAEs, including relationship to study drug and severity, as well as 
physical examination findings, vital sign measurements (supine systolic blood pressure 
[SBP] and diastolic blood pressure [DBP] and pulse), clinical laboratory results 
(hematology, including serum aminotransferases and serum lipids, coagulation, clinical 
chemistry, and urinalysis) and 12-lead ECGs. Descriptive statistics for observed values 
and change from Baseline will be calculated at each visit within each study period and by 
treatment group within cohort. 
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SAMPLE SIZE 
DETERMINATION 
The first cohort of 15 subjects is a reasonable sample size to assess safety and tolerability 
before enrolling additional subjects in Cohort B. Accounting for a 20% drop-
out/nonevaluable rate, a total sample size of 120 subjects randomized in a 1:1:1 ratio to 
2 active trifarotene cream HE1 arms and a vehicle cream arm will provide >80% power 
to detect a difference between each separate trifarotene cream HE1 arm (32 evaluable 
subjects) and the vehicle cream arm (32 evaluable subjects) 2-sided Fisher’s Exact Test 
assuming a 70% success rate and a 40% success rate, respectively. This study is not 
powered to detect a difference between the 2 active arms. 
STUDY AND 
TREATMENT 
DURATION 
The sequence and maximum duration of the study periods for each subject will be as 
follows:  
1. Screening: Up to 97 days. Before asking a subject to enter washout, investigators 
should confirm the subject meets study eligibility criteria, except for LI severity 
(Inclusion Criterion #3). Washout may be up to 90 days. After completing any 
necessary Washout Period, subjects must return to the site within 35 days before the 
Baseline Visit within the 97-day Screening Period to have their LI severity assessed 
and study eligibility requirements determined. 
2. Double-blind study drug application: Twice weekly for 90 days.  
3. Optional Open-label Extension: Twice weekly for 90 days. 
4. Follow-up: 14 days after last study drug application. 
The maximum treatment duration for each subject is approximately 90 days for subjects 
who choose not to continue into the OLE, and 180 days for those who choose to continue. 
The maximum treatment duration for each subject is 291 days. 
 
 
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2.2. Schedule of Events  
Table 2-1: 
Schedule of Events for Double-blind Period 
 
 
Double-blind Treatment Period 
 
Screening 
(-97 days to -1 day) 
Washout up to 90 daysa 
 
 
Baseline  
(Day 1) 
Telephone 
Visit 
(Day 7) 
Day 14  
± 5 days 
Day 30  
± 7 days 
Telephone 
Visit 
(Day 45) 
Day 60  
± 7 days 
Day 90b,c 
± 7 days 
(ET) 
Visit 
1 
2 
 
3d 
4d 
 
5d 
6d 
Written informed consent  
X 
 
 
 
 
 
 
Xa 
Assign screening number 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
Physical examination  
X 
Xe 
 
 
 
 
 
Xe 
Vital signs (blood pressure and pulse)  
X 
X 
 
X 
X 
 
X 
X 
Height, weight, and BMI  
X 
 
 
 
 
 
 
Xb 
IGA assessmentf 
X 
X 
 
X 
X 
 
X 
X 
VIISg assessment 
X 
X 
 
X 
X 
 
X 
X 
Roughness assessmenth 
X 
X 
 
X 
X 
 
X 
X 
Palm/sole assessment  
X 
X 
 
X 
X 
 
X 
X 
Palm/sole fissuring assessmenti 
X 
X 
 
X 
X 
 
X 
X 
Ectropion score  
X 
X 
 
X 
X 
 
X 
X 
Photographsj 
 
X 
 
 
X 
 
 
X 
Quality of life per Dermatology Life 
Quality Index (DLQI) 
 
X 
 
X 
X 
 
X 
X 
EQ-5D Quality of Life Questionnaire 
 
X 
 
X 
X 
 
X 
X 
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Double-blind Treatment Period 
Screening 
(-97 days to -1 day) 
Washout up to 90 daysa 
Baseline 
(Day 1) 
Telephone 
Visit 
(Day 7) 
Day 14 
± 5 days 
Day 30 
± 7 days 
Telephone 
Visit 
(Day 45) 
Day 60 
± 7 days 
Day 90b,c 
± 7 days 
(ET) 
Visit 
1 
2 
3d 
4d 
5d 
6d 
12-lead ECGk
X 
X 
X 
X 
Clinical laboratory tests (hematology, 
chemistry, urinalysis)l 
X 
X 
X 
X 
Serology (hepatitis B surface antigen, 
hepatitis C) 
X 
Coagulation panel 
X 
X 
X 
Pregnancy test for female subjects 
(serum at Screening; urine 
subsequently) 
X 
X 
X 
X 
X 
Randomization via IWRS 
X 
PK blood sample collectionm 
X 
X 
X 
X 
X 
Initial study drug application by clinic 
staff and measurementn 
X 
Application instructions, advice on 
emollient and sunscreen use 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug and diarieso 
X 
X 
X 
X 
(X)o
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Tolerability assessment 
X 
X 
X 
X 
X 
Adverse events (and review diaries) 
X 
X 
X 
X 
X 
X 
X 
Collect all used/unused study drugp 
X 
X 
X 
X 
Provide information about OLE option 
X 
X 
X 
X 
Abbreviations: BMI = body mass index; COVID-19 = coronavirus disease 2019; DLQI = Dermatology Life Quality Index; ECG = electrocardiogram; 
eCRF = electronic case report form; ET = early termination; HEENT = head, eyes, ears, nose, throat; ICF = informed consent form; IGA = Investigator’s Global 
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Assessment; IWRS = interactive web response system; OLE = open-label extension; PK = pharmacokinetic; WOCBP = women of childbearing potential; 
VIIS = Visual Index for Ichthyosis Severity 
a. 
Upon signing informed consent and entering the Screening Period, subjects will stop using physical and medical treatments for LI, including balneotherapy, 
and begin to washout prohibited topical and systemic treatments with designated washout periods, as applicable. Before asking a subject to enter washout, 
investigators should confirm the subject meets study eligibility criteria, except for LI severity (Inclusion Criterion #3). Washout may be up to 90 days. After 
completing any necessary Washout Period, subjects must return to the site within 35 days before the Baseline Visit within the 97-day Screening Period to 
have their LI severity assessed and study eligibility requirements determined. During washout, subjects may continue their standard of care of visible skin 
(face and scalp) for cosmetic reasons and of extremities (palms/soles) to avoid functional consequences on walking or moving their fingers. In the US/EU, 
this may include compounded emollients with keratolytics (alpha or beta hydroxyl acids) and/or urea. The investigator should approve and document these 
standard of care treatments in the electronic case report form (eCRF). If the standard of care treatments of the face and/or palms/soles contain prohibited 
medications, they must be stopped at the Baseline Visit. Subjects may shower, but not bathe or swim during the Screening Period.  
b. Day 90 procedures should be conducted for subjects who terminate the study early. If a subject discontinues IP, but continues to attend clinic visits, Day 90 
will occur as scheduled. Day 90 will be the first visit of the OLE for subjects who choose to continue. Subjects who decide to continue into the OLE will 
have the following additional procedures: 1) sign informed consent; 2) will be weighed; 3) will be instructed on study drug application; 4) will be given new 
diaries, and 5) will be provided with study drug. 
c. 
A Follow-up telephone call will be made within 14 days after Day 90 to subjects who choose not to continue into the OLE to assess any ongoing adverse 
events. 
d. Although it is preferable to conduct all necessary study assessments in person (onsite visits), this may not be possible as a result of COVID-19-related travel 
restrictions. To ensure the safety of subjects, investigators, and site staff, Visits 3-6 and unscheduled visits may be conducted remotely. Screening and 
Baseline Visits must be performed onsite only, and must be postponed or scheduled for when onsite visits can be safely conducted. 
e. 
Limited physical examination to include HEENT, cardiorespiratory, abdomen, range of motion.  
f. 
IGA: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe. 
g. VIIS scale for each body area: chest/abdomen, back, legs, and arms, for a possible overall score = 16. 
h. Roughness (0-4 scale);  
i. 
Palm/sole fissuring assessment: present/absent/number/pain (0-3 scale). 
j. 
Photography will be performed at sites with the capability for subjects who sign a photographic ICF. A central reader who will not be an investigator in the 
study will review the photographs to assess consistency of investigator scoring of LI severity as a quality check. 
k. ECG to be conducted at Screening, Baseline, Day 30, and Day 90 for all subjects. Subjects in the PK substudy will also have postdose ECGs at each serial 
blood draw on Day 1 and Day 30. 
l. 
Subjects must be fasting (i.e., at least 8 hours) for clinical laboratory tests, but not for PK blood draws. 
m. Samples for PK will be drawn from all subjects at Baseline and at each clinic visit. At selected sites among subjects who consent to participate in the PK 
substudy, samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1. On Day 30, IP will be applied in the clinic for PK substudy 
subjects, and PK samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose. Trough levels will be drawn when the subjects are in the clinic 
for other study visits (i.e., Day 14, Day 60, and Day 90). Visits for PK must occur at least 24 hours after the last application of the IP to avoid contamination 
of the blood samples with any IP that may have remained in the skin after the last application. 
n. Study staff will apply initial dose of study drug in the clinic after Baseline measurements, and the amount of study drug used will be measured (i.e., 
36-g tube will be measured before and after application to determine amount used). 
o. Study drug provided in 50-g tubes (maximum single application is 36 g). Measure study drug kits (tubes and box, but not leaflets) before dispensing; 
subjects must record days/times of study drug application in the diaries and any areas of skin not treated, e.g., due to local reactions). Dispense enough 
additional study drug until next visit (except at Day 90, unless subject consents to continue into OLE). 
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p. Confirm study drug compliance by weighing the study kits (tubes and boxes, but not leaflets) and reviewing diary.  
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Table 2-2: 
Schedule of Events for Open-label Extension  
 
Open-label Treatment Perioda 
Follow-up 
 
 
Telephone 
Visit 
(Day 97) 
Day 104  
± 5 days 
Day 120  
± 7 days 
Telephone 
Visit 
(Day 134) 
Day 150 
± 7 days 
Day 180  
± 7 
days/ET 
Day 194 or 14 days after End of 
Open-label Treatment 
Visit 
 
7a 
8a 
 
9a 
10a 
11a 
Informed consentb 
 
 
 
 
 
 
 
Physical examinationc 
 
 
 
 
 
X 
X 
Vital signs (blood pressure and 
pulse)  
 
X 
X 
X 
X 
X 
X 
Record IGAd 
 
X 
X 
 
X 
X 
X 
VIISe assessment 
 
X 
X 
 
X 
X 
X 
Roughness assessmentf 
 
X 
X 
 
X 
X 
X 
Palm/sole assessment 
 
X 
X 
 
X 
X 
X 
Palm/sole fissuring assessment 
 
X 
X 
 
X 
X 
X 
Ectropion score  
 
X 
X 
 
X 
X 
X 
Clinical laboratory tests 
(hematology, chemistry, 
urinalysis)g 
 
 
X 
 
 
X 
 
Pregnancy test for female 
subjects (urine) 
 
 
X 
 
X 
X 
X 
Coagulation panel 
 
 
X 
 
 
X 
 
12-lead ECG 
 
 
X 
 
 
X 
 
PK blood sample collectionh 
 
 
X 
 
 
X 
 
Application instructions, advice 
on emollient and sunscreen use 
X 
X 
X 
X 
 
 
 
Dispense study drug and diaries 
j 
 
X 
X 
 
X 
 
 
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Open-label Treatment Perioda 
Follow-up 
 
 
Telephone 
Visit 
(Day 97) 
Day 104  
± 5 days 
Day 120  
± 7 days 
Telephone 
Visit 
(Day 134) 
Day 150 
± 7 days 
Day 180  
± 7 
days/ET 
Day 194 or 14 days after End of 
Open-label Treatment 
Visit 
 
7a 
8a 
 
9a 
10a 
11a 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
Tolerability assessment  
 
X 
X 
 
X 
X 
 
Adverse events (and review 
diaries) 
X 
X 
X 
X 
X 
X 
X 
Collect all used/unused study 
drugk 
 
X 
X 
 
X 
X 
 
Abbreviations: ECG = electrocardiogram; ET = early termination; HEENT = head, eyes, ears, nose, throat; ICF = informed consent form; IGA = Investigator’s 
Global Assessment; PK = pharmacokinetic; OLE = open-label extension; VIIS = Visual Index for Ichthyosis Severity; WOCBP = women of childbearing 
potential 
a. Although it is preferable to conduct all necessary study assessments in person (on -site visits), this may not be possible as a result of COVID-19-related travel 
restrictions. To ensure the safety of subjects, investigators, and site staff, Visits 7-11 and unscheduled visits may be conducted remotely. 
b. Subjects will sign the OLE ICF at the Double-blind Day 90 Visit. All efficacy assessments, safety/tolerability assessments, including clinical laboratory 
testing and PK from Day 90 will be carried over for the OLE and will not be repeated.  
c. Limited physical examination to include HEENT, cardiorespiratory, abdomen, range of motion.  
d. IGA: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe  
e. VIIS scale for each body area: chest/abdomen, back, legs, and arms, for a possible overall score = 16. 
f. Roughness (0-4 scale); fissuring assessment on palms/soles: present/absent/number/pain (0-3 scale). 
g. Subjects must be fasting (at least 8 hours) for clinical chemistry testing, but not for PK only blood draws. 
h. Samples for PK will be drawn from all subjects at Day 120 and Day 180. Visits for PK must occur at least 24 hours after the last application of the IP to avoid 
contamination of the blood samples with any IP that may have remained in the skin after the last application. 
i. All subjects in the OLE will receive trifarotene 200 µg/g. Study drug provided in 50-g tubes (maximum single application is 36 g). Weigh study medication 
kits (tubes and box, but not leaflets). Dispense enough additional study drug until the next visit (except at Day 180). 
j. Subjects must record days/times of study drug application in the diaries and any areas of skin not treated (e.g., due to local reactions).  
k. Confirm study drug compliance by measuring weighing the study kits (tubes and boxes, but not leaflets) dispensed and returned and reviewing diary. 
 
 
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3. TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES ...................................................................................................3 
2. 
PROTOCOL SUMMARY ........................................................................................................4 
2.1. Synopsis ..........................................................................................................................4 
2.2. Schedule of Events ........................................................................................................14 
3. 
TABLE OF CONTENTS .......................................................................................................20 
3.1. List of In-Text Tables ...................................................................................................25 
3.2. List of In-Text Figures ..................................................................................................25 
REASONS FOR AMENDMENT ..................................................................................................26 
SUMMARY OF AMENDED SECTIONS ....................................................................................28 
AMENDED PROTOCOL .............................................................................................................45 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...........................................46 
5. 
INTRODUCTION ..................................................................................................................48 
5.1. Background and Rationale ............................................................................................48 
5.1.1 CD5789 (Trifarotene) ........................................................................................49 
5.2. Clinical Experience .......................................................................................................49 
5.3. Summary of Potential Risks and Benefits .....................................................................50 
6. 
OBJECTIVES .........................................................................................................................52 
6.1. Primary Objective .........................................................................................................52 
6.2. Secondary Objectives ....................................................................................................52 
7. 
STUDY DESIGN ...................................................................................................................52 
7.1. Overall Study Design and Plan .....................................................................................52 
7.2. Rationale and Discussion of Study Design ...................................................................57 
7.3. Selection of Doses in the Study ....................................................................................57 
7.4. Study Sites .....................................................................................................................57 
7.5. Point of Contact ............................................................................................................58 
7.6. End of Study Definition ................................................................................................58 
8. 
SUBJECT POPULATION .....................................................................................................58 
8.1. Selection of Study Population and Diagnosis ...............................................................58 
8.2. Study Entry Criteria ......................................................................................................58 
8.2.1 Inclusion Criteria ...............................................................................................58 
8.2.2 Exclusion Criteria ..............................................................................................59 
8.3. Premature Subject Withdrawal .....................................................................................60 
8.4. Subject Discontinuation of Study Intervention and Stopping Rules .............................61 
8.5. Subject Replacement Criteria ........................................................................................62 
9. 
TREATMENTS ......................................................................................................................63 
9.1. Identification of Investigational Product(s) ..................................................................63 
9.2. Treatments Administered ..............................................................................................63 
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9.3. Selection of Timing of Dose for Each Subject..............................................................64 
9.4. Dose Adjustment Criteria ..............................................................................................66 
9.5. Treatment Compliance ..................................................................................................66 
9.6. Method of Assigning Subjects to Treatment Groups ....................................................66 
9.7. Blinding and Unblinding Treatment Assignment .........................................................67 
9.8. Permitted and Prohibited Therapies ..............................................................................67 
9.8.1 Permitted Therapies ...........................................................................................68 
9.8.2 Prohibited Therapies ..........................................................................................69 
9.8.3 Restrictions ........................................................................................................69 
9.9. Treatment after End of Study ........................................................................................69 
9.10. Dispensing and Storage .................................................................................................69 
9.11. Drug Accountability ......................................................................................................70 
9.12. Labeling and Packaging ................................................................................................71 
9.12.1 Labeling .............................................................................................................71 
9.12.2 Packaging ..........................................................................................................71 
10. STUDY PROCEDURES ........................................................................................................72 
10.1. Study Duration ..............................................................................................................72 
10.1.1 Overall Study Schedule .....................................................................................72 
10.2. Study Periods and Visits ...............................................................................................72 
10.2.1 Screening and Washout .....................................................................................72 
10.2.1.1 Screening Visit (Visit 1) .......................................................................72 
10.2.2 Double-blind Treatment Period .........................................................................74 
10.2.2.1 Baseline Visit (Visit 2, Day 1) ..............................................................74 
10.2.2.2 Telephone Visit (Day 7) ........................................................................75 
10.2.2.3 Visit 3 (Day 14 ±5 days) .......................................................................75 
10.2.2.4 Visit 4 (Day 30 ±7 days) .......................................................................76 
10.2.2.5 Telephone Visit (Day 45) ......................................................................77 
10.2.2.6 Visit 5 (Day 60 ±7 days) .......................................................................77 
10.2.2.7 Visit 6 (Day 90 ±7 days) or Early Termination ....................................78 
10.2.3 Follow-up Telephone Call (±14 days after Day 90) – Only Subjects Who Do Not 
Continue into Open-label Extension .................................................................79 
10.2.4 Open-label Extension ........................................................................................79 
10.2.4.1 Telephone Visit (Day 97) ......................................................................79 
10.2.4.2 Visit 7 (Day 104 ±5 days) .....................................................................79 
10.2.4.3 Visit 8 (Day 120 ±7 days) .....................................................................80 
10.2.4.4 Telephone Visit (Day 134) ....................................................................81 
10.2.4.5 Visit 9 (Day 150 ±7 days) .....................................................................81 
10.2.4.6 Visit 10 (Day 180 ±7 days) or Early Termination ................................81 
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10.2.4.7 Follow-up Evaluation – Open-Label Extension (Day 194 or 14 days after 
End of Open label Treatment/Visit 11) .................................................82 
10.3. Assessments ..................................................................................................................82 
10.3.1 Efficacy Variables .............................................................................................83 
10.3.1.1 Investigator’s Global Assessment .........................................................83 
10.3.1.2 Visual Index for Ichthyosis Severity – Scaling .....................................83 
10.3.1.3 Individual Score for Roughness ............................................................84 
10.3.1.4 Palm/Sole Assessment ..........................................................................84 
10.3.1.5 Palm/Sole Fissuring Assessment...........................................................84 
10.3.1.6 Dermatology Life Quality Index ...........................................................84 
10.3.1.7 EQ-5D Quality of Life Questionnaire ...................................................84 
10.3.1.8 Ectropion Severity Score ......................................................................85 
10.3.1.9 Photography Substudy ..........................................................................85 
10.3.2 Clinical Pharmacology ......................................................................................85 
10.3.2.1 Pharmacokinetic Analysis Methods ......................................................85 
10.3.2.2 Pharmacokinetic Parameters .................................................................86 
10.3.3 Sample Collection .............................................................................................87 
10.3.4 Safety Variables ................................................................................................87 
10.3.4.1 Clinical Laboratory Safety Assessments ...............................................88 
10.3.4.2 Clinical Examinations ...........................................................................89 
10.3.4.3 Adverse Events .....................................................................................90 
10.4. Procedural Adjustments Due to COVID-19 .................................................................90 
11. ADVERSE EVENTS ..............................................................................................................91 
11.1. Definitions .....................................................................................................................91 
11.1.1 Adverse Events ..................................................................................................91 
11.1.2 Adverse Drug Reaction .....................................................................................91 
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction ........................................91 
11.1.4 Serious Adverse Events/Drug Reaction ............................................................92 
11.1.5 Significant Adverse Events ...............................................................................92 
11.1.6 Treatment-Emergent Adverse Events ...............................................................92 
11.2. Event Assessment and Follow-up of Adverse Events ..................................................92 
11.2.1 Assessment ........................................................................................................93 
11.2.2 Evaluation ..........................................................................................................94 
11.2.2.1 Severity of Adverse Events ...................................................................94 
11.2.2.2 Seriousness ............................................................................................94 
11.2.2.3 Action(s) Taken .....................................................................................94 
11.2.2.4 Outcome at the Time of Last Observation ............................................95 
11.2.2.5 Adverse Event Relationship to Investigational Product........................95 
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11.2.3 Documentation ..................................................................................................96 
11.2.4 Treatment of Adverse Events ............................................................................96 
11.2.5 Follow-up ..........................................................................................................96 
11.2.6 Reporting ...........................................................................................................97 
11.2.6.1 Serious Adverse Events.........................................................................97 
11.2.6.2 Adverse Drug Reactions .......................................................................98 
11.2.6.3 Nonserious Adverse Events ..................................................................98 
11.3. Special Considerations ..................................................................................................98 
11.3.1 Adverse Events of Special Interest ....................................................................98 
11.3.2 Pregnancy ..........................................................................................................98 
12. DATA SAFETY MONITORING BOARD .........................................................................100 
13. STATISTICS ........................................................................................................................100 
13.1. Statistical Analysis ......................................................................................................100 
13.1.1 Analysis Populations .......................................................................................101 
13.1.2 Study Subjects and Demographics ..................................................................101 
13.1.2.1 Disposition and Withdrawals ..............................................................101 
13.1.2.2 Protocol Deviations .............................................................................102 
13.1.2.3 Demographics and Other Baseline Characteristics .............................102 
13.1.3 Exposure and Compliance ...............................................................................102 
13.1.4 Efficacy Analysis ............................................................................................103 
13.1.4.1 Efficacy Endpoints ..............................................................................103 
13.1.4.2 Primary Analysis .................................................................................103 
13.1.4.3 Secondary Analyses ............................................................................104 
13.1.4.4 Exploratory Analyses ..........................................................................104 
13.1.4.5 Corroborative, Sensitivity, and Other Analyses ..................................104 
13.1.5 Clinical Pharmacology Analyses .....................................................................105 
13.1.5.1 Pharmacokinetics ................................................................................105 
13.1.6 Safety and Tolerability Analyses ....................................................................105 
13.1.6.1 Local Tolerability ................................................................................105 
13.1.6.2 Adverse Events ...................................................................................105 
13.1.6.3 Clinical Laboratory Evaluations .........................................................106 
13.1.6.4 Vital Signs ...........................................................................................106 
13.1.6.5 Twelve-lead Electrocardiograms ........................................................106 
13.1.6.6 Physical Examination Findings ...........................................................106 
13.1.7 Interim Analysis ..............................................................................................107 
13.2. Sample Size Determination .........................................................................................107 
14. STUDY CONDUCT .............................................................................................................108 
14.1. Sponsor and Investigator Responsibilities ..................................................................108 
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14.1.1 Sponsor Responsibilities .................................................................................108 
14.1.2 Investigator Responsibilities ...........................................................................108 
14.1.3 Confidentiality and Privacy .............................................................................108 
14.2. Site Initiation ...............................................................................................................109 
14.3. Screen Failures ............................................................................................................109 
14.4. Study Documents ........................................................................................................109 
14.4.1 Informed Consent ............................................................................................110 
14.4.2 Investigator’s Regulatory/Good Clinical Practice Documents .......................110 
14.4.3 Case Report Forms ..........................................................................................111 
14.4.4 Source Documents ...........................................................................................111 
14.5. Data Quality Control ...................................................................................................111 
14.5.1 Monitoring Procedures ....................................................................................111 
14.5.2 Data Management ............................................................................................112 
14.5.3 Quality Assurance/Audit .................................................................................112 
14.6. Study Termination .......................................................................................................113 
14.6.1 Regular Study Termination .............................................................................113 
14.6.2 Premature Study Termination .........................................................................113 
14.7. Study Site Closure .......................................................................................................114 
14.7.1 Record Retention .............................................................................................114 
14.7.2 Sample Retention ............................................................................................114 
14.8. Changes to the Protocol ..............................................................................................115 
14.9. Use of Information and Publication ............................................................................115 
15. FINAL CLINICAL STUDY REPORT ................................................................................116 
16. ETHICAL AND LEGAL CONSIDERATIONS ..................................................................117 
16.1. Declaration of Helsinki and Good Clinical Practice ...................................................117 
16.2. Subject Information and Informed Consent ................................................................117 
16.3. Approval by Institutional Review Board and Independent Ethics Committee ...........118 
16.4. Finance and Insurance .................................................................................................118 
17. REFERENCES .....................................................................................................................119 
18. ATTACHMENTS .................................................................................................................120 
18.1. Investigator’s Agreement ............................................................................................120 
APPENDICES .............................................................................................................................121 
A. 
Regulations and Good Clinical Practice Guidelines ...................................................122 
B. 
Procedural Adjustments Due to COVID-19 ...............................................................123 
 
 
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3.1. List of In-Text Tables 
Table 2-1: 
Schedule of Events for Double-blind Period .....................................................14 
Table 2-2: 
Schedule of Events for Open-label Extension ...................................................18 
Table 9-1: 
Sample Twice-weekly Dosing Schedule ...........................................................65 
Table 9-2: 
Washout Periods for Prohibited Medicationsa...................................................68 
Table 9-3: 
Amount of Study Drug Needed Per Visit ..........................................................70 
Table 10-1: 
Ectropion Severity Score ...................................................................................85 
Table 10-2: 
Pharmacokinetic Parameters .............................................................................87 
 
3.2. List of In-Text Figures 
Figure 7-1: 
Double-blind Study Design ...............................................................................55 
Figure 7-2: 
Open-label Study Design ...................................................................................56 
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REASONS FOR AMENDMENT 
Protocol Amendment 3 is a major amendment that addresses feedback from the Regulatory 
Agencies, Competent Authorities, Central Ethics Committees, and investigators. The following 
changes were made: 
1. Changed all times defined as “weeks” to “days” throughout 
2. Added new Section (Section 10.4) and Appendix B for procedural adjustments due to 
COVID-19. 
3. Updated Phoevos Hughes’ title. 
4. Changed name and title of Statistician. 
5. Clarified that Cohort A may continue enrolling subjects until the DSMB considers it safe to 
open recruitment in Cohort B. 
6. Clarified that washout periods apply to both prescription and over-the-counter medications. 
7. Clarified that subjects receiving stable thyroid hormone medications with normal thyroid-
stimulating hormone levels may be eligible for enrollment. 
8. Clarified that subjects taking stable oral doses of Vitamin D analogs for at least 1 month at 
Screening may be eligible for enrollment. 
9. Clarified and made consistent the definition of standard of care for visible skin (face and 
scalp) and of extremities (palms and soles). 
10. Deleted “fixed dose” or “same amount” of IP throughout. 
11. Aligned power calculation and parameter assumptions with the new primary endpoint. 
12. Added optional photography evaluation of scoring by a central reader who is not a study 
investigator as a quality check. 
13. Clarified that local tolerability comprises any stinging/burning, pruritus, or erythema and that 
each should be assessed on a 0-3 point scale. 
14. As requested by the ethics committee in Australia, clarified definition of women of 
childbearing potential and clarified that a hormonal vaginal ring or an IUD inserted at least 
30 days before Baseline is an acceptable second form of contraception (i.e., IUD does not 
have to be hormonal). 
15. Revised Exclusion Criterion #4 to define exclusionary levels of triglycerides and total 
cholesterol, and to allow subjects with normal levels of triglycerides and/or total cholesterol 
on stable doses of lipid-lowering agents for at least 6 months to be eligible for inclusion. 
16. Revised Exclusion Criterion #10b with regard to exclusionary total bilirubin levels at 
Screening and defined acceptable levels for subjects with known Gilbert’s Syndrome 
(>1.25 × upper limit of normal [ULN]). 
17. Clarified Exclusion Criterion #13 to remove specific PR and QRS levels and heart rates. 
18. Extended the Screening Period to allow for up to 90 days of washout, and clarified that all 
Screening procedures, with the exception of LI assessment, should be performed before a 
subject begins the Washout Period. The subject will return after completing the washout 
period for LI assessment and to confirm eligibility. 
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19. Revised Figure 7-1 and Figure 7-2 to correct typos and to change weeks to days. 
20. Revised Table 2-1 and Table 2-2 to correct timing and omissions. 
21. Clarified the intervals between IP applications and added a table to illustrate a twice-weekly 
schedule. 
22. Removed location for Catalent Pharma Solutions. 
23. Clarified that subjects who participate in the PK substudy should have their Day 30 Visit 
scheduled on a treatment day, and that investigators should contact the medical monitor if 
that is not possible. 
24. Added a coagulation panel to the study procedures. 
25. Added the composition and qualifications of the DSMB. 
 
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SUMMARY OF AMENDED SECTIONS 
Section 
Previous Text 
Revision 
Rationale 
Title throughout 
document 
A Phase 2 Randomized, 
Multicenter, Double-blind, 
Vehicle-controlled, 12-week 
Safety, Efficacy, and Systemic 
Exposure Study followed by a 
12-week Open-label Extension 
of Trifarotene (CD5789) 
Cream HE1 in Adults and 
Adolescents with Autosomal 
Recessive Ichthyosis with 
Lamellar Scale 
A Phase 2 Randomized, 
Multicenter, Double-blind, 
Vehicle-controlled, 90-Day, 
Safety, Efficacy, and Systemic 
Exposure Study followed by a 
90-Day Open-label Extension 
of Trifarotene (CD5789) 
Cream HE1 in Adults and 
Adolescents with Autosomal 
Recessive Ichthyosis with 
Lamellar Scale 
To be more precise about 
time intervals 
Document 
“Weeks” 
Changed all to days 
To be more precise about 
time intervals 
Synopsis and 
Section 7 
Approximately 15 subjects 
will be randomized into the 
first cohort of subjects (Cohort 
A) in a 1:1:1 ratio to 
trifarotene cream HE1 
100 µg/g, trifarotene cream HE 
200 µg/g, or vehicle and 
treated twice weekly for up to 
12 weeks. 
Subjects will be randomized 
into the first cohort of subjects 
(Cohort A) in a 1:1:1 ratio to 
trifarotene cream HE1 
100 µg/g, trifarotene cream 
HE1 200 µg/g, or vehicle and 
treated twice weekly for up to 
90 days 
To clarify that Cohort A 
may enroll more than 
15 subjects total. 
Synopsis and 
Section 9.8 
Upon signing informed 
consent and entering the 
Screening Period, subjects may 
begin washout, during which 
they will stop using physical 
and medical treatments for LI, 
including balneotherapy, and 
the following prohibited 
medications, as applicable. 
Upon signing informed 
consent and entering the 
Screening Period, subjects may 
begin a Washout Period of up 
to 90 days. Participants will 
stop using physical and 
medical treatments for LI, 
including balneotherapy, as 
well as the following 
prohibited medications, as 
applicable. 
Added: the following list 
applies to both prescription 
and over-the-counter 
medications: 
To clarify 
Synopsis and 
Section 9.8  
Medication interfering with 
bone activity, e.g., 
corticosteroids, thyroid 
hormones, cytotoxics, 
bisphosphonates, calcitonins, 
tetracyclines, quinolones, 
thiazides, salicylates in long-
term course, heparin, 
theophylline, barbiturates, 
colchicines. (except Vitamin D 
analogs taken at stable dose 
since at least 1 month. 
Medication interfering with 
bone activity, e.g., 
corticosteroids, thyroid 
hormones unless the dose is 
stable and thyroid-
stimulating hormone (TSH) 
is normal, cytotoxics, 
bisphosphonates, selective 
estrogen receptor 
modulators (SERM), 
teriparatide, calcitonins, 
tetracyclines, quinolones, 
thiazides, long-term use of 
salicylates, heparin, 
theophylline, barbiturates, 
colchicines. Vitamin D analogs 
Added prohibited 
medications and clarified 
which medication 
interfering with bone 
activity is acceptable. 
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taken at stable dose for at 
least 30 days are allowed. 
 
Enzyme inducers (such as 
rifampicine, phenytoin, 
carbamazepine, phenobarbital, 
St. John’s Wort) 
CYP enzyme inducers (such as 
rifampicine, phenytoin, 
carbamazepine, phenobarbital, 
St. John’s Wort) 
To clarify 
 
CYP2C9 and 2C8 inhibitors 
(not all inclusive, gemfibrozil, 
fluconazole, fluvoxamine, 
sulfaphenazole, miconazole, 
amiodarone, sertraline, 
sulfamethoxazole, valproic 
acid, voriconazole, 
trimethoprim, rosiglitazone, 
pioglitazone) 
CYP2C9 and 2C8 inhibitors 
(including, but not limited to 
the following: gemfibrozil, 
fluconazole, fluvoxamine, 
sulfaphenazole, miconazole, 
amiodarone, sertraline, 
sulfamethoxazole, valproic 
acid, voriconazole, 
trimethoprim, rosiglitazone, 
pioglitazone) 
 
 
Monoclonal antibody 
treatment (e.g., anti IL17 
Monoclonal antibodies 
 
Synopsis, 
Table 2-1 
footnote a, and 
Sections 7.1, 9.8, 
and 10.2.1.1 and 
10.2.1.1.1 
 
During washout, subjects may 
continue taking usual care of 
visible skin (face and scalp) for 
cosmetic reasons and of 
extremities (hand/feet) to avoid 
functional consequences on 
walking or moving their 
fingers. Subjects may shower, 
but not bathe or swim, during 
the Screening Period. After 
completing any necessary 
washout of prohibited 
medications, subjects will 
return to the site to complete 
the study eligibility 
requirements. Subjects may 
shower, but not bathe or swim. 
After completing any 
necessary washout of 
prohibited medications, 
subjects will return to the site 
to complete the study 
eligibility requirements. 
Added: Before asking a subject 
to enter washout of their 
prescription and over-the-
counter prohibited treatments, 
investigators should confirm 
the subject meets all study 
eligibility criteria, except for 
LI severity (Inclusion Criterion 
#3). Washout may be up to 
90 days. After completing any 
necessary Washout Period, 
subjects must return to the site 
within 35 days before the 
Baseline Visit within the 97-
day Screening Period to have 
their LI severity assessed and 
to complete study eligibility 
requirements 
 
During washout, subjects may 
continue their standard of 
care of visible skin (face and 
scalp) for cosmetic reasons and 
of extremities (palms/soles) to 
avoid functional consequences 
on walking or moving their 
fingers. In the US/EU, this 
may include compounded 
emollients with keratolytics 
(alpha or beta hydroxyl 
acids) and/or urea. The 
investigator should approve 
and document these 
standard-of-care treatments 
in the electronic case report 
form (eCRF). If the standard 
To ensure subjects do not 
have to repeat screening 
assessments after 
washout. 
To better define standard 
of care and prevent 
confusion. 
 
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of care treatments of the face 
and/or palms/soles contain 
prohibited medications, they 
must be stopped at the 
Baseline Visit. Subjects may 
shower, but not bathe or swim.  
Synopsis and 
Section 7.1 
Study staff will apply the first 
dose of study drug to each 
subject in the clinic on Day 1 
after Baseline measurements, 
and will record the amount of 
study drug applied. 
Study staff will choose 1 tube 
from the kit dispensed to the 
subject at that visit, and 
apply the first dose of study 
drug to each subject in the 
clinic on Day 1 after Baseline 
measurements; they will 
weigh the study tube before 
and after application to 
determine the amount used. 
 
Added: The kit dispensed at 
baseline must be weighed 
before the first tube is chosen 
for application by the study 
staff. Weight of the kits 
dispensed and returned by the 
subject during the study 
includes both tubes and 
cartons, but not leaflets, which 
need to be removed before 
weighing. The subject must be 
reminded to return the kits 
with tubes and cartons, 
whether used or not, when 
returning to the next visit.  
To clarify how amount 
of IP applied is 
determined 
To ensure kits are 
weighed appropriately 
before dispensing to the 
subject and upon return 
Synopsis 
Thereafter, each subject will 
apply approximately the same 
amount (up to 36 g) of study 
drug as for the first dose on up 
to 90% of BSA twice weekly, 
sparing the scalp, inguinal, and 
axillary areas.  
Thereafter, each subject will 
apply study drug on up to 90% 
of BSA twice weekly 3 to 4 
days apart, sparing the scalp, 
inguinal, and axillary areas. 
 
Added: Subjects with heavy 
facial hair should not apply 
IP to hair-bearing areas. 
 
Added: The study protocol 
limits application of IP to 36 g 
maximum; no additional tubes 
can be given, whether during 
the randomization period or 
the OLE period. If the study 
staff and subject note that there 
is insufficient volume for full 
body application, the subject 
should apply trifarotene cream 
sparingly twice weekly to the 
most affected areas, and 
always to the same skin areas. 
Study cream should be very 
Removed fixed 
amount/same amount 
because of the natural 
variations in the extent 
and severity of LI. 
To not apply IP to hair-
bearing areas for the first 
90 days. 
 
To address questions 
about the amount of 
cream to apply when a 
single tube does not 
seem to be enough 
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sparingly applied. Trifarotene 
cream 100 or 200 µg/g, is a 
highly potent topical retinoid 
and it is not necessary to apply 
much for efficacy; application 
of more will increase the risk 
of irritation and systemic 
penetration. 
Synopsis, 
Sections 7.1, 9.4, 
and 13.1.6.1 
During all clinic visits, the 
investigator will assess local 
tolerability (Scale: 0-3 [none, 
mild, moderate, severe]) for 
stinging/burning, pruritus, 
erythema) for each body area 
(chest/abdomen, back, arms, 
legs, and face/neck), and the 
following procedures will be 
followed: 
- 
If a score of 2 (moderate) 
is recorded on a local 
tolerability assessment 
scale (stinging/burning, 
pruritus, erythema) on any 
treated area, the study 
drug will be applied on 
that area only once 
weekly, until the score is 
back to <2. Continue to 
treat all other areas twice 
weekly provided the score 
is <2 on those areas. 
- 
If a score of 3 (severe) is 
recorded on a local 
tolerability assessment 
scale (stinging/burning, 
pruritus, erythema) on any 
treated area, the study 
drug will not be applied 
on that area until the score 
is back to <3 (i.e., “drug 
holiday”). Continue to 
treat all other areas twice 
weekly provided the score 
is <2 on those areas. 
During all clinic visits, the 
investigator will assess local 
tolerability (stinging/burning, 
pruritus, or erythema on 0-3 
scales [none, mild, moderate, 
severe]) for each body area 
(chest/abdomen, back, arms, 
legs, and face/neck), and the 
following procedures will be 
followed: 
- 
If a score of 2 (moderate) 
is recorded for any of the 
local tolerability 
assessment scales 
(stinging/burning, pruritus 
or erythema) on any 
treated area, the study 
drug will be applied on 
that area only once 
weekly, until the score is 
back to <2. Continue to 
treat all other areas twice 
weekly provided the score 
is <2 on those areas. 
- 
If a score of 3 (severe) is 
recorded for any of the 
local tolerability 
assessment scales 
(stinging/burning, pruritus 
or erythema) on any 
treated area, the study 
drug will not be applied 
on that area until the score 
is back to <3 (i.e., “drug 
holiday”). Continue to 
treat all other areas twice 
weekly provided the score 
is <2 on those areas. 
To clarify that any of the 
3 local tolerability 
conditions may warrant 
modification of dosing 
frequency  
Synopsis 
 
Added: The coronavirus 
disease 2019 (COVID-19) 
global pandemic has impacted 
the free movement of the 
world’s population, which has 
been restricted in order to 
control the spread of the 
disease. It is recommended 
 
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that all sites and subjects 
comply with the applicable 
local and federal guidelines 
regarding the necessary and 
proper precautions regarding 
COVID-19. 
Although it is preferable to 
conduct all necessary study 
assessments in person (onsite 
visits), this may not be 
possible as a result of COVID-
19 -related travel restrictions. 
To ensure the safety of 
subjects, investigators, and site 
staff, Visits 3-6 (Double –blind 
Period; Table 2-1), Visits 7-11 
(OLE Period; Table 2-2) and 
unscheduled visits may be 
conducted remotely. Screening 
and Baseline Visits must be 
performed on site only. These 
visits must be postponed or 
scheduled for when onsite 
visits can be safely conducted. 
The following assessments 
may occur remotely: 
• Safety Assessments 
o Concomitant 
medications and 
concomitant therapies. 
o Adverse Events and 
related information 
reported by the patient 
in the diary 
o General health status of 
the patient 
• Tolerability Assessments 
• Pregnancy Tests: Urine 
pregnancy tests along with 
the instructions on proper 
use will be sent to the 
subject’s home for women 
of childbearing potential 
(WOCBP). Study staff will 
instruct patient to perform 
the urine pregnancy at the 
applicable remote visit. 
• Study Medication Supply: 
As necessary and according 
to applicable local 
regulations, study 
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medication will be sent to 
subjects. 
• DLQI and EQ-5D 
Questionnaires: Quality of 
Life questionnaires should 
be completed on the day of 
the remote visit and prior to 
applying treatment (if the 
remote visit falls on a 
treatment day). 
Questionnaires may be sent 
to subjects electronically or 
via postal service, and 
completed questionnaires 
may be returned to the site 
in the same manner. If 
subjects are unable to send 
completed questionnaires to 
the site, investigators should 
ask and record the subject’s 
responses during the remote 
visit. 
• Patient Diary: Patient 
diaries may be sent to 
subjects electronically or 
via postal service. 
Completed diaries may be 
returned to the site in the 
same manner. 
Synopsis and 
Section 8.2.1 
7. Subject is not of 
childbearing potential, i.e., 
a female who has not yet 
begun menstruating or who 
is postmenopausal (absence 
of menstrual bleeding for 1 
year before Baseline, 
without any other medical 
reason), hysterectomy or 
bilateral oophorectomy, 
combined oral 
contraceptives (estrogens 
and progesterone), or 
implanted or injectable 
hormonal contraceptives 
with a stable dose for at 
least 1 month before 
Baseline; hormonal 
contraceptives must inhibit 
ovulation 
• hormonal intrauterine 
device (IUD) inserted at 
least 1 month before 
Baseline 
[…] 
7. Subject is not of 
childbearing potential, who 
is postmenopausal (absence 
of menstrual bleeding for 1 
year before Baseline, 
without any other medical 
reason), or has documented 
hysterectomy, bilateral 
salpingectomy, or bilateral 
oophorectomy. For 
individuals with 
permanent infertility due 
to an alternate medical 
cause other than the 
above, (e.g., Mullerian 
agenesis, androgen 
insensitivity), investigator 
discretion should be 
applied to determining 
study entry. 
OR 
Subject is a woman of 
childbearing potential 
(WOCBP) or a male subject 
with sexual partners capable 
of reproduction who agrees 
Clarified definition of 
WOCBP. Clarified that a 
hormonal vaginal ring or 
an IUD inserted at least 
30 days before Baseline 
is an acceptable form of 
contraception (i.e., IUD 
does not have to be 
hormonal). This change 
was requested from the 
RCH Human Research 
Ethics Committee 
(HREC) in Australia 
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• 
Note: Subjects who are 
premenstrual at Screening 
but begin menses during 
the study should follow the 
pregnancy testing schedule 
for WOCBP and must 
abstain 
from 
sexual 
intercourse while in the 
study and for at least 1 
month after the last study 
drug application. 
 
to use 2 effective forms of 
contraception during the 
study and for at least 1 
month after the last study 
drug application. The 
2 authorized forms of 
contraception are condom 
used with 1 of the following 
methods of contraception: 
• bilateral tubal ligation 
• combined oral 
contraceptives (estrogens 
and progesterone), vaginal 
ring, or implanted or 
injectable hormonal 
contraceptives with a 
stable dose for at least 
1 month before Baseline; 
hormonal contraceptives 
must inhibit ovulation 
• intrauterine device (IUD) 
inserted at least 30 days 
before Baseline 
[…] 
Synopsis and 
Section 8.2.2 
4. Subjects with a known lipid 
disorder 
(hypertriglyceridemia 
>200 mg/dL, 
hypercholesterolemia 
>250 mg/dL. 
a. Subjects whose 
triglyceride and/or total 
cholesterol are within 
normal limits with stable 
dose of lipid-lowering 
agents for at least 6 months 
can be included. 
4. Subject with fasting 
triglycerides >200 mg/dL 
or >2.25 mmol/L and/or 
total cholesterol 
>250 mg/dL or 
>6.5 mmol/L. Subjects 
whose triglycerides and/or 
total cholesterol are within 
normal limits with a stable 
dose of lipid-lowering 
agents for at least 6 months 
may be included. 
To clarify laboratory 
parameters per 
laboratory units 
 
7. Subject has a medical 
condition that potentially 
alters bone metabolism 
(e.g., osteoporosis, thyroid 
dysfunction, Cushing 
syndrome, Crohn’s disease, 
or ulcerative colitis). 
7. Subject has a medical 
condition that potentially 
alters bone metabolism 
(e.g., osteoporosis, thyroid 
dysfunction, Cushing 
syndrome, Crohn’s disease, 
or ulcerative colitis). 
Subjects with 
hypothyroidism who are 
on a stable dose of thyroid 
hormone replacement 
therapy and whose TSH is 
normal may be included. 
To permit subjects with 
hypothyroidism on stable 
treatment with normal 
TSH to be enrolled. 
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10. Subject with any of the 
following laboratory 
values at Screening: 
a. Aspartate 
aminotransferase or 
alanine aminotransferase 
>1.5 × upper limit of 
normal defined by the 
laboratory 
b. Total bilirubin 
>1.1 mg/dL at 
screening, or, in case of 
Gilbert’s syndrome total 
bilirubin >3 mg/dL 
10. Subject with any of the 
following 
laboratory 
values at Screening: 
a. Aspartate 
aminotransferase or 
alanine 
aminotransferase 
>1.5 × upper limit of 
normal (ULN) defined 
by the laboratory 
b. Total bilirubin 
>1.25 × ULN at 
Screening. Subjects 
with known Gilbert’s 
syndrome may be 
included with total 
bilirubin >1.25 × ULN  
To clarify laboratory 
parameters for exclusion 
 
13. Subject has a history of 
long QT syndrome or has 
clinically significant 
electrocardiogram (ECG) 
abnormalities, including 
clinically significant 
conduction disorders or 
significant arrhythmias, or 
QTcF interval >450 ms, 
PR interval is not between 
120 and 220 ms 
(inclusive), HR >100 bpm 
or <50 bpm, QRS interval 
>110 ms, or QT intervals 
that cannot be consistently 
analyzed 
13. Subject has a history of 
long QT syndrome or has 
clinically significant 
electrocardiogram (ECG) 
abnormalities, including 
clinically significant 
conduction disorders or 
significant arrhythmias, or 
QTcF interval >450 ms 
To clarify because there 
is a high number of left 
anterior hemiblocks 
without clinical 
significance among 
screened subjects. In 
these cases, the QRS 
Interval can be above 
normal 
Synopsis 
Name: Trifarotene (CD5789) 
cream HE1 
Double-blind Period dose, 
route, frequency: A fixed dose 
(up to 36 g per dose, 
determined at Visit 2) of 
100 µg/g or 200 µg/g applied 
topically twice weekly on up to 
90% BSA 
Open-label Extension dose, 
route, frequency: A fixed dose 
(up to 36 g per dose, 
determined at Visit 2) of 
200 µg/g applied topically 
twice weekly on up to 90% 
BSA 
Name: Trifarotene (CD5789) 
cream HE1 
Double-blind Period dose, 
route, frequency: Up to 36 g 
per dose of 100 µg/g or 
200 µg/g applied topically 
twice weekly on up to 90% 
BSA 
Open-label Extension dose, 
route, frequency: Up to 36 g 
per dose of 200 µg/g applied 
topically twice weekly on up to 
90% BSA 
Fixed dose is no longer 
applicable. 
Synopsis and 
Section 10 
 
Added: coagulation panel to all 
visits at which blood and urine 
are collected for laboratory 
tests 
To correct an omission 
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Synopsis and 
Section 10.1.1 
1. Screening: Up to 35 days 
(after signing informed 
consent, if necessary, 
washout may be up to 
3 months, and subjects 
should return to the site 
after washout to complete 
the study eligibility 
requirements). 
2. Double-blind study drug 
application: Twice weekly 
for up to 12 weeks. 
3. Optional Open-label 
Extension: Twice weekly 
for up to 12 weeks. 
4. Follow-up: 14 days after 
last study drug application. 
The maximum study duration 
for each subject is 
approximately 229 days (33 
weeks). 
The maximum treatment 
duration for each subject is 
24 weeks 
1. Screening: Up to 97 days. 
Before asking a subject to 
enter washout, 
investigators should 
confirm the subject meets 
study eligibility criteria, 
except for LI severity 
(Inclusion Criterion #3). 
Washout may be up to 
90 days. After completing 
any necessary Washout 
Period, subjects must 
return to the site within 
35 days before the 
Baseline Visit within the 
97-day Screening Period 
to have their LI severity 
assessed and study 
eligibility requirements 
determined 
2. Double-blind study drug 
application: Twice weekly 
for 90 days. 
3. Optional Open-label 
Extension: Twice weekly 
for 90 days. 
4. Follow-up: 14 days after 
last study drug application. 
The maximum treatment 
duration for each subject is 
approximately 90 days for 
subjects who choose not to 
continue into the OLE, and 
180 days for those who 
choose to continue. 
The maximum study duration 
for each subject is 
approximately 291 days 
To reflect the change 
from weeks to days, and 
to allow sufficient time 
for the washout period 
(up to 3 months) and 
adjust the study periods 
accordingly 
Synopsis and 
Section 13.1.4.1 
Secondary: The secondary 
endpoints are as follow: 
• The difference in mean 
scores between the active 
trifarotene cream HE1 and 
vehicle groups in the 
following assessment indices 
from Baseline through 
Week 12: 
▪ 5-point VIIS scale for 
scaling from Baseline 
through Week 12 
▪ Individual score for 
roughness (Scale: 0–4) 
overall 
• The difference in proportion 
of subjects with presence of 
fissures on palm/soles 
Secondary: The secondary 
endpoints are as follow: 
• The difference in mean 
scores between the active 
trifarotene cream HE1 and 
vehicle groups in the 
following assessment 
indices from Baseline 
through Day 90: 
▪ 5-point VIIS scale for 
scaling 
▪ Individual score for 
roughness (Scale: 0–4) 
• The difference in proportion 
of subjects with presence of 
fissures on palm/soles 
(presence/absence, number 
of fissures, and pain 
To reflect the change 
from weeks to days 
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(presence/absence, number 
of fissures, and pain 
associated with fissures [on a 
0-3 scale]) at Week 12 
between the active 
trifarotene cream HE1 and 
vehicle groups 
associated with fissures [on a 
0-3 scale]) at Day 90 
between the active 
trifarotene cream HE1 and 
vehicle groups 
Synopsis and 
Section 13.1.4.1 
Safety endpoints: 
− 
Local tolerability (Scale: 
0-3 [none, mild, moderate, 
severe], determined by the 
investigator) for each 
body area (chest/abdomen, 
back, legs, arms, and 
face/neck). 
Safety endpoints: 
− 
Local tolerability 
(stinging/burning, 
pruritus, or erythema on 
0-3 scales [none, mild, 
moderate, severe]) for 
each body area 
(chest/abdomen, back, 
legs, arms, and face/neck). 
 
Table 2-1 
 
Coagulation panel was added 
at Baseline, Day 30, and 
Day 90 
Dispense study drug and 
diaries was added at Day 90 
Added footnote: 
d Although it is preferable to 
conduct all necessary study 
assessments in person (on -
site visits), this may not be 
possible as a result of 
COVID-19-related travel 
restrictions. To ensure the 
safety of subjects, 
investigators, and site staff, 
Visits 3-6 and unscheduled 
visits may be conducted 
remotely. Screening and 
baseline visits must be 
performed onsite only, and 
must be postponed or 
scheduled for when onsite 
visits can be safely 
conducted. 
To clarify when 
procedures are to be 
done 
 
 
 
To provide procedural 
accommodations due to 
COVID-19 
Table 2-2 
 
Vital signs (blood pressure and 
pulse) was added at Day 150 
Ectropion score was added at 
Day 150 and removed at 
Day 134. 
Coagulation panel was added 
at Day 120 and Day 180 
 
Added footnote: 
a. Although it is preferable to 
conduct all necessary study 
assessments in person 
To clarify when 
procedures are to be 
done 
 
 
 
 
 
 
To provide procedural 
accommodations due to 
COVID 19 
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(onsite visits), this may not 
be possible as a result of 
COVID-19-related travel 
restrictions. To ensure the 
safety of subjects, 
investigators, and site staff, 
Visits 7-11 and 
unscheduled visits may be 
conducted remotely. 
Section 5.2 
Throughout the 30 clinical 
studies that comprise the 
clinical development program 
for CD5789 topical products, 
1976 subjects were exposed to 
CD5789 
Throughout the 31 completed 
clinical studies that comprise 
the clinical development 
program for CD5789 topical 
products, 4878 subjects were 
exposed to CD5789 
Updated for latest data 
Section 6.2 
To assess safety for up to 
24 weeks of dosing with open-
label trifarotene cream HE1 
200 µg/g. 
To assess safety for up to 
180 days of dosing with 
trifarotene cream HE1 
200 µg/g. 
Subjects will only 
receive open-label 
trifarotene cream HE1 
200 µg/g for 90 days. 
Section 10.2.4  
Subjects who successfully 
complete (i.e., have reliable 
visit attendance and 
compliance with IP 
application, in the 
investigator’s opinion) the 
initial 12-weeks of double-
blind treatment may choose to 
continue into an optional. 
During the OLE, subjects will 
return to the site at Weeks 14, 
16, 20, 24, and 26. Additional 
PK samples will be drawn at 
Week 16 and Week 24 from all 
subjects who continue into the 
OLE (Table 2-2). 
Subjects who successfully 
complete (i.e., have reliable 
visit attendance and 
compliance with IP 
application, in the 
investigator’s opinion) the 
initial 90 days of double-blind 
treatment may choose to 
continue into an optional 90 
day OLE with trifarotene 
cream HE1 200 µg/g. During 
the OLE, subjects will return 
to the site at Days 104, 120, 
150, 180, and 194. Additional 
PK samples will be drawn at 
Days 120 and 180 from all 
subjects who continue into the 
OLE. 
To be more precise with 
timing 
Section 7.2 
To ensure safety, this phase 2 
study will begin with an initial 
cohort 
(Cohort 
A) 
of 
15 subjects randomized 1:1:1 to 
trifarotene 
cream 
HE1 
100 µg/g, 200 µg/g, or vehicle 
to be applied twice weekly. 
 
To ensure safety, this phase 2 
study will begin with an initial 
cohort (Cohort A) of subjects 
randomized 1:1:1 to trifarotene 
cream HE1 100 µg/g, 
200 µg/g, or vehicle to be 
applied twice weekly. 
 
To allow flexibility in 
enrollment numbers. 
Section 8.4 
8.4 Discontinuation of Study 
Intervention 
Discontinuation from study 
treatment does not mean 
withdrawal from the study, and 
the remaining study procedures 
should be completed as 
indicated in the study protocol 
(see Section 10.2.4.5) 
8.4. 
Subject 
Discontinuation of Study 
Intervention and Stopping 
Rules 
 
Subjects who discontinue the 
study treatment will be asked 
to return to the site to 
undergo ET procedures 
(Section 10.2.4.6) 
To clarify and to link to 
correct section. 
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Section 9.1 
Added: Sodium benzoate, 
butylhydroxytoluene, and 
propylene glycol are excipients 
known to have a recognized 
action or effect to be declared 
on the labeling, according to 
the CHMP Annex to the 
excipients in labeling and 
package leaflet of medicinal 
products for human use 
(EMA/CHMP/302620/2017). 
These 3 excipients are being 
used in the trifarotene 
formulation at standard 
concentrations and are all 
necessary to ensure adequate 
protection of the formulation 
along and the shelf life. 
To fulfill request by 
French CA 
Section 9.2 
For the Double-blind 
Treatment Period, a fixed dose 
(determined at Visit 2) of 
trifarotene cream HE1 
100 µg/g or 200 µg/g or 
vehicle cream will be applied 
topically twice weekly on up to 
90% BSA of each subject. 
For the Double-blind 
Treatment Period, trifarotene 
cream HE1 100 µg/g or 200 
µg/g or vehicle cream will be 
applied topically twice weekly 
on up to 90% BSA of each 
subject. 
To remove fixed dose 
and allow dosing to be 
based on BSA 
Subjects will continue 
treatment for up to 12 weeks 
Subjects will apply treatment 
for 90 days. 
Clarification and 
precision of timing 
For the OLE, all subjects will 
receive trifarotene cream HE1 
200 µg/g and apply it the same 
fixed dose same manner as in 
the Double-blind Period for an 
additional 12 weeks. 
For the OLE, all subjects will 
receive open-label trifarotene 
cream HE1 200 µg/g and apply 
it in the same manner as in the 
Double-blind Period for an 
additional 90 days. 
Clarification and 
precision of timing 
Section 9.3 
After Day 1, on which the 
study staff will apply the first 
administration of IP in the 
clinic, each subject will apply 
approximately the same 
amount of IP on up to 90% of 
their BSA twice weekly. It is 
suggested that each subject 
choose 2 specific days per 
week, at least 3 days apart, on 
which to apply their IP (e.g., 
Tuesday and Friday), and 
maintain that regimen 
throughout the study. 
Subjects should not apply the 
IP on visit days until after the 
visit, unless they participate in 
the PK substudy, in which case 
the IP will be applied in the 
clinic on Day 30 after the 
predose PK blood draw. 
After Day 1, on which the 
study staff will apply the first 
administration of IP in the 
clinic, each subject will apply 
IP on up to 90% of their BSA 
twice weekly. It is suggested 
that each subject choose 2 
specific days per week, 3 to 4 
days apart, on which to apply 
their IP, and maintain that 
regimen each week throughout 
the study (Table 9-1). 
Subjects whose treatment 
day falls on a scheduled 
study visit day should not 
apply the IP until after the 
visit. 
Subjects who participate in 
the PK substudy should have 
their Day 30 Visit scheduled 
on a treatment day, in which 
case the IP will be applied in 
To specify that treatment 
applications should be 3 
to 4 days apart, and that 
PK substudy subjects 
must visit the clinic on 
Day 30. 
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the clinic on Day 30 after the 
predose PK blood draw. 
Added: If the Day 30 Visit 
cannot be scheduled on a 
treatment day, the 
investigators should contact 
the medical monitor. 
If a subject misses an IP 
application, they should apply 
the IP as soon as they 
remember and record the 
date/time in the subject diary. 
Added: The next application 
should be 3 to 4 days apart 
and subjects should continue 
according to their new 
regimen. 
To specify treatment day 
interval 
Subjects who continue into the 
Open-label Extension will 
receive trifarotene cream HE1 
200 µg/g and apply the same 
fixed dose in the same manner 
as in the Double-blind Period 
for an additional 12 weeks 
Subjects who continue into the 
OLE will receive trifarotene 
cream HE1 200 µg/g and apply 
in the same manner as in the 
Double-blind Period for 
90 days 
To remove fixed dose 
and allow dosing to be 
based on BSA 
Added: Table 9-1: Sample 
Twice-weekly Dosing 
Schedule 
To provide a visual 
example of dosing 
schedule options 
Section 9.4 
Deleted Section 9.4.1 Stopping 
Rules 
Section was redundant 
with Section 8.4 
Section 9.5 
Study personnel will assess 
treatment compliance with IP 
regimens by weighing IP tubes 
before dispensing and upon 
return and by questioning the 
subject, at every 
postrandomization visit. A 
participant is compliant with 
study product if he or she takes 
at least 80% of the scheduled 
doses as assessed by diary 
entries, supplemented by tube 
weight. A subject who is not 
compliant (used 80–120% of 
IP tubes) will be counseled at 
each visit on the importance of 
using the IP as instructed. 
Study personnel will assess 
treatment compliance with IP 
regimens by weighing kits 
(tubes and boxes, but not 
leaflets) before dispensing and 
upon return and by questioning 
the subject at every post 
randomization visit. At 
baseline, the kit should be 
weighed before choosing the 
first tube for application by 
the study staff. A participant 
is compliant with study 
product if he or she takes at 
least 80% of the scheduled 
doses as assessed by diary 
entries, supplemented by 
amount of cream used 
derived from weighing the IP 
kits. A subject who is not 
compliant (for example, used 
<80 or >120% of IP tubes 
[which is more than what can 
be dispensed per tube at each 
application]), the subject will 
be counseled at each visit on 
the importance of using the IP 
as instructed. 
Section 10.2.2.7 
Subjects will have up to 7 days 
to decide to enter the OLE; if 
the subject chooses to continue 
into OLE, the following 
If the subject chooses to 
continue into OLE, the 
Subjects must decide by 
Day 90 if they want to 
continue into the OLE. 
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additional procedures will be 
done: 
….Remind subjects that at 
least 24 hours must have 
elapsed since IP application 
before the PK draws at the 
Week 16 and Week 24 
Visits, and not to apply IP 
on visit days until after the 
visits. 
following additional 
procedures will be done 
Revised: Remind subjects that 
at least 24 hours must have 
elapsed since IP application 
before the PK draws at the 
Day 120 and Day 180 Visits, 
and not to apply IP on visit 
days until after the visits. 
Section 10.2.4.1 
Clinic staff will telephone 
subject to assess safety (AEs) 
and to record concomitant 
medications/therapies. Staff 
will to instruct subject on study 
drug application, to advise 
subjects regarding permitted 
emollient(s) for use on 
nontreatment days (use of 
emollient(s) on study drug 
treatment days within 4 hours 
of study drug application is 
prohibited), and to remind 
subjects not to apply IP on 
visit days until after the visit. 
Clinic staff will telephone 
subject to assess safety (AEs) 
and to record concomitant 
medications/therapies. Staff 
will to instruct subject on study 
drug application, to advise 
subjects regarding permitted 
emollient(s) for use on 
nontreatment days (use of 
emollient(s) on study drug 
treatment days within 4 hours 
of study drug application is 
prohibited), and to remind 
subjects not to apply IP on 
visit Days 120 and 180 until 
after the visit. 
Day 120 and Day 180 
include PK draws, so IP 
should be applied after 
the visit is complete. 
Section 10.2.4.2 
12. Instruct subject on study 
drug application, and 
advise subjects regarding 
permitted emollient(s) for 
use on nontreatment days; 
use of emollient(s) and/or 
sunscreen on study drug 
treatment days within 4 
hours before or after study 
drug application is 
prohibited. Remind 
subjects that 24 hours must 
have elapsed since IP 
application before the 
subject’s next visit. 
Subjects should not apply 
IP on visit days until after 
the visit at the Week 16 
and Week 24 Visits, and 
not to apply IP on visit 
days until after the visit. 
12. Instruct subject on study 
drug application, and 
advise subjects regarding 
permitted emollient(s) for 
use on nontreatment 
days; use of emollient(s) 
and/or sunscreen on study 
drug treatment days 
within 4 hours before or 
after study drug 
application is prohibited. 
Remind subjects that 24 
hours must have elapsed 
since IP application 
before the subject’s next 
visit (Day 120) and if the 
Day 120 visit coincides 
with a treatment day, 
wait until after the visit is 
complete to apply IP. 
To specify timing of IP 
application 
Section 10.2.4.5 
 
Added: 13. Remind subjects 
that 24 hours must 
have elapsed since 
IP application 
before the 
subject’s next visit 
(Day 180) and if 
the Day 180 visit 
coincides with a 
To specify timing of IP 
application 
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treatment day, wait 
until after the visit 
is complete to 
apply IP. 
Section 10.2.4.7 
10.2.4.7 Follow-up Evaluation 
– Open-Label Extension 
Week 26/Visit 11) 
10.2.4.7 Follow-up Evaluation 
– Open-Label Extension (Day 
194 or 14 days after End of 
Open label Treatment /Visit 
11) 
To be more specific 
Section 10.4 and 
Synopsis 
 
New section: 
10.4. 
Procedural 
Adjustments Due to 
COVID-19 
The coronavirus (COVID-19) 
global pandemic has impacted 
the free movement of the 
world’s population, which has 
been restricted to control the 
spread of the disease. It is 
recommended that all sites and 
subjects comply with the 
applicable local and federal 
guidelines regarding the 
necessary and proper 
precautions regarding 
COVID-19. 
 
Although it is preferable to 
conduct all necessary study 
assessments in person (onsite 
visits), this may not be 
possible as a result of 
COVID-19-related travel 
restrictions. To ensure the 
safety of subjects, 
investigators, and site staff, 
Visits 3-6 (Double-blind 
Period; Table 2-1), Visits 7-11 
(OLE Period; Table 2-2) and 
unscheduled visits may be 
conducted remotely. Screening 
and baseline visits must be 
performed onsite only, and 
must be postponed or 
scheduled for when onsite 
visits can be safely conducted. 
Appendix B details the 
procedures when it is 
inadvisable or not possible to 
conduct an onsite study visit. 
To provide 
procedures/schedule for 
COVID-19 issues. 
Section 11.2.1 
 
Added: The Tolerability 
Assessments Form at each visit 
collects a numeric severity 
score by body area for 
To specify how 
tolerability assessments 
are collected. 
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erythema, stinging/burning, 
and pruritus. 
In addition, if skin irritation is 
more than the expected 
erythema, stinging/burning, 
and pruritus with the 
application of this topical 
retinoid (i.e., clinically 
relevant), please enter the 
application site reactions in the 
Adverse Event description 
section. If a diagnosis is 
known, record the diagnosis. If 
a diagnosis is known and there 
are other signs/symptoms that 
are not generally part of the 
main diagnosis, record the 
diagnosis and each 
sign/symptom on a separate 
line. If a diagnosis is not 
known, record each 
sign/symptom on a separate 
line. Examples are allergic 
contact dermatitis, sunburn, 
skin erosion, and swelling. 
Section 11.2.2.3 
Dose reduced 
An 
indication that a medication 
schedule was modified by 
subtraction, either by changing 
or reducing the frequency, 
strength, or amount. 
Dose reduced 
An 
indication that a medication 
schedule was modified by 
reducing the frequency of 
application 
Dose cannot be reduced 
by changing the strength 
or amount. 
Section 11.3.2 
These findings must be 
reported on the Exposure in 
Utero form and forwarded to 
the designated individual(s). 
The event meets the SAE 
criterion only if it results in a 
spontaneous abortion or a 
congenital anomaly.  
Deleted: The investigator 
should contact the designated 
individual(s) who receive SAE 
notification and record 
information related to the 
pregnancy on an SAE and AE 
form (entering the event 
temporarily as nonserious on 
both forms) provided by the 
sponsor or its designee. 
These findings must be 
reported on the Pregnancy 
Data Collection Form and 
forwarded to Premier 
Research PV. The event meets 
the SAE criterion only if it 
results in a spontaneous 
abortion or a congenital 
anomaly. In such case an 
additional form (Serious 
Adverse Event Report Form) 
must be filled out by the 
Investigator and provided to 
Premier Research 
Repetitive; AE forms not 
collected by 
pharmacovigilance 
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Pharmacovigilance within 
24h of knowledge of the 
pregnancy’s serious outcome. 
Section 12 
 
Added names and 
qualifications of the DSMB 
The DSMB committee 
members are as follow: 
• Univ. Prof. Dr. med. 
Steffen Emmert, Director 
at Clinic and Polyclinic 
for Dermatology & 
Venereology 
• Jeffrey Louis Sugarman, 
M.D., Ph.D. 
• Moise L. Levy, MD, 
Pediatric Dermatologist 
• Gabriele Accetta, Ph.D. 
Biostatistician 
In accordance with 
French Ethics 
Committee 
Section 13.1.1 
 
Added: Deviations related to 
COVID-19 will also be 
evaluated in determining Per-
protocol Population eligibility. 
To provide COVID-19 
information 
Section 13.1.4 
 
Added: Efficacy endpoints will 
be based on investigator 
assessment.  
To specify that 
investigator assessment 
is primary for efficacy 
Section 13.1.4.5 
 
Added: Thorough assessment 
on the extent of missing data 
and procedural adjustments 
due to COVID-19 as it pertains 
to the primary and secondary 
efficacy endpoints will be 
conducted ahead of database 
lock and additional sensitivity 
analyses may be performed. 
Full details will be 
documented in the SAP. 
To provide contingency 
methods for COVID-19 
issues 
Section 14.3 
 
Added: Subjects may only be 
rescreened once 30 days or 
more after the original 
Screening Visit. 
Subjects should be 
rescreened if the reason 
for SF is reasonably 
believed to have been 
resolved. 
Appendix B 
 
Added new Appendix B with 
Procedural Adjustments for 
COVID-19. 
To provide guidance for 
remote visits during 
COVID-19 
 
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AMENDED PROTOCOL 
The following are the amended protocol and appendices, including all revisions specified above. 
 
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4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABBREVIATION 
EXPLANATION 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse events of special interest 
ATC 
anatomical therapeutic chemical 
AUC 
area-under-the-curve 
BMI 
body mass index 
BSA 
body surface area 
CFR 
code of federal regulations 
CI 
confidence interval 
Cmax 
maximum concentration 
COVID-19 
Coronavirus disease 2019 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
DBP 
diastolic blood pressure 
DLQI 
dermatology life quality index 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end-of-treatment 
ESS 
ectropion severity score 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GEE 
generalized estimating equations 
HR 
heart rate 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification 
IEC 
independent ethics committee 
IGA  
Investigator’s Global Assessment 
IND 
investigational new drug 
IP 
investigational product 
IRB 
institutional review board 
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ABBREVIATION 
EXPLANATION 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IWRS 
interactive web response system 
LI 
lamellar ichthyosis 
MedDRA 
medical dictionary for regulatory activities 
mITT 
modified intent-to-treat 
MMRM 
mixed model of repeated measures 
NCA 
noncompartmental analysis 
OC 
observed case 
OLE 
open-label extension 
OTC 
over-the-counter 
PG 
propylene glycol 
PK 
Pharmacokinetic(s) 
PoC 
proof-of-concept 
PP 
per-protocol 
QTc 
QT interval corrected for heart rate 
RARγ 
retinoid acid receptor γ  
RBC 
red blood count 
RR 
respiratory rate 
RXR 
retinoid X receptor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
Tmax 
time of Cmax 
TSH 
thyroid-stimulating hormone 
UAE 
unexpected adverse event 
UADR 
unexpected adverse drug reaction 
ULN 
upper limit of normal 
US 
United States 
UV 
ultraviolet 
VIIS 
Visual Index for Ichthyosis Severity 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
women of childbearing potential 
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5. INTRODUCTION 
5.1. Background and Rationale 
The ichthyoses comprise a large group of skin scaling disorders with diverse etiology. The 
stereotypic pathophysiology is epidermal hyperplasia and the formation of excess stratum corneum 
accompanied by abnormal (delayed and/or disordered) desquamation, with visible accumulation 
of squames (scales) on the skin’s surface – the clinical hallmark of all the ichthyoses. 
Lamellar ichthyosis (LI) is recognized as a severe form of ichthyosis that persists throughout life. 
During the first postnatal weeks, the hyperkeratotic membrane patients are typically born with is 
gradually shed, and is replaced by scaling and lichenification that involves the entire body 
including the intertriginous areas, palms, soles, and scalp. While usually not life threatening, LI 
can result in disability, partial deafness, poor adaptation to environmental conditions (due to 
hypohydrosis), severe discomfort (pruritus, fissuring of the skin) and significant psychosocial 
impact. 
Lamellar ichthyosis, a member of the nonsyndromic autosomal recessive congenital ichthyosis 
group of ichthyoses, has an incidence of 1 per 100,000-300,000 live births.1 Lamellar ichthyosis 
is undoubtedly a rare disease. 
Therapeutic approaches for LI are mainly based on the use of topical emollients, keratolytic agents 
(urea, lactic acid, salicylic acid), topical retinoids and, in severe cases, oral retinoids.2,3 
Oral retinoid usage in LI is mainly based on case reports and case series.4,5,6,7,8 The mechanism of 
retinoid action involves modulation of keratinocyte differentiation, keratinocyte hyperproliferation 
and tissue infiltration by inflammatory cells. Systemic retinoids (such as acitretin, etretinate, or 
isotretinoin) have been found to be efficacious in the treatment of severe ichthyoses, especially in 
LI.6 
Vahlquist, et al (2008)3 report that by combining 2 or more keratolytic agents and moisturizers in 
the same lipophilic cream base, it is often possible to achieve additive or even synergistic effects 
in LI without the need to use irritating concentrations of either agent alone. In a double-blind trial 
of 4 different cream mixtures in 20 patients with LI, a mixture of 5% lactic acid and 20% propylene 
glycol (PG) in a semi-occlusive cream for 4 weeks twice daily was significantly more effective 
than 20% PG or 5% urea alone in the same vehicle.9 Although the treatments were well tolerated, 
an efficient removal of hyperkeratosis without correcting the underlying biochemical defect in LI 
is likely to deteriorate the patient’s intrinsic barrier problem, because an excessive production of 
corneocytes probably represents a homeostatic response to an ineffective barrier. Indeed, 
transepidermal water loss increased after successful treatment of LI with either topical 
keratolytics9 or oral retinoid.10 Although this may not be noticeable by the patient, even minor 
deteriorations in the barrier function can enhance transcutaneous penetration of active cream 
ingredients or other topically applied chemicals, which is a matter of special concern in children. 
Accordingly, α-hydroxy acids and salicylic acid should not be used at all in babies and only with 
great caution when treating large, eroded skin areas in adult patients.11,12 
Many patients with LI use pumice, foot files, or gentle rubbing of the skin after a hot bath or a 
shower to remove scales and hyperkeratosis. Overnight occlusion of problematic skin areas with 
plastic sheets after applying a thick layer of emollient or keratolytic agents is another way of 
potentiating therapy, especially on the scalp, which is notoriously difficult to treat. Although 
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usually effective, all these remedies may further damage the skin barrier and lead to exaggerated 
epidermal proliferation, erythema, painful erosions and increased transcutaneous penetration.3 
Based on this information, LI has significant unmet medical need for safer and more effective 
therapies. 
5.1.1 CD5789 (Trifarotene) 
CD5789 is a new chemical entity discovered by Galderma R&D SNC and formulated for topical 
application. It is a novel retinoid acid receptor γ (RARγ) agonist, characterized by its high 
specificity to this receptor. CD5789 is selective for RARγ over RARα and RARβ (approximately 
50- and 8-fold, respectively), with no retinoid X receptor (RXR) activity. CD5789 is currently 
under clinical development for the topical treatment of various dermatoses, including acne vulgaris 
and LI. 
The pharmacological retinoid-like properties of CD5789 were confirmed in in vitro and in vivo 
models, showing its interest for its development in the treatment of LI. Therefore, it may have an 
effect on the differentiation and hyperproliferation of keratinocytes, and consequently improve 
hyperkeratotic skin of patients with lamellar ichthyosis. 
Within the overall acne development program at Galderma, CD5789 has been tested in different 
pharmaceutical forms for topical administration. As of 15-Jan-2018, 6 different formulations have 
been evaluated: a solution, a gel and 4 creams (CD5789 cream A, CD5789 cream B, 
CD5789 cream HE1 concept and its optimized version, cream HE1), with different concentrations 
(up to 400 µg/g). Therefore, several formulations at different CD5789 concentrations have been 
tested in nonclinical and clinical development programs. 
Galderma decided to develop a new cream formulation that might better address the issue of skin 
dryness in patients with LI. This formulation was named “Cream HE1 concept.” It has been 
preliminarily investigated in an exploratory trial in psoriasis at concentrations up to 400 μg/g 
(RD.03.SRE.40204E). In a proof-of-concept study (RD.03.SRE.40181E), positive results were 
also obtained in patients with LI with CD5789 cream (up to 100 µg/g) that was effective in 
decreasing scaling and roughness. Based on these results, a new CD5789 formulation (cream HE1) 
was developed for further clinical investigations in LI. The formulation cream HE1 was developed 
with the objective to obtain a formulation with appropriate stability of the active ingredient and in 
which CD5789 would be homogeneously dissolved in the oily phase at a higher concentration 
compared to the cream formulation used in the acne program. Cream HE1 contains 100, 200, or 
400 μg/g (0.01% [w/w], 0.02% [w/w], 0.04% [w/w], respectively) of CD5789. 
Galderma has granted Mayne Pharma LLC an exclusive license to develop and commercialize 
CD5789 (trifarotene) for LI and other orphan diseases; therefore, the LI indication is no longer 
pursued by Galderma. 
5.2. Clinical Experience 
The cream HE1 differs from the CD5789 cream used to treat acne vulgaris in that it contains fewer 
excipients with drying effects and therefore may be better suited for patients with LI. 
Throughout the 31 completed clinical studies that comprise the clinical development program for 
CD5789 topical products, 4878 subjects were exposed to CD5789. No systemic safety concerns 
related to CD5789 gel or creams, or cream HE1 at doses up to 400 μg/g were reported. The subjects 
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were exposed to a maximal total CD5789 dose of 36 g/day (Investigator’s Brochure for CD5789 
Cutaneous Formulation). 
One study was conducted with CD5789 50 μg/g, 100 μg/g, and placebo in subjects with ichthyosis 
(Study RD.03.SRE.40181E). Among 31 subjects treated in this study, 17 were treated with 
CD5789 100 μg/g, and 14 were treated with 50 μg/g (all subjects received placebo [vehicle] on the 
contralateral zone). Mean (SD) baseline IGA score was 5.7 ± 1.6 among the 31 subjects. 
Improvement in the investigator’s global assessment (IGA) of scaling and roughness was observed 
by Day 8 with both doses. The primary efficacy criterion was the change in IGA from the Baseline 
Visit (Day 1) to the Final Visit (Day 43). At Endpoint (intent-to-treat population, last observation 
carried forward [LOCF]), the CD5789 100 μg/g group had a statistically significant decrease from 
Baseline in IGA compared with Vehicle (-1.4±2.2; p=0.018) (Investigator’s Brochure for CD5789 
Cutaneous Formulation). 
The CD5789 PK profile was also investigated using cream HE1 (Study GD.03.SRE.103813) in 
36 healthy volunteers of Japanese and non-Japanese origin. Subjects were treated daily on up to 
90% of body surface area (BSA) for 29 days with up to 36 g of cream formulation. Both CD5789 
100 μg/g and 200 μg/g cream HE1 were investigated. Plasma PK assessment demonstrated that 
repeated topical applications of CD5789 cream HE1 resulted in low and similar CD5789 systemic 
levels in all treatment groups. In addition, no systemic safety concerns were raised from this 
healthy volunteer study in which cream HE1 200 μg/g was applied daily under maximal-use 
conditions on almost the full body. In this study, however, the level of irritation resulted in the 
need to decrease the frequency of application to twice weekly (Investigator’s Brochure for CD5789 
Cutaneous Formulation). However, it is possible that absorption in subjects with LI may be greater 
than in healthy volunteers, due to the skin being compromised. 
Based on these data, both the 100 µg/g and 200 µg/g doses showed an acceptable safety profile 
and will be used in this phase 2 LI study, to determine which of the 2 doses is most effective. The 
open-label extension (OLE) will evaluate the long-term safety of the higher dose in this patient 
population.  
5.3. Summary of Potential Risks and Benefits 
Although the primary objective of this study is safety in the patient population with LI, the 
potential benefits of study participation are that subjects with LI may experience a reduction in 
their LI symptoms as a result of treatment with trifarotene (CD5789) cream HE1. No other benefits 
of participation are anticipated. 
The potential risks of study participation include those associated with exposure to trifarotene 
(CD5789) cream HE1 and the risks of medical evaluation, including venipuncture.  
Animal studies with CD5789 have shown reproductive toxicity in the embryo-fetal studies. 
Despite low systemic levels with the CD5789 concentration of 50 μg/g used in patients with acne, 
CD5789 must not be administered during pregnancy. 
When CD5789 is used in the other formulations and/or for other indications and/or with higher 
concentrations or higher application surface areas, the potential risk of teratogenicity needs to be 
considered as the safety margin may be lower. Depending on the study population and conditions 
mentioned above, or other specific requirements, the appropriate contraception method is 
described in this protocol. 
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It is unknown whether CD5789 or its metabolites are excreted in human milk. A risk to the 
newborns/infants cannot be excluded. Lactating women are not eligible for the clinical study. 
Certain cutaneous signs and symptoms of irritation and localized reactions at the application site 
such as erythema, scaling, dryness, stinging/burning, and pruritus may be experienced with use of 
CD5789. Depending upon the severity of these side effects, subjects may be instructed to reduce 
the frequency of application or to discontinue use.  
Trifarotene cream contains propylene glycol that is mildly irritant to the skin, eyes, and mucous 
membranes. Trifarotene (CD5789) cream HE1 also contains butylated hydroxytoluene that may 
cause local skin reactions (e.g., contact dermatitis), or irritation to the eyes and mucous membranes 
and sodium benzoate that is mildly irritant to the skin, eyes, and mucous membranes. 
CD 5789 is mildly irritant to the skin, eyes, and mucous membranes. Therefore, it should not come 
into contact with the eyes, mouth, or mucous membranes.  
There is a potential risk of skin sensitization. If a reaction suggesting sensitivity to trifarotene 
(CD5789) cream HE1 occurs, the use of the trifarotene cream HE1 must be discontinued. 
There is a potential risk of photosensitivity disorder (sunburn). Excessive exposure to sunlight or 
ultraviolet (UV) radiation (i.e., occupational exposure to the sun, planned holidays in the sun 
during the study, phototherapy, tanning salon) must be avoided during the studies. In addition, 
subjects should take protective measures such as applying sunscreen (except within 4 hours before 
and/or 4 hours after study drug application), and/or wearing protective clothing (e.g., long sleeves, 
hats, and covering legs and feet) and/or seeking shade or shelter from the sun. 
As reported with other topical retinoids, there is a potential risk of pigmentation disorders. 
No clinically significant systemic risks associated with CD5789 have been identified. Given the 
mechanism of action for CD5789 Cream HE1, it is assumed that efficacy will increase as the dose 
is increased. As such, the 200 µg/g dose was selected for the OLE based on its previously 
established safety profile, expected superiority to placebo and 100 µg/g. However the Data Safety 
Monitoring Board (DSMB), who will routinely review aggregate safety and tolerability data, as 
well as any safety concerns brought to the their attention by the study investigators or medical 
monitor, may determine that the study should be modified, placed on hold, or stopped if serious 
safety issues are discovered. This is applicable for both the double-blind portion and OLE. If the 
200 µg/g dose in raises any safety concerns, the protocol will be amended and the dose will be 
reduced. 
A summary of the pharmaceutical properties and known potential risks of trifarotene (CD5789) 
cream HE1 is provided in the current version of the investigator’s brochure (IB). The investigator 
must become familiar with all sections of the trifarotene (CD5789) cream IB before the start of the 
study. 
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6. OBJECTIVES 
6.1. Primary Objective 
The primary objective is to compare the safety and efficacy of 2 concentrations of trifarotene cream 
HE1 versus vehicle in subjects with moderate to severe autosomal recessive ichthyosis with 
lamellar scale, also known as lamellar ichthyosis (LI) after 90 days of treatment. 
6.2. Secondary Objectives 
The secondary objectives are as follows: 
• To assess systemic exposure to trifarotene and its major metabolites after topical 
application of the investigational product (IP) on up to 90% BSA twice weekly. 
• To assess safety for up to 180 days of dosing with trifarotene cream HE1 200 µg/g. 
7. STUDY DESIGN 
7.1. Overall Study Design and Plan 
The first part of this study is a phase 2, randomized, 2-cohort, double-blind, vehicle-controlled, 
multicenter study of the safety, tolerability, PK, and efficacy study of trifarotene cream HE1 
100 µg/g and 200 µg/g in subjects with LI for 90 days. Subjects who complete the randomized, 
double-blind, vehicle-controlled period of the study will be eligible to continue into an open-label 
extension (OLE) and be treated with trifarotene cream HE1 200 µg/g for an additional 90 days. 
The randomized, double-blind, vehicle-controlled period of the study in subjects with moderate to 
severe LI (i.e., 3–4 on a 5-point Investigator Global Assessment [IGA] scale where 0 = clear; 
1 = almost clear; 2 = mild; 3 = moderate; and 4 = severe), is designed to compare the safety of 
2 doses of trifarotene cream HE1 with that of vehicle in the treatment of LI.  
Upon signing informed consent and entering the Screening Period, subjects will stop using 
physical and medical treatments for LI, including balneotherapy, and may begin to washout 
prohibited topical and systemic treatments with designated washout periods (Table 9-2), as 
applicable. Washout may be up to 90 days, as necessary. 
During washout, subjects may continue taking their standard of care of visible skin (face and scalp) 
for cosmetic reasons and of extremities (palms/soles) to avoid functional consequences on walking 
or moving their fingers. In the US/EU, this may include compounded emollients with keratolytics 
(alpha or beta hydroxyl acids) and/or urea. The investigator should approve and document these 
standard-of-care treatments in the electronic case report form (eCRF). If the standard of care 
treatments of the face and/or palms/soles contain prohibited medications, they must be stopped at 
the Baseline Visit. Subjects may shower, but not bathe or swim. The IGA will be evaluated on the 
rest of the body at Baseline. After completing any necessary washout of prohibited medications, 
subjects will return to the site to have their LI assessed and to complete the study eligibility 
requirements. 
Study drug will be packaged in 50-g tubes from which up to 36 g of IP may be dispensed per 
application, i.e., the maximum dose per application.  
Study staff will choose 1 tube from the kit dispensed to the subject at that visit, and apply the first 
dose of study drug to each subject in the clinic on Day 1 after Baseline measurements; they will 
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weigh the study tube before and after application to determine the amount used. If the product will 
be applied at home by someone other than the study subject, it is recommended that person assist 
with application at the first visit to learn how the IP is applied. 
The kit dispensed at baseline must be weighed before the first tube is chosen for application by 
the study staff. Weight of the kits dispensed and returned by the subject during the study includes 
both tubes and cartons, but not leaflets, which need to be removed before weighing. The subject 
must be reminded to return the kits with tubes and cartons, whether used or not, when returning to 
the next visit. 
Thereafter, subjects will apply up to 36 g of study drug on up to 90% of BSA twice weekly, sparing 
the scalp, inguinal, and axillary areas. Subjects with heavy facial hair should not apply IP to 
hair-bearing areas. Subjects will receive an adequate number of tubes to use 1 tube per application 
and will use a new tube for each treatment day. Subjects may use less than the full amount of IP 
in a tube. 
The study protocol limits application of IP to 36 g maximum; no additional tubes can be given, 
whether during the randomization period or the OLE period. If the study staff and subject note that 
there is insufficient volume for full body application, the subject should apply trifarotene cream 
sparingly twice weekly to the most affected areas, and always to the same skin areas. Study cream 
should be very sparingly applied. Trifarotene cream 100 or 200 µg/g, is a highly potent topical 
retinoid and it is not necessary to apply much for efficacy; application of more will increase the 
risk of irritation and systemic penetration. 
Enrolled subjects will receive treatment for 90 days. 
The first cohort of subjects (Cohort A) will randomize adults (≥18 years old) in a 1:1:1 ratio to 
trifarotene (CD5789) cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle. 
After the initial 15 subjects complete at least 28 days of treatment, an independent DSMB will 
review aggregate safety and tolerability data (including PK and electrocardiogram [ECG] data). If 
no safety issues are identified, additional subjects will be allowed to enroll in Cohort B. Subjects 
in Cohort B will be randomized 1:1:1 to trifarotene cream HE1 100 µg/g, trifarotene cream HE1 
200 µg/g, or vehicle and similarly treated twice weekly for up to 90 days in the same manner as 
subjects in Cohort A.  
Cohort A will continue enrolling subjects until the DSMB considers it safe to open recruitment in 
Cohort B. 
All subjects will be given diaries in which to record study drug application (days/times and any 
areas of skin not treated [e.g., due to local reactions]), any application site reactions, adverse events 
(AEs), and concomitant medications used. Subjects will also be advised on permitted emollient(s) 
and/or sunscreen(s) use on nontreatment days during the study; use of emollient(s) and/or 
sunscreen on study drug treatment days within 4 hours before or after study drug application is 
prohibited. 
At all sites with photographic capability, photographs will be taken as source data to support 
scoring at Baseline, Day 30, and Day 90. A central reader who will not be an investigator in the 
study will review the photographs to assess consistency of investigator scoring of LI severity as a 
quality check. Photographs may also be used for scientific publication purposes. Subjects will sign 
a separate, optional, photographic informed consent form (ICF).  
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Samples for PK will be drawn from all subjects at Baseline and at each clinic visit, as indicated in 
the Schedule of Events (Table 2-1). Visits for PK must occur at least 24 hours after the last 
application of the IP to avoid contamination of the blood samples with any IP that may have 
remained in the skin after the last application. Subjects should not apply IP on visit days until after 
the visit. 
In addition, a PK substudy will be conducted on Days 1 and 30 at sites with the capability to 
conduct it. Participation in the PK substudy will be optional and will include at least 30 subjects. 
Subjects who participate in the PK substudy will come from both study cohorts and will undergo 
serial blood sampling predose and at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1 and Day 30. 
Trough levels will be drawn for all subjects at specified time points. For the subjects in the PK 
substudy, postdose ECGs will be performed at each serial blood draw on Day 1 and Day 30. 
Efficacy will be assessed by the number of subjects in each treatment group who achieve “success” 
defined as clear/almost clear overall and at least a 50% reduction from Baseline at 
Day 90/end-of-treatment (EOT) in the Double-blind Period on the 5-point IGA scale (i.e., 
0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe). In addition, efficacy criteria 
include assessment scales for palm/sole, scaling, roughness, fissuring, and the Dermatology Life 
Quality Index (DLQI), and the EQ-5D Quality of Life (QoL) Questionnaire. Ectropion Severity 
Scores (ESS) between the active trifarotene cream HE1 and vehicle groups will be an exploratory 
endpoint. 
Plasma concentrations of CD5789 and its major metabolites will be measured. 
Safety will be assessed by evaluating reported adverse events (AEs), changes in clinical laboratory 
test results, vital sign measurements, physical examinations, 12-lead ECGs, and local tolerability 
(stinging/burning, pruritus, or erythema on 0-3 scales [none, mild, moderate, severe]). 
All AEs observed by the study personnel or reported by the subject during the study (from the time 
of the signing of the informed consent through the post-treatment visit) will be documented. 
Topical trifarotene cream HE1 was generally well tolerated in recently completed phase 3 pivotal 
and long-term safety studies in subjects aged 9 years and older with acne vulgaris. The local 
tolerability of the trifarotene cream HE1 formulation in subjects with LI is unknown and will be 
monitored during the study. Subjects will receive information on study drug use and stopping rules 
and will be instructed to contact the site with any safety/tolerability issues. Study personnel will 
telephone subjects in between scheduled visits (i.e., at Day 7 and Day 45) to assess safety; an 
unscheduled clinic visit may be performed, if necessary. At each clinic visit, the investigator will 
assess local tolerability (stinging/burning, pruritus, or erythema on 0-3 scales [none, mild, 
moderate, severe]) on each treated body area (chest/abdomen, back, legs, arms, and face/neck). 
All subjects (Cohort A and Cohort B) who complete the 90-day Double-blind Treatment Period 
will be eligible to enroll in the 90-day OLE. Subjects in the OLE will receive open-label trifarotene 
cream HE1 200 µg/g twice weekly. During the OLE, subjects will return to the site at Days 104, 
120, 150, 180, and 194. Additional PK samples will be drawn at Days 120 and 180 from all subjects 
who continue into the OLE (Table 2-2).  
Stopping rules and treatment modification will be defined at the subject level based on local 
tolerability, selected laboratory parameters, and AEs; see Section 9.4. 
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Figure 7-1: 
Double-blind Study Design 
 
 
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Optional 
photographs at 
Baseline, 
Day 30, and 
Day90 
Screening 
No safety issues 
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Figure 7-2: 
Open-label Study Design 
 
 
Double-blind 
Study Day 90 (±14 days) 
= first visit of open-label 
extension with 
trifarotene 200 µgig 
Continue through 90 days of treatment 
Follow-up Day 192 or 14 days after End of Treatment 
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7.2. Rationale and Discussion of Study Design 
The first part of this study is a randomized, double-blind, placebo-controlled study of the safety, 
tolerability, PK, and efficacy study of trifarotene cream HE1 100 µg/g and 200 µg/g in subjects 
with LI.  
In a previous proof-of-concept study (RD.03.SRE.40181E), subjects with LI applied trifarotene 
50 and 100 µg/g cream to limited areas and results demonstrated a decrease in scaling with good 
safety and tolerance. In a phase 1 study in healthy Japanese and non-Japanese subjects 
(RD.03.SPR.103813), repeated topical applications of trifarotene (CD5789 cream HE1) 100 µg/g 
and 200 µg/g resulted in low and similar CD5789 systemic levels in all the cohorts. These studies 
are fully described in the current IB. 
To ensure safety, this phase 2 study will begin with an initial cohort (Cohort A) of subjects 
randomized 1:1:1 to trifarotene cream HE1 100 µg/g, 200 µg/g, or vehicle to be applied twice 
weekly. An independent DSMB will review aggregate safety and tolerability data from the initial 
15 subjects’ first 28 days of treatment. If no safety issues are identified, additional subjects will be 
allowed to enroll in Cohort B and randomized to trifarotene cream HE1 100 µg/g, trifarotene cream 
HE1 200 µg/g, or vehicle and treated twice weekly in the same manner as subjects in Cohort A. 
All subjects in the randomized, double-blind portion of the study will be treated for up to 12 weeks 
and data on safety, tolerability, PK, and efficacy collected.  
Subjects who successfully complete the initial 90 days of double-blind treatment will have the 
option to enter an OLE with trifarotene cream HE1 200 ug/g twice weekly for up to 90 days.  
The OLE will collect additional safety, tolerability, PK, and efficacy data. As designed, this study 
will provide important information on safety, tolerability, and PK with dosing of subjects with LI 
for up to 180 days.  
The protocol includes appropriate monitoring for safety and tolerability. If subjects develop 
significant local application site reactions or tolerability issues, the protocol includes language for 
reducing the frequency of application or halting study drug application until the symptoms abate. 
7.3. Selection of Doses in the Study 
Based on the results from Study RD.03.SRE.40181E and Study SRE.103813, the doses of 
100 µg/g and 200 µg/g were selected for further investigation in subjects with moderate to severe 
LI to determine which of the 2 doses is most effective. The proof-of-concept (PoC) study 
demonstrated efficacious treatment with 100 µg/g in adults. The PK and tolerability study showed 
that, when the frequency of application was reduced from daily to twice weekly, the 200 µg/g 
cream HE1 had good local tolerability. 
Therefore, the current study will use these doses compared with vehicle, applied twice weekly on 
up to approximately 90% BSA in subjects with LI. The OLE will evaluate the long-term safety of 
the higher dose in this patient population. 
7.4. Study Sites 
The study will take place at approximately 40 sites in North America, Europe, Israel, and Australia.  
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7.5. Point of Contact 
A point of contact will be identified to provide information to subjects about where to obtain 
information on the study, the rights of subjects, and whom to contact in case of a study-related 
injury. This information will be provided in the subject information and informed consent form 
(ICF). 
7.6. End of Study Definition 
A clinical trial is considered completed when the last participant’s last study visit has occurred. 
8. SUBJECT POPULATION 
8.1. Selection of Study Population and Diagnosis 
Diagnosis of LI for the purposes of this study will be a clinical diagnosis. Although some younger 
subjects may have had genetic testing, older subjects may not.  
While LI is a rare disease and subject enrollment may be challenging, due to possible bias 
introduced by including household members in the same study, it is recommended that only 
1 household member be included in the study to maintain the blind and ensure all assessments are 
independent. 
8.2. Study Entry Criteria 
8.2.1 Inclusion Criteria 
A subject will be eligible for study participation if he or she meets all of the following criteria: 
1. Subject is ≥18 years old.  
2. Subject has known diagnosis of LI.  
3. Subject has moderate to severe (IGA 3–4) LI on the IGA of LI severity.  
4. Subject has signed an ICF at Screening before any investigational procedures.  
5. Subject who is participating in optional photography has signed a photography ICF. 
6. Subject who is participating in the optional PK substudy has signed a PK ICF. 
7. Subject is not of childbearing potential, i.e., a female who is postmenopausal (absence of 
menstrual bleeding for 1 year before Baseline, without any other medical reason), or has 
documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). For 
individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry.  
OR  
Subject is a woman of childbearing potential (WOCBP) or a male subject with sexual partners 
capable of reproduction who agrees to use 2 effective forms of contraception during the study 
and for at least 1 month after the last study drug application. The 2 authorized forms of 
contraception are condom used with 1 of the following methods of contraception: 
• bilateral tubal ligation 
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• combined oral contraceptives (estrogens and progesterone), vaginal ring, or implanted or 
injectable hormonal contraceptives with a stable dose for at least 1 month before Baseline; 
hormonal contraceptives must inhibit ovulation 
• intrauterine device (IUD) inserted at least 1 month before Baseline 
OR 
Agrees to abstain from heterosexual intercourse during study participation and for 1 month 
after the last application of study drug and to use a highly effective contraceptive as backup if 
he or she becomes sexually active during the study. Abstinence is only acceptable if this is the 
subject’s usual lifestyle. Periodic abstinence (calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method are not acceptable methods of contraception. 
AND 
Male subjects may not donate sperm during the study and for at least 1 month after the last 
study drug application. 
8. Women of childbearing potential must be nonlactating and have negative pregnancy test results 
at Screening (serum) and on Day 1 before study drug administration (urine). 
9. Subject is reliable and capable of adhering to the protocol and visit schedule, in the 
investigator’s judgment, and has signed informed consent. 
10. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin). 
8.2.2 Exclusion Criteria 
A subject will be excluded from the study if he or she meets any of the following criteria: 
1. Subject has any variant of ichthyosis other than LI or another disorder of keratinization, 
including syndromic ichthyoses.  
2. Subject has current moderate or severe stinging/burning at Screening. 
3. Subject has an ongoing cutaneous infection or any other significant concomitant skin disease 
(other than the LI) which, in the investigator’s opinion, may interfere with the study 
assessments. 
4. Subject with fasting triglycerides >200 mg/dL or >2.25 mmol/L and/or total cholesterol 
>250 mg/dL or >6.5 mmol/L. Subjects whose triglycerides and/or total cholesterol are within 
normal limits with a stable dose of lipid-lowering agents for at least 6 months may be included. 
5. Subject was previously treated with trifarotene/CD5789 in an acne or ichthyosis study.  
6. Subject has any other significant concomitant disease, or poorly controlled medical condition 
other than LI that in the investigator’s opinion may put him or her at risk if he or she takes part 
in the study, and/or that may interfere with the study assessments. 
7. Subject has a medical condition that potentially alters bone metabolism (e.g., osteoporosis, 
thyroid dysfunction, Cushing syndrome, Crohn’s disease, or ulcerative colitis). Subjects with 
hypothyroidism who are on a stable dose of thyroid hormone replacement therapy and whose 
thyroid-stimulating hormone (TSH) is normal may be included. 
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8. Subject is being treated for major depression disorder and/or has a history of major depression 
or suicide attempt requiring hospitalization, medications, and close psychiatric surveillance to 
prevent suicide attempts.   
9. Subject with positive serology for hepatitis B surface antigen, hepatitis C, or are known to be 
HIV positive or to have AIDS at Screening. 
10. Subject with any of the following laboratory values at Screening: 
a. Aspartate aminotransferase or alanine aminotransferase >1.5 × upper limit of normal 
(ULN) defined by the laboratory 
b. Total bilirubin >1.25 × ULN at Screening. Subjects with known 1 mg/dL or, in case of 
Gilbert’s syndrome may be included with total bilirubin >1.25 × ULN 
c. Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women 
d. Platelets <150 × 109/L or >400 × 109/L. 
11. Subject has any clinically other significant abnormal laboratory value (hematology, chemistry, 
or urinalysis) at Screening that, in the investigator’s opinion, may put the subject at risk if he 
or she takes part in the study, and/or that may interfere with the study assessments. 
12. Subject has had recent systemic malignancy (e.g., within 5 years) with exception of 
nonmelanoma skin cancer or cervical intraepithelial neoplasia of Grade 1 who are >6 months 
post-treatment. 
13. Subject has a history of long QT syndrome or has clinically significant electrocardiogram 
(ECG) abnormalities, including clinically significant conduction disorders or significant 
arrhythmias, or QTcF interval >450 ms. 
14. Subject has a known allergy or sensitivity to any of the components of the investigational 
products.  
15. Subject has been exposed to excessive UV radiations on the treated zones within 1 month 
before Baseline visit or is planning intensive UV exposure during the study (e.g., occupational 
exposure to the sun, sunbathing, phototherapy, etc.). 
16. Subject is inherently sensitive to sunlight. 
17. Subject is unable or unwilling to stop use of topical or systemic retinoids. 
18. Subject is presumed to be abusing drug or alcohol at Screening or Baseline Visits based on 
medical history or current clinical symptoms. 
19. Subject is participating in another interventional clinical trial. 
20. Subject is institutionalized. 
21. Subject is in any way related to the sponsor, investigator, or site personnel. 
8.3. Premature Subject Withdrawal 
All subjects will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. The investigator should make every reasonable 
attempt to keep subjects in the study; however, subjects must be withdrawn from the study if they 
withdraw consent to participate. Investigators must attempt to contact subjects who fail to attend 
scheduled visits by telephone or other means to exclude the possibility of an AE being the cause 
of withdrawal. Should this be the cause, the AE must be documented, reported, and followed as 
described in Section 11.2. 
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The sponsor reserves the right to request the withdrawal of a subject due to protocol deviations or 
other reasons. 
The investigator also has the right to withdraw subjects from the study at any time for lack of 
therapeutic effect that is intolerable or otherwise unacceptable to the subject, for intolerable or 
unacceptable AEs, intercurrent illness, noncompliance with study procedures, administrative 
reasons, or in the investigator’s opinion, to protect the subject’s best interest. 
If a subject is withdrawn before completing the study, the reason for withdrawal and the date of 
discontinuation will be recorded on the appropriate page of the electronic case report form (eCRF). 
Whenever possible and reasonable, the evaluations that were to be conducted at the completion of 
the study should be performed at the time of premature discontinuation. 
8.4. Subject Discontinuation of Study Intervention and Stopping Rules 
Subjects who discontinue the study treatment will be asked to return to the study site to undergo 
ET procedures (see Section 10.2.4.6). If a clinically significant finding is identified (including, but 
not limited to changes from Baseline) after enrollment, the investigator or qualified designee will 
determine if any change in participant management is needed. Any new clinically relevant finding 
will be reported as an AE. 
An investigator must discontinue a participant’s study treatment for any of the following reasons: 
• Pregnancy 
• Significant study intervention noncompliance  
• If any clinical AE, laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would result in a significant burden to the 
participant 
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for discontinuation of study treatment will be recorded on the eCRF. Subjects who sign 
the informed consent form and are randomized but do not receive the study intervention may be 
replaced. Subjects who sign the informed consent form, are randomized, and receive the study 
intervention, and subsequently discontinue study treatment, or are withdrawn from the study will 
not be replaced. 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site will attempt to contact the participant and reschedule the missed visit and counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study. 
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• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
8.5. Subject Replacement Criteria 
Withdrawn subjects will not be replaced. If a substantial number of subjects are withdrawn from 
the study, the sponsor will evaluate the need for developing replacement criteria. 
Randomized subjects withdrawn from the study may not reenter. The subject number for a 
withdrawn subject will not be reassigned to another subject. 
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9. TREATMENTS 
9.1. Identification of Investigational Product(s) 
Trifarotene cream HE1 is a cream containing 100 or 200 μg/g (0.01% [w/w] or 0.02% [w/w], 
respectively) of CD5789 and the following excipients: purified water, propylene glycol, allantoin, 
glycerin, medium-chain triglycerides, polypropylene glycol 15 stearyl ether, cyclomethicone, 
phenoxyethanol, copolymer of acrylamide and sodium acryloyldimethyltaurate, dispersion 40% in 
isohexadecane (simulgel 600 PHA), sodium benzoate, butylated hydroxytoluene, and 
gluconolactone. It is an RARγ agonist characterized by its high specificity to this receptor. 
Sodium benzoate, butylhydroxytoluene, and propylene glycol are excipients known to have a 
recognized action or effect to be declared on the labeling, according to the Committee for 
Medicinal Products for Human Use Annex to the excipients in labeling and package leaflet of 
medicinal products for human use (EMA/CHMP/302620/2017). These 3 excipients are being used 
in the trifarotene formulation at standard concentrations and are all necessary to ensure adequate 
protection of the formulation along and the shelf life. 
Vehicle contains the same ingredients, without the CD5789. 
Trifarotene cream HE1 and vehicle will be provided in cream form for topical application and will 
be supplied in 50-g tubes from which a maximum of 36 g of IP may be extracted. 
Trifarotene cream HE1 and vehicle will be supplied by G. Production, Inc. (Galderma) in 
Baie-D'Urfé, QC, Canada. 
9.2. Treatments Administered  
For the Double-blind Treatment Period, trifarotene cream HE1 100 µg/g or 200 µg/g or vehicle 
cream will be applied topically twice weekly on up to 90% BSA of each subject. The IP should be 
applied thinly and gently rubbed in. 
Study staff will apply the first administration of IP in the clinic on Day 1 after Baseline 
measurements, and the amount of IP used will be measured (i.e., 50-g tube will be measured before 
and after application to determine amount used). If the product will be applied at home by someone 
other than the study subject, it is recommended that this person assist with application at the first 
visit to learn how the IP is applied. 
The maximum dose per application is 36 g (i.e., 1 tube). Subjects will receive an adequate number 
of tubes to use 1 tube per application and will use a new tube for each treatment day. Subjects may 
use less than full amount of product in a tube. Subjects will apply treatment for 90 days. 
After the Day 1 visit, subjects will apply up to 36 g of study drug as for the first dose on up to 90% 
of BSA twice weekly, sparing the scalp, inguinal, and axillary areas. Subjects with heavy facial 
hair should not apply IP to hair-bearing areas. Persons other than the study subject applying the 
study drug must wash their hands after application or use disposable vinyl gloves. In addition, a 
long-handled applicator will be provided for application on the back. The applicator must be 
washed with warm water and soap after every application.  
Trifarotene cream should not come into contact with the eyes, mouth, angles of the nose, or mucous 
membranes. For the ectropion treatment, Q-tips are recommended for precise application on 
eyelids, without contact to the eye or conjunctiva. If the IP gets into the eye, it must be flushed 
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immediately with warm water. In case of eye irritation, the subject must be seen by an 
ophthalmologist.  
For the OLE, all subjects will receive open-label trifarotene cream HE1 200 µg/g and apply it in 
the same manner as in the Double-blind Period for an additional 90 days. 
Visits for PK must occur at least 24 hours after the last application of the IP to avoid contamination 
of the blood samples with any IP that may have remained in the skin after the last application. 
Subjects should not apply IP on visit days until after the visit, unless they are participating in the 
PK substudy, in which case the IP will be applied in the clinic on Day 1 and Day 30 after the blood 
draw. Among subjects participating in the PK substudy, ensure the PK line is inserted before study 
drug application to prevent contamination with the IP and to protect the skin around the needle 
insertion point from study drug application. 
9.3. Selection of Timing of Dose for Each Subject 
Subjects will be randomized in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g or 200 µg/g or 
vehicle cream. After Day 1, on which the study staff will apply the first administration of IP in the 
clinic, each subject will apply IP on up to 90% of their BSA twice weekly. It is suggested that each 
subject choose 2 specific days per week 3 to 4 days apart on which to apply their IP, and maintain 
that regimen each week throughout the study (Table 9-1). Visits for PK must occur at least 24 
hours after the last application of the IP to avoid contamination of the blood samples with any IP 
that may have remained on the skin after the last application. Subjects whose treatment day falls 
on a scheduled study visit day should not apply the IP until after the visit. Subjects who participate 
in the PK substudy should have their Day 30 Visit scheduled on a treatment day, in which case the 
IP will be applied in the clinic on Day 30 after the predose PK blood draw. If the Day 30 Visit 
cannot be scheduled on a treatment day, the investigator should contact the medical monitor.  
All subjects will be provided with diaries in which to record study drug application (days/times) 
and any areas of skin not treated (e.g., due to local reactions). 
If a subject misses an IP application, they should apply the IP as soon as they remember and record 
the date/time in the subject diary. The next application should be 3 to 4 days apart, and subjects 
should continue according to their new regimen. 
Subjects should not shower, bathe, or swim for at least 4 hours after IP application. No occlusive 
dressings should be used on areas to which IP is applied. 
Subjects who continue into the OLE will receive trifarotene cream HE1 200 µg/g and apply it in 
the same manner as in the Double-blind Period for an additional 90 days.
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Table 9-1: 
Sample Twice-weekly Dosing Schedule 
 
Week 1 
Subsequent Weeks 
 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
Option 1 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
Option 2 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Option 3 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
Option 4 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Option 5 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Option 6 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
Option 7 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
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9.4. Dose Adjustment Criteria 
Local tolerance will be followed very carefully during the study. Subjects will receive information 
on study drug use and stopping rules and will be instructed to contact the site with any 
safety/tolerability issues. Study personnel will telephone subjects in between scheduled visits (i.e., 
at Day 7 and Day 45) to assess safety; an unscheduled clinic visit may be performed, if necessary. 
During all clinic visits, the investigator will assess local tolerability (stinging/burning, pruritus, or 
erythema on 0-3 scales [none, mild, moderate, severe]) for each treated body area (chest/abdomen, 
back, arms, legs, and face/neck), and the following procedures will be followed: 
− If a score of 2 (moderate) is recorded for any of the local tolerability assessment scales 
(stinging/burning, pruritus, or erythema) on any treated area (e.g., the face), the study drug 
will be applied on this area only once weekly, until the score returns to <2. Continue to 
treat all other areas twice weekly provided the score is <2 on those areas. 
− If a score of 3 (severe) is recorded for any of the local tolerability assessment scales 
(stinging/burning, pruritus, or erythema) on any treated area, the study drug will not be 
applied on that area until the score is back to <3 (i.e., “drug holiday”). Continue to treat all 
other areas twice weekly provided the score is <2 on those areas. 
Any changes in dosing must be documented in the subject diary and the eCRF. 
9.5. Treatment Compliance 
Subjects will be asked to record their twice-weekly applications of IP in the diary during both the 
Double-blind Period and the OLE. Deviations from the planned doses (missed dose or timing) will 
be recorded on the subject’s eCRF. Study personnel will review diaries at each visit and diaries 
will be collected as source documents. Information from subject diaries will be transcribed on the 
appropriate eCRF pages for documentation of subject compliance with the IP. 
Study personnel will assess treatment compliance with IP regimens by weighing kits (tubes and 
boxes, but not leaflets) before dispensing and upon return and by questioning the subject, at every 
postrandomization visit. At Baseline, the kit should be weighed before choosing the first tube for 
application by the study staff. A participant is compliant with study product if he or she takes at 
least 80% of the scheduled doses as assessed by diary entries, supplemented by amount of cream 
used derived from weighing the IP kits. A subject who is not compliant (for example, used 
80-120% of IP tubes [which is more than what can be dispensed per tube at each application]) will 
be counseled at each visit on the importance of using the IP as instructed.  
Subjects who taper to once-weekly application or who take a “drug holiday” for tolerability will 
not be reported as having deviated from the protocol (see Section 9.4 for dose adjustment and 
stopping rules); any changes in dosing must be documented in the subject diary and the eCRF. 
9.6. Method of Assigning Subjects to Treatment Groups 
In the double-blind, parallel-group, randomized period of the study, subjects who meet study entry 
criteria will be randomly assigned in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g or 200 µg/g 
or vehicle cream. The randomization schedule will be computer generated using a permuted block 
algorithm and will randomly allocate IP to randomization numbers. The randomization numbers 
will be assigned sequentially through a central interactive web response system (IWRS) as subjects 
are entered into the study. Study center will not be a blocking factor in the randomization schedule. 
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Premier Research will prepare the randomization schedule before the start of the study. No one 
involved in the study performance will have access to the randomization schedule before the 
official unblinding of treatment assignments. No subject will be randomized into this study more 
than once. 
In the OLE, all subjects will receive trifarotene cream HE1 200 µg/g. 
9.7. Blinding and Unblinding Treatment Assignment 
All subjects, investigators, and study personnel involved in the conduct of the Double-blind Period 
of the study, including data management, will be blinded to treatment assignment with the 
exception of a specified unblinded statistician and programmer from Premier Research who will 
have access to the randomization code. The statistician will have access to unblinded data if there 
is an unblinded DSMB review.  
Study personnel will make every effort to safeguard the integrity of the study blind to minimize 
bias in the conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
subject’s treatment assignment. 
The investigator may discuss with the medical monitor in advance of unblinding a subject, if 
possible, if it is not deemed an emergency. However, the investigator has the ultimate decision for 
unblinding a subject for medical treatment and no procedures will prevent or delay necessary 
unblinding in an emergency for the subject’s safety. For emergency unblinding, study personnel 
will use the IWRS code. If the investigator is not able to discuss treatment unblinding in advance, 
then he/she must notify the medical monitor as soon as possible about the unblinding incident 
without revealing the subject’s treatment assignment.  
The investigator or designee must record the date and reason for treatment unblinding on the 
appropriate eCRF for that subject. In all cases that are not emergencies, the investigator must 
discuss the event with the medical monitor prior to unblinding the subject’s treatment assignment. 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
that subject’s treatment assignment without unblinding the treatment assignments for the 
remaining subjects in the study. Thus, the overall study blind will not be compromised. If a 
subject’s treatment assignment is unblinded, he/she may or may not be asked to withdraw from 
the study. The investigator will make this decision after consultation with the medical monitor. 
The primary analysis period is the first 90 days of treatment (i.e., the Double-blind Period). Overall 
unblinding will take place at the end of the Double-blind Period of the study only after database 
lock has been achieved. A second analysis will take place for endpoints assessed from Day 90 
through the OLE. 
9.8. Permitted and Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate eCRF. 
Upon signing informed consent and entering the Screening Period, subjects may begin a Washout 
Period of up to 90 days. Participants will stop using physical and medical treatments for LI, 
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including balneotherapy, as well as the following prohibited medications, as applicable (Table 
9-2). 
Table 9-2: 
Washout Periods for Prohibited Medicationsa 
Medication 
Washout Period 
Topical Treatments 
Corticosteroids (except inhaled and ophthalmic corticoids) 
2 weeks 
Retinoids (e.g., tretinoin, tazarotene) 
4 weeks 
Vitamin D analogues 
2 weeks 
Immunosuppressants (e.g., tacrolimus) 
2 weeks 
Antracen derivatives, tar and salicylic preparations 
2 weeks 
Keratolytics (such as urea, lactic acid, propylene glycol, salicylic acid) except keratolytic 
shampoo 
2 weeks 
Systemic treatments 
Retinoids 
8 weeks 
Oral Vitamin A supplementation more than 3500 IU per day 
2 weeks 
Medication interfering with bone activity, e.g., corticosteroids, thyroid hormones unless the 
dose is stable and TSH is normal, cytotoxics, bisphosphonates, selective estrogen receptor 
modulators (SERM), teriparatide, calcitonins, tetracyclines, quinolones, thiazides, long-term 
salicylates, heparin, theophylline, barbiturates, colchicines. Vitamin D analogs taken at stable 
dose for at least 1 month are allowed) 
8 weeks 
QT-prolonging drugs 
5 half lives 
CYP Enzyme inducers (such as rifampicine, phenytoin, carbamazepine, phenobarbital, 
St. John’s Wort) 
3 months 
CYP2C9 and 2C8 inhibitors (including, but not limited to the following: gemfibrozil, 
fluconazole, fluvoxamine, sulfaphenazole, miconazole, amiodarone, sertraline, 
sulfamethoxazole, valproic acid, voriconazole, trimethoprim, rosiglitazone, pioglitazone) 
5 half lives 
Monoclonal antibodies 
5 half lives 
a 
Note: This list applies to both prescription and over-the-counter (OTC) medications
During washout, subjects may continue their standard of care of visible skin (face and scalp) for 
cosmetic reasons and of extremities (palms/soles) to avoid functional consequences on walking or 
moving their fingers. In the US/EU, this may include compounded emollients with keratolytics 
(alpha or beta hydroxyl acids) and/or urea. The investigator should approve and document these 
standard-of-care treatments in the eCRF. If the standard of care treatments of the face and/or 
palms/soles contain prohibited medications, they must be stopped at the Baseline Visit. Subjects 
may shower, but not bathe or swim. The IGA will be evaluated on the rest of the body at Baseline. 
After completing any necessary washout of prohibited medications, subjects will return to the site 
to complete the study eligibility requirements. 
9.8.1 Permitted Therapies 
Subjects will be advised on permitted emollient(s) for use as often as needed on nontreatment days 
during the study; on treatment days, the use of emollient(s) is permitted except within 4 hours 
before or after study drug application. Similarly, protective sunscreen should be applied as often 
as needed, except within 4 hours before or after study drug application. Subjects may use their 
standard of care treatment on their faces and/or palms/soles after the Day 30 assessment if they 
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experience a worsening of IGA in those areas. In the US/EU, this may include compounded 
emollients with keratolytics (alpha or beta hydroxyl acids) and/or urea. These standard of care 
treatments should be approved by the investigator and documented in the eCRF.  
Subjects who enter the OLE must stop standard of care treatment. If they experience a worsening 
of IGA they may use standard of care treatment on their faces and/or palms/soles after the Day 120 
Visit if the standard of care does not contain prohibited medications. If those standard of care 
treatments include prohibited medications, the subject should be discontinued from the study. 
Other concomitant medications are allowed (e.g., analgesics, antihistamines), but should be limited 
to those medications considered necessary. All concomitant medications, both prescribed and 
over-the-counter, should be recorded in the eCRF. 
9.8.2 Prohibited Therapies 
The medications listed in Table 9-2 are prohibited during the study. Balneotherapy is also 
prohibited during the Screening Period and during the study. 
Subjects may not use concomitant keratolytics such as urea, salicylic acid, alpha, or beta 
hydroxyacids. Subjects may not use topical or systemic retinoids. Subjects may not take more than 
3500 IU/day Vitamin A (e.g., as in a multivitamin). Use of benzoyl peroxide is permitted on 
nontreatment days for subjects with concomitant acne only); it must not be applied on treatment 
days due to risk of inactivation of trifarotene by benzoyl peroxide. 
Subjects receiving excluded therapies will be ineligible for study enrollment or for continued 
treatment in the study, at the investigator’s discretion with consultation with Mayne Pharma LLC 
and the medical monitor. For enrolled subjects who require prescription of a systemic azole, the 
principal investigator should discuss with the medical monitor whether the subject may continue 
in the study.  
9.8.3 Restrictions 
Subjects should not shower, bathe, or swim for at least 4 hours after study drug application. No 
occlusive dressings should be applied to areas where study drug was applied.  
Subjects should only use investigator-approved emollients and should not use them on treatment 
days within at least 4 hours before and after study drug application.  
In addition, subjects should take protective measures to avoid exposure of treated areas to sunlight, 
such as applying sunscreen (except within 4 hours before and/or 4 hours after study drug 
application), and/or wearing protective clothing (e.g., long sleeves, hats, and covering legs and 
feet), and/or seeking shade or shelter from the sun. 
9.9. Treatment after End of Study 
After the end of the study, each subject will be treated according to standard clinical practice. 
9.10. Dispensing and Storage 
The test product supplied by Mayne Pharma LLC is to be used exclusively in the clinical study 
according to the instructions of this protocol. The investigator is responsible for dispensing the IP 
according to the dosage scheme and for ensuring proper storage of the IP. 
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The investigator must confirm the receipt of the IP with his or her signature. A copy of this receipt 
must be kept by the investigator and another copy will be stored at Premier Research. Until the IP 
is dispensed to the subjects, it must be stored at 20–25°C (68–77°F), with excursions permitted to 
15–30°C (59–86°F); do not freeze and with the tube kept tightly closed in a securely locked area 
that is not generally accessible. 
The key to the storage area is to be kept by the investigator or designee responsible for the IP. The 
store will be accessible only to those persons authorized by the investigator to dispense the IP. 
9.11. Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the IPs, including the date, quantity, batch or code number, and identification of 
subjects (subject number) who received the IP. The investigator will not supply the IP to any 
person except those named as subinvestigators on the Form Food and Drug Administration 
(FDA) 1572, designated study personnel, and subjects in this study. The investigator will not 
dispense the IP from any study sites other than those listed on the Form FDA 1572. Investigational 
product(s) may not be relabeled or reassigned for use by other subjects. If any of the IP is not 
dispensed, is lost, stolen, spilled, unusable, or is received in a damaged container, this information 
must be documented and reported to the sponsor and appropriate regulatory agencies, as required. 
Each subject will be given enough tubes of study drug to apply up to 1 tube-full (approximately 
36 g of clinical trial material) per treatment day until the next study visit. Tubes will be packed 
2 to a carton, and each subject will receive enough cartons to have the maximum number of tubes 
needed until the next study visit. The number of study drug tubes the subject needs to provide 
enough IP until the next visit is shown in Table 9-3.  
Table 9-3: 
Amount of Study Drug Needed Per Visit 
Treatment Period 
Number of Cartons 
Number of Tubes 
Double-blind Treatment Period 
Baseline 
3 
6 
Day 14 
4 
8 
Day 30 
6 
12 
Day 60 
6 
12 
OLE 
Day 90 
3 
6 
Day 104 
4 
8 
Day 120 
6 
12 
Day 150 
6 
12 
Each carton will be weighed before dispensing (tubes and boxes, but not leaflets) and subjects are 
to bring all cartons and tubes back at each study visit, whereupon study staff will weigh them again 
to estimate study drug use and compliance. 
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Upon completion of the study, the IP (partly used, unused, and empty tubes) must be left in the 
original packaging and returned to the sponsor or designee for destruction. 
9.12. Labeling and Packaging 
Labeling and packaging of IP will be performed by Catalent Pharma Solutions.  
Tubes will be packaged in cartons comprising 2 tubes each. Tubes will be labeled with inner and 
outer booklet labels, and carton number. Each carton will also be labeled with inner and outer 
booklet labels and numbered.  
9.12.1 Labeling 
The tubes will have a label affixed that meets the applicable regulatory requirements and may 
include, but is not limited to, the following: subject identifier, IP name, lot number, protocol 
number, carton number, caution statement, storage, and sponsor identification. 
All empty packaging or packaging containing unused tubes should be saved for final disposition 
by the sponsor or contract pharmacy. 
Final labeling will comply with the regulatory requirements of each country where the study will 
be conducted. 
9.12.2 Packaging 
Investigational products will be packaged in high-density polyethylene, 35×100 mm tubes 
weighing 50 g from which a maximum of 36 g of IP can be extracted. Trifarotene cream HE1 and 
vehicle will be packaged so as to be blinded to the investigator, the study clinic personnel, and the 
subjects. 
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10. STUDY PROCEDURES 
Subjects must provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
Subjects who agree to participate in the photography and/or PK substudy must provide written 
informed consent before photographs or serial blood samples are collected. 
For the timing of assessments and procedures throughout the study, refer to the Schedule of 
Events (Section 2.2). Throughout the study, every reasonable effort should be made by study 
personnel to follow the timing of assessments and procedures in the Schedule of Events for each 
subject. If a subject misses a study visit for any reason, the visit should be rescheduled as soon as 
possible. 
10.1. Study Duration 
10.1.1 Overall Study Schedule 
The planned sequence and maximum duration of the study periods for each subject will be as 
follows: 
1. Screening: up to 97 days. Before asking a subject to enter washout, investigators should 
confirm the subject meets study eligibility criteria, except for LI severity (inclusion 
criterion #3). Washout may be up to 90 days. After completing any necessary Washout 
Period, subjects must return to the site within 35 days before the Baseline Visit within the 
97-day Screening Period to have their LI severity assessed and study eligibility 
requirements determined.  
2. Double-blind treatment: Twice weekly for 90 days. 
3. Optional Open-label Extension treatment: Twice weekly for 90 days. 
4. Follow-up: 14 days after last study drug application. 
The maximum treatment duration for each subject is approximately 90 days for subjects who 
choose not to continue into the OLE, and 180 days for those who choose to continue.  
The maximum study duration for each subject is approximately 291 days. 
10.2. Study Periods and Visits 
It is suggested that quality of life assessments be conducted first to avoid any bias, and that the 
IGA be recorded as the first LI assessment at every visit. 
10.2.1 Screening and Washout 
10.2.1.1 Screening Visit (Visit 1) 
Written informed consent must be obtained before any study-related procedures are performed. 
Before asking a subject to enter Washout (Section 10.2.1.1.1), investigators should confirm the 
subject meets study eligibility criteria, except for LI severity (Inclusion Criterion #3). Washout 
may be up to 90 days. After completing any necessary Washout Period, subjects must return to the 
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site within 35 days before the Baseline Visit within the 97-day Screening Period to have their LI 
severity assessed and study eligibility requirements determined. 
The following procedures will be performed during Screening: 
1. Obtain written informed consent.
2. Assign a screening number when a subject begins screening.
3. Assess inclusion/exclusion criteria.
4. Collect demographic information.
5. Record medical history, including current therapies (e.g., prescription and nonprescription
medications).
6. Perform a physical examination.
7. Measure vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and
pulse).
8. Measure height, weight, and calculate body mass index (BMI).
9. Record IGA.
10. Record VIIS.
11. Record roughness assessment.
12. Record palm/sole assessment.
13. Record palm/sole assessment of fissuring.
14. Record ectropion score.
15. Perform a 12-lead ECG.
16. Collect blood and urine for laboratory tests, coagulation panel, and serology.
17. Perform serum pregnancy test for WOCBP.
18. Record concomitant medications.
Procedures for rescreening subjects who initially fail to meet study entry criteria are described in 
Section 14.3. 
10.2.1.1.1 Washout 
Upon signing informed consent and entering the Screening Period, subjects will stop using 
physical and medical treatments for LI, including balneotherapy, and begin to washout the 
prohibited topical and systemic treatments with designated washout periods, as applicable (Table 
9-2). Washout may be up to 90 days, as necessary.
After completing any necessary Washout Period, subjects must return to the site within 35 days 
before the Baseline Visit within the 97-day Screening Period to have their LI severity assessed and 
to complete any eligibility requirements. During washout, subjects may continue their standard of 
care of visible skin (face and scalp) for cosmetic reasons and of extremities (palms/soles) to avoid 
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functional consequences on walking or moving their fingers. In the US/EU, this may include 
compounded emollients with keratolytics (alpha or beta hydroxyl acids) and/or urea. The 
investigator should approve and document these standard-of-care treatments in the eCRF. If the 
standard of care treatments of the face and/or palms/soles contain prohibited medications, they 
must be stopped at the Baseline Visit. Subjects may shower but not bathe or swim. The IGA will 
be evaluated on the rest of the body at Baseline. 
10.2.2 Double-blind Treatment Period  
Eligible subjects who have washed out prohibited medications will be randomized to double-blind 
study drug. 
10.2.2.1 Baseline Visit (Visit 2, Day 1) 
The following procedures will be performed on Day 1 in the study clinic: 
1. Review inclusion/exclusion criteria. 
2. Record responses to DLQI and EQ-5D Quality of Life Questionnaires. 
3. Perform a limited physical examination.  
4. Record vital signs (blood pressure and pulse).  
5. Record concomitant medications and concomitant therapies. 
6. Record IGA.  
7. Record VIIS.  
8. Record roughness assessment.  
9. Record palm/sole assessment. 
10. Record palm/sole assessment of fissuring. 
11. Record ectropion score.  
12. At sites where the photographic substudy is conducted, take photographs of subjects who 
have provided informed consent for the photography. 
13. Perform a 12-lead ECG. 
14. Perform urine pregnancy test for WOCBP. 
15. Collect blood and urine for routine laboratory tests (subject must be fasting; i.e., at least 
8 hours) and coagulation panel. 
16. Randomize via IWRS. 
17. Collect a predose PK blood sample (all subjects).  
18. Among subjects who consent to participate in the PK substudy, ensure that PK lines are 
placed before IP application. The IP will be applied in the clinic at this visit, and samples 
for PK will be taken at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1.  
19. Among subjects in the PK study, perform additional ECGs at times of serial sampling. 
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20. Clinic staff instructs subject on study drug application, applies initial study drug dose and 
measures amount used (i.e., study staff will weigh kits (tubes and boxes, but not leaflets) 
before and after the first application. If the product will be applied at home by someone 
other than the study subject, it is recommended that this person assist with application at 
this visit to learn how the IP is applied. 
21. Assess and record local tolerance/AEs. 
22. Dispense study drug and diaries. 
23. Advise subjects regarding permitted emollient(s) for use on nontreatment days; use of 
emollient(s) and/or sunscreen on study drug treatment days within 4 hours before or after 
study drug application is prohibited. Remind subjects that at least 24 hours must have 
elapsed since IP application before their next visit. Subjects should not to apply IP on visit 
days until after the visit. 
10.2.2.2 Telephone Visit (Day 7) 
Clinic staff will telephone subject to assess safety and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient(s) and/or 
sunscreen on study drug treatment days within 4 hours before or after study drug application is 
prohibited), and remind subjects that at least 24 hours must have elapsed since IP application 
before their next visit. Subjects should not apply IP on visit days until after the visit. An 
unscheduled clinic visit may be performed, if necessary. 
10.2.2.3 Visit 3 (Day 14 ±5 days) 
The following procedures will be performed on Day 14 in the study clinic: 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires.  
2. Record concomitant medications and concomitant therapies. 
3. Record vital signs (blood pressure and pulse). 
4. Record IGA.   
5. Record VIIS. 
6. Record roughness assessment.  
7. Record palm/sole assessment. 
8. Record palm/sole assessment of fissuring 
9. Record ectropion score. 
10. Assess local tolerance. 
11. Record AEs and review diary. 
12. Collect a PK blood sample (all subjects). 
13. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries.  
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14. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
Remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit. Subjects should not apply IP on visit days until after the visit.  
15. Weigh new study drug kits (tubes and boxes, but not leaflets) and dispense enough 
additional study drug until next visit, and new diary. 
10.2.2.4 Visit 4 (Day 30 ±7 days) 
The following procedures will be performed on Day 30 in the study clinic: 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires. 
2. Record concomitant medications and concomitant therapies. 
3. Record vital signs (blood pressure and pulse). 
4. Record IGA. 
5. Record VIIS. 
6. Record roughness assessment.  
7. Record palm/sole assessment. 
8. Record palm/sole assessment of fissuring 
9. Record ectropion score.  
10. At sites where the optional photographic substudy is conducted, take photographs of 
subjects who have provided informed consent for the substudy. 
11. Assess local tolerance. 
12. Record AEs and review diary. 
16. Perform a 12-lead ECG 
17. Perform a urine pregnancy test for WOCBP. 
18. Collect blood and urine for routine laboratory tests (subject must be fasting at least 8 hours) 
and coagulation panel. 
19. Collect a PK blood sample (all subjects). 
20. Among subjects who consent to participate in the PK substudy, ensure that PK lines are 
placed before IP application. The IP will be applied in the clinic at this visit, and samples 
will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose. 
21. Among subjects in the PK study, perform an additional ECGs at times of serial sampling. 
22. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries.  
23. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) on study 
drug treatment days within 4 hours before and after study drug application is prohibited. 
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Remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit. Subjects should not apply IP on visit days until after the visit.  
24. Weigh new study drug kits (tubes and boxes, but not leaflets) and dispense enough 
additional study drug until next visit, and new diary. 
25. Provide information about OLE option to study subject. 
10.2.2.5 Telephone Visit (Day 45) 
Clinic staff will telephone subject to assess safety and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) and/or sunscreen for use on nontreatment days (use of 
emollient(s) on study drug treatment days within 4 hours before or after study drug application is 
prohibited), and remind subjects that 24 hours must have elapsed since IP application before the 
subject’s next visit. Subjects should not to apply IP on visit days until after the visit. An 
unscheduled clinic visit may be performed, if necessary. Staff will remind subject about OLE 
option. 
10.2.2.6 Visit 5 (Day 60 ±7 days) 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires. 
2. Record concomitant medications and concomitant therapies. 
3. Record vital signs (blood pressure and pulse).  
4. Perform a urine pregnancy test for WOCBP. 
5. Record IGA.  
6. Record VIIS.   
7. Record roughness assessment.  
8. Record palm/sole assessment. 
9. Record palm/sole assessment of fissuring 
10. Record ectropion score.  
11. Assess local tolerance.  
12. Record AEs and review diary. 
13. Collect a PK blood sample (all subjects). 
14. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries.  
15. Weigh new study drug kits (tubes and boxes, but not leaflets) and dispense enough 
additional study drug until next visit, and new diary. 
16. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) and/or 
sunscreen on study drug treatment days within 4 hours before and after study drug 
application is prohibited. Remind subjects that 24 hours must have elapsed since IP 
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application before the subject’s next visit. Subjects should not apply IP on visit days until 
after the visit. 
17. Provide information about OLE option. 
10.2.2.7 Visit 6 (Day 90 ±7 days) or Early Termination 
The following procedures will be performed on Day 90 in the study clinic: 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires. 
2. Perform a limited physical examination. 
3. Record vital signs (blood pressure and pulse). 
4. Record concomitant medications and concomitant therapies. 
5. Record IGA. 
6. Record VIIS. 
7. Record roughness assessment.  
8. Record palm/sole assessment. 
9. Record palm/sole assessment of fissuring. 
10. Record ectropion score.  
11. At sites where the optional photographic substudy is conducted, take photographs of 
subjects who have provided informed consent for the substudy. 
12. Assess local tolerance. 
13. Record AEs and review diary. 
14. Perform a 12-lead ECG. 
15.  Perform a urine pregnancy test for WOCBP. 
16. Collect blood and urine for routine laboratory tests (subject must be fasting at least 8 hours) 
and coagulation panel. 
17. Collect a PK blood sample (all subjects). 
18. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries.  
For subjects who successfully complete (i.e., have reliable visit attendance and compliance with 
IP application, in the investigator’s opinion) the initial 90 days of double-blind treatment and 
choose to continue into the OLE, this visit will be the first visit of that portion of the study. All 
efficacy assessments, safety/tolerability assessments, including clinical laboratory testing, PK 
from Day 90 will be carried over to the OLE and will not be repeated. If the subject chooses to 
continue into OLE, the following additional procedures will be done: 
1. Have the subject sign OLE-specific informed consent.  
2. Measure subject’s weight. 
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3. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
Remind subjects that at least 24 hours must have elapsed since IP application before the 
PK draws at the Day 120 and Day 180 Visits, and not to apply IP on visit days until after 
the visits. 
4. Weigh new study drug kits (tubes and boxes, but not leaflets) and dispense enough 
additional study drug until next visit (only for subjects who choose to continue into the 
OLE). 
5. Dispense study diary. 
10.2.3 Follow-up Telephone Call (±14 days after Day 90) – Only Subjects Who Do Not 
Continue into Open-label Extension 
Clinic staff will telephone subjects who choose not to continue into the Open-label Extension 
within 14 days after Day 90 to assess any ongoing AEs.  
10.2.4 Open-label Extension  
Subjects who successfully complete (i.e., have reliable visit attendance and compliance with IP 
application, in the investigator’s opinion) the initial 90 days of double-blind treatment may choose 
to continue into an optional 90 day OLE with trifarotene cream HE1 200 µg/g. During the OLE, 
subjects will return to the site at Days 104, 120, 150, 180 and 194. Additional PK samples will be 
drawn at Days 120 and 180 from all subjects who continue into the OLE.  
10.2.4.1 Telephone Visit (Day 97) 
Clinic staff will telephone subject to assess safety (AEs) and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient(s) on study drug 
treatment days within 4 hours of study drug application is prohibited), and remind subjects not to 
apply IP on visit days until after the visit. An unscheduled clinic visit may be performed, if 
necessary. 
10.2.4.2 Visit 7 (Day 104 ±5 days) 
The following procedures will be performed at this study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Record IGA.   
4. Record VIIS. 
5. Record assessment of roughness. 
6. Record palm/sole assessment. 
7. Record palm/sole assessment of fissuring. 
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8. Record ectropion score. 
9. Assess and record local tolerance/AEs and review diary. 
10. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries.  
11. Weigh new study drug kits (tubes and boxes, but not leaflets) and dispense enough 
additional study drug until next visit, and new diary. 
12. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) and/or sunscreen on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
Remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit (Day 120), and if the Day 120 visit day coincides with a treatment day, wait until 
after the visit is complete to apply IP. 
10.2.4.3 Visit 8 (Day 120 ±7 days) 
The following procedures will be performed at this study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Record IGA. 
4. Record VIIS.   
5. Record assessment of roughness. 
6. Record palm/sole assessment.  
7. Record palm/sole assessment of fissuring. 
8. Record ectropion score. 
9. Assess and record local tolerance/AEs and review diary. 
10. Perform a 12-lead ECG. 
11. Perform a urine pregnancy test for WOCBP. 
12. Collect blood and urine for routine laboratory tests (subject must be fasting at least 8 hours) 
and coagulation panel. 
13. Collect a PK blood sample (all subjects) 
14. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries.  
15. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
16. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) and/or sunscreen on study 
drug treatment days within 4 hours before or after study drug application is prohibited.  
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10.2.4.4 Telephone Visit (Day 134) 
Clinic staff will telephone subject to assess safety (AEs) and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) and/or sunscreen for use on nontreatment days (use of 
emollient(s) on study drug treatment days within 4 hours of study drug application is prohibited), 
and remind subjects that 24 hours must have elapsed since IP application before the subject’s next 
visit. An unscheduled clinic visit may be performed, if necessary. 
10.2.4.5 Visit 9 (Day 150 ±7 days) 
The following procedures will be performed at this study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Record IGA. 
4. Record VIIS.   
5. Record assessment of roughness. 
6. Record palm/sole assessment.  
7. Record palm/sole assessment of fissuring. 
8. Record ectropion score. 
9. Assess and record local tolerance/AEs and review diary. 
10. Perform a urine pregnancy test for WOCBP. 
11. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries.  
12. Weigh new study drug kits (tubes and boxes, but not leaflets) and dispense enough 
additional study drug until next visit, and new diary. 
13. Remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit (Day 180) and if the Day 180 visit coincides with a treatment day, wait until after 
the visit is complete to apply IP. 
10.2.4.6 Visit 10 (Day 180 ±7 days) or Early Termination 
The following procedures will be performed at this study clinic visit: 
1. Perform a physical examination. 
2. Record vital signs (blood pressure and pulse). 
3. Record concomitant medications and concomitant therapies. 
4. Record IGA. 
5. Record VIIS. 
6. Assess roughness. 
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7. Record palm/sole assessment.  
8. Record palm/sole assessment of fissuring. 
9. Record ectropion score.  
10. Assess local tolerance 
11. Record AEs and review diary. 
12. Perform a 12-lead ECG. 
13. Perform a urine pregnancy test for WOCBP. 
14. Collect blood and urine for routine laboratory tests (subject must be fasting at least 8 hours) 
and coagulation panel. 
15. Collect a PK blood sample (all subjects) 
16. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries.  
10.2.4.7 Follow-up Evaluation – Open-Label Extension (Day 194 or 14 days after End of 
Open label Treatment/Visit 11) 
At 14 days after the last administration of the IP, the following procedures will be performed: 
1. Perform a limited physical examination. 
2. Record vital signs (blood pressure and pulse). 
3. Record any concomitant medications/therapies. 
4. Record IGA. 
5. Record VIIS.   
6. Assess roughness. 
7. Record palm/sole assessment.  
8. Record palm/sole assessment of fissuring. 
9. Record ectropion score.  
10. Assess and record AEs occurring since the last evaluation and review diary.  
11. Perform a urine pregnancy test for WOCBP. 
10.3. Assessments 
The 5-point IGA is a valid measure of disease severity and meets the need for a clinically 
meaningful measure of success for ichthyosis studies. The IGA scale was developed with the 
support of experts from academic reference centers for the treatment of ichthyosis. Each level of 
severity will consider both the severity of scaling and the severity of roughness (Section 10.3.1.2). 
While retinoid treatment is expected to reduce scale, it may increase erythema; therefore, in this 
study, erythema will be evaluated as part of local tolerability. 
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10.3.1 Efficacy Variables 
All efficacy measurements will use scales previously used for dermatological studies or as defined 
in the following sections. 
10.3.1.1 Investigator’s Global Assessment 
The primary endpoint is the number of subjects in each treatment group who experience successful 
resolution of LI where “success” is defined as clear/almost clear and at least a 2-grade change from 
Baseline at Day 90/EOT in the Double-blind Period on a 5-point IGA full body scale. 
The investigator will rate the subject’s condition using the 5-point IGA at each time point shown 
in the Schedule of Events (Section 2.2).  
The IGA will be measured on a 5-point scale, excluding the following areas: knees, elbows, neck, 
palms, soles, axillae, groin, and scalp: 
0 
Clear 
No scaling and no roughness 
1 
Almost Clear 
Occasional fine scales; hardly palpable roughness 
(mostly smooth) 
2 
Mild 
Small and fine scales predominate; no more than a few 
large scales; mild roughness on palpation 
3 
Moderate 
Some large scales that may be thick; coarse roughness 
on palpation 
4 
Severe 
Confluent, primarily large (>1 cm), thick scales with 
plate-like hyperkeratosis  
10.3.1.2 Visual Index for Ichthyosis Severity – Scaling 
The secondary endpoint is the number of subjects in each treatment group who experience a 
severity score of 0 or 1 at Day 90/EOT on the overall 16-point VIIS for scaling. 
The investigator will rate the subject’s condition using the 5-point VIIS for each body area 
(chest/abdomen, back, legs, and arms) and an overall score at each time point shown in the 
Schedule of Events (Section 2.2): 
0 
Normal skin; no perceptible scale or smoothening 
1 
Areas of normal skin intermixed with areas showing smoothening (diminished fine skin 
markings, shininess, waxiness) or small scales (visibly separated/fractured stratum 
corneum) 
2 
Confluent smoothening (diminished fine skin markings, shininess, waxiness) or small 
scales (visibly separated/fractured stratum corneum) 
3 
Confluent scales (visibly separated/fractured stratum corneum) including some large 
(>1 cm), thick scales 
4 
Confluent, primarily large, thick scales 
 
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10.3.1.3 Individual Score for Roughness 
The amount of roughness of the skin overall will be measured on a 5-point scale. 
0 Clear 
Smooth skin 
1 Almost Clear 
Hardly palpable roughness 
2 Mild 
Mild roughness (fine sand paper-like) 
3 Moderate 
Moderate, coarse roughness (coarse sand paper-like) 
4 Severe 
Very coarse skin (broken cornflakes-like) 
10.3.1.4 Palm/Sole Assessment 
Thickening of the skin on the palms and soles will be measured on a 5-point scale. 
0 Clear 
No thickening, no roughness, no fissure 
1 Almost Clear 
Only slight thickening, minimal to no roughness, no 
fissures 
2 Mild 
Some thickening, mild roughness on palpation, few 
fissures may be present 
3 Moderate 
Substantial and diffuse thickening, coarse roughness on 
palpation may be present, fissures may be present 
4 Severe 
Very thickened and rough skin, numerous fissures 
10.3.1.5 Palm/Sole Fissuring Assessment 
Fissuring will be assessed by recording the presence or absence of fissures, the number of fissures 
present, and the pain associated with each fissure. A fissure is a longitudinal and deep crack that 
separates the stratum corneum and may penetrate down to the dermis, causing pain and sometimes 
bleeding. The subject will assess pain associated with fissures as ranging from 0-3 (none, mild, 
moderate, severe).  
10.3.1.6 Dermatology Life Quality Index 
The DLQI is a dermatology-specific Quality of Life instrument. It is a simple 10-question validated 
questionnaire with 6 domains (symptoms and feelings, daily activities, leisure, work and school, 
personal relationships, and treatment); higher scores indicate poorer quality of life. The DLQI is 
the most frequently used instrument in studies of randomized controlled trials in dermatology.  
10.3.1.7 EQ-5D Quality of Life Questionnaire 
The EQ-5D is a standardized instrument developed by the EuroQol Group as a measure of health-
related quality of life used in a wide range of health conditions and treatments. The EQ-5D consists 
of a descriptive system and the EQ visual analog scale (VAS).   
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The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. The EQ VAS records the subject’s self-rated health on a 
vertical 0-100 VAS. This can be used as a quantitative measure of health outcome that reflects the 
subject’s own judgment. 
10.3.1.8 Ectropion Severity Score  
The ESS has a maximum score of 8 points. A higher score indicates a worse ectropion. The score 
takes the severity of ectropion in terms of lateral and medial apposition, scleral show, conjunctival 
show, and roundness of the eye into account and gives an indication of the functional aspects 
involved in ectropion by scoring redness, excess tear film, and the position of the lacrimal 
punctum.14 
 
Table 10-1: 
Ectropion Severity Score 
 
Points per Item 
0 
0.5 
1 
Lateral apposition 
Nonaffected 
— 
Affected 
Medial apposition 
Nonaffected 
— 
Affected 
Scleral show 
No 
≤1 mm 
>1 mm 
Conjunctival show 
No 
— 
Yes 
Excess tear film 
No 
— 
Yes 
Redness of the eye 
No 
— 
Yes 
Round canthus 
No 
— 
Yes 
Punctum lacrimale 
Invisible 
Emerging 
Visible 
Maximum score 
 
 
8 points 
Source: Korteweg SFS, Stenekes MW, van Zyl FE, Werker PMN. Paralytic Ectropion treatment with lateral periosteal 
flap canthoplasty and introduction of the ectropion severity score. Plast Reconstr Surg Glob Open. 2014;2(5):e151. 
10.3.1.9 Photography Substudy 
All sites that have photographic capability will take photographs as source data to support scoring 
at Baseline, Day 30, and Day 90. A central reader who will not be an investigator in the study will 
review the photographs to assess consistency of investigator scoring of LI severity as a quality 
check. Photographs may also be used for scientific publication purposes. Subjects will sign a 
separate, optional photographic informed consent form (ICF). 
10.3.2 Clinical Pharmacology 
10.3.2.1 Pharmacokinetic Analysis Methods  
The pharmacokinetic characterization of drug concentrations for each dose to be profiled will use 
noncompartmental analysis (NCA).  
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10.3.2.2 Pharmacokinetic Parameters 
Samples for PK will be drawn from all subjects at Baseline and at each clinic visit for trough 
values.  
Subjects who provide written informed consent to participate in the optional PK substudy will 
provide blood samples for PK analysis predose on Day 1 and at 1, 2, 4, 8, 12, and 24 hours postdose 
on Day 1 and Day 30. 
The PK parameter estimates will be completed using WinNonlin (Pharsight Corporation) software 
using the actual elapsed times from dose administration to sample collection (i.e., not nominal 
time). 
Standard PK parameters assessed will include measures of the extent of absorption using estimates 
of the area-under-the-curve (AUC) and rate-of-absorption using the maximum concentration 
(Cmax) and the time of Cmax (Tmax). Additional details of the parameters and their calculation and 
evaluation will be included in the statistical analysis plan (SAP). 
Table 10-2 shows the PK parameters that will be computed for each subject for samples obtained 
over the planned sampling intervals. 
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Table 10-2: 
Pharmacokinetic Parameters 
Parameter 
Description of Parameter 
Cmax 
Maximum (or peak) serum concentration  
Tmax 
Time at which Cmax is observed 
AUC(0-t) 
Area under the plasma concentration-time curve from time 0 to the time of the last 
quantifiable plasma concentration 
AUC(0-inf) 
Area under the plasma concentration-time curve from time 0 to infinity (if data permit) 
t1/2 
Apparent first order terminal elimination half-life 
λz 
Apparent terminal phase rate constant (if data permit) 
10.3.3 Sample Collection 
Samples will be collected at the time points specified in the Schedule of Events (Section 2.2). 
Specimen preparation, handling, shipment, and storage for the complete blood count, chemistry, 
and urinalysis are described in the study laboratory manual. Finding veins in subjects with this 
disease can be challenging. Blood draws will be done at the corresponding study visits before 
application of the IP and should be 24 hours after IP application. Subjects must not apply the IP to 
the area where blood will be drawn within 24 hours before their next study visit to avoid 
contamination of the blood by IP that remained in the skin. For subjects in the PK substudy, a 
cannula should be placed before IP application and the cannula site may be occluded to prevent 
contamination with IP.  
Actual PK sample times for subjects in the PK substudy will be recorded in the eCRF. 
Blood 
For subjects not in PK substudy: 
The expected amount of blood to be drawn at each visit varies from approximately 6 mL to a 
maximum of 21 mL (Screening Visit only). The total amount of blood drawn for the study will be 
about 123 mL per subject, unless the subject takes part in the PK substudy. 
 
For subjects in PK substudy: 
For subjects who opt to participate in the PK substudy, extra blood samples will be drawn at Visit 2 
and at Visit 4 for PK analysis. The amount of blood to be drawn per subject at each of these visits 
will be approximately 54 mL. For subjects taking part in the substudy, the total amount of blood 
drawn for the entire study will be approximately 195 mL. 
Urine 
Urinalysis will be performed at central laboratory. Dipstick and urine pregnancy tests will be 
conducted on site.  
10.3.4 Safety Variables 
Safety assessments will include the evaluation of AEs, including local tolerability 
(stinging/burning, pruritus, and erythema), clinical laboratory assessments, vital signs, 12-lead 
ECGs, and physical examinations. 
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10.3.4.1 Clinical Laboratory Safety Assessments 
10.3.4.1.1 Clinical Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points specified in the 
Schedule of Events (Section 2.2). 
Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
platelet count (or estimate), white blood cell count including differential 
Serum Chemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, 
creatinine, glucose, sodium, potassium, chloride, bicarbonate, lactate 
dehydrogenase, uric acid, total cholesterol, high-density lipoprotein, low-
density lipoprotein, triglycerides 
Coagulation Panel: prothrombin time, partial thromboplastin time, fibrinogen 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones 
Pregnancy Test: 
for women of childbearing potential only; serum at Screening, urine at 
each other visit. 
Serology 
Hepatitis B surface antigen, and hepatitis C 
 
All blood samples for the clinical laboratory tests must be taken in a fasting state, at least 8 hours 
after the previous drug application.  
Blood and urine samples for hematology, and serum chemistry will be sent to a central laboratory 
for analysis. Urine pregnancy tests and dipstick will be conducted at the study sites. 
10.3.4.1.2 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens in 
both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
In addition to appropriate handling of subject samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples. Procedures and regulations for the packaging and shipping 
of infectious samples are outlined in the study laboratory manual. The investigator is responsible 
for ensuring that all study samples that are to be transported to another location are packed and 
shipped appropriately according to the applicable regulations.  
Samples for assessment of clinical laboratory tests will be transported to the Clinical Reference 
Laboratory (see the study laboratory manual for addresses). 
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10.3.4.1.3 Evaluation of Clinical Laboratory Values 
The normal ranges of values for the clinical laboratory assessments in this study will be provided 
by the responsible laboratory and submitted to Mayne Pharma LLC prior to beginning the study. 
They will be regarded as the reference ranges on which decisions will be made. 
If a laboratory value is out of the reference range, it is not necessarily clinically significant. The 
investigator must evaluate the out-of-range values and record his or her assessment of the clinical 
significance in the appropriate eCRF. 
All clinical laboratory values that in the investigator’s opinion show clinically significant or 
pathological changes during or after termination of treatment must be reported as AEs and 
followed, as described in Section 11.2.5. 
All measurements described in this section are recognized standard methods. 
10.3.4.2 Clinical Examinations 
10.3.4.2.1 Vital Signs 
Vital signs, including height and weight (only assessed at Screening), blood pressure, and pulse 
will be measured.  
10.3.4.2.2 Twelve-lead Electrocardiogram 
A standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes. 
All ECG recordings will be identified with the subject number, date, and time of the recording. 
Gel ECG electrodes may be used for ECGs because they are more conductive and cause less 
trauma on compromised skin. Efficacy assessments should be conducted before ECGs to avoid 
possible artefact/changes from the ECG.  
For subjects in the PK substudy, additional ECGs will be performed postdose during serial blood 
sampling on Day 1 and Day 30. 
If there is a marked prolongation of the QT/QTc interval during treatment, a subject should be 
discontinued from the IP but remain in the study until full resolution of the event. The DSMB will 
be informed immediately of such an occurrence. 
10.3.4.2.3 Physical Examination 
A complete physical examination excluding the genitourinary examination will be performed at 
Screening, while limited physical examinations (to include head, eyes, ears, nose, and throat, 
cardiorespiratory, abdomen, and range of motion) will be performed as indicated in the Schedule 
of Events (Section 2.2). 
10.3.4.2.4 Other Safety Variables 
Local tolerability will be assessed on a 0-3 scale (none, mild, moderate, severe). All application 
site reactions will be recorded as TEAEs in the diary. These should include the date and severity 
of the TEAE. 
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10.3.4.3 Adverse Events 
The definitions and management of AEs, and any special considerations for AEs, are provided in 
Section 11. 
10.4. Procedural Adjustments Due to COVID-19 
The coronavirus disease 2019 (COVID-19) global pandemic has impacted the free movement of 
the world’s population, which has been restricted to control the spread of the disease. It is 
recommended that all sites and subjects comply with the applicable local and federal guidelines 
regarding the necessary and proper precautions regarding COVID-19. 
Although it is preferable to conduct all necessary study assessments in person (onsite visits), this 
may not be possible as a result of COVID-19-related travel restrictions. To ensure the safety of 
subjects, investigators, and site staff, Visits 3-6 (Double-blind Period; Table 2-1), Visits 7-11 
(OLE Period; Table 2-2) and unscheduled visits may be conducted remotely. Screening and 
baseline visits must be performed onsite only, and must be postponed or scheduled for when onsite 
visits can be safely conducted. 
Procedural adjustments due to COVID-19 when it is inadvisable or not possible to conduct an 
onsite study visit are detailed in Appendix B. 
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11. ADVERSE EVENTS 
11.1. Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not related to the medicinal product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a 
pre-existing condition is considered an AE.) 
Events that occur in subjects treated with control product are also considered AEs. 
11.1.2 Adverse Drug Reaction 
All noxious and unintended responses to an investigational product related to any dose should be 
considered adverse drug reactions (ADRs). 
The phrase “responses to an investigational product” means that a causal relationship between an 
investigational product and an AE is at least a reasonable possibility, i.e., the relationship cannot 
be ruled out. All AEs judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship to an IP qualify as ADRs. 
All AEs for which the judgment of relationship to IP is “possible” or higher will be considered 
ADRs. If a relationship to IP is not provided, then the AE must be treated as if it were “possible.”  
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction 
An expected AE or ADR is one for which the nature or severity is consistent with the known AE 
profile of the product. For a preapproval test product, the known information is contained in the 
IB. For a marketed product, the known information is contained in the current package insert for 
the product. 
An unexpected adverse event (UAE) or unexpected adverse drug reaction (UADR) is one for 
which the nature or severity of which is not consistent with the applicable product information 
(e.g., IB for an unapproved investigational product or package insert/summary of product 
characteristics for an approved product). For example, hepatic necrosis would be unexpected 
(greater severity) if the IB only listed elevated hepatic enzymes or hepatitis. Likewise, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (greater specificity) if the IB only 
listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction constitute unexpected events.  
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11.1.4 Serious Adverse Events/Drug Reaction 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. 
An elective hospital admission to treat a condition present before exposure to the IP, or a 
hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or 
event as an SAE. Further, an overnight stay in the hospital that is only due to transportation, 
organization, or accommodation problems and without medical background does not need 
to be considered an SAE. 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the IP 
during pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject that has 
received an IP is not considered an SAE unless it is suspected that the IP(s) interacted with 
a contraceptive method and led to the pregnancy.  
• is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result 
in hospitalization, development of drug dependency, or drug abuse. The occurrence of 
malignant tumors is also to be considered serious.  
11.1.5 Significant Adverse Events 
Other significant AEs are defined as marked hematological and other laboratory abnormalities 
(other than those meeting the definition of serious) and any events that led to an intervention, 
including withdrawal of test drug, dose reduction, or significant additional concomitant therapy. 
11.1.6 Treatment-Emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening is after the first application 
of IP (trifarotene or vehicle) and not more than 14 days after the last application of IP. 
11.2. Event Assessment and Follow-up of Adverse Events 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care or upon review by a study 
monitor. 
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All reported AEs, including local and systemic AEs not meeting the criteria for SAEs, will be 
captured on the appropriate eCRF. Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event. 
All reported AEs occurring while on study must be documented appropriately regardless of 
relationship. All reported AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
Changes in the severity of a reported AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
Study clinic personnel will record all reportable events with start dates occurring any time after 
informed consent is obtained until 14 (for nonserious AEs) or 30 days (for SAEs) after the last day 
of study participation. At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit. Events will be followed for outcome information until resolution or 
stabilization. 
11.2.1 Assessment 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. In addition, 
although local tolerability will be assessed on a 0-3 scale, all application site reactions should be 
recorded as AEs. 
The Tolerability Assessments Form at each visit collects a numeric severity score by body area for 
erythema, stinging/burning, and pruritus. 
In addition, if skin irritation is more than the expected erythema, stinging/burning, and pruritus 
with the application of this topical retinoid (i.e., clinically relevant), please enter the application 
site reactions in the Adverse Event description section. If a diagnosis is known, record the 
diagnosis. If a diagnosis is known and there are other signs/symptoms that are not generally part 
of the main diagnosis, record the diagnosis and each sign/symptom on a separate line. If a diagnosis 
is not known, record each sign/symptom on a separate line. Examples are allergic contact 
dermatitis, sunburn, skin erosion, and swelling. 
 
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11.2.2 Evaluation 
11.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as follows: 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.4. 
11.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.4. 
11.2.2.3 Action(s) Taken 
All AEs will be treated/managed according to standard practice. The following actions may be 
taken with regard to the IP. Section 9.4 describes dose adjustment and stopping rules for individual 
subjects. 
Action(s) taken may consist of the following: 
Dose not changed 
An indication that a medication schedule was maintained. 
Dose reduced 
An indication that a medication schedule was modified by reducing the 
frequency of application. 
Drug interrupted 
An indication that a medication schedule was modified by temporarily 
terminating a prescribed regimen of medication. 
Drug withdrawn 
An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
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11.2.2.4 Outcome at the Time of Last Observation 
The outcome of an AE at the time of last observation will be classified as follows: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
*Only select fatal as an outcome when the AE results in death. If more than one AE is judged to 
be possibly related to the subject’s death, the outcome of death should be indicated for each such 
AE. Although “fatal” is usually an event outcome, events such as sudden death or unexplained 
death should be reported as SAEs. 
11.2.2.5 Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AE’s relationship to the IP. The categories for 
classifying the investigator’s opinion of the relationship are as follows: 
Not related 
An AE with sufficient evidence to accept that there is no causal relationship 
to IP administration (e.g., no temporal relationship to drug administration, 
because the drug was administered after onset of event; investigation shows 
that the drug was not administered; another cause was proven.) 
Unlikely 
related 
An AE, including laboratory test abnormality, with a temporal relationship to 
IP administration that makes a causal relationship improbable, and in which 
other drugs, events, or underlying disease provide plausible explanations. 
Possibly related An AE with a reasonable time sequence to administration of the IP, but that 
could also be explained by concurrent disease or other drugs or events. 
Information on drug withdrawal may be lacking or unclear. 
Related 
An AE occurring in a causal plausible time relationship to IP administration 
that cannot be attributed to a concurrent disease or other drugs, chemicals, or 
events. The AE relationship to the IP must be assessed separately by the 
investigator and Mayne Pharma LLC. 
 
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11.2.3 Documentation 
Any AE that occurs during the Screening Period will be captured as on the AE page of the eCRF 
(not medical history). All AEs that occur within the period of observation for the study must be 
documented in the eCRF with the following information, where appropriate. (The period of 
observation for the study is described in Section 11.2.) 
• AE name or term 
• When the AE first occurred (start date and time) 
• When the AE stopped (stop date and time or an indication of “ongoing”) 
• Severity of the AE 
• Seriousness (hospitalization, death, etc.) 
• Actions taken 
• Outcome 
• Investigator opinion regarding the AE relationship to the IP(s) 
11.2.4 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. If such treatment constitutes a deviation from the protocol, the subject may be withdrawn 
for treatment but continue to be followed for efficacy and safety in the study. The decision about 
whether the subject may continue in the study will be made by the sponsor after consultation with 
the investigator and/or medical monitor. 
If AEs occur in a subject that are not tolerable, the investigator must decide whether to stop the 
subject’s involvement in the study and/or treat the subject. Special procedures may be 
recommended for the specific IP, such as the collection of a serum sample for determining blood 
concentrations of IP, specific tapering procedures, or treatment regimens, as appropriate. 
It is not necessary to unblind a subject’s treatment assignment in most circumstances, even if an 
SAE has occurred. If unblinding is necessary, see Section 9.6 for a description of the unblinding 
procedures. 
11.2.5 Follow-up 
Any AE will be followed (up to a maximum of 14 days after the last dose of IP) to a satisfactory 
resolution, until it becomes stable, or until it can be explained by another known cause(s) (i.e., 
concurrent condition or medication) and clinical judgment indicates that further evaluation is not 
warranted. All findings relevant to the final outcome of an AE must be reported in the subject’s 
medical record and recorded on the eCRF page.  
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11.2.6 Reporting 
11.2.6.1 Serious Adverse Events 
The investigator or designee must report all SAEs promptly to Premier Research within 24 hours 
of first becoming aware of the event by e.g., completing, signing and dating the Serious Adverse 
Event Report Form, verifying the accuracy of the information recorded in the form with the source 
documents and eCRF, and sending the SAE form to the Premier Research by one of the following 
methods:  
Email: globalPV-US@premier-research.com 
Email: PVDS-ROW@premier-research.com 
Fax number: +1 215 972 8765 
Fax number: +421 2 6820 3713 
This written report should be submitted on the SAE form provided for this purpose. At the time of 
first notification, the investigator or designee should provide the following information, if 
available: 
•
Protocol number
•
Reporter (study site and investigator)
•
Suspect IP
•
Subject’s study number
•
Subject’s year of birth
•
Subject’s gender
•
Date of first dose of IP(s)
•
Date of last dose of IP(s), if applicable
•
Adverse event term
•
Date of occurrence of the event
•
A brief description of the event, outcome to date, and any actions taken
•
The seriousness criteria(on) that were met
•
Concomitant medication at onset of the event
•
Relevant medical history information
•
Relevant laboratory test findings
•
Investigator’s opinion of the relationship to IP(s) (“Is there a reasonable possibility that
the IP caused the SAE? Yes or No?”)
•
Whether and when the investigator was unblinded as to the subject’s treatment
assignment
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Any missing or additional relevant follow-up information concerning the SAE should be sent to 
the sponsor/sponsor representative via the same contact details above as soon as possible on a 
follow-up SAE Report Form, together with the following minimal information (initial report, 
adverse event, date of occurrence, subject identification (ID), study ID, IP, and site number); this 
will allow the follow-up information to be linked to the initial SAE report.  
Specific information may be requested by the Premier Research Pharmacovigilance Department 
using a follow-up request form or via email communication. 
The investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his or her health authorities, institutional review board 
(IRB)/independent ethics committee (IEC), principal and coordinating investigators, study 
investigators, and institutions. Each investigator is obligated to learn about the reporting 
requirements for investigators in his/her country. The study monitor may be able to assist with 
this. 
11.2.6.2 Adverse Drug Reactions 
All ADRs should be reported by the investigator in the eCRF.  
Suspected serious ADRs must be reported to the sponsor immediately, regardless of the time 
elapsed since the end of the observation period. 
11.2.6.3 Nonserious Adverse Events 
Nonserious AEs will be recorded in the eCRF and reported by Premier Research to Mayne Pharma 
LLC in aggregate monthly status reports. 
11.3. Special Considerations 
11.3.1 Adverse Events of Special Interest 
Since topical retinoids are associated with local application site AEs, particularly when beginning 
treatment, these events will be followed closely during the study and considered AEs of special 
interest (AESIs). 
11.3.2 Pregnancy 
All WOCBP who participate in the study should be counseled on the need to practice highly 
effective birth control and on the importance of avoiding pregnancy during study participation. 
Women should be instructed to contact the investigator or study staff immediately if pregnancy 
occurs or is suspected. 
Pregnancy testing will be conducted prior to administration of the IP on every woman of 
childbearing potential. A woman who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered to be a screening failure. 
A woman who becomes pregnant during IP treatment will be immediately discontinued from study 
treatment. The investigator must report the pregnancy of any woman who becomes pregnant 
during or within 30 days after discontinuing treatment as if it were an SAE within 24 hours of 
learning of the pregnancy, to Premier Research Pharmacovigilance using the Pregnancy Data 
Collection Form via the same fax number and/or email address as for SAE reporting. If a partner 
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of a male study subject becomes pregnant, the investigator must report the pregnancy as soon as 
possible after learning of it to the Premier Research Pharmacovigilance using the Pregnancy Data 
Collection Form. A separate pregnant partner ICF will be required. 
Early Termination Visit assessments are required as soon as possible after learning of the 
pregnancy in a study subject. The investigator is also responsible for following the pregnancy until 
delivery or termination. These findings must be reported on the Pregnancy Data Collection Form 
and forwarded to Premier Research Pharmacovigilance. The event meets the SAE criterion only if 
it results in a spontaneous abortion or a congenital anomaly. In such case, an additional form 
(Serious Adverse Event Report Form) must be filled out by the investigator and provided to 
Premier Research Pharmacovigilance within 24 hours of knowledge of the pregnancy’s serious 
outcome. 
Among the clinical studies, 12 pregnancies were reported: 4 resulted in normal births; 5 resulted 
in spontaneous abortions (none of which was considered related to CD5789); 1 was electively 
aborted, and 2 were lost to follow-up (IB for CD5789 Cutaneous Formulation). 
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12. DATA SAFETY MONITORING BOARD 
Safety oversight will be under the direction of a DSMB composed of individuals with the 
appropriate expertise, including LI. Members of the DSMB should be independent from the study 
conduct and free of conflict of interest, or measures should be in place to minimize perceived 
conflict of interest. The DSMB will operate under a charter that will be finalized prior to the start 
of the study. The DSMB will meet at least 3 times during the conduct of the study: when the study 
begins, when 15 subjects have enrolled in Cohort A and have completed at least 28 days of 
treatment, and after 60 subjects have enrolled in the study. 
The DSMB will meet after 15 subjects in Cohort A have completed at least 28 days of double-blind 
treatment to review aggregate safety and tolerability data (including PK and ECG results). The 
safety data will be unblinded to the DSMB. At that time, the DSMB will decide whether Cohort B 
may begin enrolling. The DSMB will have the authority to recommend to the sponsor that the 
study be modified, placed on hold, or stopped if serious safety issues are discovered. The DSMB 
will provide its input to Mayne Pharma LLC. Any protocol changes the DSMB may suggest will 
be submitted to all applicable regulatory bodies for review and approval. 
In case of significant toxicity, the DSMB may choose to review the available safety data and 
recommend stopping recruitment in a particular dose group. 
Stopping rules for individual subjects are in Section 8.4. The DSMB committee members are as 
follow: 
• Univ. Prof. Dr. med. Steffen Emmert, Director at Clinic and Polyclinic for Dermatology 
& Venereology University Medical Center Rostock 
• Jeffrey Louis Sugarman, MD, PhD Pediatric Dermatologist 
• Moise L. Levy, MD, Pediatric Dermatologist 
• Gabriele Accetta, PhD, Biostatistician 
 
13. STATISTICS 
13.1. Statistical Analysis 
This section presents a summary of the planned statistical analyses. A SAP that describes the 
details of the analyses to be conducted will be written prior to database lock.  
Unless otherwise indicated, all testing of statistical significance will be two-sided, and a difference 
resulting in a P value of ≤ 0.05 will be considered statistically significant.  
Summary statistics will be provided for the variables described below. For continuous variables, 
these statistics will include the number of subjects, mean, standard deviation (SD), median, 
minimum, and maximum. For categorical variables, these statistics will include the number and 
percentage of subjects in each category. 
The primary analysis period is the first 90 days of treatment (i.e., the Double-blind Period). Overall 
unblinding will take place at the end of the Double-blind Period of the study only after the database 
is locked. A second analysis will take place for endpoints assessed from Day 90 through the OLE 
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Period. The baseline for the safety and efficacy parameters will be measured at Visit 1 or Visit 2, 
per the Schedule of Events for both the Double-blind Period (Table 2-1) and OLE (Table 2-2). 
13.1.1 Analysis Populations 
The following 5 analysis populations are planned for the Double-blind Period of this study:  
• Safety: all subjects who are randomized to treatment and receive at least 1 application of 
study drug in the Double-blind Period. This population will be the primary population for 
analyses of safety. 
• Intent-to-treat (ITT): all randomized subjects. This population will be used as the primary 
population for the analysis of efficacy for the Double-blind Period of the study. 
• Modified intent-to-treat (mITT): all subjects in the safety population with at least 
1 postbaseline assessment of efficacy in the Double-blind Period.  
• Per-protocol (PP): subjects in the mITT Population who met all inclusion criteria and no 
exclusion criteria, were compliant with study drug application, and who had no 
significant protocol deviations. 
• Pharmacokinetic: all subjects in the Safety Population who have at least 1 plasma sample 
with quantifiable concentration. This population will be used to summarize all PK 
endpoints. 
The following analysis populations are planned for the OLE of this study: 
• OLE Safety: all subjects who complete the 90-day Double-blind Treatment Period and 
receive at least 1 application of study drug in the OLE. 
• OLE ITT: all subjects who complete the 90-day Double-blind Treatment Period and sign 
the OLE informed consent. 
• OLE mITT: all subjects in the OLE safety population with at least 1 assessment of 
efficacy after Visit 6. 
• OLE PP: all subjects in the OLE mITT population who met all inclusion criteria and no 
exclusion criteria, were compliant with study drug application from baseline through 
EOT, and who had no significant protocol deviations throughout the study. 
Inclusion in the analysis populations will be determined prior to database lock. Deviations related 
to COVID-19 will also be evaluated in determining PP population eligibility. 
If a subject is randomized incorrectly or is administered the incorrect IP, analyses of the ITT and 
mITT populations will be based on the assigned treatment whereas all other analyses will be based 
on the actual treatment received. 
13.1.2 Study Subjects and Demographics 
13.1.2.1 Disposition and Withdrawals 
For the Double-blind Period, the numbers of subjects randomized, completing Day 90 of the study, 
and withdrawing early from the Double-blind Period, along with reasons for withdrawal, will be 
tabulated overall and by randomized treatment group. The number of subjects in each analysis 
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population will be reported. The number of subjects completing study milestones will also be 
tabulated by randomized treatment group. This analysis will be conducted for the ITT population. 
For the OLE, the number of subjects entering the OLE, completing the study, and withdrawing 
early, along with reasons for withdrawal, will be tabulated overall. The number of subjects in each 
analysis population will be reported. The number of subjects completing study milestones will also 
be tabulated. This analysis will be conducted for the OLE ITT population. 
13.1.2.2 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol or International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) requirements. The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions are 
to be developed by the site and implemented promptly.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations promptly. All deviations must be addressed in study source documents, and reported to 
Premier Research or Mayne Pharma LLC. Protocol deviations must be sent to the reviewing IRB 
per their policies. The site investigator is responsible for knowing and adhering to the reviewing 
IRB requirements. Further details about the handling of protocol deviations will be included in the 
protocol deviation guidance plan. 
Subjects who taper to once-weekly application or who take a “drug holiday” will not be reported 
as having deviated from the protocol. 
13.1.2.3 Demographics and Other Baseline Characteristics 
These analyses will be conducted for the ITT and OLE ITT populations.  
Demographic variables will include age, sex, race, ethnicity, height, weight, and BMI. Baseline 
subject characteristics will include medical history, physical examination findings, and IGA score. 
Prior and concomitant medications will be summarized by randomized treatment group, by the 
number and percentage of subjects taking each medication, and classified using World Health 
Organization Drug Dictionary (WHO-DD) Anatomical Therapeutic Chemical (ATC) classes and 
preferred terms. 
13.1.3 Exposure and Compliance 
Investigational product administration will be summarized in terms of each subject’s dose, and in 
terms of duration of exposure for each period. Descriptive statistics for these quantities, including 
the mean, median, SD, minimum, maximum, and quartiles, will be provided by treatment group. 
Additionally, the number of subjects who are compliant with investigational product will be 
presented by treatment group for the Double-blind Period and overall for the OLE.  
Subjects who taper to once-weekly application or who take a “drug holiday” will not be reported 
as having deviated from the protocol. 
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13.1.4 Efficacy Analysis 
The ITT population will be used as the primary population for the primary analysis of efficacy at 
Day 90. Select efficacy analyses will be repeated as secondary analyses in the ITT and PP 
populations for the Double-blind Period. Efficacy analyses will also be repeated in the OLE using 
the OLE ITT, OLE mITT, and OLE PP populations. No formal inferential analyses will be 
conducted for efficacy variables in the OLE. 
Efficacy endpoints will be based on investigator assessment. 
13.1.4.1 Efficacy Endpoints 
Primary efficacy endpoint: The proportion of subjects in each treatment group who experience 
successful resolution of LI where “success” is defined as clear/almost clear overall and at least a 
2-grade change from Baseline at Day 90/EOT in the Double-blind Period on the 5-point IGA scale.  
Secondary: The secondary endpoints are as follow: 
• The difference in mean scores between the active trifarotene cream HE1 and 
vehicle groups in the following assessment indices from Baseline through Day 90: 
▪ 5-point VIIS scale for scaling  
▪ Individual score for roughness (Scale: 0–4)  
▪ Palm/sole Assessment (Scale: 0–4)  
▪ Quality of life per DLQI  
• The difference in proportion of subjects with presence of fissures on palm/soles 
(presence/absence, number of fissures, and pain associated with fissures [on a 
0-3 scale]) at Day 90 between the active trifarotene cream HE1 and vehicle 
groups  
Exploratory: The exploratory endpoints are as follow: 
• The difference in mean ectropion scores (ESS of 0–8) between the active trifarotene 
cream HE1 and vehicle groups from Baseline through Day 90 
• The difference in quality of life per EQ-5D-5L scores between the active trifarotene 
cream HE1 and vehicle groups from Baseline through Day 90 
13.1.4.2 Primary Analysis 
For the Double-blind Period only, the number and proportion of subjects in each treatment group 
with successful resolution of LI by Day 90/EOT will be presented. The primary efficacy endpoint 
will be analyzed using a logistic regression model with treatment and age group as factors. Other 
baseline characteristics and interactions may be included. The odds ratios and 95% CIs for the 
odds ratios will be presented. The difference in proportions between the active trifarotene cream 
HEI and vehicle cream group, 95% CIs for the differences, and P-values for the differences in 
treatment will also be presented. 
Descriptive summaries (such as mean, standard error, median, minimum, and maximum) and the 
changes from baseline will be provided for IGA scores for both periods.  
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13.1.4.3 Secondary Analyses 
Secondary and exploratory efficacy endpoints will be analyzed separately for each period 
(Double-blind and OLE) using descriptive statistics.  
Additionally, for the Double-blind Period only, change from Baseline in continuous secondary 
endpoints through Day 90 will be presented and analyzed using a mixed model for repeated 
measures (MMRM). The model will include the change from baseline score as the dependent 
variable, treatment group as a fixed effect, subject as a random effect, and baseline score value as 
a covariate.  
For subjects who report having fissures, descriptive summaries of the number of fissures and pain 
related to fissures will also be presented by treatment group and body area for each period. 
The DLQI scores will also be analyzed using descriptive statistics through Day 90. 
The proportion of subjects with at least a 50% reduction in IGA score from Baseline will be 
analyzed using the same logistic regression analysis described in Section 13.1.4.2. 
13.1.4.4 Exploratory Analyses 
Descriptive summaries and the changes from baseline will be provided for ectropion scores and 
EQ-5D-5L scores by visit for each period. No formal inferential analyses will be conducted for 
exploratory endpoints. 
13.1.4.5 Corroborative, Sensitivity, and Other Analyses 
To assess the effect of missing data on the primary efficacy analysis, a sensitivity analysis will be 
performed using multiple imputation (MI) for the Double-blind Period only. Multiple-imputations 
will be used to replace missing IGA outcomes using multiple draws from the posterior predictive 
distribution estimated from the treatment groups. IGA scores will be imputed and then categorized 
as treatment success according to Section 13.1.4.1. Imputation will not be performed for the OLE. 
Full details will be specified in the SAP. 
Thorough assessment on the extent of missing data and procedural adjustments due to COVID-19 
as it pertains to the primary and secondary efficacy endpoints will be conducted ahead of database 
lock, and additional sensitivity analyses may be performed. Full details will be documented in the 
SAP. 
The proportion of subjects who experience a 2-grade change from baseline to Day 90 in individual 
score for roughness and palm/sole assessment will also be explored using a logistic regression 
model with treatment and age group as factors. Other baseline characteristics and interactions may 
be included. The odds ratios and 95% CIs for the odds ratios will be presented. The difference in 
proportions between the active trifarotene cream HEI and vehicle cream group and the 95% CIs 
for the differences will be presented. 
For analyses involving study site, if the number of subjects per site is small, sites may be pooled 
for safety and efficacy analysis or omitted from statistical models as the anticipated number of 
subjects per site is small, treatment is self-administered, and the sites are using standardized 
procedures for all assessments. If the distribution of enrollments at sites is such that one or few are 
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enrolling a majority of subjects, a subgroup analysis by site may be performed. The final 
determination will be made prior to database lock.  
Details of these analyses will be further detailed in the SAP. 
13.1.5 Clinical Pharmacology Analyses 
13.1.5.1 Pharmacokinetics 
For noncompartmental analysis, plasma concentrations will be listed and summarized at each time 
point using descriptive statistics. Descriptive statistics reported will include the arithmetic mean, 
SD, CV%, geometric mean, minimum, maximum, and median. Only the range and the median will 
be reported for Tmax, as this is a categorical parameter. The PK parameters will also be summarized 
by treatment using descriptive statistics.  
Individual plasma concentration plots and mean data graphs will be produced using both linear 
and semi-logarithmic scales. Mean data graphs will show plasma concentration profiles by 
treatment group. 
Pharmacokinetic plasma parameter estimates and summaries will be completed for the subjects in 
the PK population. Testing of PK parameters will be outlined in the SAP. 
13.1.6 Safety and Tolerability Analyses 
Safety analyses through Day 90 of the Double-blind Period will be conducted using data from the 
Safety Population and safety analyses in the OLE will be conducted using the OLE Safety 
Population (as defined in Section 13.1.1). Safety variables include treatment-emergent AEs, 
clinical laboratory values, vital signs, ECG readings, and physical examination results. No formal 
inferential analyses will be conducted for safety variables in either period. 
13.1.6.1 Local Tolerability 
During all clinic visits, the investigator will assess local tolerability (stinging/burning, pruritus, or 
erythema on 0-3 scales [none, mild, moderate, severe]) for each treated body area (chest/abdomen, 
back, arms, legs, and face/neck). Descriptive summaries will be presented by period, treatment 
group, and visit. 
13.1.6.2 Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 20.1 or higher.  
Treatment-emergent AEs are defined as: 
• AEs with onset at the time of or following the start of treatment with IP through the 
Follow-up Visit or Early Termination Visit, whichever occurs first, or 
• AEs starting prior to the start of treatment but increasing in severity or relationship at the 
time of, or following, the start of treatment with IP through the Follow-up Visit or Early 
Termination Visit, whichever occurs first. 
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The number and percentage of subjects with AEs will be displayed by each treatment group in the 
Double-blind Period and overall in the OLE by system organ class and preferred term. Summaries 
of AEs by severity and relationship to IP will also be provided. Serious adverse events and AEs 
resulting in discontinuation of IP will be summarized separately in a similar manner. Subject 
listings of AEs, SAEs, and AEs causing discontinuation of IP will be produced. 
13.1.6.3 Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from baseline values will be presented for clinical laboratory values for each treatment 
group at each time point in each period. 
The number of subjects with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from baseline (shift tables) for each clinical 
laboratory parameter by treatment group and by study visit in each period.  
Laboratory values that are outside the normal range will also be flagged in the data listings and 
presented with the corresponding normal ranges. Any out-of-range values that are identified by 
the investigator as being clinically significant will also be shown in a data listing. 
13.1.6.4 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for systolic blood pressure (SBP), diastolic blood pressure 
(DBP), and pulse for each period. 
The number of subjects with vital signs values categorized as below, within, or above normal 
ranges will be tabulated showing change from baseline (shift tables) for each parameter by period, 
by treatment group and by study visit. Pre- and post-treatment values may also be presented with 
an analysis of mean changes from baseline. 
13.1.6.5 Twelve-lead Electrocardiograms 
The number and percentage of subjects with normal and abnormal ECG findings will be 
summarized for each treatment group at each time point in each period. Abnormal results will be 
grouped as clinically significant and not clinically significant. 
A comparison of QT results will be presented. Summary statistics will be displayed by period, by 
treatment group, and by visit for QT and the QT interval corrected for heart rate (QTc) calculated 
using Fridericia’s QT correction methods.  
Descriptive summaries (mean, SD, median, minimum, and maximum) will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTcF interval (Fredericia’s correction 
methods), and HR for each treatment group at each time point in each period. 
13.1.6.6 Physical Examination Findings 
The number and percentage of subjects with normal and abnormal findings in the complete 
physical examination will be displayed for each treatment group in each period. 
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13.1.7 Interim Analysis 
No interim analyses are planned.  
13.2. Sample Size Determination 
Accounting for a 20% drop-out/nonevaluable rate, a total sample size of 120 subjects randomized 
in a 1:1:1 ratio to 2 active trifarotene cream HE1 arms and a vehicle cream arm will provide 
>80% power to detect a difference between each separate trifarotene cream HE1 arm (32 evaluable 
subjects) and the vehicle cream arm (32 evaluable subjects) 2-sided Fisher’s Exact Test assuming 
a 70% success rate and a 40% success rate, respectively. This study is not powered to detect a 
difference between the 2 active arms. 
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14. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
14.1. Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 16). The sponsor reserves the right to withdraw a subject from the study (Section 8.3), to 
terminate participation of a study site at any time (Section 14.7), and/or to discontinue the study 
(Section 14.6). 
Mayne Pharma LLC agrees to provide the investigator with sufficient material and support to 
permit the investigator to conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 18.1), the investigator indicates that he or she 
has read the protocol carefully, fully understands the requirements, and agrees to conduct the study 
in accordance with the procedures and requirements described in this protocol.  
The trial will be conducted in accordance with ICH GCP, and the applicable United States (US) 
Code of Federal Regulations (CFR). The principal investigator will assure that no deviation from, 
or changes to, the protocol will take place without prior agreement from the Investigational New 
Drug (IND) sponsor, funding agency and documented approval from the IRB, except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection and ICH GCP training. 
Investigators should ensure that all persons who are delegated study-related responsibilities are 
adequately qualified and informed about the protocol, the IP(s), and their specific duties within the 
context of the study. Investigators are responsible for providing Mayne Pharma LLC with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
14.1.3 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying study product may inspect all 
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documents and records required to be maintained by the investigator, including, but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. 
The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at Premier Research. This will not include the participant’s contact 
or identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by clinical sites and by Premier Research staff will be secured and password protected. At the end 
of the study, all study databases will be de-identified and archived at the Premier Research 
14.2. Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from the sponsor or its designee that the study can be initiated at the study site. The study site will 
not be authorized for study initiation until: 
1. The study site has received the appropriate IRB/IEC approval for the protocol and the 
appropriate ICF. 
2. All regulatory/GCP documents have been submitted to and approved by the sponsor or its 
designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
14.3. Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study. Subjects may 
only be rescreened once 30 days or more after the original Screening Visit. If a subject is eligible 
to enter the study after having previously failed screening, the subject will be assigned a new 
subject identification number. 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
14.4. Study Documents 
All documentation and material provided by Mayne Pharma LLC for this study are to be retained 
in a secure location and treated as confidential material. 
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14.4.1 Informed Consent 
Consent forms describing in detail the study intervention, study procedures, and risks are given to 
the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. The informed consent forms are submitted with this 
protocol. 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be 
IRB-approved and the participant will be asked to read and review the document. The investigator 
will explain the research study to the participant and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants. Participants 
will have the opportunity to carefully review the written consent forms and ask questions before 
signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it before agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must 
be informed that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. A copy of the informed consent document will be given to the participants for 
their records. The informed consent process will be conducted and documented in the source 
document (including the date) and the form signed before the participant undergoes any 
study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
14.4.2 Investigator’s Regulatory/Good Clinical Practice Documents 
The regulatory/GCP documents are listed below. 
• Signed original protocol (i.e., Investigator’s Agreement) 
• Curricula vitae of all investigators and subinvestigators 
• Name and address of the laboratories 
• List of laboratory reference ranges, and if available, a quality certificate 
• Form Signature Log/Delegation of Study-related Duties 
• Approved ICF and subject materials 
• FDA1572 and financial disclosure forms, as applicable (US sites) 
• Any other relevant GCP documents 
The regulatory/GCP documents must be received from the investigator and reviewed and approved 
by Mayne Pharma LLC or its designee before the study site can initiate the study and before Mayne 
Pharma LLC will authorize shipment of IP to the study site. Copies of the investigator’s 
regulatory/GCP documents must be retained at the study site in a secure location. Additional 
documents, including a copy of the protocol and applicable amendment(s), the trifarotene 
(CD5789) Cream IB, eCRF completion guidelines, copies of regulatory references, copies of 
IRB/IEC correspondence, and IP accountability records should also be retained as part of the 
investigator’s regulatory/GCP documents. It is the investigator’s responsibility to ensure that 
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copies of all required regulatory/GCP documents are organized, current, and available for 
inspection. 
14.4.3 Case Report Forms 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign an 
ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the study to ensure that the study information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered in the electronic data capture 
(EDC) system according to the completion guidelines provided by the sponsor or its designee. 
The eCRFs must be signed by the investigator or a subinvestigator. These signatures serve to attest 
that the information contained in the eCRF is accurate and true. 
14.4.4 Source Documents 
Information recorded in the EDC system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
Clinical laboratory data required by the protocol will be electronically transferred from the 
central/local laboratory to the sponsor or its designee. A paper copy of the laboratory results will 
be provided to the study site and should be retained with each subject’s source data. 
14.5. Data Quality Control 
Mayne Pharma LLC and its designees will perform quality control checks on this clinical study. 
14.5.1 Monitoring Procedures 
Mayne Pharma LLC and/or its designee will conduct site visits to monitor the study and ensure 
compliance with the protocol, GCP, and applicable regulations and guidelines. The assigned 
clinical research associate(s) (CRA[s]) will visit the investigator and study site at periodic intervals 
and maintain periodic communication. The investigator agrees to allow the CRA(s) and other 
authorized Mayne Pharma LLC personnel access. The CRA(s) will maintain current personal 
knowledge of the study through observation, review of study records and source documentation, 
and discussion of the conduct of the study with the investigator and staff. While on site, the CRA(s) 
will review 
• regulatory documents, directly comparing entries in the EDC system with the source 
documents 
• consenting procedures 
• AE procedures 
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• storage and accountability of IP and study materials 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRF will be provided to the sites. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow Mayne Pharma LLC or designee auditors or inspectors from regulatory agencies 
to review records and to assist the inspectors in their duties, if requested.  
For additional information, please refer to the clinical monitoring plan (CMP). 
14.5.2 Data Management 
Mayne Pharma LLC or designee will be responsible for activities associated with the data 
management of this study. The standard procedures for handling and processing records will be 
followed per GCP and Premier Research’s standard operating procedures. A comprehensive data 
management plan (DMP) will be developed, including a data management overview, description 
of database contents, annotated CRF, pre-entry review list, self-evident correction conventions, 
query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries will be provided to the sites. 
14.5.3 Quality Assurance/Audit 
This study will be subject to audit by Mayne Pharma LLC or its designee. Audits may be performed 
to check compliance with GCP guidelines and can include: 
• site audits 
• Trial Master File audits 
• database audits 
• document audits (e.g., protocol and/or clinical study report [CSR]) 
Mayne Pharma LLC or its designee may conduct additional audits on a selection of study sites, 
requiring access to subject notes, study documentation, and facilities or laboratories used for the 
study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB/IEC or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify Mayne Pharma LLC immediately. 
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14.6. Study Termination 
The study may be terminated at Mayne Pharma LLC’s discretion at any time and for any reason. 
The DSMB may recommend discontinuation of the study if they find evidence of unacceptable 
risk to subjects. 
14.6.1 Regular Study Termination 
The end of this study is defined as the date of the last visit of the last subject (last subject out or 
last subject last visit) participating in the study. Within 90 days of the end of the clinical study, 
Mayne Pharma LLC or designee will notify the IECs and regulatory authorities about the regular 
termination of the study as required according to national laws and regulations. 
14.6.2 Premature Study Termination 
The study may be temporarily suspended or terminated prematurely if there is sufficient reasonable 
cause at any time by Mayne Pharma LLC, IECs, regulatory authorities, respective steering 
committees, or the coordinating investigator. A decision to prematurely terminate the study is 
binding to all investigators of all study sites. 
Within 15 days of premature termination of a clinical study, Mayne Pharma LLC or its designee 
will notify the IECs and regulatory authorities about the premature termination as required 
according to national laws and regulations. Mayne Pharma LLC or its designee must clearly 
explain the reasons for premature termination. 
Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigator, funding agency, the IND 
or IDE sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the 
PI will promptly inform study participants, the IRB, and sponsor and will provide the reason(s) for 
the termination or suspension. Study participants will be contacted, as applicable, and be informed 
of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
If the study is terminated prematurely, all investigators have to inform their subjects and take care 
of appropriate follow-up and further treatment of the subjects to ensure protection of the subjects’ 
interests. Study sites may be asked to have all subjects currently participating in the study complete 
all of the assessments for the Follow-up Visit. 
The study might resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB/IEC and/or FDA. 
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14.7. Study Site Closure 
At the end of the study, all study sites will be closed. Mayne Pharma LLC may terminate 
participation of a study site at any time. Examples of conditions that may require premature 
termination of a study site include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate subject enrollment 
14.7.1 Record Retention 
For sites in the US, the investigator shall retain and preserve 1 copy of all data generated in the 
course of the study, specifically including, but not limited to, those defined by GCP as essential 
until 1 of the following occurs: 
• At least 2 years after the last marketing authorization for the IP has been approved or the 
sponsor has discontinued its research with the IP, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development of 
the IP. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor has 30 days to respond to the investigator’s notice, and the 
sponsor has further opportunity to retain such materials at the sponsor’s expense. 
Outside of the US, after completing the study, Mayne Pharma LLC will receive the original eCRFs 
or at least a legible copy and retain the documents for at least 5 years after the completion of the 
study. 
One copy will remain with the investigator. The investigator shall arrange for the retention of the 
subject identification codes, subject files and other source data until at least 5 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or until at least 2 years have elapsed since 
the formal discontinuation of the clinical development of the product. These documents need to be 
retained for a longer period of time if required by applicable regulatory authorities or by agreement 
with the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor shall have 30 days to respond to the investigator’s notice, 
and the sponsor shall have a further opportunity to retain such materials at the sponsor’s expense. 
Copies of these study records (and all study-related documents, including source data) shall be 
kept by the investigator for the maximum period of time permitted by the hospital, institution, or 
private practice. 
14.7.2 Sample Retention 
Blood samples will be used for purposes related to this study only, and will not be stored for future 
research. The samples will be stored until they are no longer needed, and the decision has been 
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made that none of the samples needs to be reanalyzed. In addition, identifiable samples can be 
destroyed at any time at the request of the subject. 
Data collected for this study will be analyzed and stored at Premier Research.  
14.8. Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Mayne Pharma LLC. The protocol amendment must be signed by 
the investigator and approved by the IRB or IEC before it may be implemented. Protocol 
amendments will be filed with the appropriate regulatory agency(s) having jurisdiction over the 
conduct of the study. 
14.9. Use of Information and Publication 
All information concerning trifarotene (CD5789) cream HE1, Mayne Pharma LLC’s operations, 
patent applications, formula, manufacturing processes, basic scientific data, and formulation 
information supplied by Mayne Pharma LLC or its designee to the investigator, and not previously 
published, is considered confidential and remains the sole property of Mayne Pharma LLC. Case 
report forms also remain the property of Mayne Pharma LLC. The investigator agrees to use this 
information for purposes of study execution through finalization and will not use it for other 
purposes without the written consent of the sponsor. 
The information developed in this study will be used by Mayne Pharma LLC in connection with 
the continued development of trifarotene (CD5789) cream HE1 and thus, may be disclosed as 
required to other clinical investigators or government regulatory agencies. 
The information generated by this study is the property of Mayne Pharma LLC. Publication or 
other public presentation of trifarotene (CD5789) cream HE1 data resulting from this study 
requires prior review and written approval of Mayne Pharma LLC. Abstracts, manuscripts, and 
presentation materials should be provided to Mayne Pharma LLC for review and approval at least 
30 days prior to the relevant submission deadline. Data from individual study sites must not be 
published separately. 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition, or publication by the investigator until Mayne Pharma LLC has reviewed and 
commented on such a presentation or manuscript for publication. If applicable, this study will be 
registered at ClinicalTrials.gov, and results information from this study will be submitted to 
ClinicalTrials.gov. 
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15. FINAL CLINICAL STUDY REPORT 
Mayne Pharma LLC will retain ownership of the data. 
The final CSR will be written within 1 year of completion of the study. This report will include a 
summary of the study results based on a statistical evaluation and clinical assessment of the 
protocol-defined endpoints. 
The final CSR may be submitted to the regulatory authorities.  
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16. ETHICAL AND LEGAL CONSIDERATIONS 
16.1. Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry GCP 
E6 (including archiving of essential study documents), the Integrated Addendum to ICH E6 (R2) 
of November 2016, the Declaration of Helsinki, the applicable regulations of the country(ies) in 
which the study is conducted, and with the Commission Directives 2001/20/EC and 2005/28/EC. 
16.2. Subject Information and Informed Consent 
A properly constituted, valid IRB or IEC must review and approve the protocol, the investigator’s 
ICF, and related subject information and recruitment materials before the start of the study. 
It is the responsibility of the investigator to ensure that written informed consent is obtained from 
the subject before any activity or procedure is undertaken that is not part of routine care. 
According to the Declaration of Helsinki and ICH GCP, subjects must provide their written 
informed consent prior to enrollment in a clinical study and before any protocol-specified 
procedures are performed. Subjects must declare their consent by personally signing and dating 
the ICF. The written ICF will embody the elements of informed consent as described in the 
Declaration of Helsinki and will also comply with local regulations.  
Each subject should be made aware by the investigator of the nature of the study (objectives, 
methods, and potential hazards and benefits) and the procedures involved, using the information 
on the ICF. Information should be given in both oral and written form whenever possible and 
deemed appropriate by the IRB/IEC. Subjects, their relatives, or, if necessary, legal representatives 
must be given ample opportunity to inquire about details of the study.  
Subject information and the ICF must be in a language fully comprehensible to the prospective 
subject. The written information must be provided to the subject to give him or her sufficient time 
to understand the information and to prepare questions before being asked for his or her consent. 
The investigator must confirm that the text was understood by the subject. The subject will then 
sign and date the IRB/IEC-approved consent form indicating that he or she has given his or her 
consent to participate in the study. The signature confirms that the consent is based on information 
that has been understood. The form will also be signed by the investigator obtaining the consent 
and annotated with the study subject number. Each subject’s signed ICF must be kept on file by 
the investigator for possible inspection by regulatory authorities, Mayne Pharma LLC, and/or the 
sponsor’s designee. Collection of informed consent has to be documented in the eCRF. 
Furthermore, the subject will be informed that if he or she wishes to drop out or withdraw (see 
Section 8.3) at any time during the study, this will not have any negative consequences. Subjects 
may be withdrawn by the investigator if any change related to safety or ethics precludes further 
participation in the study. Subjects will be asked to agree to a final assessment in the event of an 
early termination of the study. 
Subjects will be informed that data from their case may be stored in a computer without inclusion 
of their name and that such data will not be revealed to any unauthorized third party. Data will be 
reviewed by the monitor, an independent auditor, and possibly by representatives of regulatory 
authorities and/or IRBs/IECs. The terms of the local data protection legislation will be applied as 
appropriate. 
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16.3. Approval by Institutional Review Board and Independent Ethics Committee 
A valid IRB/IEC must review and approve this protocol before study initiation. Written 
notification of approval is to be provided by the investigator to the sponsor’s or the sponsor’s 
representative before shipment of investigational drug supplies, and will include the date of the 
committee’s approval and the chairperson’s signature. This written approval must follow local 
country requirements. 
Until written approval by the IRB/IEC has been received by the investigator, no subject may 
undergo any procedure not part of routine care for the subject’s condition. 
Protocol amendments must also be reviewed and approved by the IRB/IEC. Written approval from 
the IRB/IEC, or a designee, must be received by Mayne Pharma LLC before implementation.  
16.4. Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator 
and the sponsor. 
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17. REFERENCES 
1. Vahlquist A, Blockhuys S, Steijlen P, 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 Derm. 2014;170(1):173-181. 
2. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited 
ichthyoses: results of the first ichthyosis consensus conference in sorèze 2009. J Am Acad 
Dermatol. 2010;63(4):607–-641. 
3. Vahlquist A, Gånemo A, Virtanen M. Congenital ichthyosis: an overview of current and 
emerging therapies. Acta Derm Venereol. 2008;88(1):4–14. 
4. Blanchet-Bardon C, Nazzaro V, Rognin C, Geiger JM, Puissant A. Acitretin in the 
treatment of severe disorders of keratinization. J Am Acad Dermatol. 1991;24(6):982–986. 
5. Kullavanijaya P and Kulthanan K. Clinical efficacy and side effects of acitretin on the 
disorders of keratinization: a one-year study. J Dermatol. 1993;20:501–506. 
6. Lacour M, Nikhar-Mehta B, Atherton DJ, Harper JI. An appraisal of acitretin therapy in 
children with inherited disorders of keratinization. Br J Dermatol. 1996;134:1023–1029. 
7. Steijlen PM, Van Dooren-Greebe RJ, Van De Kerkhof PCM. Acitretin in the treatment of 
lamellar ichthyosis. Br J Dermatol. 1994;130(2):211–214. 
8. Katugampola RP, Finlay AY. Oral retinoid therapy for disorders of keratinization: single-
centre retrospective 25 years’ experience on 23 patients. Br J Dermatol. 
2006;154(2):267-276. 
9. Gånemo A, Virtanen M, Vahlquist A. Improved topical treatment of lamellar ichthyosis: a 
double‐blind study of four different cream formulations. Br J Derm. 1999;141(6):1027–
1032. 
10. Kiistala R, Lauharanta J, Kanerva L. Transepidermal water loss and sweat gland response 
in lamellar ichthyosis before and during treatment with etretinate: report of three cases. 
Acta Derm Venereol. 1982;62(3):268–270. 
11. Ramirez ME, Youseef WF, Romero RG. Acute percutaneous lactic acid poisoning in a 
child. Pediatr Dermatol. 2006;23(3):282–285. 
12. Chiaretti A, Wismayer DS, Tortorolo L, Piastra M, Polidori G. Salicylate intoxication using 
a skin ointment. Acta Paediatr. 1997;86(3):330-331. 
13. Marukian NV, Deng Y, Gan G, et al. Establishing and validating an ichthyosis severity 
index. J Invest Dermatol. 2017;137(9):1834-1841. 
14. Korteweg SFS, Stenekes MW, van Zyl FE, Werker PMN. Paralytic ectropion treatment 
with lateral periosteal flap canthoplasty and introduction of the ectropion severity score. 
Plast Reconstr Surg Glob Open. 2014;2(5):e151. 
 
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18. ATTACHMENTS 
18.1. Investigator’s Agreement 
 
PROTOCOL NUMBER: 18-ICH-001 
PROTOCOL TITLE: 
A Phase 2 Randomized, Multicenter, Double-blind, 
Vehicle-controlled, 90-day, Safety, Efficacy, and Systemic Exposure 
Study followed by a 90-day Open-label Extension of Trifarotene 
(CD5789) Cream HE1 in Subjects with Autosomal Recessive 
Ichthyosis with Lamellar Scale 
FINAL PROTOCOL 
DATE: 
v4.0 for Ukraine, 19-Nov-2020 
The undersigned acknowledges possession of and has read the product information 
(e.g., investigator’s brochure) on the IP and has discussed these data with the study monitor. 
Having considered fully all the available information, the undersigned considers that it is ethically 
justifiable to give the IP to selected subjects in his/her care, according to the study protocol. 
He or she agrees to use the study material, including IP, only as specified in the protocol. He or 
she understands that changes cannot be made to the protocol without prior written approval of 
Mayne Pharma LLC. 
He or she understands that any deviation from the protocol may lead to early termination of the 
study. 
He or she agrees to report to Mayne Pharma LLC within time any clinical AE or abnormal 
laboratory value that is serious, whether or not considered related to the administration of IP. 
He or she agrees to comply with Mayne Pharma LLC and regulatory requirements for the 
monitoring and auditing of this study. In addition, he or she agrees that the study will be carried 
out in accordance ICH, the Declaration of Helsinki, and the local laws and regulations relevant to 
the use of new therapeutic agents. 
I, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the study. 
Principal Investigator: 
 
Printed Name: 
 
 
 
Signature: 
 
 
 
Date: 
 
 
 
Investigator’s name and address (stamp) 
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APPENDICES 
A. Regulations and Good Clinical Practice Guidelines 
B. Procedural Adjustments Due to COVID-19 
 
 
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A. Regulations and Good Clinical Practice Guidelines 
1. Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
Refer to the following European Directives (and applicable regulations/guidances): 
• European Directive 2001/20/EC and related guidance documents 
• European Directive 2005/28/EC and related guidance documents> 
2. Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URLs: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf 
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B. Procedural Adjustments Due to COVID-19
The coronavirus disease 2019 (COVID-19) global pandemic has impacted the free movement of 
the world’s population, which has been restricted to control the spread of the disease. It is 
recommended that all sites and subjects comply with the applicable local and federal guidelines 
regarding the necessary and proper precautions regarding COVID-19. 
Trifarotene cream HE1 does not increase the risk for contracting COVID-19. 
Although it is preferable to conduct all necessary study assessments in person (onsite visits), it 
may not be possible as a result of COVID-19-related travel restrictions, site closures, or subject 
confinement. If the subject becomes infected with COVID-19, the investigator or the treating 
physician will decide on continuation of the study treatment; note that topical trifarotene does not 
modify immunity. 
The skin of individuals with LI is thick, scaly, and often dry, tight, and inelastic. This rigidity may 
produce major discomfort through formation of painful cracks in the skin and open areas. Extreme 
thickening of the skin on the soles of the feet can make walking difficult for many patients, and 
cracks and fissures on the fingers can make even simple tasks difficult or painful. Tight skin can 
interfere with joint mobility, and over time, lead to decreased joint mobility. Some individuals may 
be unable to close their eyes completely (ectropion) because of the tightness of the skin around the 
eyes and eyelids and may seem to "sleep with their eyes open." In addition, the general aspect of 
this chronic and difficult to manage skin disease often causes depression. For these reasons, as 
well as the lack of treatment options for individuals with LI, Mayne Pharma thinks it is important 
for this patient population to continue having access to the treatment offered in this study. 
The best way to ensure the reliability of the data collected is to follow the Study Protocol. 
However, the subjects’ safety and wellbeing is a top priority. Therefore, in extraordinary situations 
when it is inadvisable or not possible to conduct an onsite study visit, please follow these 
procedures. 
❑Subject visits:
Visits 3 to 6 of the Double-blind Period, Visits 7 to 11 of the OLE Period, and unscheduled visits 
may be conducted remotely (i.e., via telephone or video call). Screening and Baseline Visits must 
be performed onsite only and must be postponed or scheduled for when onsite visits can be safely 
conducted.  The schedule of  telephone visits will continue as indicated in  the study protocol 
(Table 2-1 and Table 2-2); however, onsite visits will be postponed or rescheduled as possible.
When it is not possible to postpone or reschedule the onsite visit, and to ensure the safety of the 
subjects and to not jeopardize the study procedures and the scientific value of the trial, onsite visits 
will be changed into telephone visits. As soon as the COVID-19 situation that triggered the use of 
these procedural adjustments is resolved, the schedule of onsite visits will resume. Information 
collected during the telephone visits will focus on safety data and primary objective endpoints. 
The following information is expected to be collected by the investigator/study staff during the 
telephone visits, as applicable per protocol: 
•
Ask/remind the subject about any required study procedure considered necessary
and according to the protocol. For example:
o
Ask the subject about study drug application
o
Remind the subject to complete the subject diary
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o Advise subjects regarding permitted emollient(s) and/or sunscreen for use 
on nontreatment days 
• Record concomitant medications and concomitant therapies 
• Record adverse events and information reported in the subject diary 
• Record the subject’s general health status 
• Assess local tolerance at the application sites 
• For efficacy assessments, use videoconference for precise scoring; if this is not 
possible, ask subject if status is the better, worse, or unchanged for the following 
assessments and enter the outcome for reference in the source data: 
o Investigator’s Global Assessment (IGA) 
o Visual Index for Ichthyosis Severity (VIIS) 
o Roughness 
o Palm/sole 
o Palm/sole fissuring 
o Ectropion 
• Record urine pregnancy test result for female subjects 
• Evaluate treatment compliance, including frequency of application and check if 
there is cream left in the tubes after application and approximately how much in 
conjunction with the subject’s diary 
• Adjust the treatment if necessary, as per study protocol, according to application 
site tolerance and treatment compliance 
 
Remote visits are not possible in the following instances: 
• Baseline visits will be canceled if the subject is unable to go to the site. If this 
occurs, rescreening may be necessary when the COVID-19 outbreak is resolved. 
• End-of-Treatment visits are recommended to occur onsite. Therefore, the telephone 
visit will be completed, followed by an onsite visit when the COVID-19 outbreak 
is resolved. 
❑ Pregnancy Tests 
Retinoids are potentially teratogenic and, therefore, monthly pregnancy tests for women of 
childbearing potential (WOCBP) are considered critical for subject safety. Consequently, urine 
pregnancy tests, along with the instructions on how to use them, will be sent to the subject’s home. 
The study staff will instruct the subjects how to properly perform the test during the telephone 
visits and will document it and the result. 
❑ Supply of Study Medication 
All randomized subjects who have already attended the Baseline Visit (Day 1) and have had study 
staff apply the first administration of the study drug in the clinic and instructed the subject, should 
continue their treatments to ensure the reliability of the study data and the scientific value of the 
trial. Therefore, if the subject is not able to travel to the site, the site will ship the study drug and 
diary to the subject’s home using either powers of the study site or an independent distributor 
contracted by the sponsor, Mayne Pharma LLC or their designee CRO, who will collect the IP at 
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the site and will ship it to the patient’s home ensuring temperature control and confidentiality. 
Patient diaries may be sent to subjects electronically or via postal service. Completed diaries may 
be returned to the site in the same manner. 
Investigators/site staff will properly record that the subject has been told their study medication 
will be sent to their home, and when the study medication was received (to be confirmed with the 
subject using telephone or via e-mail). Subjects should retain any unused IP and return them to the 
study site at the next onsite visit, when the study staff will weigh the kits (tubes and boxes, but not 
leaflets). 
❑ Quality of Life per Dermatology Life Quality Index (DLQI) and EQ-5D Quality of Life 
Questionnaire 
Quality of Life questionnaires should be completed on the day of the remote visit and prior to 
applying treatment (if the remote visit falls on a treatment day). Questionnaires may be sent to 
subjects electronically or via postal service, and completed questionnaires may be returned to the 
site in the same manner. If subjects are unable to send completed questionnaires to the site, 
investigators should ask and record the subject’s responses during the remote visit. 
However, questions relative to social interaction might not be relevant due to social distancing 
and/or quarantining. This will be captured in the questionnaires and can be differentiated in the 
analysis. 
❑ Monitoring visits: 
If onsite monitoring visits are not possible as a consequence of COVID-19 outbreak, remote visits 
(via telephone) will be arranged in agreement with the study sites to assist the study progression 
and to ensure study compliance, without reducing the level of monitoring. 
❑ Participant Information 
Participating subjects must be promptly informed about changes in the study conduct during 
COVID-19 outbreak. Information about the changes should first be communicated to subjects via 
a telephone conversation. 
In addition, a Subject Information Sheet and Consent Form have been created to tell subjects about 
how the above-mentioned changes might impact their usual participation in the study. The 
investigators/study staff will send the information sheet and consent form to the subject by the 
appropriate means (for example, via email, regular mail, or courier). Investigators/study staff will 
confirm and document in the medical history the date the patient was informed via telephone and 
the date the Subject Information Sheet and Consent form were mailed to and received by the 
subjects, and that the subject provides verbal consent. 
❑ Informed consent and/or assent process recommendations 
Where country regulation requires that the COVID-19 Information Sheet is signed by the subjects 
to express their consent to the changes in the study procedures due to COVID-19 or a subject is 
completing the double-blind part of the study and needs to consent to continue in the open label 
extension part, the process will be as follows: 
1) First option is to collect face-to-face written consent with the investigator according to ICH 
E6 (R2) and local regulation. 
2) When face-to-face written consent is not possible, trial participants can be contacted via 
phone or video call to obtain remote consents as follows: 
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a. Informed consent document/assent, if applicable, is emailed, faxed, or sent via 
courier or regular mail by site staff to subject prior to remote visit. 
• If document is emailed, subject should print document prior to visit. 
b. Subject will be contacted via phone or video call by the investigator/designee. 
Informed consent/assent discussion with the subject will be facilitated by the 
Investigator or staff delegated to perform this task. 
• Investigator/designee will document details of the remote informed consent 
process in the trial participant’s medical records. 
c. Subject will sign and date informed consent/assent while on phone or video call 
with investigator/designee. 
• During the call or video call, the subject should provide verbal consent and 
supplement it with an e-mail confirmation 
• Investigator/designee will document the time and date that they witness the 
signing of the informed consent/assent via phone or video call in the trial 
participant’s medical records. 
d. Investigator/designee will sign and date copy of the informed consent/assent 
documenting that they witnessed the verbal consent of the subject via phone or 
video call 
e. When subject returns to the site, subject will bring the signed consent form (if 
possible) and will give consent again face-to-face with site staff according to ICH 
E6 (R2) and local requirements. 
f. Investigator/designee will attach the subject signed informed consent/assent to the 
copy signed and dated by investigator/designee upon receipt. 
 
 
 
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Page 1 of 123 
PROTOCOL/CLINICAL INVESTIGATION PLAN AMENDMENT 
 
PRODUCT NAME/NUMBER: 
Trifarotene (CD5789) Cream HE1 
PROTOCOL NUMBER: 
18-ICH-001 
IND NUMBER: 
140538 
NCT NUMBER:  
NCT03738800 
EUDRACT NUMBER: 
2018-003272-12 
DEVELOPMENT PHASE: 
2 
PROTOCOL TITLE: 
A Phase 2 Randomized, Multicenter, Double-blind, 
Vehicle-controlled, 90-Day, Safety, Efficacy, and Systemic 
Exposure Study followed by a 90-Day Open-label 
Extension of Trifarotene (CD5789) Cream HE1 in Adults 
and Adolescents with Autosomal Recessive Ichthyosis with 
Lamellar Scale  
PROTOCOL DATE: 
Original: 28-Nov-2018 
AMENDMENT 1 DATE: 
Final v2.0, 10-Jul-2019 
AMENDMENT 2 DATE: 
Final v3.0 28-Oct-2020 
COORDINATING/PRINCIPAL 
INVESTIGATOR: 
Keith A. Choate, MD 
Department of Dermatology, Yale University School of 
Medicine,  
PO Box 208059 
333 Cedar Street 
New Haven, CT 06520, USA 
+1 203 789 1249 
SPONSORED BY: 
 
Mayne Pharma LLC 
1240 Sugg Parkway  
Greenville, NC 27834, USA  
+1 984 242 1400 
CONTRACT RESEARCH 
ORGANIZATION: 
Premier Research  
One Park Drive, Suite 150 
Durham, NC 27709, USA 
+1 919 627 9100 
This study will be performed in compliance with ICH Good Clinical Practices and applicable regulatory requirements, 
including the archiving of essential documents. Information contained in this protocol is confidential in nature and 
may not be used, divulged, published, or otherwise disclosed to others except to the extent necessary to obtain approval 
of the institutional review board or independent ethics committee, or as required by law. Persons to whom this 
information is disclosed should be informed that it is confidential and may not be further disclosed without the express 
permission of Mayne Pharma LLC. 
pharma 
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1.
APPROVAL SIGNATURES
PROTOCOL NUMBER: 
18-ICH-001 
PROTOCOL TITLE: 
A Phase 2 Randomized, Multicenter, Double-blind, 
Vehicle-controlled, 90-Day, Safety, Efficacy, and Systemic 
Exposure Study followed by a 90-Day Open-label Extension of 
Trifarotene (CD5789) Cream HE1 in Adults and Adolescents with 
Autosomal Recessive Ichthyosis with Lamellar Scale 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge, it 
accurately describes the planned conduct of the study. 
SIGNATURE 
DATE: 
Phoevos Hughes, JD 
Head of Medical and Clinical Affairs 
Mayne Pharma LLC 
Marlis Sarkany, MD 
Senior Medical Director 
Premier Research 
Adrienne Kuxhausen, MS 
Senior Biostatistician 
Premier Research 
30-Oct-2020 | 10:24:26 EDT
30-Oct-2020 | 10:27:46 EDT
30-Oct-2020 | 10:59:39 PDT
r
DocuSigned by: 
I Rou..os.¾~r 
l(J 
Signer Name: Phoevos Hughes 
t
Signing Reason: I approve this document 
-
Si§AiA§ Tiffie: 30 Oct 2020 110:69:36 PDT 
201 DC 1 CA65A848718371307 AF875E4CE 
(
DocuSigned by: 
I 
1"/,.,/4,, 
l(J 
Signer Name: Marlis Sarkany 
[
Signing Reason· I have reviewed this doc11meot 
Signing Time: 30-0ct-2020 110:27:37 EDT 
16E1C8AEDC854CDC86688C1FD466E26F 
(
DocuSigned by: 
I abi.UAJAL, b.-)oiuw.sUA. 
l(J 
Signer Name: Adrienne Kuxhausen 
[
Signing Reason· I appcnve Ibis darnment 
Signing Time: 30-0ct-2020 110:24:18 EDT 
6E6B87C6B98740819F26B8O5A7O662CF 
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2. PROTOCOL SUMMARY 
2.1. Synopsis 
PRODUCT 
NAME/NUMBER 
Trifarotene (CD5789) Cream HE1 
PROTOCOL NUMBER 
18-ICH-001 
EUDRACT NUMBER 
2018-003272-12 
DEVELOPMENT 
PHASE 
2 
PROTOCOL TITLE 
A Phase 2 Randomized, Multicenter, Double-blind, Vehicle-controlled, 90-Day, 
Safety, and Efficacy, and Systemic Exposure Study followed by a 90-Day Open-label 
Extension of Trifarotene (CD5789) Cream HE1 in Adults and Adolescents with 
Autosomal Recessive Ichthyosis with Lamellar Scale  
INDICATION 
Lamellar ichthyosis 
OBJECTIVES 
Primary: To compare the safety and efficacy of 2 concentrations of trifarotene cream 
HE1 versus vehicle in adults and adolescents with moderate to severe autosomal 
recessive ichthyosis with lamellar scale, also known as lamellar ichthyosis (LI) after 
90 days of treatment. 
Secondary: 
• 
To assess systemic exposure to trifarotene and its major metabolites after topical 
application of the investigational product (IP) on up to 90% body surface area 
(BSA) twice weekly. 
• 
To assess safety for up to 180 days of dosing with trifarotene cream HE1 
200 µg/g. 
STUDY DESIGN 
 
This is a 2-cohort, multicenter study in subjects with moderate to severe LI (i.e., 3–4 
on a 5-point Investigator’s Global Assessment [IGA] where 0 = clear; 1 = almost clear; 
2 = mild; 3 = moderate; 4 = severe). Adults and adolescents will be randomized in a 
double-blind fashion to 1 of 2 doses of trifarotene cream HE1 or vehicle and treated 
twice weekly for 90 days. Subjects who complete the randomized, Double-blind 
Period of the study will be eligible to enter a 90-Day, Open-label Extension (OLE) in 
which additional PK, safety, and efficacy data will be collected. 
The first cohort of subjects (Cohort A) will randomize adults (≥18 years old) in a 1:1:1 
ratio to trifarotene (CD5789) cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, 
or vehicle.  After the initial 15 subjects complete at least 28 days of treatment, an 
independent data safety monitoring board (DSMB) will review aggregate safety and 
tolerability data (including PK and electrocardiogram [ECG] data). If no safety issues 
are identified, adolescents (ages 12 to 17 years, inclusive) will be allowed to enroll 
together with adults in Cohort B. Subjects in Cohort B will be randomized 1:1:1 to 
trifarotene cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle and 
treated twice weekly for 90 days in the same manner as subjects in Cohort A. Cohort 
A will continue enrolling only adult subjects until the DSMB considers it safe to open 
recruitment in Cohort B. All subjects (Cohort A and Cohort B) who complete the 90-
day Double-blind Treatment Period will be eligible to enroll in the 90-day OLE. 
Subjects in the OLE will receive open-label trifarotene cream HE1 200 µg/g twice 
weekly for 90 days. 
Written informed consent will be obtained from a parent/legal guardian for any minor 
and minors will provide assent before any study-related procedures are performed. 
Upon signing informed consent and entering the Screening Period, subjects may begin 
a Washout Period of 90 days. Participants will stop using physical and medical 
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treatments for LI, including balneotherapy, as well as the following prohibited 
medications, as applicable. The following list applies to both prescription and over-
the-counter medications: 
a. 
Topical treatments 
Medication 
Washout  
Corticosteroids (except inhaled and ophthalmic corticoids) 
2 weeks 
Retinoids (e.g., tretinoin, tazarotene) 
4 weeks 
Vitamin D analogs 
2 weeks 
Immunosuppressants (e.g., tacrolimus) 
2 weeks 
Antracen derivatives, tar and salicylic preparations 
2 weeks 
Keratolytics (such as urea, lactic acid, propylene glycol, 
salicylic acid) except keratolytic shampoo 
2 weeks 
b. Systemic treatments 
Medication 
Washout  
Retinoids 
8 weeks 
Oral Vitamin A supplementation more than 3500 IU per day 
2 weeks 
Medication interfering with bone activity, e.g., corticosteroids, 
thyroid hormones unless the dose is stable and thyroid-
stimulating hormone (TSH) is normal, cytotoxics, 
bisphosphonates, selective estrogen receptor modulators 
(SERM), teriparatide, calcitonins, tetracyclines, quinolones, 
thiazides, long-term use of salicylates, heparin, theophylline, 
barbiturates, colchicines. Vitamin D analogs taken at stable dose 
for at least 30 days are allowed. 
8 weeks 
QT-prolonging drugs 
5 half lives 
CYP enzyme inducers (such as rifampicine, phenytoin, 
carbamazepine, phenobarbital, St. John’s Wort) 
3 months 
CYP2C9 and 2C8 inhibitors (including, but not limited to the 
following: gemfibrozil, fluconazole, fluvoxamine, 
sulfaphenazole, miconazole, amiodarone, sertraline, 
sulfamethoxazole, valproic acid, voriconazole, trimethoprim, 
rosiglitazone, pioglitazone) 
5 half lives 
Monoclonal antibodies 
5 half lives 
Before asking a subject to washout of their prescription and over-the-counter 
prohibited treatments, investigators should confirm the subject meets all study 
eligibility criteria except for LI severity (inclusion criterion #3). After completing the 
necessary washout period, subjects will return to the site to have their LI severity 
assessed and to complete study eligibility requirements. 
During washout, subjects may continue their standard of care of visible skin (face and 
scalp) for cosmetic reasons and of extremities (palms/soles) to avoid functional 
consequences on walking or moving their fingers. In the US/EU, this may include 
compounded emollients with keratolytics (alpha or beta hydroxyl acids) and/or urea. 
The investigator should approve and document these standard of care treatments in 
the electronic case report form (eCRF). If the standard of care treatments of the face 
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and/or palms/soles contain prohibited medications, they must be stopped at the 
Baseline Visit. 
Subjects may shower but not bathe or swim during the Screening Period. 
Study drug will be packaged in 50-g tubes from which up to 36 g of investigational 
product (IP) may be dispensed per application, i.e., the maximum dose per application. 
Study staff will choose 1 tube from the kit dispensed to the subject at that visit, and 
apply the first dose of study drug to each subject in the clinic on Day 1 after Baseline 
measurements; they will weigh the study tube before and after application to 
determine the amount used. If the product will be applied at home by someone other 
than the study subject, it is recommended that person assist with application at the first 
visit to learn how the IP is applied. 
The kit dispensed at baseline must be weighed before the first tube is chosen for 
application by the study staff. Weight of the kits dispensed and returned by the subject 
during the study includes both tubes and cartons, but not leaflets, which need to be 
removed before weighing. The subject must be reminded to return the kits with tubes 
and cartons, whether used or not, when returning to the next visit. 
Thereafter, each subject will apply up to 36 g of study drug as for the first dose on up 
to 90% of BSA twice weekly 3 to 4 days apart, sparing the scalp, inguinal, and axillary 
areas. Subjects with heavy facial hair should not apply IP to hair-bearing areas. 
Subjects will receive an adequate number of tubes to use 1 tube per application and 
will use a new tube for each treatment day. Subjects may use less than the full amount 
of product in a tube. Subjects will record the date and time of study treatment 
administration in the subject diary. 
The study protocol limits application of IP to 36 g maximum; no additional tubes can 
be given, whether during the randomization period or the OLE period. If the study 
staff and subject note that there is insufficient volume for full body application, the 
subject should apply trifarotene cream sparingly twice weekly to the most affected 
areas, and always to the same skin areas. Study cream should be very sparingly 
applied. Trifarotene cream 100 or 200 µg/g, is a highly potent topical retinoid and it 
is not necessary to apply much for efficacy; application of more will increase the risk 
of irritation and systemic penetration. 
Local tolerability may differ in subjects with LI compared to healthy subjects, as their 
skin is drier and may be more sensitive. Local tolerability will be followed very 
carefully during the study. Subjects will receive information on study drug use and 
stopping rules and will be instructed to contact the site with any safety/tolerability 
issues. Study personnel will telephone subjects in between scheduled visits (i.e., at 
Day 7 and Day 45 in the Double-blind Period; at Day 97 and 134 in the OLE) to assess 
safety; an unscheduled clinic visit may be performed, if necessary. If the treatment 
causes application site reactions, the frequency of application will be reduced or 
interrupted only on the area of concern, as indicated herein. During all clinic visits, 
the investigator will assess local tolerability (stinging/burning, pruritus, or erythema 
on 0-3 scales [none, mild, moderate, severe]) for each body area (chest/abdomen, 
back, arms, legs, and face/neck), and the following procedures will be followed: 
- 
If a score of 2 (moderate) is recorded for any of the local tolerability assessment 
scales (stinging/burning, pruritus or erythema) on any treated area, the study 
drug will be applied on that area only once weekly, until the score is back to <2. 
Continue to treat all other areas twice weekly provided the score is <2 on those 
areas. 
- 
If a score of 3 (severe) is recorded for any of the local tolerability assessment 
scales (stinging/burning, pruritus or erythema) on any treated area, the study 
drug will not be applied on that area until the score is back to <3 (i.e., “drug 
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holiday”). Continue to treat all other areas twice weekly provided the score is 
<2 on those areas. 
Stopping rules and treatment modification will be defined at the subject level based 
on local tolerability, selected laboratory parameters, and adverse events (AEs). Any 
changes in dosing must be documented in the subject diary and the electronic case 
report form. 
All subjects will be provided with diaries in which to record study drug application 
(days/times and any areas of skin not treated [e.g., due to local reactions]) and any 
AEs, including application site reactions and concomitant medications used. Subjects 
will also be advised on permitted emollient(s) use on nontreatment days during the 
study; use of emollient(s) and/or sunscreen(s) on study drug treatment days within 
4 hours before or after study drug application is prohibited. 
At all sites with photographic capability, photographs will be taken as source data to 
support scoring at Baseline, Day 30, and Day 90. A central reader who will not be an 
investigator in the study will review the photographs to assess consistency of 
investigator scoring of LI severity as a quality check. Photographs may also be used 
for scientific publication purposes. Subjects will sign a separate, optional 
photographic informed consent form (ICF). 
Samples for pharmacokinetic (PK) analysis will be drawn from all subjects at Baseline 
and at each clinic visit. Visits for PK must occur at least 24 hours after the last 
application of the IP to avoid contamination of the blood samples with any IP that 
may have remained on the skin after the last application. Subjects should not apply IP 
on visit days until after the visit. 
In addition, a PK substudy will be conducted on Days 1 and 30 at sites with the 
capability to conduct it. Participation in the PK substudy will be optional and will 
include at least 30 subjects, 15 adults and 15 adolescents. Subjects who participate in 
the PK substudy will come from both study cohorts and will undergo serial blood 
sampling predose and at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1 and Day 30. 
Trough levels will be drawn for these subjects at each of the other clinic visits. For 
the subjects in the PK substudy, postdose ECGs will be performed at each serial blood 
draw on Day 1 and Day 30. 
Subjects who complete the Double-blind Treatment Period will have the option to 
continue into the OLE to assess safety for an additional 90 days with trifarotene cream 
HE1 200 µg/g twice weekly, on up to 90% of BSA, sparing the scalp, inguinal, and 
axillary areas. During the study, subjects with heavy facial hair should not apply IP to 
hair-bearing areas. During the OLE, subjects will return to the site at Days 104, 120, 
150, 180, and 194 for safety, tolerability, and efficacy assessments. Blood samples 
will be drawn for clinical laboratory safety tests and PK at Days 120 and 180. Study 
personnel will telephone subjects in between scheduled visits (i.e., at Day 97 and 
Day 134) to assess safety; an unscheduled clinic visit may be performed, if necessary. 
The coronavirus disease 2019 (COVID-19) global pandemic has impacted the free 
movement of the world’s population, which has been restricted in order to control the 
spread of the disease. It is recommended that all sites and subjects comply with the 
applicable local and federal guidelines regarding the necessary and proper precautions 
regarding COVID-19. 
Although it is preferable to conduct all necessary study assessments in person (onsite 
visits), this may not be possible as a result of COVID-19 -related travel restrictions. 
To ensure the safety of subjects, investigators, and site staff, Visits 3-6 (Double-blind 
Period; Table 2-1), Visits 7-11 (OLE Period; Table 2-2) and unscheduled visits may 
be conducted remotely. Screening and Baseline Visits must be performed on site only. 
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These visits must be postponed or scheduled for when onsite visits can be safely 
conducted. The following assessments may occur remotely: 
• Safety Assessments 
o Concomitant medications and concomitant therapies. 
o Adverse Events and related information reported by the patient in the diary 
o General health status of the patient 
• Tolerability Assessments 
• Pregnancy Tests: Urine pregnancy tests along with the instructions on proper use 
will be sent to the subject’s home for women of childbearing potential (WOCBP). 
Study staff will instruct patient to perform the urine pregnancy at the applicable 
remote visit. 
• Study Medication Supply: As necessary and according to applicable local 
regulations, study medication will be sent to subjects. 
• DLQI and EQ-5D Questionnaires: Quality of Life questionnaires should be 
completed on the day of the remote visit and prior to applying treatment (if the 
remote visit falls on a treatment day). Questionnaires may be sent to subjects 
electronically or via postal service, and completed questionnaires may be returned 
to the site in the same manner. If subjects are unable to send completed 
questionnaires to the site, investigators should ask and record the subject’s 
responses during the remote visit. 
• Patient Diary: Patient diaries may be sent to subjects electronically or via postal 
service. Completed diaries may be returned to the site in the same manner. 
PLANNED NUMBER 
OF SUBJECTS 
Approximately 120 total subjects; 15 adult subjects in Cohort A and 105 adult and 
adolescent subjects in Cohort B. 
STUDY ENTRY 
CRITERIA 
Inclusion criteria: 
1. For Cohort A: subject is ≥18 years old; for Cohort B: subject is ≥12 years old. 
2. Subject has known diagnosis of LI. 
3. Subject has moderate to severe (IGA 3-4) LI on the IGA of LI severity. 
4. Subject has signed an ICF at Screening before any investigational procedures. 
Subjects <18 years of age (or Age of Majority) must sign an assent form in 
conjunction with an ICF signed by the parent/legal representative. 
5. Subject who is participating in photography has signed a photography ICF. 
6. Subject who is participating in the optional PK substudy has signed a PK ICF. 
Minors, in the event of their reaching majority during the study, should be 
capable of giving consent to take part in the PK substudy. 
7. Subject is not of childbearing potential, who is postmenopausal (absence of 
menstrual bleeding for 1 year before Baseline, without any other medical 
reason), or has documented hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy. For individuals with permanent infertility due to an alternate 
medical cause other than the above, (e.g., Mullerian agenesis, androgen 
insensitivity), investigator discretion should be applied to determining study 
entry. 
OR 
Subject is a woman of childbearing potential (WOCBP), i.e. a female ≥12 years 
of age (regardless of whether they have experienced/reported menarche), or a 
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male subject with sexual partners capable of reproduction who agrees to use 2 
effective forms of contraception during the study and for at least 1 month after 
the last study drug application. The 2 authorized forms of contraception are 
condom used with 1 of the following methods of contraception: 
• bilateral tubal ligation 
• combined oral contraceptives (estrogens and progesterone), vaginal ring, or 
implanted or injectable hormonal contraceptives with a stable dose for at least 
1 month before Baseline; hormonal contraceptives must inhibit ovulation 
• intrauterine device (IUD) inserted at least 30 days before Baseline 
OR 
Agrees to abstain from heterosexual intercourse during study participation and 
for 1 month after the last application of study drug and to use a highly effective 
contraceptive as backup if he or she becomes sexually active during the study. 
Abstinence is only acceptable if this is the subject’s usual lifestyle. Periodic 
abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception. 
AND 
Male subjects may not donate sperm during the study and for at least 1 month 
after the last study drug application. 
Note: Female subjects who are premenstrual at screening should nonetheless 
follow the pregnancy testing schedule for WOCBP even if they abstain from 
sexual intercourse while in the study and for at least 1 month after the last study 
drug application. 
8. Women of childbearing potential must be nonlactating and have negative 
pregnancy test results at Screening (serum) and on Day 1 before study drug 
administration (urine). 
9. Subject is reliable and capable of adhering to the protocol and visit schedule, in 
the investigator’s judgment, and has signed informed consent/assent, as 
applicable. 
10. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin). 
 
Exclusion criteria: 
1. Subject has any variant of ichthyosis other than LI or another disorder of 
keratinization, including syndromic ichthyoses. 
2. Subject has current moderate or severe stinging/burning at Screening. 
3. Subject has an ongoing cutaneous infection or any other significant concomitant 
skin disease (other than the LI) which, in the investigator’s opinion, may interfere 
with the study assessments. 
4. Subject with fasting triglycerides >200 mg/dL or >2.25 mmol/L and/or total 
cholesterol >250 mg/dL or >6.5 mmol/L. Subjects whose triglycerides and/or 
total cholesterol are within normal limits with a stable dose of lipid-lowering 
agents for at least 6 months may be included. 
5. Subject was previously treated with trifarotene/CD5789 in an acne or ichthyosis 
study. 
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6. Subject has any other significant concomitant disease, or poorly controlled 
medical condition other than LI that in the investigator’s opinion may put him or 
her at risk if he or she takes part in the study, and/or that may interfere with the 
study assessments. 
7. Subject has a medical condition that potentially alters bone metabolism 
(e.g., osteoporosis, thyroid dysfunction, Cushing syndrome, Crohn’s disease, or 
ulcerative colitis). Subjects with hypothyroidism who are on a stable dose of 
thyroid hormone replacement therapy and whose TSH is normal may be included. 
8. Subject is being treated for major depression disorder and/or has a history of 
major depression or suicide attempt requiring hospitalization, medications, and 
close psychiatric surveillance to prevent suicide attempts. 
9. Subject with positive serology for hepatitis B surface antigen, hepatitis C, or are 
known to be HIV positive or to have AIDS at Screening. 
10. Subject with any of the following laboratory values at Screening: 
a. 
Aspartate aminotransferase or alanine aminotransferase >1.5 × upper 
limit of normal (ULN) defined by the laboratory 
b. Total bilirubin >1.25 × ULN at Screening. Subjects with known 
Gilbert’s syndrome may be included with total bilirubin >1.25 × ULN 
c. 
Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women 
d. Platelets <150 × 109/L or >400 × 109/L 
11. Subject has any clinically other significant abnormal laboratory value 
(hematology, chemistry, or urinalysis) at Screening that, in the investigator’s 
opinion, may put the subject at risk if he or she takes part in the study, and/or that 
may interfere with the study assessments. 
12. Subject has had recent systemic malignancy (e.g., within 5 years) with exception 
of nonmelanoma skin cancer or cervical intraepithelial neoplasia of Grade 1 who 
are >6 months post-treatment. 
13. Subject has a history of long QT syndrome or has clinically significant 
electrocardiogram (ECG) abnormalities, including clinically significant 
conduction disorders or significant arrhythmias, or QTcF interval >450 ms. 
14. Subject has a known allergy or sensitivity to any of the components of the 
investigational products. 
15. Subject has been exposed to excessive ultraviolet (UV) radiations on the treated 
zones within 1 month before Baseline visit or is planning intensive UV exposure 
during the study (e.g., occupational exposure to the sun, sunbathing, 
phototherapy, etc.). 
16. Subject is inherently sensitive to sunlight. 
17. Subject is unable or unwilling to stop use of topical or systemic retinoids. 
18. Subject is presumed to be abusing drugs or alcohol at Screening or Baseline Visits 
based on medical history or current clinical symptoms. 
19. Subject is participating in another interventional clinical trial. 
20. Subject is institutionalized. 
21. Subject is in any way related to the sponsor, investigator, or site personnel. 
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INVESTIGATIONAL 
PRODUCT 
Name: Trifarotene (CD5789) cream HE1 
Double-blind Period dose, route, frequency: Up to 36 g per dose of 100 µg/g or 200 
µg/g applied topically twice weekly on up to 90% BSA 
Open-label Extension dose, route, frequency: Up to 36 g per dose of 200 µg/g applied 
topically twice weekly on up to 90% BSA 
REFERENCE 
PRODUCT(S) 
Name: Vehicle cream 
Double-blind Period dose, route, frequency: Up to 36 g per doseapplied topically 
twice weekly on up to 90% BSA  
TREATMENT 
REGIMENS 
Topical application twice weekly to all affected skin except the scalp, axillae, and 
inguinal area.  
COORDINATING/ 
PRINCIPAL 
INVESTIGATOR 
Keith A. Choate, MD 
Department of Dermatology, Yale University School of Medicine 
New Haven, CT 06520, USA 
PLANNED STUDY 
SITES 
Approximately 40 sites across North America, Europe, Israel, and Australia 
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CRITERIA FOR 
EVALUATION 
Primary efficacy endpoint: The proportion of subjects in each treatment group who 
experience successful resolution of LI where “success” is defined as clear/almost clear 
on treated areas and at least a 2-grade change from Baseline at Day 90/end-of-
treatment (EOT) in the Double-blind Period on the 5-point IGA full body scale. 
Secondary endpoints: 
− 
The difference in mean scores between the active trifarotene cream HE1 and 
vehicle groups in the following assessment indices from Baseline through 
Day 90: 
− 
5-point Visual Index for Ichthyosis Severity (VIIS) for scaling (overall 
16 points for scaling, i.e. 0-4 points for 4 body areas: chest/abdomen, 
back, arms and legs) 
− 
Individual score for roughness (Scale: 0–4) 
− 
Palm/sole Assessment (Scale: 0–4) 
− 
Quality of life per Dermatology Life Quality Index (DLQI) and 
children’s DLQI (cDLQI) 
− 
The difference in proportion of subjects with presence of fissures on palms/soles 
(presence/absence, number of fissures, and pain associated with fissures on a 
0-3 scale) at Day 90 between the active trifarotene cream HE1 and vehicle 
groups 
Exploratory endpoints: 
− 
The difference in mean ectropion (Ectropion Severity Score [ESS] of 0–8) scores 
between the active trifarotene cream HE1 and vehicle groups from Baseline 
through Day 90 
− 
The difference in quality of life per EQ-5D-5L and EQ-5D-Y score between the 
active trifarotene cream HE1 and vehicle groups from Baseline through Day 90 
Safety endpoints: 
− 
Reported serious adverse events (SAEs), treatment-emergent AEs (TEAEs), and 
changes in clinical laboratory tests, vital signs, physical examinations, and 12-
lead ECGs 
− 
Local tolerability (stinging/burning, pruritus, or erythema on 0-3 scales [none, 
mild, moderate, severe]) for each body area (chest/abdomen, back, legs, arms, 
and face/neck). 
Pharmacokinetic endpoints: Plasma concentrations of CD5789 and its major 
metabolites will be measured. 
STATISTICAL 
METHODS 
Analysis Populations: 
The following are planned for the Double-blind Period of the study: 
The Safety population will be the primary population for analyses of safety and 
tolerability and will comprise all subjects who are randomized to treatment and receive 
at least 1 application of study drug. 
The intent-to-treat (ITT) population will comprise all randomized subjects. This 
population will be used as the primary population for the analysis of efficacy for the 
Double-blind Period of the study. 
The modified intent-to-treat (mITT) population comprises all subjects in the safety 
population with at least 1 postbaseline assessment of efficacy in the Double-blind 
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Period. This population will be used as the primary population for the analysis of 
efficacy for the Double-blind Period of the study. 
The Per-protocol (PP) Population will be defined prior to database lock and will 
comprise subjects in the mITT population who met all inclusion criteria and no 
exclusion criteria, were compliant with study drug application, and who had no 
significant protocol deviations. 
The PK Population includes all subjects in the Safety Population who have at least 
1 plasma sample with quantifiable concentration. The PK population will be used to 
summarize all PK endpoints. 
The following populations are planned for the OLE of this study: 
The OLE Safety Population: all subjects who complete the 90-day Double-blind 
Treatment Period and receive at least 1 application of study drug in the OLE. 
OLE ITT Population: all subjects who complete the 90-day Double-blind Period and 
who sign the OLE informed consent. 
The OLE mITT Population: all subjects in the OLE safety population with at least 
1 assessment of efficacy after Visit 6. 
The OLE PP Population: all subjects in the OLE mITT population who met all 
inclusion criteria and no exclusion criteria, were compliant with study drug application 
from baseline through EOT, and who had no significant protocol deviations 
throughout the study. 
Subject Characteristics and Disposition: Descriptive statistics will be used to 
summarize demographic characteristics (age, sex, ethnicity, and race) and baseline 
characteristics for all enrolled subjects. Medical history, physical examination 
findings, and vital sign measurements for all randomized subjects will be presented in 
listings. 
Efficacy Analyses: The number and proportion of subjects in each treatment group 
with successful resolution of LI by Day 90/EOT in the Double-blind Period will be 
presented. The primary efficacy endpoint will be analyzed using a logistic regression 
model with treatment and age group as factors. Other baseline characteristics and 
interactions may be included. The odds ratios and 95% CIs for the odds ratios will be 
presented. The difference in proportions between the active trifarotene cream HEI and 
vehicle cream groups, 95% CIs for the differences, and P-values for the differences in 
treatment will also be presented. 
The IGA scores as well as secondary and exploratory efficacy endpoints will be 
analyzed by visit using descriptive statistics through Day 180 (end of OLE treatment 
period). Change from Baseline through Day 90 will be presented and analyzed using 
a mixed model for repeated measures (MMRM). The model will include the change 
from Baseline score as the dependent variable, treatment group as a fixed effect, 
subject as a random effect, and Baseline score value as a covariate. Frequencies of 
results and 95% confidence intervals will also be reported, and scores will be analyzed 
as categorical variables using the Cochran-Mantel-Haenszel test. For subjects who 
report having fissures, the number of fissures and pain related to fissures will also be 
presented on a scale of 0-3 (none, mild, moderate, severe). 
Clinical Pharmacology Analyses: Noncompartmental PK analysis will be performed 
for the PK subset of subjects, as data permit. Plasma concentrations of CD5789 and 
its major metabolites will be measured and will be listed by subject. 
Safety Analyses: Safety and tolerability will be assessed based on the incidence of 
reported TEAEs, and SAEs, including relationship to study drug and severity, as well 
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as physical examination findings, vital sign measurements (supine systolic blood 
pressure [SBP] and diastolic blood pressure [DBP] and pulse), clinical laboratory 
results (hematology, including serum aminotransferases and serum lipids, 
coagulation, clinical chemistry, and urinalysis) and 12-lead ECGs. Descriptive 
statistics for observed values and change from Baseline will be calculated at each visit 
within each study period and by treatment group within cohort. 
SAMPLE SIZE 
DETERMINATION 
The first cohort of 15 adult subjects is a reasonable sample size to assess safety and 
tolerability before enrolling adolescents. Accounting for a 20% drop-out/nonevaluable 
rate, a total sample size of 120 subjects randomized in a 1:1:1 ratio to 2 active 
trifarotene cream HE1 arms and a vehicle cream arm will provide >80% power to 
detect a difference between each separate trifarotene cream HE1 arm (32 evaluable 
subjects) and the vehicle cream arm (32 evaluable subjects) 2-sided Fisher’s Exact 
Test assuming a 70% success rate and a 40% success rate, respectively.. This study is 
not powered to detect a difference between the 2 active arms. 
STUDY AND 
TREATMENT 
DURATION 
The sequence and maximum duration of the study periods for each subject will be as 
follows: 
1. Screening: Up to 97 days. Before asking a subject to enter washout, investigators 
should confirm the subject meets study eligibility criteria, except for LI severity 
(Inclusion Criterion #3). Washout may be up to 90 days. After completing any 
necessary Washout Period, subjects must return to the site within 35 days before 
the Baseline Visit within the 97-day Screening Period to have their LI severity 
assessed and study eligibility requirements determined. 
2. Double-blind study drug application: Twice weekly for 90 days. 
3. Optional Open-label Extension: Twice weekly for 90 days. 
4. Follow-up: 14 days after last study drug application. 
The maximum treatment duration for each subject is approximately 90 days for 
subjects who choose not to continue into the OLE, and 180 days for those who choose 
to continue. 
The maximum study duration for each subject is approximately 
291 days. 
 
 
 
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2.2. Schedule of Events 
Table 2-1: 
Schedule of Events for Double-blind Period 
 
 
Double-blind Treatment Period 
Screening 
(--97 days to -1 day) 
Washout up to 90 Days a 
 
Baseline  
(Day 1) 
Telephone 
Visit 
(Day 7) 
Day 14  
± 5 days 
Day 30  
± 7 days 
Telephone 
Visit 
(Day 45) 
Day 60  
± 7 days 
Day 90b,c 
± 7 days 
(ET) 
Visit 
1 
2 
 
3d 
4d 
 
5d 
6d 
Written informed consent/assent  
X 
 
 
 
 
 
 
X 
Assign screening number 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
Physical examination  
X 
Xe 
 
 
 
 
 
Xe 
Vital signs (blood pressure and pulse)  
X 
X 
 
X 
X 
 
X 
X 
Height, weight, and BMI  
X 
 
 
 
 
 
 
Xb 
IGA assessmentf 
X 
X 
 
X 
X 
 
X 
X 
VIISg assessment 
X 
X 
 
X 
X 
 
X 
X 
Roughness assessmenth 
X 
X 
 
X 
X 
 
X 
X 
Palm/sole assessment  
X 
X 
 
X 
X 
 
X 
X 
Palm/sole fissuring assessmenti 
X 
X 
 
X 
X 
 
X 
X 
Ectropion score  
X 
X 
 
X 
X 
 
X 
X 
Photographsj 
 
X 
 
 
X 
 
 
X 
Quality of life per Dermatology Life 
Quality Index (DLQI) 
 
X 
 
X 
X 
 
X 
X 
EQ-5D Quality of Life Questionnaire 
 
X 
 
X 
X 
 
X 
X 
12-lead ECGk 
X 
X 
 
 
X 
 
 
X 
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Double-blind Treatment Period 
Screening 
(--97 days to -1 day) 
Washout up to 90 Days a 
 
Baseline  
(Day 1) 
Telephone 
Visit 
(Day 7) 
Day 14  
± 5 days 
Day 30  
± 7 days 
Telephone 
Visit 
(Day 45) 
Day 60  
± 7 days 
Day 90b,c 
± 7 days 
(ET) 
Visit 
1 
2 
 
3d 
4d 
 
5d 
6d 
Clinical laboratory tests (hematology, 
chemistry, urinalysis)l 
X 
X 
 
 
X 
 
 
X 
Serology (hepatitis B surface antigen, 
hepatitis C) 
X 
 
 
 
 
 
 
 
Coagulation panel 
 
X 
 
 
X 
 
 
X 
Pregnancy test for female subjects 
(serum at Screening; urine 
subsequently)m 
X 
X 
 
 
X 
 
X 
X 
Randomization via IWRS 
 
X 
 
 
 
 
 
 
PK blood sample collectionn 
 
X 
 
X 
X 
 
X 
X 
Initial study drug application by clinic 
staff and measuremento 
 
X 
 
 
 
 
 
 
Application instructions, advice on 
emollient and sunscreen use 
 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug and diariesp 
 
X 
 
Xp 
Xp 
 
Xp 
(X)p 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
Tolerability assessment  
 
X 
 
X 
X 
 
X 
X 
Adverse events (and review diaries) 
 
X 
X 
X 
X 
X 
X 
X 
Collect all used/unused study drugq 
 
 
 
X 
X 
 
X 
X 
Provide information about OLE option 
 
 
 
 
X 
X 
X 
X 
Abbreviations: BMI = body mass index; DLQI = Dermatology Life Quality Index; ECG = electrocardiogram; ET = early termination; HEENT = head, eyes, ears, 
nose, throat; ICF = informed consent form; IGA = Investigator’s Global Assessment; IWRS = interactive web response system; OLE = open-label extension; 
PK = pharmacokinetic; WOCBP = women of childbearing potential; VIIS = Visual Index for Ichthyosis Severity 
a. 
Upon signing informed consent and entering the Screening Period, subjects will stop using physical and medical treatments for LI, including balneotherapy, 
and begin to washout prohibited topical and systemic treatments with designated washout periods, as applicable. Before asking a subject to enter washout, 
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investigators should confirm the subject meets study eligibility criteria, except for LI severity (Inclusion Criterion #3). Washout may be up to 90 days. After 
completing any necessary Washout Period, subjects must return to the site within 35 days before the Baseline Visit within the 97-day Screening Period to 
have their LI severity assessed and study eligibility requirements determined. During washout, subjects may continue their standard of care of visible skin 
(face and scalp) for cosmetic reasons and of extremities (palms/soles) to avoid functional consequences on walking or moving their fingers. In the US/EU, 
this may include compounded emollients with keratolytics (alpha or beta hydroxyl acids) and/or urea. The investigator should approve and document these 
standard of care treatments in the electronic case report form (eCRF). If the standard of care treatments of the face and/or palms/soles contain prohibited 
medications, they must be stopped at the Baseline Visit. Subjects may shower, but not bathe or swim, during the Screening Period. 
b. Day 90 procedures should be conducted for subjects who terminate the study early. If a subject discontinues IP, but continues to attend clinic visits, Day 90 
will occur as scheduled. Day 90 will be the first visit of the OLE for subjects who choose to continue. Subjects who decide to continue into the OLE will 
have the following additional procedures: 1) sign informed consent; 2) will be weighed; 3) will be instructed on study drug application; 4) will be given new 
diaries, and 5) will be provided with study drug. 
c. 
A Follow-up telephone call will be made within 14 days after Day 90 to subjects who choose not to continue into the OLE to assess any ongoing adverse 
events. 
d. Although it is preferable to conduct all necessary study assessments in person (onsite visits), this may not be possible as a result of COVID-19-related travel 
restrictions. To ensure the safety of subjects, investigators, and site staff, Visits 3-6 and unscheduled visits may be conducted remotely. Screening and 
Baseline Visits must be performed onsite only, and must be postponed or scheduled for when onsite visits can be safely conducted. 
e. 
Limited physical examination to include HEENT, cardiorespiratory, abdomen, range of motion. 
f. 
IGA: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe. 
g. VIIS scale for each body area: chest/abdomen, back, legs, and arms, for a possible overall score = 16. 
h. Roughness (0-4 scale); 
i. 
Palm/sole fissuring assessment: present/absent/number/pain (0-3 scale). 
j. 
Photography will be performed at sites with the capability for subjects who sign a photographic ICF. A central reader who will not be an investigator in the 
study will review the photographs to assess consistency of investigator scoring of LI severity as a quality check. 
k. ECG to be conducted at Screening, Baseline, Day 30, and Day 90 for all subjects. Subjects in the PK substudy will also have postdose ECGs at each serial 
blood draw on Day 1 and Day 30. 
l. 
Subjects must be fasting (i.e., at least 8 hours) for clinical laboratory tests, but not for PK blood draws. 
m. Note: Subjects who are premenstrual at Screening but begin menses during the course of the study should follow the pregnancy testing schedule for WOCBP 
correlating to the visit menses began. 
n. Samples for PK will be drawn from all subjects at Baseline and at each clinic visit. At selected sites among subjects who consent to participate in the PK 
substudy, samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1. On Day 30, IP will be applied in the clinic for PK substudy 
subjects, and PK samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose. Trough levels will be drawn when the subjects are in the clinic 
for other study visits (i.e., Day 14, Day 60, and Day 90). Visits for PK must occur at least 24 hours after the last application of the IP to avoid contamination 
of the blood samples with any IP that may have remained in the skin after the last application. 
o. Study staff will apply initial dose of study drug in the clinic after Baseline measurements, and the amount of study drug used will be measured (i.e., 
36-g tube will be measured before and after application to determine amount used). 
p. Study drug provided in 50-g tubes (maximum single application is 36 g). Measure study drug kits (tubes and box, but not leaflets) before dispensing; 
subjects must record days/times of study drug application in the diaries and any areas of skin not treated, e.g., due to local reactions. Dispense enough 
additional study drug until next visit (except at Day 90, unless subject consents to continue into OLE). 
q. Confirm study drug compliance by weighing the study kits (tubes and boxes, but not leaflets) and reviewing diary. 
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Table 2-2: 
Schedule of Events for Open-label Extension 
 
Open-label Treatment Perioda 
Follow-up 
 
 
Telephone 
Visit 
(Day 97)  
Day 104  
± 5 days 
Day 120  
± 7 days 
Telephone 
Visit 
(Day 134) 
Day 150 
± 7 days 
Day 180  
± 7 
days/ET 
Day 194 or 14 days after End of 
Open-label Treatment 
Visit 
 
7a 
8a 
 
9a 
10  
11a 
Informed consentb 
 
 
 
 
 
 
 
Physical examinationc 
 
 
 
 
 
X 
X 
Vital signs (blood pressure and 
pulse)  
 
X 
X 
X 
X 
X 
X 
Record IGAd 
 
X 
X 
 
X 
X 
X 
VIISe assessment 
 
X 
X 
 
X 
X 
X 
Roughness assessmentf 
 
X 
X 
 
X 
X 
X 
Palm/sole assessment 
 
X 
X 
 
X 
X 
X 
Palm/sole fissuring assessment 
 
X 
X 
 
X 
X 
X 
Ectropion score  
 
X 
X 
 
X 
X 
X 
Clinical laboratory tests 
(hematology, chemistry, 
urinalysis)g 
 
 
X 
 
 
X 
 
Pregnancy test for female 
subjects (urine)h 
 
 
X 
 
X 
X 
X 
Coagulation panel 
 
 
X 
 
 
X 
 
12-lead ECG 
 
 
X 
 
 
X 
 
PK blood sample collectioni 
 
 
X 
 
 
X 
 
Application instructions, advice 
on emollient and sunscreen usej 
X 
X 
X 
X 
 
 
 
Dispense study drug and 
diariesk 
 
X 
X 
 
X 
 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
Tolerability assessment  
 
X 
X 
 
X 
X 
 
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Open-label Treatment Perioda 
Follow-up 
 
 
Telephone 
Visit 
(Day 97)  
Day 104  
± 5 days 
Day 120  
± 7 days 
Telephone 
Visit 
(Day 134) 
Day 150 
± 7 days 
Day 180  
± 7 
days/ET 
Day 194 or 14 days after End of 
Open-label Treatment 
Visit 
 
7a 
8a 
 
9a 
10  
11a 
Adverse events (and review 
diaries) 
X 
X 
X 
X 
X 
X 
X 
Collect all used/unused study 
drugl  
 
X 
X 
 
X 
X 
 
Abbreviations: ECG = electrocardiogram; ET = early termination; HEENT = head, eyes, ears, nose, throat; ICF = informed consent form; IGA = Investigator’s 
Global Assessment; PK = pharmacokinetic; OLE = open-label extension; VIIS = Visual Index for Ichthyosis Severity; WOCBP = women of childbearing 
potential 
a. Although it is preferable to conduct all necessary study assessments in person (on -site visits), this may not be possible as a result of COVID-19-related travel 
restrictions. To ensure the safety of subjects, investigators, and site staff, Visits 7-11 and unscheduled visits may be conducted remotely. 
b. Subjects will sign the OLE ICF at the Double-blind Day 90 Visit. All efficacy assessments, safety/tolerability assessments, including clinical laboratory 
testing and PK from Day 90 will be carried over for the OLE and will not be repeated. 
c. Limited physical examination to include HEENT, cardiorespiratory, abdomen, range of motion. 
d. IGA: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe 
e. VIIS scale for each body area: chest/abdomen, back, legs, and arms, for a possible overall score = 16. 
f. Roughness (0-4 scale); fissuring assessment on palms/soles: present/absent/number/pain (0-3 scale). 
g. Subjects must be fasting (at least 8 hours) for clinical chemistry testing, but not for PK only blood draws. 
h. Subjects who are premenstrual at Screening but begin menses during the course of the study should follow the pregnancy testing schedule for WOCBP 
correlating to the visit menses began. 
i. Samples for PK will be drawn from all subjects at Day 120 and Day 180. Visits for PK must occur at least 24 hours after the last application of the IP to avoid 
contamination of the blood samples with any IP that may have remained in the skin after the last application. 
j. Subjects must record days/times of study drug application in the diaries and any areas of skin not treated (e.g., due to local reactions). 
k. All subjects in the OLE will receive trifarotene 200 µg/g. Study drug provided in 50-g tubes (maximum single application is 36 g). Weigh study medication 
kits (tubes and box, but not leaflets). Dispense enough additional study drug until the next visit (except at Day 180). 
l. Confirm study drug compliance by weighing the study kits (tubes and boxes, but not leaflets) dispensed and returned and reviewing diary. 
 
 
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3. TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES ............................................................................................... 2 
2. 
PROTOCOL SUMMARY ................................................................................................... 3 
2.1. Synopsis ..................................................................................................................... 3 
2.2. Schedule of Events .................................................................................................... 14 
3. 
TABLE OF CONTENTS ................................................................................................... 19 
3.1. List of In-Text Tables ............................................................................................... 24 
3.2. List of In-Text Figures .............................................................................................. 24 
REASONS FOR AMENDMENT.............................................................................................. 25 
SUMMARY OF AMENDED SECTIONS – SUBSTANTIVE AMENDMENT ........................ 27 
AMENDED PROTOCOL ......................................................................................................... 46 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................... 47 
5. 
INTRODUCTION ............................................................................................................. 49 
5.1. Background and Rationale ........................................................................................ 49 
5.1.1 CD5789 (Trifarotene) .................................................................................... 50 
5.2. Clinical Experience ................................................................................................... 50 
5.3. Summary of Potential Risks and Benefits .................................................................. 51 
6. 
OBJECTIVES .................................................................................................................... 52 
6.1. Primary Objective ..................................................................................................... 52 
6.2. Secondary Objectives ................................................................................................ 53 
7. 
STUDY DESIGN ............................................................................................................... 53 
7.1. Overall Study Design and Plan .................................................................................. 53 
7.2. Rationale and Discussion of Study Design ................................................................ 58 
7.3. Selection of Doses in the Study ................................................................................. 58 
7.4. Study Sites ................................................................................................................ 58 
7.5. Point of Contact ........................................................................................................ 59 
7.6. End of Study Definition ............................................................................................ 59 
8. 
SUBJECT POPULATION ................................................................................................. 59 
8.1. Selection of Study Population and Diagnosis ............................................................ 59 
8.2. Study Entry Criteria .................................................................................................. 59 
8.2.1 Inclusion Criteria ........................................................................................... 59 
8.2.2 Exclusion Criteria .......................................................................................... 60 
8.3. Premature Subject Withdrawal .................................................................................. 62 
8.4. Subject Discontinuation of Study Intervention and Stopping Rules ........................... 62 
8.5. Subject Replacement Criteria .................................................................................... 63 
9. 
TREATMENTS ................................................................................................................. 63 
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9.1. Identification of Investigational Product .................................................................... 63 
9.2. Treatments Administered .......................................................................................... 64 
9.3. Selection of Timing of Dose for Each Subject ........................................................... 64 
9.4. Dose Adjustment Criteria .......................................................................................... 67 
9.5. Treatment Compliance .............................................................................................. 67 
9.6. Method of Assigning Subjects to Treatment Groups .................................................. 67 
9.7. Blinding and Unblinding Treatment Assignment ....................................................... 68 
9.8. Permitted and Prohibited Therapies ........................................................................... 68 
9.8.1 Permitted Therapies ....................................................................................... 69 
9.8.2 Prohibited Therapies ...................................................................................... 70 
9.8.3 Restrictions .................................................................................................... 70 
9.9. Treatment after End of Study .................................................................................... 70 
9.10. Dispensing and Storage ............................................................................................. 71 
9.11. Drug Accountability .................................................................................................. 71 
9.12. Labeling and Packaging ............................................................................................ 72 
9.12.1 Labeling ........................................................................................................ 72 
9.12.2 Packaging ...................................................................................................... 72 
10. STUDY PROCEDURES .................................................................................................... 72 
10.1. Study Duration .......................................................................................................... 73 
10.1.1 Overall Study Schedule.................................................................................. 73 
10.2. Study Periods and Visits ........................................................................................... 73 
10.2.1 Screening and Washout.................................................................................. 73 
10.2.1.1 Screening Visit (Visit 1)..................................................................... 73 
10.2.2 Double-blind Treatment Period ...................................................................... 74 
10.2.2.1 Baseline Visit (Visit 2, Day 1) ........................................................... 74 
10.2.2.2 Telephone Visit (Day 7) ..................................................................... 76 
10.2.2.3 Visit 3 (Day 14 ±5 days) .................................................................... 76 
10.2.2.4 Visit 4 (Day 30 ±7 days) .................................................................... 76 
10.2.2.5 Telephone Visit (Day 45) ................................................................... 78 
10.2.2.6 Visit 5 (Day 60 ±7 days) .................................................................... 78 
10.2.2.7 Visit 6 (Day 90 ±7 days) or Early Termination ................................... 79 
10.2.3 Follow-up Telephone Call (±14 days after Day 90) – Only Subjects Who Do Not 
Continue into Open-label Extension ............................................................... 80 
10.2.4 Open-label Extension ..................................................................................... 80 
10.2.4.1 Telephone Visit (Day 97) ................................................................... 80 
10.2.4.2 Visit 7 (Day 104 ±5 days) .................................................................. 80 
10.2.4.3 Visit 8 (Day 120 ±7 days) .................................................................. 81 
10.2.4.4 Telephone Visit (Day 134) ................................................................. 81 
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10.2.4.5 Visit 9 (Day 150 ±7 days) .................................................................. 82 
10.2.4.6 Visit 10 (Day 180 ±7 days) or Early Termination ............................... 82 
10.2.4.7 Follow-up Evaluation – Open-Label Extension (Day 194 or 14 days after 
End of Open label Treatment /Visit 11) .............................................................. 83 
10.3. Assessments .............................................................................................................. 83 
10.3.1 Efficacy Variables ......................................................................................... 83 
10.3.1.1 Investigator’s Global Assessment....................................................... 84 
10.3.1.2 Visual Index for Ichthyosis Severity – Scaling ................................... 84 
10.3.1.3 Individual Score for Roughness ......................................................... 84 
10.3.1.4 Palm/Sole Assessment ....................................................................... 85 
10.3.1.5 Palm/Sole Fissuring Assessment ........................................................ 85 
10.3.1.6 Dermatology Life Quality Index ........................................................ 85 
10.3.1.7 EQ-5D Quality of Life Questionnaires ............................................... 85 
10.3.1.8 Ectropion Severity Score.................................................................... 86 
10.3.1.9 Photography Substudy ....................................................................... 86 
10.3.2 Clinical Pharmacology ................................................................................... 87 
10.3.2.1 Pharmacokinetic Analysis Methods.................................................... 87 
10.3.2.2 Pharmacokinetic Parameters .............................................................. 87 
10.3.3 Sample Collection.......................................................................................... 87 
10.3.4 Safety Variables............................................................................................. 88 
10.3.4.1 Clinical Laboratory Safety Assessments ............................................. 88 
10.3.4.2 Clinical Examinations ........................................................................ 90 
10.3.4.3 Adverse Events .................................................................................. 90 
10.4. Procedural Adjustments Due to COVID-19 ............................................................... 90 
11. ADVERSE EVENTS ......................................................................................................... 91 
11.1. Definitions ................................................................................................................ 91 
11.1.1 Adverse Events .............................................................................................. 91 
11.1.2 Adverse Drug Reaction .................................................................................. 91 
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction ....................................... 91 
11.1.4 Serious Adverse Events/Drug Reaction .......................................................... 92 
11.1.5 Significant Adverse Events ............................................................................ 92 
11.1.6 Treatment-Emergent Adverse Events ............................................................. 92 
11.2. Event Assessment and Follow-up of Adverse Events ................................................ 93 
11.2.1 Assessment .................................................................................................... 93 
11.2.2 Evaluation ..................................................................................................... 94 
11.2.2.1 Severity of Adverse Events ................................................................ 94 
11.2.2.2 Seriousness ........................................................................................ 94 
11.2.2.3 Action(s) Taken ................................................................................. 94 
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11.2.2.4 Outcome at the Time of Last Observation .......................................... 94 
11.2.2.5 Adverse Event Relationship to Investigational Product ...................... 95 
11.2.3 Documentation .............................................................................................. 95 
11.2.4 Treatment of Adverse Events ......................................................................... 96 
11.2.5 Follow-up ...................................................................................................... 96 
11.2.6 Reporting ....................................................................................................... 96 
11.2.6.1 Serious Adverse Events ..................................................................... 96 
11.2.6.2 Adverse Drug Reactions .................................................................... 98 
11.2.6.3 Nonserious Adverse Events................................................................ 98 
11.3. Special Considerations .............................................................................................. 98 
11.3.1 Adverse Events of Special Interest ................................................................. 98 
11.3.2 Pregnancy ...................................................................................................... 98 
12. DATA SAFETY MONITORING BOARD ........................................................................ 99 
13. STATISTICS ..................................................................................................................... 99 
13.1. Statistical Analysis .................................................................................................... 99 
13.1.1 Analysis Populations ................................................................................... 100 
13.1.2 Study Subjects and Demographics ............................................................... 101 
13.1.2.1 Disposition and Withdrawals ........................................................... 101 
13.1.2.2 Protocol Deviations .......................................................................... 101 
13.1.2.3 Demographics and Other Baseline Characteristics............................ 101 
13.1.3 Exposure and Compliance ........................................................................... 101 
13.1.4 Efficacy Analysis ......................................................................................... 102 
13.1.4.1 Efficacy Endpoints ........................................................................... 102 
13.1.4.2 Primary Analysis ............................................................................. 102 
13.1.4.3 Secondary Analyses ......................................................................... 103 
13.1.4.4 Exploratory Analyses ....................................................................... 103 
13.1.4.5 Corroborative, Sensitivity, and Other Analyses ................................ 103 
13.1.5 Clinical Pharmacology Analyses .................................................................. 104 
13.1.5.1 Pharmacokinetics ............................................................................. 104 
13.1.6 Safety and Tolerability Analyses.................................................................. 104 
13.1.6.1 Local Tolerability ............................................................................ 104 
13.1.6.2 Adverse Events ................................................................................ 104 
13.1.6.3 Clinical Laboratory Evaluations ....................................................... 105 
13.1.6.4 Vital Signs ....................................................................................... 105 
13.1.6.5 Twelve-lead Electrocardiograms ...................................................... 105 
13.1.6.6 Physical Examination Findings ........................................................ 106 
13.1.7 Interim Analysis .......................................................................................... 106 
13.2. Sample Size Determination ..................................................................................... 106 
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14. STUDY CONDUCT ........................................................................................................ 106 
14.1. Sponsor and Investigator Responsibilities ............................................................... 106 
14.1.1 Sponsor Responsibilities .............................................................................. 106 
14.1.2 Investigator Responsibilities ........................................................................ 106 
14.1.3 Confidentiality and Privacy.......................................................................... 107 
14.2. Site Initiation .......................................................................................................... 107 
14.3. Screen Failures ....................................................................................................... 108 
14.4. Study Documents .................................................................................................... 108 
14.4.1 Informed Consent ........................................................................................ 108 
14.4.2 Investigator’s Regulatory/Good Clinical Practice Documents ...................... 108 
14.4.3 Case Report Forms ...................................................................................... 109 
14.4.4 Source Documents ....................................................................................... 109 
14.5. Data Quality Control ............................................................................................... 109 
14.5.1 Monitoring Procedures................................................................................. 110 
14.5.2 Data Management ........................................................................................ 110 
14.5.3 Quality Assurance/Audit .............................................................................. 110 
14.6. Study Termination .................................................................................................. 111 
14.6.1 Regular Study Termination .......................................................................... 111 
14.6.2 Premature Study Termination ...................................................................... 111 
14.7. Study Site Closure .................................................................................................. 112 
14.7.1 Record Retention ......................................................................................... 112 
14.7.2 Sample Retention ......................................................................................... 113 
14.8. Changes to the Protocol .......................................................................................... 113 
14.9. Use of Information and Publication ......................................................................... 113 
15. FINAL CLINICAL STUDY REPORT ............................................................................. 114 
16. ETHICAL AND LEGAL CONSIDERATIONS ............................................................... 114 
16.1. Declaration of Helsinki and Good Clinical Practice ................................................. 114 
16.2. Subject Information and Informed Consent and/or Assent ....................................... 114 
16.3. Approval by Institutional Review Board and Independent Ethics Committee .......... 115 
16.4. Finance and Insurance ............................................................................................. 115 
17. REFERENCES ................................................................................................................ 116 
18. ATTACHMENTS ............................................................................................................ 117 
18.1. Investigator’s Agreement ........................................................................................ 117 
APPENDICES ........................................................................................................................ 118 
A. 
Regulations and Good Clinical Practice Guidelines ................................................. 119 
B. 
Procedural Adjustments Due to COVID-19 ............................................................. 120 
 
 
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3.1. List of In-Text Tables 
Table 2-1: 
Schedule of Events for Double-blind Period .................................................. 14 
Table 2-2: 
Schedule of Events for Open-label Extension................................................. 17 
Table 9-1: 
Sample Twice-weekly Dosing Schedule ........................................................ 66 
Table 9-2: 
Washout Periods for Prohibited Medicationsa ................................................ 69 
Table 9-3: 
Amount of Study Drug Needed Per Visit ....................................................... 71 
Table 10-1: 
Ectropion Severity Score ............................................................................... 86 
Table 10-2: 
Pharmacokinetic Parameters .......................................................................... 87 
 
3.2. List of In-Text Figures 
Figure 7-1: 
Double-blind Study Design ............................................................................ 56 
Figure 7-2: 
Open-label Study Design ............................................................................... 57 
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REASONS FOR AMENDMENT 
Protocol Amendment 2 is a substantive amendment that addresses feedback from the Regulatory 
Agencies, Competent Authorities, Central Ethics Committees, and investigators. The following 
changes were made: 
1. Changed all times defined as “weeks” to “days” throughout
2. Added new Section (Section 10.4) and Appendix B for procedural adjustments due to 
COVID-19.
3. Updated Phoevos Hughes’ title.
4. Clarified that Cohort A may continue enrolling subjects until the DSMB considers it safe to 
open recruitment in Cohort B.
5. Clarified that washout periods apply to both prescription and over-the-counter medications.
6. Clarified that subjects receiving stable thyroid hormone medications with normal thyroid-
stimulating hormone levels may be eligible for enrollment.
7. Clarified that subjects taking stable oral doses of Vitamin D analogs for at least 1 month at 
Screening may be eligible for enrollment.
8. Clarified and made consistent the definition of standard of care for visible skin (face and 
scalp) and of extremities (palms and soles).
9. Deleted “fixed dose” or “same amount” of IP throughout.
10. Aligned power calculation and parameter assumptions with the new primary endpoint.
11. Added optional photography evaluation of scoring by a central reader who is not a study 
investigator as a quality check.
12. Clarified that local tolerability comprises any stinging/burning, pruritus, or erythema and that 
each should be assessed on a 0-3 point scale.
13. As requested by the ethics committee in Germany, clarified that minor participants who reach 
majority during the study should be capable of providing informed consent for the PK 
substudy.
14. As requested by the ethics committee in Australia, clarified definition of women of 
childbearing potential and clarified that a hormonal vaginal ring or an IUD inserted at least 30 
days before Baseline is an acceptable second form of contraception (i.e., IUD does not have 
to be hormonal).
15. Revised Exclusion Criterion #4 to define exclusionary levels of triglycerides and total 
cholesterol, and to allow subjects with normal levels of triglycerides and/or total cholesterol 
on stable doses of lipid-lowering agents for at least 6 months to be eligible for inclusion.
16. Revised Exclusion Criterion #10b with regard to exclusionary total bilirubin levels at 
Screening and defined acceptable levels for subjects with known Gilbert’s Syndrome (>1.25 
× upper limit of normal [ULN]).
17. Clarified Exclusion Criterion #13 to remove specific PR and QRS levels and heart rates.
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18. Extended the Screening Period to allow for up to 90 days of washout, and clarified that all 
Screening procedures, with the exception of LI assessment, should be performed before a 
subject begins the Washout Period. The subject will return after completing the washout 
period for LI assessment and to confirm eligibility. 
19. Revised Figure 7-1 and Figure 7-2 to correct typos and to change weeks to days. 
20. Revised Table 2-1 and Table 2-2 to correct timing and omissions. 
21. Clarified the intervals between IP applications and added a table to illustrate a twice-weekly 
schedule. 
22. Removed location for Catalent Pharma Solutions. 
23. Clarified that subjects who participate in the PK substudy should have their Day-30 Visit 
scheduled on a treatment day, and that investigators should contact the medical monitor if 
that is not possible. 
24. Added a coagulation panel to the study procedures. 
25. Added the composition and qualifications of the DSMB. 
 
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SUMMARY OF AMENDED SECTIONS – SUBSTANTIVE AMENDMENT 
Section 
Previous Text 
Revision 
Rationale 
Title 
throughout 
document 
A Phase 2 Randomized, Multicenter, 
Double-blind, Vehicle-controlled, 12-
week Safety, Efficacy, and Systemic 
Exposure Study followed by a 12-week 
Open-label Extension of Trifarotene 
(CD5789) Cream HE1 in Adults and 
Adolescents with Autosomal Recessive 
Ichthyosis with Lamellar Scale 
A Phase 2 Randomized, Multicenter, 
Double-blind, Vehicle-controlled, 
90-Day, Safety, Efficacy, and 
Systemic Exposure Study followed 
by a 90-Day Open-label Extension of 
Trifarotene (CD5789) Cream HE1 in 
Adults and Adolescents with 
Autosomal Recessive Ichthyosis with 
Lamellar Scale 
To be more precise 
about time intervals 
Document 
“Weeks” 
Changed all to days 
To be more precise 
about time intervals 
Synopsis and 
Section 7 
Adults (Cohort A) and adults and 
adolescents (Cohort B) will be 
randomized in a double-blind fashion 
to 1 of 2 doses of trifarotene cream 
HE1 or vehicle and treated twice 
weekly for 12 weeks. 
Adults and adolescents will be 
randomized in a double-blind fashion 
to 1 of 2 doses of trifarotene cream 
HE1 or vehicle and treated twice 
weekly for 90 days. 
To clarify 
 
If no safety issues are identified, both 
adults and adolescents (ages 12 to 17 
years, inclusive) will be allowed to 
enroll together with adults in Cohort B. 
Subjects in Cohort B will be 
randomized 1:1:1 to trifarotene cream 
HE1 100 µg/g, trifarotene cream HE1 
200 µg/g, or vehicle and treated twice 
weekly for up to 12 weeks in the same 
manner as subjects in Cohort A. 
If no safety issues are identified, 
adolescents (ages 12 to 17 years, 
inclusive) will be allowed to enroll 
together with adults in Cohort B. 
Subjects in Cohort B will be 
randomized 1:1:1 to trifarotene 
cream HE1 100 µg/g, trifarotene 
cream HE1 200 µg/g, or vehicle and 
treated twice weekly for 90 days in 
the same manner as subjects in 
Cohort A. 
Added: Cohort A will continue 
enrolling only adult subjects until the 
DSMB considers it safe to open 
recruitment in Cohort B 
To clarify and 
ensure protocol 
memo 
(nonsubstantial 
change) is captured 
in the protocol 
Synopsis and 
Section 9.8 
Upon signing informed consent and 
entering the Screening Period, subjects 
may begin washout, during which they 
will stop using physical and medical 
treatments for LI, including 
balneotherapy, and the following 
prohibited medications, as applicable. 
Upon signing informed consent and 
entering the Screening Period, 
subjects may begin a Washout 
Period of up to 90 days. Participants 
will stop using physical and medical 
treatments for LI, including 
balneotherapy, as well as the 
following prohibited medications, as 
applicable. 
Added: the following list applies to 
both prescription and over-the-
counter medications: 
To clarify 
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Section 
Previous Text 
Revision 
Rationale 
Synopsis and 
Section 9.8  
Medication interfering with bone 
activity, e.g., corticosteroids, thyroid 
hormones, cytotoxics, bisphosphonates, 
calcitonins, tetracyclines, quinolones, 
thiazides, salicylates in long-term 
course, heparin, theophylline, 
barbiturates, colchicines. (except 
Vitamin D analogs taken at stable dose 
since at least 1 month. 
Medication interfering with bone 
activity, e.g., corticosteroids, thyroid 
hormones unless the dose is stable 
and thyroid-stimulating hormone 
(TSH) is normal, cytotoxics, 
bisphosphonates, selective estrogen 
receptor modulators (SERM), 
teriparatide, calcitonins, 
tetracyclines, quinolones, thiazides, 
long-term use of salicylates, heparin, 
theophylline, barbiturates, 
colchicines. Vitamin D analogs taken 
at stable dose for at least 30 days 
are allowed. 
Added prohibited 
medications and 
clarified which 
medication 
interfering with bone 
activity is 
acceptable. 
 
Enzyme inducers (such as rifampicine, 
phenytoin, carbamazepine, 
phenobarbital, St. John’s Wort) 
CYP enzyme inducers (such as 
rifampicine, phenytoin, 
carbamazepine, phenobarbital, St. 
John’s Wort) 
To clarify 
 
CYP2C9 and 2C8 inhibitors (not all 
inclusive, gemfibrozil, fluconazole, 
fluvoxamine, sulfaphenazole, 
miconazole, amiodarone, sertraline, 
sulfamethoxazole, valproic acid, 
voriconazole, trimethoprim, 
rosiglitazone, pioglitazone) 
CYP2C9 and 2C8 inhibitors 
(including, but not limited to the 
following: gemfibrozil, fluconazole, 
fluvoxamine, sulfaphenazole, 
miconazole, amiodarone, sertraline, 
sulfamethoxazole, valproic acid, 
voriconazole, trimethoprim, 
rosiglitazone, pioglitazone) 
 
 
Monoclonal antibody treatment (e.g., 
anti IL17 
Monoclonal antibodies 
 
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Section 
Previous Text 
Revision 
Rationale 
Synopsis, 
Table 2-1 
footnote a, 
and Sections 
7.1, 9.8, and 
10.2.1.1 and 
10.2.1.1.1 
 
During washout, subjects may continue 
taking usual care of visible skin (face 
and scalp) for cosmetic reasons and of 
extremities (hand/feet) to avoid 
functional consequences on walking or 
moving their fingers. Subjects may 
shower, but not bathe or swim, during 
the Screening Period. After completing 
any necessary washout of prohibited 
medications, subjects will return to the 
site to complete the study eligibility 
requirements. Subjects may shower, 
but not bathe or swim. 
After completing any necessary 
washout of prohibited medications, 
subjects will return to the site to 
complete the study eligibility 
requirements. 
Added: Before asking a subject to 
enter washout of their prescription 
and over-the-counter prohibited 
treatments, investigators should 
confirm the subject meets all study 
eligibility criteria, except for LI 
severity (Inclusion Criterion #3). 
Washout may be up to 90 days. After 
completing any necessary Washout 
Period, subjects must return to the 
site within 35 days before the 
Baseline Visit within the 97-day 
Screening Period to have their LI 
severity assessed and to complete 
study eligibility requirements 
 
During washout, subjects may 
continue their standard of care of 
visible skin (face and scalp) for 
cosmetic reasons and of extremities 
(palms/soles) to avoid functional 
consequences on walking or moving 
their fingers. In the US/EU, this 
may include compounded 
emollients with keratolytics (alpha 
or beta hydroxyl acids) and/or 
urea. The investigator should 
approve and document these 
standard-of-care treatments in the 
electronic case report form 
(eCRF). If the standard of care 
treatments of the face and/or 
palms/soles contain prohibited 
medications, they must be stopped 
at the Baseline Visit. Subjects may 
shower, but not bathe or swim.  
To ensure subjects 
do not have to repeat 
Screening 
assessments after 
washout. 
To better define 
standard of care and 
prevent confusion. 
 
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Section 
Previous Text 
Revision 
Rationale 
Synopsis and 
Section 7.1 
Study staff will apply the first dose of 
study drug to each subject in the clinic 
on Day 1 after Baseline measurements, 
and will record the amount of study 
drug applied. 
Study staff will choose 1 tube from 
the kit dispensed to the subject at 
that visit, and apply the first dose 
of study drug to each subject in the 
clinic on Day 1 after Baseline 
measurements; they will weigh the 
study tube before and after 
application to determine the 
amount used. 
 
Added: The kit dispensed at baseline 
must be weighed before the first tube 
is chosen for application by the study 
staff. Weight of the kits dispensed 
and returned by the subject during 
the study includes both tubes and 
cartons, but not leaflets, which need 
to be removed before weighing. The 
subject must be reminded to return 
the kits with tubes and cartons, 
whether used or not, when returning 
to the next visit.  
To clarify how 
amount of IP applied 
is determined 
To ensure kits are 
weighed 
appropriately before 
dispensing to the 
subject and upon 
return 
Synopsis 
Thereafter, each subject will apply 
approximately the same amount (up to 
36 g) of study drug as for the first dose 
on up to 90% of BSA twice weekly, 
sparing the scalp, inguinal, and axillary 
areas.  
Thereafter, each subject will apply 
study drug on up to 90% of BSA 
twice weekly 3 to 4 days apart, 
sparing the scalp, inguinal, and 
axillary areas. 
 
Added: Subjects with heavy facial 
hair should not apply IP to hair-
bearing areas. 
 
Added: The study protocol limits 
application of IP to 36 g maximum; 
no additional tubes can be given, 
whether during the randomization 
period or the OLE period. If the 
study staff and subject note that there 
is insufficient volume for full body 
application, the subject should apply 
trifarotene cream sparingly twice 
weekly to the most affected areas, 
and always to the same skin areas. 
Study cream should be very 
sparingly applied. Trifarotene cream 
100 or 200 µg/g, is a highly potent 
topical retinoid and it is not 
necessary to apply much for efficacy; 
application of more will increase the 
risk of irritation and systemic 
penetration. 
Removed fixed 
amount/same 
amount because of 
the natural variations 
in the extent and 
severity of LI. 
To not apply IP to 
hair-bearing areas 
for the first 90 days. 
 
To address questions 
about the amount of 
cream to apply when 
a single tube does 
not seem to be 
enough 
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Synopsis, 
Sections 7.1, 
9.4, and 
13.1.6.1 
During all clinic visits, the investigator 
will assess local tolerability (Scale: 0-3 
[none, mild, moderate, severe]) for 
stinging/burning, pruritus, erythema) 
for each body area (chest/abdomen, 
back, arms, legs, and face/neck), and 
the following procedures will be 
followed: 
- 
If a score of 2 (moderate) is 
recorded on a local tolerability 
assessment scale (stinging/burning, 
pruritus, erythema) on any treated 
area, the study drug will be applied 
on that area only once weekly, 
until the score is back to <2. 
Continue to treat all other areas 
twice weekly provided the score is 
<2 on those areas. 
- 
If a score of 3 (severe) is recorded 
on a local tolerability assessment 
scale (stinging/burning, pruritus, 
erythema) on any treated area, the 
study drug will not be applied on 
that area until the score is back to 
<3 (i.e., “drug holiday”). Continue 
to treat all other areas twice 
weekly provided the score is <2 on 
those areas. 
During all clinic visits, the 
investigator will assess local 
tolerability (stinging/burning, 
pruritus, or erythema on 0-3 scales 
[none, mild, moderate, severe]) for 
each body area (chest/abdomen, 
back, arms, legs, and face/neck), and 
the following procedures will be 
followed: 
- 
If a score of 2 (moderate) is 
recorded for any of the local 
tolerability assessment scales 
(stinging/burning, pruritus or 
erythema) on any treated area, 
the study drug will be applied on 
that area only once weekly, until 
the score is back to <2. Continue 
to treat all other areas twice 
weekly provided the score is <2 
on those areas. 
- 
If a score of 3 (severe) is 
recorded for any of the local 
tolerability assessment scales 
(stinging/burning, pruritus or 
erythema) on any treated area, 
the study drug will not be 
applied on that area until the 
score is back to <3 (i.e., “drug 
holiday”). Continue to treat all 
other areas twice weekly 
provided the score is <2 on those 
areas. 
To clarify that any 
of the 3 local 
tolerability 
conditions may 
warrant modification 
of dosing frequency  
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Synopsis 
 
Added: The coronavirus disease 
2019 (COVID-19) global pandemic 
has impacted the free movement of 
the world’s population, which has 
been restricted in order to control the 
spread of the disease. It is 
recommended that all sites and 
subjects comply with the applicable 
local and federal guidelines 
regarding the necessary and proper 
precautions regarding COVID-19. 
Although it is preferable to conduct 
all necessary study assessments in 
person (onsite visits), this may not be 
possible as a result of COVID-19 -
related travel restrictions. To ensure 
the safety of subjects, investigators, 
and site staff, Visits 3-6 (Double –
blind Period; Table 2-1), Visits 7-11 
(OLE Period; Table 2-2) and 
unscheduled visits may be conducted 
remotely. Screening and Baseline 
Visits must be performed on site 
only. These visits must be postponed 
or scheduled for when onsite visits 
can be safely conducted. The 
following assessments may occur 
remotely: 
• Safety Assessments 
o Concomitant medications and 
concomitant therapies. 
o Adverse Events and related 
information reported by the 
patient in the diary 
o General health status of the 
patient 
• Tolerability Assessments 
• Pregnancy Tests: Urine pregnancy 
tests along with the instructions on 
proper use will be sent to the 
subject’s home for women of 
childbearing potential (WOCBP). 
Study staff will instruct patient to 
perform the urine pregnancy at the 
applicable remote visit. 
• Study Medication Supply: As 
necessary and according to 
applicable local regulations, study 
medication will be sent to 
subjects. 
 
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• DLQI and EQ-5D Questionnaires: 
Quality of Life questionnaires 
should be completed on the day of 
the remote visit and prior to 
applying treatment (if the remote 
visit falls on a treatment day). 
Questionnaires may be sent to 
subjects electronically or via 
postal service, and completed 
questionnaires may be returned to 
the site in the same manner. If 
subjects are unable to send 
completed questionnaires to the 
site, investigators should ask and 
record the subject’s responses 
during the remote visit. 
• Patient Diary: Patient diaries may 
be sent to subjects electronically 
or via postal service. Completed 
diaries may be returned to the site 
in the same manner. 
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Synopsis and 
Section 8.2.1 
6. Subject who is participating in the 
optional PK substudy has signed a 
PK ICF. 
7. Subject is not of childbearing 
potential, i.e., a female who has not 
yet begun menstruating or who is 
postmenopausal (absence of 
menstrual bleeding for 1 year before 
Baseline, without any other medical 
reason), hysterectomy or bilateral 
oophorectomy, combined oral 
contraceptives (estrogens and 
progesterone), or implanted or 
injectable hormonal contraceptives 
with a stable dose for at least 1 month 
before Baseline; hormonal 
contraceptives must inhibit ovulation 
• hormonal intrauterine device (IUD) 
inserted at least 1 month before 
Baseline 
[…] 
• 
Note: 
Subjects 
who 
are 
premenstrual at Screening but begin 
menses during the study should 
follow 
the 
pregnancy 
testing 
schedule for WOCBP and must 
abstain from sexual intercourse 
while in the study and for at least 1 
month after the last study drug 
application. 
 
6. Subject who is participating in the 
optional PK substudy has signed a 
PK ICF. Minors, in the event of 
their reaching majority during 
the study, should be capable of 
giving consent to take part in 
the PK study. 
7. Subject is not of childbearing 
potential, who is postmenopausal 
(absence of menstrual bleeding for 
1 year before Baseline, without 
any other medical reason), or has 
documented hysterectomy, 
bilateral salpingectomy, or 
bilateral oophorectomy. For 
individuals with permanent 
infertility due to an alternate 
medical cause other than the 
above, (e.g., Mullerian agenesis, 
androgen insensitivity), 
investigator discretion should be 
applied to determining study 
entry. 
OR 
Subject is a woman of childbearing 
potential (WOCBP), i.e. a female 
≥12 years of age (regardless of 
whether they have 
experienced/reported menarche), 
or a male subject with sexual 
partners capable of reproduction 
who agrees to use 2 effective forms 
of contraception during the study 
and for at least 1 month after the 
last study drug application. The 
2 authorized forms of 
contraception are condom used 
with 1 of the following methods of 
contraception: 
• bilateral tubal ligation 
• combined oral contraceptives 
(estrogens and progesterone), 
vaginal ring, or implanted or 
injectable hormonal 
contraceptives with a stable dose 
for at least 1 month before 
Baseline; hormonal 
contraceptives must inhibit 
ovulation 
• intrauterine device (IUD) 
inserted at least 30 days before 
Baseline 
[…] 
• 
Note: Female subjects who are 
premenstrual at screening should 
nonetheless follow the 
The change in 
Inclusion Criterion 
#6 was requested by 
the German Central 
Ethics Committee. 
Clarified definition 
of WOCBP. 
Clarified that a 
hormonal vaginal 
ring or an IUD 
inserted at least 
30 days before 
Baseline is an 
acceptable form of 
contraception (i.e., 
IUD does not have 
to be hormonal). 
This change was 
requested from the 
RCH Human 
Research Ethics 
Committee (HREC) 
in Australia 
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pregnancy testing schedule for 
WOCBP even if they abstain 
from sexual intercourse while in 
the study and for at least 1 
month after the last study drug 
application. 
Synopsis and 
Section 8.2.2 
4. Subjects with a known lipid disorder 
(hypertriglyceridemia >200 mg/dL, 
hypercholesterolemia >250 mg/dL. 
a. Subjects whose triglyceride 
and/or total cholesterol are within 
normal limits with stable dose of 
lipid-lowering agents for at least 
6 months can be included. 
4. Subject with fasting triglycerides 
>200 mg/dL or >2.25 mmol/L 
and/or total cholesterol 
>250 mg/dL or >6.5 mmol/L. 
Subjects whose triglycerides 
and/or total cholesterol are within 
normal limits with a stable dose of 
lipid-lowering agents for at least 
6 months may be included. 
To clarify laboratory 
parameters per 
laboratory units 
 
7. Subject has a medical condition that 
potentially alters bone metabolism 
(e.g., osteoporosis, thyroid 
dysfunction, Cushing syndrome, 
Crohn’s disease, or ulcerative 
colitis). 
7. Subject has a medical condition 
that potentially alters bone 
metabolism (e.g., osteoporosis, 
thyroid dysfunction, Cushing 
syndrome, Crohn’s disease, or 
ulcerative colitis). Subjects with 
hypothyroidism who are on a 
stable dose of thyroid hormone 
replacement therapy and whose 
TSH is normal may be included. 
To permit subjects 
with hypothyroidism 
on stable treatment 
with normal TSH to 
be enrolled. 
 
10. Subject with any of the following 
laboratory values at Screening: 
a. Aspartate aminotransferase or 
alanine aminotransferase >1.5 × 
upper limit of normal defined by 
the laboratory 
b. Total bilirubin >1.1 mg/dL at 
screening, or, in case of Gilbert’s 
syndrome total bilirubin >3 
mg/dL 
10. Subject with any of the following 
laboratory values at Screening: 
a. Aspartate aminotransferase or 
alanine aminotransferase >1.5 
× upper limit of normal 
(ULN) defined by the 
laboratory 
b. Total bilirubin >1.25 × ULN 
at Screening. Subjects with 
known Gilbert’s syndrome 
may be included with total 
bilirubin >1.25 × ULN  
To clarify laboratory 
parameters for 
exclusion 
 
13. Subject has a history of long QT 
syndrome or has clinically 
significant electrocardiogram 
(ECG) abnormalities, including 
clinically significant conduction 
disorders or significant 
arrhythmias, or QTcF interval 
>450 ms, PR interval is not 
between 120 and 220 ms 
(inclusive), HR >100 bpm or <50 
bpm, QRS interval >110 ms, or QT 
intervals that cannot be 
consistently analyzed 
13. Subject has a history of long QT 
syndrome or has clinically 
significant electrocardiogram 
(ECG) abnormalities, including 
clinically significant conduction 
disorders or significant 
arrhythmias, or QTcF interval 
>450 ms 
To clarify because 
there is a high 
number of left 
anterior hemiblocks 
without clinical 
significance among 
screened subjects. In 
these cases, the QRS 
Interval can be 
above normal 
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Synopsis 
Name: Trifarotene (CD5789) cream 
HE1 
Double-blind Period dose, route, 
frequency: A fixed dose (up to 36 g per 
dose, determined at Visit 2) of 100 µg/g 
or 200 µg/g applied topically twice 
weekly on up to 90% BSA 
Open-label Extension dose, route, 
frequency: A fixed dose (up to 36 g per 
dose, determined at Visit 2) of 200 µg/g 
applied topically twice weekly on up to 
90% BSA 
Name: Trifarotene (CD5789) cream 
HE1 
Double-blind Period dose, route, 
frequency: Up to 36 g per dose of 
100 µg/g or 200 µg/g applied 
topically twice weekly on up to 90% 
BSA 
Open-label Extension dose, route, 
frequency: Up to 36 g per dose of 
200 µg/g applied topically twice 
weekly on up to 90% BSA 
Fixed dose is no 
longer applicable. 
Synopsis and 
Section 10 
 
Added: coagulation panel to all visits 
at which blood and urine are 
collected for laboratory tests 
To correct an 
omission 
Synopsis and 
Section 
10.1.1 
1. Screening: Up to 35 days (after 
signing informed consent, if 
necessary, washout may be up to 
3 months, and subjects should return 
to the site after washout to complete 
the study eligibility requirements). 
2. Double-blind study drug 
application: Twice weekly for up to 
12 weeks. 
3. Optional Open-label Extension: 
Twice weekly for up to 12 weeks. 
4. Follow-up: 14 days after last study 
drug application. 
The maximum study duration for each 
subject is approximately 229 days (33 
weeks). 
The maximum treatment duration for 
each subject is 24 weeks 
1. Screening: Up to 97 days. Before 
asking a subject to enter 
washout, investigators should 
confirm the subject meets study 
eligibility criteria, except for LI 
severity (Inclusion Criterion 
#3). Washout may be up to 
90 days. After completing any 
necessary Washout Period, 
subjects must return to the site 
within 35 days before the 
Baseline Visit within the 97-day 
Screening Period to have their 
LI severity assessed and study 
eligibility requirements 
determined 
2. Double-blind study drug 
application: Twice weekly for 90 
days. 
3. Optional Open-label Extension: 
Twice weekly for 90 days. 
4. Follow-up: 14 days after last 
study drug application. 
The maximum treatment duration for 
each subject is approximately 
90 days for subjects who choose 
not to continue into the OLE, and 
180 days for those who choose to 
continue. 
The maximum study duration for 
each subject is approximately 
291 days 
To reflect the 
change from weeks 
to days, and to allow 
sufficient time for 
the washout period 
(up to 3 months) and 
adjust the study 
periods accordingly 
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Synopsis and 
Section 
13.1.4.1 
Secondary: The secondary endpoints 
are as follow: 
• The difference in mean scores 
between the active trifarotene cream 
HE1 and vehicle groups in the 
following assessment indices from 
Baseline through Week 12: 
▪ 5-point VIIS scale for scaling 
from Baseline through Week 12 
▪ Individual score for roughness 
(Scale: 0–4) overall 
• The difference in proportion of 
subjects with presence of fissures on 
palm/soles (presence/absence, 
number of fissures, and pain 
associated with fissures [on a 0-3 
scale]) at Week 12 between the active 
trifarotene cream HE1 and vehicle 
groups 
Secondary: The secondary endpoints 
are as follow: 
• The difference in mean scores 
between the active trifarotene 
cream HE1 and vehicle groups in 
the following assessment indices 
from Baseline through Day 90: 
▪ 5-point VIIS scale for scaling 
▪ Individual score for roughness 
(Scale: 0–4) 
• The difference in proportion of 
subjects with presence of fissures 
on palm/soles (presence/absence, 
number of fissures, and pain 
associated with fissures [on a 0-3 
scale]) at Day 90 between the 
active trifarotene cream HE1 and 
vehicle groups 
To reflect the 
change from weeks 
to days 
Synopsis and 
Section 
13.1.4.1 
Safety endpoints: 
− 
Local tolerability (Scale: 0-3 
[none, mild, moderate, severe], 
determined by the investigator) for 
each body area (chest/abdomen, 
back, legs, arms, and face/neck). 
Safety endpoints: 
− 
Local tolerability 
(stinging/burning, pruritus, or 
erythema on 0-3 scales [none, 
mild, moderate, severe]) for each 
body area (chest/abdomen, back, 
legs, arms, and face/neck). 
 
Table 2-1 
 
Height, weight, and BMI were added 
to Screening from Baseline 
Coagulation panel was added at 
Baseline, Day 30, and Day 90 
Dispense study drug and diaries was 
added at Day 90 
Added footnote: 
d Although it is preferable to 
conduct all necessary study 
assessments in person (on -site 
visits), this may not be possible as 
a result of COVID-19-related 
travel restrictions. To ensure the 
safety of subjects, investigators, 
and site staff, Visits 3-6 and 
unscheduled visits may be 
conducted remotely. Screening 
and baseline visits must be 
performed onsite only, and must 
be postponed or scheduled for 
when onsite visits can be safely 
conducted. 
To clarify when 
procedures are to be 
done 
 
 
 
 
To provide 
procedural 
accommodations 
due to COVID-19 
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Table 2-2 
 
Vital signs (blood pressure and pulse) 
was added at Day 150 
Ectropion score was added at Day 104 
and Day 150 and removed at Day 134. 
Coagulation panel was added at Day 
120 and Day 180 
 
Added footnote: 
a. Although it is preferable to 
conduct all necessary study 
assessments in person (on -site 
visits), this may not be possible as 
a result of COVID-19-related 
travel restrictions. To ensure the 
safety of subjects, investigators, 
and site staff, Visits 7-11 and 
unscheduled visits may be 
conducted remotely. 
To clarify when 
procedures are to be 
done 
 
 
 
 
 
To provide 
procedural 
accommodations 
due to COVID 19 
Section 5.2 
Throughout the 30 clinical studies that 
comprise the clinical development 
program for CD5789 topical products, 
1976 subjects were exposed to CD5789 
Throughout the 31 completed 
clinical studies that comprise the 
clinical development program for 
CD5789 topical products, 4878 
subjects were exposed to CD5789 
Updated for latest 
data 
Section 6.2 
• 
To assess safety for up to 24 weeks 
of dosing with open-label 
trifarotene cream HE1 200 µg/g. 
• 
To assess safety for up to 
180 days of dosing with 
trifarotene cream HE1 
200 µg/g. 
Subjects will only 
receive open-label 
trifarotene cream 
HE1 200 µg/g for 
90 days. 
Synopsis, 
Section 7.1, 
and Section 
10.2.4 (OLE) 
The first cohort of subjects (Cohort A) 
will randomize approximately 15 adults 
(≥18 years old) in a 1:1:1 ratio to 
trifarotene (CD5789) cream HE1 100 
µg/g, trifarotene cream HE1 200 µg/g, 
or vehicle…. 
 
All subjects (Cohort A and Cohort B) 
who complete the 12-week Double-
blind Treatment Period will be eligible 
to enroll in the 12-week OLE. Subjects 
in the OLE will receive open-label 
trifarotene cream HE1 200 µg/g twice 
weekly for up to 12 weeks. During the 
OLE, subjects will return to the site at 
Weeks 14, 16, 20, 24, and 26. 
Additional PK samples will be drawn at 
Week 16 and Week 24 from all 
subjects who continue into the OLE 
(Table 2-2). 
The first cohort of subjects (Cohort 
A) will randomize adults (≥18 years 
old) in a 1:1:1 ratio to trifarotene 
(CD5789) cream HE1 100 µg/g, 
trifarotene cream HE1 200 µg/g, or 
vehicle…. 
 
All subjects who complete the 
Double-blind Treatment Period will 
be eligible to enroll in the OLE. 
Subjects in the OLE will receive 
open-label trifarotene cream HE1 
200 µg/g twice weekly. During the 
OLE, subjects will return to the site 
at Days 104, 120, 150, 180, and 194. 
Additional PK samples will be drawn 
at Days 120 and 180 from all 
subjects who continue into the OLE 
(Table 2-2). 
To allow more than 
15 subjects to enroll 
in Cohort A 
(because it will 
continue enrolling 
only adult subjects 
until the DSMB 
considers it safe to 
open recruitment in 
Cohort B. 
To be more precise 
with timing 
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Section 7.2 
To ensure safety, this phase 2 study will 
begin with an initial cohort (Cohort A) 
of 15 adults randomized 1:1:1 to 
trifarotene cream HE1 100 µg/g, 
200 µg/g, or vehicle to be applied twice 
weekly. 
If no safety issues are identified, 
105 adults and adolescents (ages 12–17 
years, inclusive) will be allowed to 
enroll in Cohort B and randomized to 
trifarotene cream HE1 100 µg/g, 
trifarotene cream HE1 200 µg/g, or 
vehicle and treated twice weekly in the 
same manner as subjects in Cohort A. 
To ensure safety, this phase 2 study 
will begin with an initial cohort 
(Cohort A) of adults randomized 
1:1:1 to trifarotene cream HE1 
100 µg/g, 200 µg/g, or vehicle to be 
applied twice weekly. 
If no safety issues are identified, 
adults and adolescents (ages 12–17 
years, inclusive) will be allowed to 
enroll in Cohort B and randomized to 
trifarotene cream HE1 100 µg/g, 
trifarotene cream HE1 200 µg/g, or 
vehicle and treated twice weekly in 
the same manner as subjects in 
Cohort A. 
To allow flexibility 
in enrollment 
numbersTo align 
power calculation 
and parameter 
assumptions with 
the new primary 
endpoint. 
Section 8.4 
8.4 Discontinuation of Study 
Intervention 
Discontinuation from study treatment 
does not mean withdrawal from the 
study, and the remaining study 
procedures should be completed as 
indicated in the study protocol (see 
Section 10.2.4.5) 
8.4. 
Subject Discontinuation of 
Study Intervention and Stopping 
Rules 
 
Subjects who discontinue the study 
treatment will be asked to return 
to the site to undergo ET 
procedures (Section 10.2.4.6) 
To clarify and to 
link to correct 
section. 
Section 9.1 
 
Added: Sodium benzoate, 
butylhydroxytoluene, and propylene 
glycol are excipients known to have a 
recognized action or effect to be 
declared on the labeling, according to 
the CHMP Annex to the excipients in 
labeling and package leaflet of 
medicinal products for human use 
(EMA/CHMP/302620/2017). These 
3 excipients are being used in the 
trifarotene formulation at standard 
concentrations and are all necessary 
to ensure adequate protection of the 
formulation along and the shelf life. 
To fulfill request by 
French CA 
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Section 9.2 
For the Double-blind Treatment Period, 
a fixed dose (determined at Visit 2) of 
trifarotene cream HE1 100 µg/g or 200 
µg/g or vehicle cream will be applied 
topically twice weekly on up to 90% 
BSA of each subject. 
To remove fixed 
dose and allow 
dosing to be based 
on BSA 
Subjects will continue treatment for up 
to 12 weeks 
Clarification and 
precision of timing 
For the OLE, all subjects will receive 
trifarotene cream HE1 200 µg/g and 
apply it the same fixed dose same 
manner as in the Double-blind Period 
for an additional 12 weeks. 
Clarification and 
precision of timing 
Section 9.3 
After Day 1, on which the study staff 
will apply the first administration of IP 
in the clinic, each subject will apply 
approximately the same amount of IP 
on up to 90% of their BSA twice 
weekly. It is suggested that each 
subject choose 2 specific days per 
week, at least 3 days apart, on which to 
apply their IP (e.g., Tuesday and 
Friday), and maintain that regimen 
throughout the study. 
Subjects should not apply the IP on 
visit days until after the visit, unless 
they participate in the PK substudy, in 
which case the IP will be applied in the 
clinic on Day 30 after the predose PK 
blood draw. 
To specify that 
treatment 
applications should 
be 3 to 4 days apart, 
and that PK 
substudy subjects 
must visit the clinic 
on Day 30. 
If a subject misses an IP application, 
they should apply the IP as soon as they 
remember and record the date/time in 
the subject diary. 
To specify treatment 
day interval 
Subjects who continue into the Open-
label Extension will receive trifarotene 
cream HE1 200 µg/g and apply the 
same fixed dose in the same manner as 
in the Double-blind Period for an 
additional 12 weeks 
To remove fixed 
dose and allow 
dosing to be based 
on BSA 
For the Double-blind Treatment 
Period, trifarotene cream HE1 
100 µg/g or 200 µg/g or vehicle 
cream will be applied topically twice 
weekly on up to 90% BSA of each 
subject. 
Subjects will apply treatment for 90 
days. 
For the OLE, all subjects will receive 
open-label trifarotene cream HE1 
200 µg/g and apply it in the same 
manner as in the Double-blind Period 
for an additional 90 days. 
After Day 1, on which the study staff 
will apply the first administration of 
IP in the clinic, each subject will 
apply IP on up to 90% of their BSA 
twice weekly. It is suggested that 
each subject choose 2 specific days 
per week, 3 to 4 days apart, on 
which to apply their IP, and maintain 
that regimen each week throughout 
the study (Table 9-1). 
Subjects whose treatment day falls 
on a scheduled study visit day 
should not apply the IP until after the 
visit. 
Subjects who participate in the PK 
substudy should have their Day 30 
Visit scheduled on a treatment day, 
in which case the IP will be applied 
in the clinic on Day 30 after the 
predose PK blood draw. 
Added: If the Day 30 Visit cannot 
be scheduled on a treatment day, 
the investigators should contact the 
medical monitor. 
Added: The next application should 
be 3 to 4 days apart and subjects 
should continue according to their 
new regimen. 
Subjects who continue into the OLE 
will receive trifarotene cream HE1 
200 µg/g and apply in the same 
manner as in the Double-blind Period 
for 90 days 
Added: Table 9-1: Sample Twice-
weekly Dosing Schedule 
To provide a visual 
example of dosing 
schedule options 
Section 9.4 
Deleted Section 9.4.1 Stopping Rules 
Section was 
redundant with 
Section 8.4 
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Section 9.5 
Study personnel will assess treatment 
compliance with IP regimens by 
weighing IP tubes before dispensing 
and upon return and by questioning the 
subject, at every postrandomization 
visit. A participant is compliant with 
study product if he or she takes at least 
80% of the scheduled doses as assessed 
by diary entries, supplemented by tube 
weight. A subject who is not compliant 
(used 80–120% of IP tubes) will be 
counseled at each visit on the 
importance of using the IP as 
instructed. 
Study personnel will assess treatment 
compliance with IP regimens by 
weighing kits (tubes and boxes, but 
not leaflets) before dispensing and 
upon return and by questioning the 
subject at every post randomization 
visit. At baseline, the kit should be 
weighed before choosing the first 
tube for application by the study 
staff. A participant is compliant with 
study product if he or she takes at 
least 80% of the scheduled doses as 
assessed by diary entries, 
supplemented by amount of cream 
used derived from weighing the IP 
kits. A subject who is not compliant 
(for example, used <80 or >120% of 
IP tubes [which is more than what 
can be dispensed per tube at each 
application]), the subject will be 
counseled at each visit on the 
importance of using the IP as 
instructed. 
 
Section 
10.2.2.7 
Subjects will have up to 7 days to 
decide to enter the OLE; if the subject 
chooses to continue into OLE, the 
following additional procedures will be 
done: 
….Remind subjects that at least 
24 hours must have elapsed since IP 
application before the PK draws at 
the Week 16 and Week 24 Visits, 
and not to apply IP on visit days 
until after the visits. 
If the subject chooses to continue 
into OLE, the following additional 
procedures will be done 
Revised: Remind subjects that at 
least 24 hours must have elapsed 
since IP application before the PK 
draws at the Day 120 and Day 180 
Visits, and not to apply IP on visit 
days until after the visits. 
Subjects must 
decide by Day 90 if 
they want to 
continue into the 
OLE. 
 
Section 
10.2.4.1 
Clinic staff will telephone subject to 
assess safety (AEs) and to record 
concomitant 
medications/therapies. 
Staff will to instruct subject on study 
drug application, to advise subjects 
regarding permitted emollient(s) for use 
on 
nontreatment 
days 
(use 
of 
emollient(s) on study drug treatment 
days within 4 hours of study drug 
application is prohibited), and to remind 
subjects not to apply IP on visit days 
until after the visit. 
Clinic staff will telephone subject to 
assess safety (AEs) and to record 
concomitant medications/therapies. 
Staff will to instruct subject on study 
drug application, to advise subjects 
regarding permitted emollient(s) for 
use on nontreatment days (use of 
emollient(s) on study drug treatment 
days within 4 hours of study drug 
application is prohibited), and to 
remind subjects not to apply IP on 
visit Days 120 and 180 until after the 
visit. 
Day 120 and Day 
180 include PK 
draws, so IP should 
be applied after the 
visit is complete. 
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Section 
Previous Text 
Revision 
Rationale 
Section 
10.2.4.2 
12. Instruct subject on study drug 
application, and advise subjects 
regarding permitted emollient(s) for 
use on nontreatment days; use of 
emollient(s) and/or sunscreen on 
study drug treatment days within 4 
hours before or after study drug 
application is prohibited. Remind 
subjects that 24 hours must have 
elapsed since IP application before 
the subject’s next visit. Subjects 
should not apply IP on visit days 
until after the visit at the Week 16 
and Week 24 Visits, and not to 
apply IP on visit days until after the 
visit. 
12. Instruct subject on study drug 
application, and advise subjects 
regarding permitted 
emollient(s) for use on 
nontreatment days; use of 
emollient(s) and/or sunscreen 
on study drug treatment days 
within 4 hours before or after 
study drug application is 
prohibited. Remind subjects 
that 24 hours must have elapsed 
since IP application before the 
subject’s next visit (Day 120) 
and if the Day 120 visit 
coincides with a treatment 
day, wait until after the visit is 
complete to apply IP. 
To specify timing of 
IP application 
Section 
10.2.4.5 
 
Added: 13. Remind subjects that 24 
hours must have elapsed 
since IP application 
before the subject’s next 
visit (Day 180) and if the 
Day 180 visit coincides 
with a treatment day, 
wait until after the visit is 
complete to apply IP. 
To specify timing of 
IP application 
Section 
10.2.4.7 
10.2.4.7 Follow-up Evaluation – Open-
Label Extension Week 26/Visit 11) 
10.2.4.7 Follow-up Evaluation – 
Open-Label Extension (Day 194 or 
14 days after End of Open label 
Treatment /Visit 11) 
To be more specific 
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Section 
Previous Text 
Revision 
Rationale 
Section 10.4 
and Synopsis 
 
New section: 
10.4. 
Procedural Adjustments 
Due to COVID-19 
The coronavirus (COVID-19) global 
pandemic has impacted the free 
movement of the world’s population, 
which has been restricted to control 
the spread of the disease. It is 
recommended that all sites and 
subjects comply with the applicable 
local and federal guidelines regarding 
the necessary and proper precautions 
regarding COVID-19. 
 
Although it is preferable to conduct 
all necessary study assessments in 
person (onsite visits), this may not be 
possible as a result of COVID-19-
related travel restrictions. To ensure 
the safety of subjects, investigators, 
and site staff, Visits 3-6 (Double-
blind Period; Table 2-1), Visits 7-11 
(OLE Period; Table 2-2) and 
unscheduled visits may be conducted 
remotely. Screening and baseline 
visits must be performed onsite only, 
and must be postponed or scheduled 
for when onsite visits can be safely 
conducted. 
Appendix B details the procedures 
when it is inadvisable or not possible 
to conduct an onsite study visit. 
To provide 
procedures/schedule 
for COVID-19 
issues. 
Section 
11.2.1 
 
Added: The Tolerability Assessments 
Form at each visit collects a numeric 
severity score by body area for 
erythema, stinging/burning, and 
pruritus. 
In addition, if skin irritation is more 
than the expected erythema, 
stinging/burning, and pruritus with 
the application of this topical retinoid 
(i.e., clinically relevant), please enter 
the application site reactions in the 
Adverse Event description section. If 
a diagnosis is known, record the 
diagnosis. If a diagnosis is known 
and there are other signs/symptoms 
that are not generally part of the main 
diagnosis, record the diagnosis and 
each sign/symptom on a separate 
line. If a diagnosis is not known, 
record each sign/symptom on a 
separate line. Examples are allergic 
contact dermatitis, sunburn, skin 
erosion, and swelling. 
To specify how 
tolerability 
assessments are 
collected. 
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Section 
Previous Text 
Revision 
Rationale 
Section 
11.2.2.3 
Dose reduced 
An indication that a 
medication schedule was modified by 
subtraction, either by changing or 
reducing the frequency, strength, or 
amount. 
Dose reduced 
An indication that a 
medication schedule was modified by 
reducing the frequency of 
application 
Dose cannot be 
reduced by changing 
the strength or 
amount. 
Section 
11.3.2 
These findings must be reported on the 
Exposure in Utero form and forwarded 
to the designated individual(s). The 
event meets the SAE criterion only if it 
results in a spontaneous abortion or a 
congenital anomaly.  
Deleted: The investigator should 
contact the designated individual(s) 
who receive SAE notification and 
record information related to the 
pregnancy on an SAE and AE form 
(entering the event temporarily as 
nonserious on both forms) provided 
by the sponsor or its designee. 
These findings must be reported on 
the Pregnancy Data Collection 
Form and forwarded to Premier 
Research Pharmacovigilance. The 
event meets the SAE criterion only if 
it results in a spontaneous 
abortion or a congenital anomaly. 
In such case an additional form 
(Serious Adverse Event Report 
Form) must be filled out by the 
Investigator and provided to 
Premier Research 
Pharmacovigilance within 24h of 
knowledge of the pregnancy’s 
serious outcome. 
Repetitive; AE 
forms not collected 
by 
pharmacovigilance 
Section 12 
 
Added names and qualifications of 
the DSMB 
The DSMB committee members are 
as follow: 
• Univ. Prof. Dr. med. Steffen 
Emmert, Director at Clinic and 
Polyclinic for Dermatology & 
Venereology 
• Jeffrey Louis Sugarman, 
M.D., Ph.D. 
• Moise L. Levy, MD, Pediatric 
Dermatologist 
• Gabriele Accetta, Ph.D. 
Biostatistician 
In accordance with 
French Ethics 
Committee 
Section 
13.1.1 
 
Added: Deviations related to 
COVID-19 will also be evaluated in 
determining Per-protocol Population 
eligibility. 
To provide COVID-
19 information 
Section 
13.1.4 
 
Added: Efficacy endpoints will be 
based on investigator assessment.  
To specify that 
investigator 
assessment is 
primary for efficacy 
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Section 
Previous Text 
Revision 
Rationale 
Section 
13.1.4.5 
 
Added: Thorough assessment on the 
extent of missing data and procedural 
adjustments due to COVID-19 as it 
pertains to the primary and secondary 
efficacy endpoints will be conducted 
ahead of database lock and additional 
sensitivity analyses may be 
performed. Full details will be 
documented in the SAP. 
To provide 
contingency 
methods for 
COVID-19 issues 
Section 14.3 
 
Added: Subjects may only be 
rescreened once 30 days or more 
after the original Screening Visit. 
Subjects should be 
rescreened if the 
reason for SF is 
reasonably believed 
to have been 
resolved. 
Section 15 
The final CSR will be written within 1 
year of completion of the clinical part 
of the study. For pediatric studies, the 
final CSR will be written within 
6 months. 
The final CSR will be written within 
6 months of completion of the study.  
This study involves 
pediatric subjects. 
Appendix B 
 
Added new Appendix B with 
Procedural Adjustments for 
COVID-19 
To provide guidance 
for remote visits 
during COVID-19 
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AMENDED PROTOCOL 
The following are the amended protocol and appendices, including all revisions specified above. 
 
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4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABBREVIATION 
EXPLANATION 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse events of special interest 
ATC 
anatomical therapeutic chemical 
AUC 
area-under-the-curve 
BMI 
body mass index 
BSA 
body surface area 
CFR 
code of federal regulations 
CI 
confidence interval 
Cmax 
maximum concentration 
COVID-19 
Coronavirus disease 2019 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
DBP 
diastolic blood pressure 
DLQI 
dermatology life quality index 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
ESS 
ectropion severity score 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GEE 
generalized estimating equations 
HR 
heart rate 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification 
IEC 
independent ethics committee 
IGA  
Investigator’s Global Assessment 
IND 
investigational new drug 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IWRS 
interactive web response system 
LI 
lamellar ichthyosis 
MedDRA 
medical dictionary for regulatory activities 
mITT 
modified intent-to-treat 
MMRM 
mixed model of repeated measures 
NCA 
noncompartmental analysis 
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ABBREVIATION 
EXPLANATION 
OC 
observed case 
OLE 
open-label extension 
OTC 
over-the-counter 
PG 
propylene glycol 
PK 
Pharmacokinetic(s) 
PoC 
proof-of-concept 
PP 
per-protocol 
QTc 
QT interval corrected for heart rate 
RARγ 
retinoid acid receptor γ  
RBC 
red blood count 
RR 
respiratory rate 
RXR 
retinoid X receptor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
Tmax 
time of Cmax 
TSH 
thyroid-stimulating hormone 
UAE 
unexpected adverse event 
UADR 
unexpected adverse drug reaction 
ULN 
upper limit of normal 
US 
United States 
UV 
ultraviolet 
VIIS 
Visual Index for Ichthyosis Severity 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
women of childbearing potential 
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5. INTRODUCTION 
5.1. Background and Rationale 
The ichthyoses comprise a large group of skin scaling disorders with diverse etiology. The 
stereotypic pathophysiology is epidermal hyperplasia and the formation of excess stratum corneum 
accompanied by abnormal (delayed and/or disordered) desquamation, with visible accumulation 
of squames (scales) on the skin’s surface – the clinical hallmark of all the ichthyoses. 
Lamellar ichthyosis (LI) is recognized as a severe form of ichthyosis that persists throughout life. 
During the first postnatal weeks, the hyperkeratotic membrane patients are typically born with is 
gradually shed, and is replaced by scaling and lichenification that involves the entire body 
including the intertriginous areas, palms, soles, and scalp. While usually not life threatening, LI 
can result in disability, partial deafness, poor adaptation to environmental conditions (due to 
hypohydrosis), severe discomfort (pruritus, fissuring of the skin) and significant psychosocial 
impact. 
Lamellar ichthyosis, a member of the nonsyndromic autosomal recessive congenital ichthyosis 
group of ichthyoses, has an incidence of 1 per 100,000-300,000 live births.1 Lamellar ichthyosis 
is undoubtedly a rare disease. 
Therapeutic approaches for LI are mainly based on the use of topical emollients, keratolytic agents 
(urea, lactic acid, salicylic acid), topical retinoids and, in severe cases, oral retinoids.2,3 
Oral retinoid usage in LI is mainly based on case reports and case series.4,5,6,7,8 The mechanism of 
retinoid action involves modulation of keratinocyte differentiation, keratinocyte hyperproliferation 
and tissue infiltration by inflammatory cells. Systemic retinoids (such as acitretin, etretinate, or 
isotretinoin) have been found to be efficacious in the treatment of severe ichthyoses, especially in 
LI.6 
Vahlquist, et al (2008)3 report that by combining 2 or more keratolytic agents and moisturizers in 
the same lipophilic cream base, it is often possible to achieve additive or even synergistic effects 
in LI without the need to use irritating concentrations of either agent alone. In a double-blind trial 
of 4 different cream mixtures in 20 patients with LI, a mixture of 5% lactic acid and 20% propylene 
glycol (PG) in a semi-occlusive cream for 4 weeks twice daily was significantly more effective 
than 20% PG or 5% urea alone in the same vehicle.9 Although the treatments were well tolerated, 
an efficient removal of hyperkeratosis without correcting the underlying biochemical defect in LI 
is likely to deteriorate the patient’s intrinsic barrier problem, because an excessive production of 
corneocytes probably represents a homeostatic response to an ineffective barrier. Indeed, 
transepidermal water loss increased after successful treatment of LI with either topical 
keratolytics9 or oral retinoid.10 Although this may not be noticeable by the patient, even minor 
deteriorations in the barrier function can enhance transcutaneous penetration of active cream 
ingredients or other topically applied chemicals, which is a matter of special concern in children. 
Accordingly, α-hydroxy acids and salicylic acid should not be used at all in babies and only with 
great caution when treating large, eroded skin areas in adult patients.11,12 
Many patients with LI use pumice, foot files, or gentle rubbing of the skin after a hot bath or a 
shower to remove scales and hyperkeratosis. Overnight occlusion of problematic skin areas with 
plastic sheets after applying a thick layer of emollient or keratolytic agents is another way of 
potentiating therapy, especially on the scalp, which is notoriously difficult to treat. Although 
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usually effective, all these remedies may further damage the skin barrier and lead to exaggerated 
epidermal proliferation, erythema, painful erosions and increased transcutaneous penetration.3 
Based on this information, LI has significant unmet medical need for safer and more effective 
therapies. 
5.1.1 CD5789 (Trifarotene) 
CD5789 is a new chemical entity discovered by Galderma R&D SNC and formulated for topical 
application. It is a novel retinoid acid receptor γ (RARγ) agonist, characterized by its high 
specificity to this receptor. CD5789 is selective for RARγ over RARα and RARβ (approximately 
50- and 8-fold, respectively), with no retinoid X receptor (RXR) activity. CD5789 is currently 
under clinical development for the topical treatment of various dermatoses, including acne vulgaris 
and LI. 
The pharmacological retinoid-like properties of CD5789 were confirmed in in vitro and in vivo 
models, showing its interest for its development in the treatment of LI. Therefore, it may have an 
effect on the differentiation and hyperproliferation of keratinocytes, and consequently improve 
hyperkeratotic skin of patients with lamellar ichthyosis. 
Within the overall acne development program at Galderma, CD5789 has been tested in different 
pharmaceutical forms for topical administration. As of 15-Jan-2018, 6 different formulations have 
been evaluated: a solution, a gel and 4 creams (CD5789 cream A, CD5789 cream B, CD5789 
cream HE1 concept and its optimized version, cream HE1), with different concentrations (up to 
400 µg/g). Therefore, several formulations at different CD5789 concentrations have been tested in 
nonclinical and clinical development programs. 
Galderma decided to develop a new cream formulation that might better address the issue of skin 
dryness in patients with LI. This formulation was named “Cream HE1 concept.” It has been 
preliminarily investigated in an exploratory trial in psoriasis at concentrations up to 400 μg/g 
(RD.03.SRE.40204E). In a proof-of-concept study (RD.03.SRE.40181E), positive results were 
also obtained in patients with LI with CD5789 cream (up to 100 µg/g) that was effective in 
decreasing scaling and roughness. Based on these results, a new CD5789 formulation (cream HE1) 
was developed for further clinical investigations in LI. The formulation cream HE1 was developed 
with the objective to obtain a formulation with appropriate stability of the active ingredient and in 
which CD5789 would be homogeneously dissolved in the oily phase at a higher concentration 
compared to the cream formulation used in the acne program. Cream HE1 contains 100, 200, or 
400 μg/g (0.01% [w/w], 0.02% [w/w], 0.04% [w/w], respectively) of CD5789. 
Galderma has granted Mayne Pharma LLC an exclusive license to develop and commercialize 
CD5789 (trifarotene) for LI and other orphan diseases; therefore, the LI indication is no longer 
pursued by Galderma. 
5.2. Clinical Experience 
The cream HE1 differs from the CD5789 cream used to treat acne vulgaris in that it contains fewer 
excipients with drying effects and therefore may be better suited for patients with LI. 
Throughout the 31 completed clinical studies that comprise the clinical development program for 
CD5789 topical products, 4878 subjects were exposed to CD5789. No systemic safety concerns 
related to CD5789 gel or creams, or cream HE1 at doses up to 400 μg/g were reported. The subjects 
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were exposed to a maximal total CD5789 dose of 36 g/day (Investigator’s Brochure for CD5789 
Cutaneous Formulation). 
One study was conducted with CD5789 50 μg/g, 100 μg/g, and placebo in subjects with ichthyosis 
(Study RD.03.SRE.40181E). Among 31 subjects treated in this study, 17 were treated with 
CD5789 100 μg/g, and 14 were treated with 50 μg/g (all subjects received placebo [vehicle] on the 
contralateral zone). Mean (SD) baseline IGA score was 5.7 ± 1.6 among the 31 subjects. 
Improvement in the investigator’s global assessment (IGA) of scaling and roughness was observed 
by Day 8 with both doses. The primary efficacy criterion was the change in IGA from the Baseline 
Visit (Day 1) to the Final Visit (Day 43). At Endpoint (intent-to-treat population, last observation 
carried forward [LOCF]), the CD5789 100 μg/g group had a statistically significant decrease from 
Baseline in IGA compared with Vehicle (-1.4±2.2; p=0.018) (Investigator’s Brochure for CD5789 
Cutaneous Formulation). 
The CD5789 PK profile was also investigated using cream HE1 (Study GD.03.SRE.103813) in 
36 healthy volunteers of Japanese and non-Japanese origin. Subjects were treated daily on up to 
90% of body surface area (BSA) for 29 days with up to 36 g of cream formulation. Both CD5789 
100 μg/g and 200 μg/g cream HE1 were investigated. Plasma PK assessment demonstrated that 
repeated topical applications of CD5789 cream HE1 resulted in low and similar CD5789 systemic 
levels in all treatment groups. In addition, no systemic safety concerns were raised from this 
healthy volunteer study in which cream HE1 200 μg/g was applied daily under maximal-use 
conditions on almost the full body. In this study, however, the level of irritation resulted in the 
need to decrease the frequency of application to twice weekly (Investigator’s Brochure for CD5789 
Cutaneous Formulation). However, it is possible that absorption in subjects with LI may be greater 
than in healthy volunteers, due to the skin being compromised. 
Based on these data, both the 100 µg/g and 200 µg/g doses showed an acceptable safety profile 
and will be used in this phase 2 LI study, to determine which of the 2 doses is most effective. The 
open-label extension (OLE) will evaluate the long-term safety of the higher dose in this patient 
population. 
5.3. Summary of Potential Risks and Benefits 
Although the primary objective of this study is safety in the patient population with LI, the 
potential benefits of study participation are that subjects with LI may experience a reduction in 
their LI symptoms as a result of treatment with trifarotene (CD5789) cream HE1. No other benefits 
of participation are anticipated. 
The potential risks of study participation for all subjects include those associated with exposure to 
trifarotene (CD5789) cream HE1 and the risks of medical evaluation, including venipuncture. The 
study population will comprise adults and adolescents aged 12 to 17 years. 
Animal studies with CD5789 have shown reproductive toxicity in the embryo-fetal studies. 
Despite low systemic levels with the CD5789 concentration of 50 μg/g used in patients with acne, 
CD5789 must not be administered during pregnancy. 
When CD5789 is used in the other formulations and/or for other indications and/or with higher 
concentrations or higher application surface areas, the potential risk of teratogenicity needs to be 
considered as the safety margin may be lower. Depending on the study population and conditions 
mentioned above, or other specific requirements, the appropriate contraception method is 
described in this protocol. 
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It is unknown whether CD5789 or its metabolites are excreted in human milk. A risk to the 
newborns/infants cannot be excluded. Lactating women are not eligible for the clinical study. 
Certain cutaneous signs and symptoms of irritation and localized reactions at the application site 
such as erythema, scaling, dryness, stinging/burning, and pruritus may be experienced with use of 
CD5789. Depending upon the severity of these side effects, subjects may be instructed to reduce 
the frequency of application or to discontinue use. 
Trifarotene cream contains propylene glycol that is mildly irritant to the skin, eyes, and mucous 
membranes. Trifarotene (CD5789) cream HE1 also contains butylated hydroxytoluene that may 
cause local skin reactions (e.g., contact dermatitis), or irritation to the eyes and mucous membranes 
and sodium benzoate that is mildly irritant to the skin, eyes, and mucous membranes. 
CD 5789 is mildly irritant to the skin, eyes, and mucous membranes. Therefore, it should not come 
into contact with the eyes, mouth, or mucous membranes. 
There is a potential risk of skin sensitization. If a reaction suggesting sensitivity to trifarotene 
(CD5789) cream HE1 occurs, the use of the trifarotene cream HE1 must be discontinued. 
There is a potential risk of photosensitivity disorder (sunburn). Excessive exposure to sunlight or 
ultraviolet (UV) radiation (i.e., occupational exposure to the sun, planned holidays in the sun 
during the study, phototherapy, tanning salon) must be avoided during the studies. In addition, 
subjects should take protective measures such as applying sunscreen (except within 4 hours before 
and/or 4 hours after study drug application), and/or wearing protective clothing (e.g., long sleeves, 
hats, and covering legs and feet) and/or seeking shade or shelter from the sun. 
As reported with other topical retinoids, there is a potential risk of pigmentation disorders. 
No clinically significant systemic risks associated with CD5789 have been identified. Given the 
mechanism of action for CD5789 Cream HE1, it is assumed that efficacy will increase as the dose 
is increased. As such, the 200 µg/g dose was selected for the OLE based on its previously 
established safety profile, expected superiority to placebo and 100 µg/g. However the Data Safety 
Monitoring Board (DSMB), who will routinely review aggregate safety and tolerability data, as 
well as any safety concerns brought to the their attention by the study investigators or medical 
monitor, may determine that the study should be modified, placed on hold, or stopped if serious 
safety issues are discovered. This is applicable for both the double-blind portion and OLE. If the 
200 µg/g dose in raises any safety concerns, the protocol will be amended and the dose will be 
reduced. 
A summary of the pharmaceutical properties and known potential risks of trifarotene (CD5789) 
cream HE1 is provided in the current version of the investigator brochure (IB). The investigator 
must become familiar with all sections of the trifarotene (CD5789) cream IB before the start of the 
study. 
6. OBJECTIVES 
6.1. Primary Objective 
The primary objective is to compare the safety and efficacy of 2 concentrations of trifarotene cream 
HE1 versus vehicle in adults and adolescents with moderate to severe autosomal recessive 
ichthyosis with lamellar scale, also known as lamellar ichthyosis (LI) after 90 days of treatment. 
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6.2. Secondary Objectives 
The secondary objectives are as follows: 
• To assess systemic exposure to trifarotene and its major metabolites after topical 
application of the investigational product (IP) on up to 90% BSA twice weekly. 
• To assess safety for up to 180 days of dosing with trifarotene cream HE1 200 µg/g. 
7. STUDY DESIGN 
7.1. Overall Study Design and Plan 
The first part of this study is a phase 2, randomized, 2-cohort, double-blind, vehicle-controlled, 
multicenter study of the safety, tolerability, PK, and efficacy study of trifarotene cream HE1 
100 µg/g and 200 µg/g in adults and adolescents with LI for 90 days. Adult and adolescent subjects 
who complete the randomized, double-blind, vehicle-controlled period of the study will be eligible 
to continue into an open-label extension (OLE) and be treated with trifarotene cream HE1 200 µg/g 
for an additional 90 days. 
The randomized, double-blind, vehicle-controlled period of the study in subjects with moderate to 
severe LI (i.e., 3–4 on a 5-point Investigator Global Assessment [IGA] scale where 0 = clear; 1 = 
almost clear; 2 = mild; 3 = moderate; and 4 = severe), is designed to compare the safety of 2 doses 
of trifarotene cream HE1 with that of vehicle in the treatment of LI. 
Written informed consent will be obtained from a parent/legal guardian for any minor and minors 
will provide assent before any study-related procedures are performed. 
Upon signing informed consent and entering the Screening Period, subjects will stop using 
physical and medical treatments for LI, including balneotherapy, and may begin to washout 
prohibited topical and systemic treatments with designated washout periods (Table 9-2), as 
applicable. Washout may be up to 90 days, as necessary. 
During washout, subjects may continue taking their standard of care of visible skin (face and scalp) 
for cosmetic reasons and of extremities (palms/soles) to avoid functional consequences on walking 
or moving their fingers. In the US/EU, this may include compounded emollients with keratolytics 
(alpha or beta hydroxyl acids) and/or urea. The investigator should approve and document these 
standard-of-care treatments in the electronic case report form (eCRF). If the standard of care 
treatments of the face and/or palms/soles contain prohibited medications, they must be stopped at 
the Baseline Visit. Subjects may shower, but not bathe or swim. The IGA will be evaluated on the 
rest of the body at Baseline. After completing any necessary washout of prohibited medications, 
subjects will return to the site to have their LI assessed and to complete the study eligibility 
requirements. 
Study drug will be packaged in 50-g tubes from which up to 36 g of IP may be dispensed per 
application, i.e., the maximum dose per application. 
Study staff will choose 1 tube from the kit dispensed to the subject at that visit, and apply the first 
dose of study drug to each subject in the clinic on Day 1 after Baseline measurements; they will 
weigh the study tubebefore and after application to determine the amount used. If the product will 
be applied at home by someone other than the study subject, it is recommended that person assist 
with application at the first visit to learn how the IP is applied. 
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The kit dispensed at baseline must be weighed before the first tube is chosen for application by 
the study staff. Weight of the kits dispensed and returned by the subject during the study includes 
both tubes and cartons, but not leaflets, which need to be removed before weighing. The subject 
must be reminded to return the kits with tubes and cartons, whether used or not, when returning to 
the next visit.  
Thereafter, subjects will apply up to 36 g of study drug on up to 90% of BSA twice weekly, sparing 
the scalp, inguinal, and axillary areas. Subjects with heavy facial hair should not apply IP to hair-
bearing areas. Subjects will receive an adequate number of tubes to use 1 tube per application and 
will use a new tube for each treatment day. Subjects may use less than the full amount of IP in a 
tube. 
The study protocol limits application of IP to 36 g maximum; no additional tubes can be given, 
whether during the randomization period or the OLE period. If the study staff and subject note that 
there is insufficient volume for full body application, the subject should apply trifarotene cream 
sparingly twice weekly to the most affected areas, and always to the same skin areas. Study cream 
should be very sparingly applied. Trifarotene cream 100 or 200 µg/g, is a highly potent topical 
retinoid and it is not necessary to apply much for efficacy; application of more will increase the 
risk of irritation and systemic penetration. 
Enrolled subjects will receive treatment for 90 days. 
The first cohort of subjects (Cohort A) will randomize adults (≥18 years old) in a 1:1:1 ratio to 
trifarotene (CD5789) cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle. 
After the initial 15 subjects complete at least 28 days of treatment, an independent DSMB will 
review aggregate safety and tolerability data (including PK and electrocardiogram [ECG] data). If 
no safety issues are identified, adolescents (ages 12–17 years, inclusive) will be allowed to enroll 
together with adults in Cohort B. Subjects in Cohort B will be randomized 1:1:1 to trifarotene 
cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle and similarly treated twice 
weekly for 90 days in the same manner as subjects in Cohort A. 
Cohort A will continue enrolling only adult subjects until the DSMB considers it safe to open 
recruitment in Cohort B. 
All subjects will be given diaries in which to record study drug application (days/times and any 
areas of skin not treated [e.g., due to local reactions]), any application site reactions, adverse events 
(AEs), and concomitant medications used. Subjects will also be advised on permitted emollient(s) 
and/or sunscreen(s) use on nontreatment days during the study; use of emollient(s) and/or 
sunscreen on study drug treatment days within 4 hours before or after study drug application is 
prohibited. 
At all sites with photographic capability photographs will be taken as source data to support 
scoring at Baseline, Day 30, and Day 90. A central reader who will not be an investigator in the 
study will review the photographs to assess consistency of investigator scoring of LI severity as a 
quality check. Photographs may also be used for scientific publication purposes. Subjects will sign 
a separate, optional, photographic informed consent form (ICF). 
Samples for PK will be drawn from all subjects at Baseline and at each clinic visit, as indicated in 
the Schedule of Events (Table 2-1). Visits for PK must occur at least 24 hours after the last 
application of the IP to avoid contamination of the blood samples with any IP that may have 
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remained in the skin after the last application. Subjects should not apply IP on visit days until after 
the visit. 
In addition, a PK substudy will be conducted on Days 1 and 30 at sites with the capability to 
conduct it. Participation in the PK substudy will be optional and will include at least 15 adults and 
15 adolescents. Subjects who participate in the PK substudy will come from both study cohorts 
and will undergo serial blood sampling predose and at 1, 2, 4, 8, 12, and 24 hours postdose on 
Day 1 and Day 30. Trough levels will be drawn for all subjects at specified time points. For the 
subjects in the PK substudy, postdose ECGs will be performed at each serial blood draw on Day 1 
and Day 30. 
Efficacy will be assessed by the number of subjects in each treatment group who achieve “success” 
defined as clear/almost clear overall and at least a 50% reduction from Baseline at 
Day 90/end-of-treatment (EOT) in the Double-blind Period on the 5-point IGA scale (i.e., 0 = 
clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe). In addition, efficacy criteria include 
assessment scales for palm/sole, scaling, roughness, fissuring, and the Dermatology Life Quality 
Index (DLQI), and the EQ-5D Quality of Life (QoL) Questionnaire. Ectropion Severity Scores 
(ESS) between the active trifarotene cream HE1 and vehicle groups will be an exploratory 
endpoint. 
Plasma concentrations of CD5789 and its major metabolites will be measured. 
Safety will be assessed by evaluating reported AEs, changes in clinical laboratory test results, vital 
sign measurements, physical examinations, 12-lead ECGs, and local tolerability (stinging/burning, 
pruritus, or erythema on 0-3 scales [none, mild, moderate, severe]). 
All AEs observed by the study personnel or reported by the subject during the study (from the time 
of the signing of the informed consent and/or assent through the post-treatment visit) will be 
documented. 
Topical trifarotene cream HE1 was generally well tolerated in recently completed phase 3 pivotal 
and long-term safety studies in subjects aged 9 years and older with acne vulgaris. The local 
tolerability of the trifarotene cream HE1 formulation in subjects with LI is unknown and will be 
monitored during the study. Subjects will receive information on study drug use and stopping rules 
and will be instructed to contact the site with any safety/tolerability issues. Study personnel will 
telephone subjects in between scheduled visits (i.e., at Day 7 and Day 45) to assess safety; an 
unscheduled clinic visit may be performed, if necessary. At each clinic visit, the investigator will 
assess local tolerability (stinging/burning, pruritus, or erythema on 0-3 scales [none, mild, 
moderate, severe]) on each treated body area (chest/abdomen, back, legs, arms, and face/neck). 
All subjects who complete the Double-blind Treatment Period will be eligible to enroll in the OLE. 
Subjects in the OLE will receive open-label trifarotene cream HE1 200 µg/g twice weekly. During 
the OLE, subjects will return to the site at Days 104, 120, 150, 180, and 194. Additional 
PK samples will be drawn at Days 120 and 180 from all subjects who continue into the OLE (Table 
2-2). 
Stopping rules and treatment modification will be defined at the subject level based on local 
tolerability, selected laboratory parameters, and AEs; see Section 9.4. 
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Figure 7-1: 
Double-blind Study Design 
 
 
 
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Optional 
photographs at 
Baseline, 
Day 30, and 
Day90 
Screening 
D S1ffi reviews 
safety data 
(15 adullts wlth at 
le'8.St 2& day:s 
treatment) 
-o s.afety issues 
Cohort B ~Qlh 
(subjects aged ~12 years) 
Continue through 90 days of tre-atment 
Optional PK substudy 
Serial blood s.ampling 
predose and at 1, 2, 4, 8, 
12, and 24 hours postdose 
on Day 1 and Day 28 
Additional 
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Figure 7-2: 
Open-label Study Design 
 
Double-blind 
Study Hay 90 (±7 days) = 
first visit of open-label 
extension with 
trifarntene 200 µgig 
Continue through 90 days of treatment 
Follow-up Day 194 m 14 days after End of Treatment 
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7.2. Rationale and Discussion of Study Design 
The first part of this study is a randomized, double-blind, placebo-controlled study of the safety, 
tolerability, PK, and efficacy study of trifarotene cream HE1 100 µg/g and 200 µg/g in adults and 
adolescents with LI. 
In a previous proof-of-concept study (RD.03.SRE.40181E), subjects with LI applied trifarotene 
50 and 100 µg/g cream to limited areas and results demonstrated a decrease in scaling with good 
safety and tolerance. In a phase 1 study in healthy Japanese and non-Japanese subjects 
(RD.03.SPR.103813), repeated topical applications of trifarotene (CD5789 cream HE1) 100 µg/g 
and 200 µg/g resulted in low and similar CD5789 systemic levels in all the cohorts. These studies 
are fully described in the current Investigational Brochure. 
To ensure safety, this phase 2 study will begin with an initial cohort (Cohort A) of adults 
randomized 1:1:1 to trifarotene cream HE1 100 µg/g, 200 µg/g, or vehicle to be applied twice 
weekly. An independent DSMB will review aggregate safety and tolerability data from the initial 
15 subjects’ first 28 days of treatment. If no safety issues are identified, adults and adolescents 
(ages 12–17 years, inclusive) will be allowed to enroll in Cohort B and randomized to trifarotene 
cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle and treated twice weekly in the 
same manner as subjects in Cohort A. All subjects in the randomized, double-blind portion of the 
study will be treated for 90 days and data on safety, tolerability, PK, and efficacy collected. 
Adult and adolescent subjects who successfully complete the initial 90 days of double-blind 
treatment will have the option to enter an OLE with trifarotene cream HE1 200 ug/g twice weekly 
for 90 days. 
The OLE will collect additional safety, tolerability, PK, and efficacy data. As designed, this study 
will provide important information on safety, tolerability, and PK with dosing of adolescents and 
adults with LI for up to 180 days. 
The protocol includes appropriate monitoring for safety and tolerability. If subjects develop 
significant local application site reactions or tolerability issues, the protocol includes language for 
reducing the frequency of application or halting study drug application until the symptoms abate. 
7.3. Selection of Doses in the Study 
Based on the results from Study RD.03.SRE.40181E and Study SRE.103813, the doses of 
100 µg/g and 200 µg/g were selected for further investigation in adult and adolescent subjects with 
moderate to severe LI to determine which of the 2 doses is most effective. The proof-of-concept 
(PoC) study demonstrated efficacious treatment with 100 µg/g in adults. The PK and tolerability 
study showed that, when the frequency of application was reduced from daily to twice weekly, the 
200 µg/g cream HE1 had good local tolerability. 
Therefore, the current study will use these doses compared with vehicle, applied twice weekly on 
up to approximately 90% BSA in subjects with LI. The OLE will evaluate the long-term safety of 
the higher dose in this patient population. 
7.4. Study Sites 
The study will take place at approximately 40 sites in North America, Europe, Israel, and Australia. 
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7.5. Point of Contact 
A point of contact will be identified to provide information to subjects about where to obtain 
information on the study, the rights of subjects, and whom to contact in case of a study-related 
injury. This information will be provided in the subject information and informed consent form 
(ICF). 
7.6. End of Study Definition 
A clinical trial is considered completed when the last participant’s last study visit has occurred. 
8. SUBJECT POPULATION 
8.1. Selection of Study Population and Diagnosis 
Diagnosis of LI for the purposes of this study will be a clinical diagnosis. Although some younger 
subjects may have had genetic testing, older subjects may not. 
While LI is a rare disease and subject enrollment may be challenging, due to possible bias 
introduced by including household members in the same study, it is recommended that only 
1 household member be included in the study to maintain the blind and ensure all assessments are 
independent. 
8.2. Study Entry Criteria 
8.2.1 Inclusion Criteria 
A subject will be eligible for study participation if he or she meets all of the following criteria: 
1. For Cohort A: subject is ≥18 years old; for Cohort B: subject is ≥12 years old. 
2. Subject has known diagnosis of LI. 
3. Subject has moderate to severe (IGA 3–4) LI on the IGA of LI severity. 
4. Subject has signed an ICF at Screening before any investigational procedures. Subjects 
<18 years of age (or Age of Majority) must sign an assent form in conjunction with an ICF 
signed by the parent/legal representative. 
5. Subject who is participating in optional photography has signed a photography ICF. 
6. Subject who is participating in the optional PK substudy has signed a PK ICF. Minors, in the 
event of their reaching majority during the study, should be capable of giving consent to take 
part in the PK substudy. 
7. Subject is not of childbearing potential, who is postmenopausal (absence of menstrual 
bleeding for 1 year before Baseline, without any other medical reason), or has documented 
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. For individuals with 
permanent infertility due to an alternate medical cause other than the above, (e.g., Mullerian 
agenesis, androgen insensitivity), investigator discretion should be applied to determining 
study entry. 
OR 
• Subject is a woman of childbearing potential (WOCBP), i.e., a female ≥12 years of age 
(regardless of whether they have experienced/reported menarche), or a male subject with 
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sexual partners capable of reproduction who agrees to use 2 effective forms of contraception 
during the study and for at least 1 month after the last study drug application. The 
2 authorized forms of contraception are condom used with 1 of the following methods of 
contraception: 
• bilateral tubal ligation 
• combined oral contraceptives (estrogens and progesterone), vaginal ring, or implanted or 
injectable hormonal contraceptives with a stable dose for at least 1 month before Baseline; 
hormonal contraceptives must inhibit ovulation 
• intrauterine device (IUD) inserted at least 1 month before Baseline 
OR 
Agrees to abstain from heterosexual intercourse during study participation and for 1 month 
after the last application of study drug and to use a highly effective contraceptive as backup if 
he or she becomes sexually active during the study. Abstinence is only acceptable if this is the 
subject’s usual lifestyle. Periodic abstinence (calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method are not acceptable methods of contraception. 
AND 
Male subjects may not donate sperm during the study and for at least 1 month after the last 
study drug application. 
Note: Female subjects who are premenstrual at screening should nonetheless follow the 
pregnancy testing schedule for WOCBP even if they abstain from sexual intercourse while in 
the study and for at least 1 month after the last study drug application. 
8. Women of childbearing potential must be nonlactating and have negative pregnancy test results 
at Screening (serum) and on Day 1 before study drug administration (urine). 
9. Subject is reliable and capable of adhering to the protocol and visit schedule, in the 
investigator’s judgment, and has signed informed consent/assent, as applicable. 
10. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin). 
8.2.2 Exclusion Criteria 
A subject will be excluded from the study if he or she meets any of the following criteria: 
1. Subject has any variant of ichthyosis other than LI or another disorder of keratinization, 
including syndromic ichthyoses. 
2. Subject has current moderate or severe stinging/burning at Screening. 
3. Subject has an ongoing cutaneous infection or any other significant concomitant skin disease 
(other than the LI) which, in the investigator’s opinion, may interfere with the study 
assessments. 
4. Subject with fasting triglycerides >200 mg/dL or >2.25 mmol/L and/or total cholesterol 
>250 mg/dL or >6.5 mmol/L. Subjects whose triglycerides and/or total cholesterol are within 
normal limits with a stable dose of lipid-lowering agents for at least 6 months may be included. 
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5. Subject was previously treated with trifarotene/CD5789 in an acne or ichthyosis study. 
6. Subject has any other significant concomitant disease, or poorly controlled medical condition 
other than LI that in the investigator’s opinion may put him or her at risk if he or she takes part 
in the study, and/or that may interfere with the study assessments. 
7. Subject has a medical condition that potentially alters bone metabolism (e.g., osteoporosis, 
thyroid dysfunction, Cushing syndrome, Crohn’s disease, or ulcerative colitis). Subjects with 
hypothyroidism who are on a stable dose of thyroid hormone replacement therapy and whose 
thyroid-stimulating hormone (TSH) is normal may be included 
8. Subject is being treated for major depression disorder and/or has a history of major depression 
or suicide attempt requiring hospitalization, medications, and close psychiatric surveillance to 
prevent suicide attempts. 
9. Subject with positive serology for hepatitis B surface antigen, hepatitis C, or are known to be 
HIV positive or to have AIDS at Screening. 
10. Subject with any of the following laboratory values at Screening: 
a. Aspartate aminotransferase or alanine aminotransferase >1.5 × upper limit of normal 
defined by the laboratory 
b. Total bilirubin >1.25 × ULN at Screening. Subjects with known Gilbert’s syndrome 
may be included with total bilirubin >1.25 × ULN 
c. Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women 
d. Platelets <150 × 109/L or >400 × 109/L. 
11. Subject has any clinically other significant abnormal laboratory value (hematology, chemistry, 
or urinalysis) at Screening that, in the investigator’s opinion, may put the subject at risk if he 
or she takes part in the study, and/or that may interfere with the study assessments. 
12. Subject has had recent systemic malignancy (e.g., within 5 years) with exception of 
nonmelanoma skin cancer or cervical intraepithelial neoplasia of Grade 1 who are >6 months 
post-treatment. 
13. Subject has a history of long QT syndrome or has clinically significant electrocardiogram 
(ECG) abnormalities, including clinically significant conduction disorders or significant 
arrhythmias, or QTcF interval >450 ms. 
14. Subject has a known allergy or sensitivity to any of the components of the investigational 
products. 
15. Subject has been exposed to excessive UV radiations on the treated zones within 1 month 
before Baseline visit or is planning intensive UV exposure during the study (e.g., occupational 
exposure to the sun, sunbathing, phototherapy, etc.). 
16. Subject is inherently sensitive to sunlight. 
17. Subject is unable or unwilling to stop use of topical or systemic retinoids. 
18. Subject is presumed to be abusing drug or alcohol at Screening or Baseline Visits based on 
medical history or current clinical symptoms. 
19. Subject is participating in another interventional clinical trial. 
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20. Subject is institutionalized. 
21. Subject is in any way related to the sponsor, investigator, or site personnel. 
8.3. Premature Subject Withdrawal 
All subjects will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. The investigator should make every reasonable 
attempt to keep subjects in the study; however, subjects must be withdrawn from the study if they 
withdraw consent to participate. Investigators must attempt to contact subjects who fail to attend 
scheduled visits by telephone or other means to exclude the possibility of an AE being the cause 
of withdrawal. Should this be the cause, the AE must be documented, reported, and followed as 
described in Section 11.2. 
The sponsor reserves the right to request the withdrawal of a subject due to protocol deviations or 
other reasons. 
The investigator also has the right to withdraw subjects from the study at any time for lack of 
therapeutic effect that is intolerable or otherwise unacceptable to the subject, for intolerable or 
unacceptable AEs, intercurrent illness, noncompliance with study procedures, administrative 
reasons, or in the investigator’s opinion, to protect the subject’s best interest. 
If a subject is withdrawn before completing the study, the reason for withdrawal and the date of 
discontinuation will be recorded on the appropriate page of the electronic case report form (eCRF). 
Whenever possible and reasonable, the evaluations that were to be conducted at the completion of 
the study should be performed at the time of premature discontinuation. 
8.4. Subject Discontinuation of Study Intervention and Stopping Rules 
Subjects who discontinue the study treatment will be asked to return to the site to undergo ET 
procedures (see Section 10.2.4.6). If a clinically significant finding is identified (including, but not 
limited to changes from Baseline) after enrollment, the investigator or qualified designee will 
determine if any change in participant management is needed. Any new clinically relevant finding 
will be reported as an AE. 
An investigator must discontinue a participant’s study treatment for any of the following reasons: 
• Pregnancy 
• Significant study intervention noncompliance 
• If any clinical AE, laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would result in a significant burden to the 
participant 
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for discontinuation of study treatment will be recorded on the eCRF. Subjects who sign 
the informed consent form and are randomized but do not receive the study intervention may be 
replaced. Subjects who sign the informed consent form, are randomized, and receive the study 
intervention, and subsequently discontinue study treatment, or are withdrawn from the study will 
not be replaced. 
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A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site will attempt to contact the participant and reschedule the missed visit and counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file. 
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
8.5. Subject Replacement Criteria 
Withdrawn subjects will not be replaced. If a substantial number of subjects are withdrawn from 
the study, the sponsor will evaluate the need for developing replacement criteria. 
Randomized subjects withdrawn from the study may not reenter. The subject number for a 
withdrawn subject will not be reassigned to another subject. 
9. TREATMENTS 
9.1. Identification of Investigational Product 
Trifarotene cream HE1 is a cream containing 100 or 200 μg/g (0.01% [w/w] or 0.02% [w/w], 
respectively) of CD5789 and the following excipients: purified water, propylene glycol, allantoin, 
glycerin, medium-chain triglycerides, polypropylene glycol 15 stearyl ether, cyclomethicone, 
phenoxyethanol, copolymer of acrylamide and sodium acryloyldimethyltaurate, dispersion 40% in 
isohexadecane (simulgel 600 PHA), sodium benzoate, butylated hydroxytoluene, and 
gluconolactone. It is a potent RARγ agonist characterized by its high specificity to this receptor. 
Sodium benzoate, butylhydroxytoluene, and propylene glycol are excipients known to have a 
recognized action or effect to be declared on the labeling, according to the CHMP Annex to the 
excipients in labeling and package leaflet of medicinal products for human use 
(EMA/CHMP/302620/2017). These 3 excipients are being used in the trifarotene formulation at 
standard concentrations and are all necessary to ensure adequate protection of the formulation 
along and the shelf life. 
Vehicle contains the same ingredients, without the CD5789. 
Trifarotene cream HE1 and vehicle will be provided in cream form for topical application and will 
be supplied in 50-g tubes from which a maximum of 36 g of IP may be extracted, 
Trifarotene cream HE1 and vehicle will be supplied by G. Production, Inc. (Galderma) in 
Baie-D'Urfé, QC, Canada. 
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9.2. Treatments Administered 
For the Double-blind Treatment Period, trifarotene cream HE1 100 µg/g or 200 µg/g or vehicle 
cream will be applied topically twice weekly on up to 90% BSA of each subject. The IP should be 
applied thinly and gently rubbed in. 
Study staff will apply the first administration of IP in the clinic on Day 1 after Baseline 
measurements, and the amount of IP used will be measured (i.e., 50-g tube will be measured before 
and after application to determine amount used). If the product will be applied at home by someone 
other than the study subject, it is recommended that person assist with application at the first visit 
to learn how the IP is applied. 
The maximum dose per application is 36 g (i.e., 1 tube). Subjects will receive an adequate number 
of tubes to use 1 tube per application and will use a new tube for each treatment day. Subjects may 
use less than full amount of product in a tube. Subjects will apply treatment for 90 days. 
After the Day 1 visit, subjects will apply up to 36 g of study drug as for the first dose on up to 90% 
of BSA twice weekly, sparing the scalp, inguinal, and axillary areas. Subjects with heavy facial 
hair should not apply IP to hair-bearing areas. Persons other than the study subject applying the 
study drug must wash their hands after application or use disposable vinyl gloves. In addition, a 
long-handled applicator will be provided for application on the back. The applicator must be 
washed with warm water and soap after every application. 
Trifarotene cream should not come into contact with the eyes, mouth, angles of the nose, or mucous 
membranes. For the ectropion treatment, Q-tips are recommended for precise application on 
eyelids, without contact to the eye or conjunctiva. If the IP gets into the eye, it must be flushed 
immediately with warm water. In case of eye irritation, the subject must be seen by an 
ophthalmologist. 
For the OLE, all subjects will receive open-label trifarotene cream HE1 200 µg/g and apply it in 
the same manner as in the Double-blind Period for an additional 90 days. 
Visits for PK must occur at least 24 hours after the last application of the IP to avoid contamination 
of the blood samples with any IP that may have remained in the skin after the last application. 
Subjects should not apply IP on visit days until after the visit, unless they are participating in the 
PK substudy, in which case the IP will be applied in the clinic on Day 1 and Day 30 after the blood 
draw. Among subjects participating in the PK substudy, ensure the PK line is inserted before study 
drug application to prevent contamination with the IP and to protect the skin around the needle 
insertion point from study drug application. 
9.3. Selection of Timing of Dose for Each Subject 
Subjects will be randomized in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g or 200 µg/g or 
vehicle cream. After Day 1, on which the study staff will apply the first administration of IP in the 
clinic, each subject will apply IP on up to 90% of their BSA twice weekly. It is suggested that each 
subject choose 2 specific days per week, 3 to 4 days apart on which to apply their IP and maintain 
that regimen each week throughout the study (Table 9-1). Visits for PK must occur at least 24 
hours after the last application of the IP to avoid contamination of the blood samples with any IP 
that may have remained on the skin after the last application. Subjects whose treatment day falls 
on a scheduled study visit day should not apply the IP until after the visit. 
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Subjects who participate in the PK substudy should have their Day 30 Visit scheduled on a 
treatment day, in which case the IP will be applied in the clinic on Day 30 after the predose PK 
blood draw. If the Day 30 Visit cannot be scheduled on a treatment day, the investigator should 
contact the medical monitor. 
All subjects will be provided with diaries in which to record study drug application (days/times) 
and any areas of skin not treated (e.g., due to local reactions). 
If a subject misses an IP application, they should apply the IP as soon as they remember and record 
the date/time in the subject diary. The next application should be 3 to 4 days apart, and subjects 
should continue according to their new regimen. 
Subjects should not shower, bathe, or swim for at least 4 hours after IP application. No occlusive 
dressings should be used on areas to which IP is applied. 
Subjects who continue into the OLE will receive trifarotene cream HE1 200 µg/g and apply it in 
the same manner as in the Double-blind Period for 90 days.
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Table 9-1: 
Sample Twice-weekly Dosing Schedule 
 
Week 1 
Subsequent Weeks 
 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
Option 1 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
Option 2 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Option 3 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
Option 4 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Option 5 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Option 6 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
Option 7 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
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9.4. Dose Adjustment Criteria 
Local tolerance will be followed very carefully during the study. Subjects will receive information 
on study drug use and stopping rules and will be instructed to contact the site with any 
safety/tolerability issues. Study personnel will telephone subjects in between scheduled visits (i.e., 
at Day 7 and Day 45) to assess safety; an unscheduled clinic visit may be performed, if necessary. 
During all clinic visits, the investigator will assess local tolerability (stinging/burning, pruritus, or 
erythema on 0-3 scales [none, mild, moderate, severe]) for each treated body area (chest/abdomen, 
back, arms, legs, and face/neck), and the following procedures will be followed: 
− If a score of 2 (moderate) is recorded for any of the local tolerability assessment scales 
(stinging/burning, pruritus or erythema) on any treated area (e.g., the face), the study drug 
will be applied on this area only once weekly, until the score returns to <2. Continue to 
treat all other areas twice weekly provided the score is <2 on those areas. 
− If a score of 3 (severe) is recorded any of the local tolerability assessment scales 
(stinging/burning, pruritus or erythema) on any treated area, the study drug will not be 
applied on that area until the score is back to <3 (i.e., “drug holiday”). Continue to treat all 
other areas twice weekly provided the score is <2 on those areas. 
Any changes in dosing must be documented in the subject diary and the eCRF. 
9.5. Treatment Compliance 
Subjects will be asked to record their twice-weekly applications of IP in the diary during both the 
Double-blind Period and the OLE. Deviations from the planned doses (missed dose or timing) will 
be recorded on the subject’s eCRF. Study personnel will review diaries at each visit and diaries 
will be collected as source documents. Information from subject diaries will be transcribed on the 
appropriate eCRF pages for documentation of subject compliance with the IP. 
Study personnel will assess treatment compliance with IP regimens by weighing kits (tubes and 
boxes, but not leaflets) before dispensing and upon return and by questioning the subject, at every 
postrandomization visit. At baseline, the kit should be weighed before choosing the first tube for 
application by the study staff. A participant is compliant with study product if he or she takes at 
least 80% of the scheduled doses as assessed by diary entries, supplemented by amount of cream 
used derived from weighing the IP kits. A subject who is not compliant (for example, used 80–
120% of IP tubes [which is more than what can be dispensed per tube at each application]) will be 
counseled at each visit on the importance of using the IP as instructed. 
Subjects who taper to once-weekly application or who take a “drug holiday” for tolerability will 
not be reported as having deviated from the protocol (see Section 9.4 for dose adjustment and 
stopping rules); any changes in dosing must be documented in the subject diary and the eCRF. 
9.6. Method of Assigning Subjects to Treatment Groups 
In the double-blind, parallel-group, randomized period of the study, subjects who meet study entry 
criteria will be randomly assigned in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g or 200 µg/g 
or vehicle cream. The randomization schedule will be computer generated using a permuted block 
algorithm and will randomly allocate IP to randomization numbers. The randomization numbers 
will be assigned sequentially through a central interactive web response system (IWRS) as subjects 
are entered into the study. Study center will not be a blocking factor in the randomization schedule. 
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Premier Research will prepare the randomization schedule before the start of the study. No one 
involved in the study performance will have access to the randomization schedule before the 
official unblinding of treatment assignments. No subject will be randomized into this study more 
than once. 
In the OLE, all subjects will receive trifarotene cream HE1 200 µg/g. 
9.7. Blinding and Unblinding Treatment Assignment 
All subjects, investigators, and study personnel involved in the conduct of the Double-blind Period 
of the study, including data management, will be blinded to treatment assignment with the 
exception of a specified unblinded statistician and programmer from Premier Research who will 
have access to the randomization code. The statistician will have access to unblinded data if there 
is an unblinded DSMB review. 
Study personnel will make every effort to safeguard the integrity of the study blind to minimize 
bias in the conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
subject’s treatment assignment. 
The investigator may discuss with the medical monitor in advance of unblinding a subject, if 
possible, if it is not deemed an emergency. However, the investigator has the ultimate decision for 
unblinding a subject for medical treatment and no procedures will prevent or delay necessary 
unblinding in an emergency for the subject’s safety. For emergency unblinding, study personnel 
will use the IWRS code. If the investigator is not able to discuss treatment unblinding in advance, 
then he/she must notify the medical monitor as soon as possible about the unblinding incident 
without revealing the subject’s treatment assignment. 
The investigator or designee must record the date and reason for treatment unblinding on the 
appropriate eCRF for that subject. In all cases that are not emergencies, the investigator must 
discuss the event with the medical monitor prior to unblinding the subject’s treatment assignment. 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
that subject’s treatment assignment without unblinding the treatment assignments for the 
remaining subjects in the study. Thus, the overall study blind will not be compromised. If a 
subject’s treatment assignment is unblinded, he/she may or may not be asked to withdraw from 
the study. The investigator will make this decision after consultation with the medical monitor. 
The primary analysis period is the first 90 days of treatment (i.e., the Double-blind Period). Overall 
unblinding will take place at the end of the Double-blind Period of the study only after database 
lock has been achieved. A second analysis will take place for endpoints assessed from Day 90 
through the OLE. 
9.8. Permitted and Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate eCRF. 
Upon signing informed consent and entering the Screening Period, subjects may begin a Washout 
Period of up to 90 days. Participants will stop using physical and medical treatments for LI, 
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including balneotherapy, as well as the following prohibited medications, as applicable 
(Table 9-2). 
Table 9-2: 
Washout Periods for Prohibited Medicationsa 
Medication 
Washout Period 
Topical Treatments 
Corticosteroids (except inhaled and ophthalmic corticoids) 
2 weeks 
Retinoids (e.g., tretinoin, tazarotene) 
4 weeks 
Vitamin D analogs 
2 weeks 
Immunosuppressants (e.g., tacrolimus) 
2 weeks 
Antracen derivatives, tar and salicylic preparations 
2 weeks 
Keratolytics (such as urea, lactic acid, propylene glycol, salicylic acid) except keratolytic 
shampoo 
2 weeks 
Systemic treatments 
Retinoids 
8 weeks 
Oral Vitamin A supplementation more than 3500 IU per day 
2 weeks 
Medication interfering with bone activity, e.g., corticosteroids, thyroid hormones unless the 
dose is stable and TSH is normal, cytotoxics, bisphosphonates, selective estrogen receptor 
modulators (SERM), teriparatide, calcitonins, tetracyclines, quinolones, thiazides, long-term 
use of salicylates, heparin, theophylline, barbiturates, colchicines. Vitamin D analogs taken at 
stable dose for at least 1 month are allowed 
8 weeks 
QT-prolonging drugs 
5 half lives 
CYP Enzyme inducers (such as rifampicine, phenytoin, carbamazepine, phenobarbital, 
St. John’s Wort) 
3 months 
CYP2C9 and 2C8 inhibitors (including, but not limited to the following: gemfibrozil, 
fluconazole, fluvoxamine, sulfaphenazole, miconazole, amiodarone, sertraline, 
sulfamethoxazole, valproic acid, voriconazole, trimethoprim, rosiglitazone, pioglitazone) 
5 half lives 
Monoclonal antibodies  
5 half lives 
a 
Note: This list applies to both prescription and over-the-counter (OTC) medications 
 
During washout, subjects may continue their standard of care of visible skin (face and scalp) for 
cosmetic reasons and of extremities (palms/soles) to avoid functional consequences on walking or 
moving their fingers. In the US/EU, this may include compounded emollients with keratolytics 
(alpha or beta hydroxyl acids) and/or urea. The investigator should approve and document these 
standard-of-care treatments in the eCRF. If the standard of care treatments of the face and/or 
palms/soles contain prohibited medications, they must be stopped at the Baseline Visit. Subjects 
may shower, but not bathe or swim. The IGA will be evaluated on the rest of the body at Baseline. 
After completing any necessary washout of prohibited medications, subjects will return to the site 
to complete the study eligibility requirements. 
9.8.1 Permitted Therapies 
Subjects will be advised on permitted emollient(s) for use as often as needed on nontreatment days 
during the study; on treatment days, the use of emollient(s) is permitted except within 4 hours 
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before or after study drug application. Similarly, protective sunscreen should be applied as often 
as needed, except within 4 hours before or after study drug application. Subjects may use their 
standard of care treatment on their faces and/or palms/soles after the Day 30 assessment if they 
experience a worsening of IGA in those areas. In the US/EU, this may include compounded 
emollients with keratolytics (alpha or beta hydroxyl acids) and/or urea. These standard of care 
treatments should be approved by the investigator and documented in the eCRF. 
Subjects who enter the OLE must stop standard of care treatment. If they experience a worsening 
of IGA they may use standard of care treatment on their faces and/or palms/soles after the Day 120 
Visit if the standard of care does not contain prohibited medications. If those standard of care 
treatments include prohibited medications, the subject should be discontinued from the study. 
Other concomitant medications are allowed (e.g., analgesics, antihistamines), but should be limited 
to those medications considered necessary. All concomitant medications, both prescribed and 
over-the-counter, should be recorded in the eCRF. 
9.8.2 Prohibited Therapies 
The medications listed in Table 9-2 are prohibited during the study. Balneotherapy is also 
prohibited during the Screening Period and during the study. 
Subjects may not use concomitant keratolytics such as urea, salicylic acid, alpha, or beta 
hydroxyacids. Subjects may not use topical or systemic retinoids. Subjects may not take more than 
3500 IU/day Vitamin A (e.g., as in a multivitamin). Use of benzoyl peroxide is permitted on 
nontreatment days for subjects with concomitant acne only); it must not be applied on treatment 
days due to risk of inactivation of trifarotene by benzoyl peroxide. 
Subjects receiving excluded therapies will be ineligible for study enrollment or for continued 
treatment in the study, at the investigator’s discretion with consultation with Mayne Pharma LLC 
and the medical monitor. For enrolled subjects who require prescription of a systemic azole, the 
principal investigator should discuss with the medical monitor whether the subject may continue 
in the study. 
9.8.3 Restrictions 
Subjects should not shower, bathe, or swim for at least 4 hours after study drug application. No 
occlusive dressings should be applied to areas where study drug was applied. 
Subjects should only use investigator-approved emollients, and should not use them on treatment 
days within at least 4 hours before and after study drug application. 
In addition, subjects should take protective measures to avoid exposure of treated areas to sunlight, 
such as applying sunscreen (except within 4 hours before and/or 4 hours after study drug 
application), and/or wearing protective clothing (e.g., long sleeves, hats, and covering legs and 
feet), and/or seeking shade or shelter from the sun. 
9.9. Treatment after End of Study 
After the end of the study, each subject will be treated according to standard clinical practice. 
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9.10. Dispensing and Storage 
The test product supplied by Mayne Pharma LLC is to be used exclusively in the clinical study 
according to the instructions of this protocol. The investigator is responsible for dispensing the IP 
according to the dosage scheme and for ensuring proper storage of the IP. 
The investigator must confirm the receipt of the IP with his or her signature. A copy of this receipt 
must be kept by the investigator and another copy will be stored at Premier Research. Until the IP 
is dispensed to the subjects, it must be stored at 20–25°C (68–77°F), with excursions permitted to 
15–30°C (59–86°F); do not freeze and with the tube kept tightly closed in a securely locked area 
that is not generally accessible. 
The key to the storage area is to be kept by the investigator or designee responsible for the IP. The 
store will be accessible only to those persons authorized by the investigator to dispense the IP. 
9.11. Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the IPs, including the date, quantity, batch or code number, and identification of 
subjects (subject number) who received the IP. The investigator will not supply the IP to any 
person except those named as subinvestigators on the Form Food and Drug Administration 
(FDA) 1572, designated study personnel, and subjects in this study. The investigator will not 
dispense the IP from any study sites other than those listed on the Form FDA 1572. Investigational 
product(s) may not be relabeled or reassigned for use by other subjects. If any of the IP is not 
dispensed, is lost, stolen, spilled, unusable, or is received in a damaged container, this information 
must be documented and reported to the sponsor and appropriate regulatory agencies, as required. 
Each subject will be given enough tubes of study drug to apply up to 1 tube-full (approximately 
36 g of clinical trial material) per treatment day until the next study visit. Tubes will be packed 
2 to a carton, and each subject will receive enough cartons to have the maximum number of tubes 
needed until the next study visit. The number of study drug tubes the subject needs to provide 
enough IP until the next visit is shown in Table 9-3. 
Table 9-3: 
Amount of Study Drug Needed Per Visit 
Treatment Period 
Number of Cartons 
Number of Tubes 
Double-blind Treatment Period 
Baseline 
3 
6 
Day 14 
4 
8 
Day 30 
6 
12 
Day 60 
6 
12 
OLE  
Day 90 
3 
6 
Day 104 
4 
8 
Day 120 
6 
12 
Day 150 
6 
12 
 
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Each carton will be weighed before dispensing (tubes and boxes, but not leaflets) and subjects are 
to bring all cartons and tubes back at each study visit, whereupon study staff will weigh them again 
to estimate study drug use and compliance. 
Upon completion of the study, the IP (partly used, unused, and empty tubes) must be left in the 
original packaging and returned to the sponsor or designee for destruction. 
9.12. Labeling and Packaging 
Labeling and packaging of IP will be performed by Catalent Pharma Solutions. 
Tubes will be packaged in cartons comprising 2 tubes each. Tubes will be labeled with inner and 
outer booklet labels, and carton number. Each carton will also be labeled with inner and outer 
booklet labels and numbered. 
9.12.1 Labeling 
The tubes will have a label affixed that meets the applicable regulatory requirements and may 
include, but is not limited to, the following: subject identifier, IP name, lot number, protocol 
number, carton number, caution statement, storage, and sponsor identification. 
All empty packaging or packaging containing unused tubes should be saved for final disposition 
by the sponsor or contract pharmacy. 
Final labeling will comply with the regulatory requirements of each country where the study will 
be conducted. 
9.12.2 Packaging 
Investigational products will be packaged in high-density polyethylene, 35×100 mm tubes 
weighing 50 g from which a maximum of 36 g of IP can be extracted. Trifarotene cream HE1 and 
vehicle will be packaged so as to be blinded to the investigator, the study clinic personnel, and the 
subjects. 
10. STUDY PROCEDURES 
Subjects must provide written informed consent and/or assent before any study-related procedures 
are initiated, including the cessation of prohibited concomitant therapy. Written informed consent 
will be obtained from a parent/legal guardian for any minor and minors will provide assent before 
any study-related procedures are performed. 
Subjects who agree to participate in the photography and/or PK substudy must provide written 
informed consent before photographs or serial blood samples are collected. 
For the timing of assessments and procedures throughout the study, refer to the Schedule of Events 
(Section 2.2). Throughout the study, every reasonable effort should be made by study personnel to 
follow the timing of assessments and procedures in the Schedule of Events for each subject. If a 
subject misses a study visit for any reason, the visit should be rescheduled as soon as possible. 
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10.1. Study Duration 
10.1.1 Overall Study Schedule 
The planned sequence and maximum duration of the study periods for each subject will be as 
follows: 
1. Screening: up to 97 days. Before asking a subject to enter washout, investigators should 
confirm the subject meets study eligibility criteria, except for LI severity (inclusion 
criterion #3). Washout may be up to 90 days. After completing any necessary Washout 
Period, subjects must return to the site within 35 days before the Baseline Visit within the 
97-day Screening Period to have their LI severity assessed and study eligibility 
requirements determined. 
2. Double-blind treatment: Twice weekly for 90 days. 
3. Optional Open-label Extension treatment: Twice weekly for 90 days. 
4. Follow-up: 14 days after last study drug application. 
The maximum treatment duration for each subject is approximately 90 days for subjects who 
choose not to continue into the OLE, and 180 days for those who choose to continue. 
The maximum study duration for each subject is approximately 291 days. 
10.2. Study Periods and Visits 
It is suggested that quality of life assessments be conducted first to avoid any bias, and that the 
IGA be recorded as the first LI assessment at every visit. 
10.2.1 Screening and Washout 
10.2.1.1 Screening Visit (Visit 1) 
Written informed consent must be obtained before any study-related procedures are performed. 
Before asking a subject to enter Washout (Section 10.2.1.1.1), investigators should confirm the 
subject meets study eligibility criteria, except for LI severity (Inclusion Criterion #3). Washout 
may be up to 90 days. After completing any necessary Washout Period, subjects must return to the 
site within 35 days before the Baseline Visit within the 97-day Screening Period to have their LI 
severity assessed and study eligibility requirements determined. 
The following procedures will be performed during Screening: 
1. Obtain written informed consent and/or assent. 
2. Assign a screening number when a subject begins screening. 
3. Assess inclusion/exclusion criteria. 
4. Collect demographic information. 
5. Record medical history, including current therapies (e.g., prescription and nonprescription 
medications). 
6. Perform a physical examination. 
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7. Measure vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and 
pulse). 
8. Measure height, weight, and calculate body mass index (BMI). 
9. Record IGA. 
10. Record VIIS. 
11. Record roughness assessment. 
12. Record palm/sole assessment. 
13. Record palm/sole assessment of fissuring. 
14. Record ectropion score. 
15. Perform a 12-lead ECG 
16. Collect blood and urine for laboratory tests, coagulation panel, and serology. 
17. Perform serum pregnancy test for WOCBP. 
18. Record concomitant medications. 
Procedures for rescreening subjects who initially fail to meet study entry criteria are described in 
Section 14.3. 
10.2.1.1.1 Washout 
Upon signing informed consent and entering the Screening Period, subjects will stop using 
physical and medical treatments for LI, including balneotherapy, and begin to washout the 
prohibited topical and systemic treatments with designated washout periods, as applicable 
(Table 9-2). Washout may be up to 90 days, as necessary. 
After completing any necessary Washout Period, subjects must return to the site within 35 days 
before the Baseline Visit within the 97-day Screening Period to have their LI severity assessed and 
to complete any eligibility requirements. During washout, subjects may continue their standard of 
care of visible skin (face and scalp) for cosmetic reasons and of extremities (palms/soles) to avoid 
functional consequences on walking or moving their fingers. In the US/EU, this may include 
compounded emollients with keratolytics (alpha or beta hydroxyl acids) and/or urea. The 
investigator should approve and document these standard-of-care treatments in the eCRF. If the 
standard of care treatments of the face and/or palms/soles contain prohibited medications, they 
must be stopped at the Baseline Visit. Subjects may shower but not bathe or swim. The IGA will 
be evaluated on the rest of the body at Baseline. 
10.2.2 Double-blind Treatment Period 
Eligible subjects who have washed out prohibited medications will be randomized to double-blind 
study drug. 
10.2.2.1 Baseline Visit (Visit 2, Day 1) 
The following procedures will be performed on Day 1 in the study clinic: 
1. Review inclusion/exclusion criteria. 
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2. Record responses to DLQI and EQ-5D Quality of Life Questionnaires (see Sections 
10.3.1.5 and 10.3.1.6 for which version of questionnaire to use). 
3. Perform a limited physical examination. 
4. Record vital signs (blood pressure and pulse). 
5. Record concomitant medications and concomitant therapies. 
6. Record IGA. 
7. Record VIIS. 
8. Record roughness assessment. 
9. Record palm/sole assessment. 
10. Record palm/sole assessment of fissuring. 
11. Record ectropion score. 
12. At sites where the photographic substudy is conducted, take photographs of subjects who 
have provided informed consent for the photography. 
13. Perform a 12-lead ECG. 
14. Perform urine pregnancy test for WOCBP. 
15. Collect blood and urine for routine laboratory tests (subject must be fasting; i.e., at least 
8 hours) and coagulation panel. 
16. Randomize via IWRS. 
17. Collect a predose PK blood sample (all subjects). 
18. Among subjects who consent to participate in the PK substudy, ensure that PK lines are 
placed before IP application. The IP will be applied in the clinic at this visit, and samples 
for PK will be taken at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1. 
19. Among subjects in the PK substudy, perform additional ECGs at times of serial sampling. 
20. Clinic staff instructs subject on study drug application, applies initial study drug dose and 
measures amount used (i.e., study staff will weigh the kits (tubes and boxes, but not 
leaflets)before and after the first application. If the product will be applied at home by 
someone other than the study subject, it is recommended that person assists with 
application at this visit to learn how the IP is applied. 
21. Assess and record local tolerance/AEs. 
22. Dispense study drug and diaries. 
23. Advise subjects regarding permitted emollient(s) for use on nontreatment days; use of 
emollient(s) and/or sunscreen on study drug treatment days within 4 hours before or after 
study drug application is prohibited. Remind subjects that at least 24 hours must have 
elapsed since IP application before their next visit. Subjects should not to apply IP on visit 
days until after the visit. 
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10.2.2.2 Telephone Visit (Day 7) 
Clinic staff will telephone subject to assess safety and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient(s) and/or 
sunscreen on study drug treatment days within 4 hours before or after study drug application is 
prohibited), and remind subjects that at least 24 hours must have elapsed since IP application 
before their next visit. Subjects should not apply IP on visit days until after the visit. An 
unscheduled clinic visit may be performed, if necessary. 
10.2.2.3 Visit 3 (Day 14 ±5 days) 
The following procedures will be performed on Day 14 in the study clinic: 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires (see 
Sections 10.3.1.6 and 10.3.1.7 for which version of questionnaire to use). 
2. Record concomitant medications and concomitant therapies. 
3. Record vital signs (blood pressure and pulse). 
4. Record IGA. 
5. Record VIIS. 
6. Record roughness assessment. 
7. Record palm/sole assessment. 
8. Record palm/sole assessment of fissuring 
9. Record ectropion score. 
10. Assess local tolerance. 
11. Record AEs and review diary. 
12. Collect a PK blood sample (all subjects). 
13. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries. 
14. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
Remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit. Subjects should not apply IP on visit days until after the visit. 
15. Weigh new study drug kits (tubes and boxes, but not leaflets) and dispense enough 
additional study drug until next visit, and new diary. 
10.2.2.4 Visit 4 (Day 30 ±7 days) 
The following procedures will be performed on Day 30 in the study clinic: 
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1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires (see 
Sections 10.3.1.6 and 10.3.1.7 for which version of questionnaire to use). 
2. Record concomitant medications and concomitant therapies. 
3. Record vital signs (blood pressure and pulse). 
4. Record IGA. 
5. Record VIIS. 
6. Record roughness assessment. 
7. Record palm/sole assessment. 
8. Record palm/sole assessment of fissuring 
9. Record ectropion score. 
10. At sites where the optional photographic substudy is conducted, take photographs of 
subjects who have provided informed consent for the substudy. 
11. Assess local tolerance. 
12. Record AEs and review diary. 
16. Perform a 12-lead ECG 
17. Perform a urine pregnancy test for WOCBP. 
18. Collect blood and urine for routine laboratory tests (subject must be fasting at least 8 hours) 
and coagulation panel. 
19. Collect a PK blood sample (all subjects). 
20. Among subjects who consent to participate in the PK substudy, ensure that PK lines are 
placed before IP application. The IP will be applied in the clinic at this visit, and samples 
will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose. 
21. Among subjects in the PK substudy, perform an additional ECGs at times of serial 
sampling. 
22. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries. 
23. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) on study 
drug treatment days within 4 hours before and after study drug application is prohibited. 
Remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit. Subjects should not apply IP on visit days until after the visit. 
24. Weigh new study drug kits (tubes and boxes, but not leaflets) and dispense enough 
additional study drug until next visit, and new diary. 
25. Provide information about OLE option to study subject. 
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10.2.2.5 Telephone Visit (Day 45) 
Clinic staff will telephone subject to assess safety and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) and/or sunscreen for use on nontreatment days (use of 
emollient(s) on study drug treatment days within 4 hours before or after study drug application is 
prohibited), and remind subjects that 24 hours must have elapsed since IP application before the 
subject’s next visit. Subjects should not to apply IP on visit days until after the visit. An 
unscheduled clinic visit may be performed, if necessary. Staff will remind subject about OLE 
option. 
10.2.2.6 Visit 5 (Day 60 ±7 days) 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires (see 
Sections 10.3.1.6 and 10.3.1.7 for which version of questionnaire to use). 
2. Record concomitant medications and concomitant therapies. 
3. Record vital signs (blood pressure and pulse). 
4. Perform a urine pregnancy test for WOCBP. 
5. Record IGA. 
6. Record VIIS. 
7. Record roughness assessment. 
8. Record palm/sole assessment. 
9. Record palm/sole assessment of fissuring 
10. Record ectropion score. 
11. Assess local tolerance. 
12. Record AEs and review diary. 
13. Collect a PK blood sample (all subjects). 
14. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries. 
15. Weigh new study drug kits (tubes and boxes, but not leaflets) and dispense enough 
additional study drug until next visit, and new diary. 
16. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) and/or 
sunscreen on study drug treatment days within 4 hours before and after study drug 
application is prohibited. Remind subjects that Added reminder that 24 hours must have 
elapsed since IP application before the subject’s next visit. Subjects should not apply IP on 
visit days until after the visit. 
17. Provide information about OLE option. 
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10.2.2.7 Visit 6 (Day 90 ±7 days) or Early Termination 
The following procedures will be performed on Day 90 in the study clinic: 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires (see 
Sections 10.3.1.6 and 10.3.1.7 for which version of questionnaire to use). 
2. Perform a limited physical examination. 
3. Record vital signs (blood pressure and pulse). 
4. Record concomitant medications and concomitant therapies. 
5. Record IGA. 
6. Record VIIS. 
7. Record roughness assessment. 
8. Record palm/sole assessment. 
9. Record palm/sole assessment of fissuring. 
10. Record ectropion score. 
11. At sites where the optional photographic substudy is conducted, take photographs of 
subjects who have provided informed consent for the substudy. 
12. Assess local tolerance. 
13. Record AEs and review diary. 
14. Perform a 12-lead ECG. 
15.  Perform a urine pregnancy test for WOCBP. 
16. Collect blood and urine for routine laboratory tests (subject must be fasting at least 8 hours) 
and coagulation panel. 
17. Collect a PK blood sample (all subjects). 
18. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries. 
For subjects who successfully complete (i.e., have reliable visit attendance and compliance with 
IP application, in the investigator’s opinion) the initial 90 days of double-blind treatment and 
choose to continue into the OLE, this visit will be the first visit of that portion of the study. All 
efficacy assessments, safety/tolerability assessments, including clinical laboratory testing, PK 
from Day 90 will be carried over to the OLE and will not be repeated. If the subject chooses to 
continue into OLE, the following additional procedures will be done: 
1. Have the subject sign OLE-specific informed consent. 
2. Measure subject’s weight. 
3. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
Remind subjects that at least 24 hours must have elapsed since IP application before the 
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PK draws at the Day 120 and Day 180 Visits, and not to apply IP on visit days until after 
the visits. 
4. Weigh new study drug kits (tubes and boxes, but not leaflets) and dispense enough 
additional study drug until next visit (only for subjects who choose to continue into the 
OLE). 
5. Dispense study diary. 
10.2.3 Follow-up Telephone Call (±14 days after Day 90) – Only Subjects Who Do Not 
Continue into Open-label Extension 
Clinic staff will telephone subjects who choose not to continue into the Open-label Extension 
within 14 days after Day 90 to assess any ongoing AEs. 
10.2.4 Open-label Extension 
Subjects who successfully complete (i.e., have reliable visit attendance and compliance with IP 
application, in the investigator’s opinion) the initial 90 days of double-blind treatment may choose 
to continue into an optional 90-day OLE with trifarotene cream HE1 200 µg/g. During the OLE, 
subjects will return to the site at Days 104, 120, 150, 180, and 194. Additional PK samples will be 
drawn at Days 120 and 180 from all subjects who continue into the OLE. 
10.2.4.1 Telephone Visit (Day 97) 
Clinic staff will telephone subject to assess safety (AEs) and to record concomitant 
medications/therapies. Staff will to instruct subject on study drug application, to advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient(s) on study drug 
treatment days within 4 hours of study drug application is prohibited), and to remind subjects not 
to apply IP on visit days until after the visit. An unscheduled clinic visit may be performed, if 
necessary. 
10.2.4.2 Visit 7 (Day 104 ±5 days) 
The following procedures will be performed at this study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Record IGA. 
4. Record VIIS. 
5. Record assessment of roughness. 
6. Record palm/sole assessment. 
7.  Record palm/sole assessment of fissuring. 
8. Record ectropion score. 
9. Assess and record local tolerance/AEs and review diary. 
10. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries. 
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11. Weigh new study drug kits (tubes and boxes, but not leaflets) and dispense enough 
additional study drug until next visit, and new diary. 
12. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) and/or sunscreen on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
Remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit (Day 120), and if the Day 120 visit coincides with a treatment day, wait until 
after the visit is complete to apply IP. 
10.2.4.3 Visit 8 (Day 120 ±7 days) 
The following procedures will be performed at this study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Record IGA. 
4. Record VIIS. 
5. Record assessment of roughness. 
6. Record palm/sole assessment. 
7. Record palm/sole assessment of fissuring. 
8. Record ectropion score. 
9. Assess and record local tolerance/AEs and review diary. 
10. Perform a 12-lead ECG. 
11. Perform a urine pregnancy test for WOCBP. 
12. Collect blood and urine for routine laboratory tests (subject must be fasting at least 8 hours) 
and coagulation panel. 
13. Collect a PK blood sample (all subjects) 
14. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries. 
15. Weigh new study drug kits (tubes and boxes, but not leaflets) and dispense enough 
additional study drug until next visit, and new diary. 
16. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) and/or sunscreen on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
10.2.4.4 Telephone Visit (Day 134) 
Clinic staff will telephone subject to assess safety (AEs) and to record concomitant 
medications/therapies. Staff will to instruct subject on study drug application, to advise subjects 
regarding permitted emollient(s) and/or sunscreen for use on nontreatment days (use of 
emollient(s) on study drug treatment days within 4 hours of study drug application is prohibited), 
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and to remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit. An unscheduled clinic visit may be performed, if necessary. 
10.2.4.5 Visit 9 (Day 150 ±7 days) 
The following procedures will be performed at this study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Record IGA. 
4. Record VIIS. 
5. Record assessment of roughness. 
6. Record palm/sole assessment. 
7. Record palm/sole assessment of fissuring. 
8. Record ectropion score. 
9. Assess and record local tolerance/AEs and review diary. 
10. Perform a urine pregnancy test for WOCBP. 
11. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries. 
12. Weigh new study drug kits (tubes and boxes, but not leaflets) and dispense enough 
additional study drug until next visit, and new diary. 
13. Remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit (Day 180) and if the Day 180 visit coincides with a treatment day, wait until after 
the visit is complete to apply IP. 
10.2.4.6 Visit 10 (Day 180 ±7 days) or Early Termination 
The following procedures will be performed at this study clinic visit: 
1. Perform a physical examination. 
2. Record vital signs (blood pressure and pulse). 
3. Record concomitant medications and concomitant therapies. 
4. Record IGA. 
5. Record VIIS. 
6. Assess roughness. 
7. Record palm/sole assessment. 
8. Record palm/sole assessment of fissuring. 
9. Record ectropion score. 
10. Assess local tolerance 
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11. Record AEs and review diary. 
12. Perform a 12-lead ECG. 
13. Perform a urine pregnancy test for WOCBP. 
14. Collect blood and urine for routine laboratory tests (subject must be fasting at least 8 hours) 
and coagulation panel. 
15. Collect a PK blood sample (all subjects) 
16. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
kits (tubes and boxes, but not leaflets) and reviewing diaries. 
10.2.4.7 Follow-up Evaluation – Open-Label Extension (Day 194 or 14 days after End of 
Open label Treatment /Visit 11) 
At 14 days after the last administration of the IP, the following procedures will be performed: 
1. Perform a limited physical examination. 
2. Record vital signs (blood pressure and pulse). 
3. Record any concomitant medications/therapies. 
4. Record IGA. 
5. Record VIIS. 
6. Assess roughness. 
7. Record palm/sole assessment. 
8. Record palm/sole assessment of fissuring. 
9. Record ectropion score. 
10. Assess and record AEs occurring since the last evaluation and review diary. 
11. Perform a urine pregnancy test for WOCBP. 
10.3. Assessments 
The 5-point IGA is a valid measure of disease severity and meets the need for a clinically 
meaningful measure of success for ichthyosis studies. The IGA scale was developed with the 
support of experts from academic reference centers for the treatment of ichthyosis. Each level of 
severity will consider both the severity of scaling and the severity of roughness (Section 10.3.1.2). 
While retinoid treatment is expected to reduce scale, it may increase erythema; therefore, in this 
study, erythema will be evaluated as part of local tolerability. 
10.3.1 Efficacy Variables 
All efficacy measurements will use scales previously used for dermatological studies or as defined 
in the following sections. 
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10.3.1.1 Investigator’s Global Assessment 
The primary endpoint is the number of subjects in each treatment group who experience successful 
resolution of LI where “success” is defined as clear/almost clear and at least a 2-grade change from 
Baseline at Day 90/EOT in the Double-blind Period on a 5-point IGA full body scale. 
The investigator will rate the subject’s condition using the 5-point IGA at each time point shown 
in the Schedule of Events (Section 2.2). 
The IGA will be measured on a 5-point scale, excluding the following areas: knees, elbows, neck, 
palms, soles, axillae, groin, and scalp: 
0 
Clear 
No scaling and no roughness 
1 
Almost Clear 
Occasional fine scales; hardly palpable roughness 
(mostly smooth) 
2 
Mild 
Small and fine scales predominate; no more than a few 
large scales; mild roughness on palpation 
3 
Moderate 
Some large scales that may be thick,; coarse roughness 
on palpation 
4 
Severe 
Confluent, primarily large (>1 cm), thick scales with 
plate-like hyperkeratosis  
10.3.1.2 Visual Index for Ichthyosis Severity – Scaling 
The secondary endpoint is the number of subjects in each treatment group who experience a 
severity score of 0 or 1 at Day 90/EOT on the overall 16-point VIIS for scaling. 
The investigator will rate the subject’s condition using the 5-point VIIS for each body area 
(chest/abdomen, back, legs, and arms) and an overall score at each time point shown in the 
Schedule of Events (Section 2.2): 
0 
Normal skin; no perceptible scale or smoothening 
1 
Areas of normal skin intermixed with areas showing smoothening (diminished fine skin 
markings; shininess; waxiness) or small scales (visibly separated/fractured stratum 
corneum) 
2 
Confluent smoothening (diminished fine skin markings; shininess; waxiness) or small 
scales (visibly separated/fractured stratum corneum) 
3 
Confluent scales (visibly separated/fractured stratum corneum) including some large 
(>1 cm), thick scales 
4 
Confluent, primarily large, thick scales 
 
10.3.1.3 Individual Score for Roughness 
The amount of roughness of the skin overall will be measured on a 5-point scale. 
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0 Clear 
Smooth skin 
1 Almost Clear 
Hardly palpable roughness 
2 Mild 
Mild roughness (fine sand paper-like) 
3 Moderate 
Moderate, coarse roughness (coarse sand paper-like) 
4 Severe 
Very coarse skin (broken cornflakes-like) 
10.3.1.4 Palm/Sole Assessment 
Thickening of the skin on the palms and soles will be measured on a 5-point scale. 
0 Clear 
No thickening, no roughness, no fissure 
1 Almost Clear 
Only slight thickening, minimal to no roughness, no 
fissures 
2 Mild 
Some thickening, mild roughness on palpation, few 
fissures may be present 
3 Moderate 
Substantial and diffuse thickening, coarse roughness on 
palpation may be present, fissures may be present 
4 Severe 
Very thickened and rough skin, numerous fissures 
10.3.1.5 Palm/Sole Fissuring Assessment 
Fissuring will be assessed by recording the presence or absence of fissures, the number of fissures 
present, and the pain associated with each fissure. A fissure is a longitudinal and deep crack that 
separates the stratum corneum and may penetrate down to the dermis, causing pain and sometimes 
bleeding. The subject will assess pain associated with fissures as ranging from 0-3 (none, mild, 
moderate, severe). 
10.3.1.6 Dermatology Life Quality Index 
The DLQI is a dermatology-specific Quality of Life instrument for subjects aged 17 years and 
older (1992). The child DLQI (cDLQI; May 1993) is for subjects aged 12 to 16 years. It is a simple 
10-question validated questionnaire with 6 domains (symptoms and feelings, daily activities, 
leisure, work and school, personal relationships, and treatment); higher scores indicate poorer 
quality of life. The DLQI is the most frequently used instrument in studies of randomized 
controlled trials in dermatology. The investigator should use his or her judgment of the maturity 
of the subject to decide which version of the questionnaire to use; the same version must be used 
for the subject throughout the study. 
10.3.1.7 EQ-5D Quality of Life Questionnaires 
The EQ-5D is a standardized instrument developed by the EuroQol Group as a measure of health-
related quality of life used in a wide range of health conditions and treatments. The EQ-5D consists 
of a descriptive system and the EQ visual analog scale (VAS). The EQ-5D-5L (2009) is intended 
for use in adult subjects, while the EQ-5D-Y (2012) is to be used for children and adolescents. The 
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investigator should use his or her judgment of the maturity of the subject to decide which version 
of the EQ-5D to use; the same version must be used for the subject throughout the study. 
The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. The EQ VAS records the subject’s self-rated health on a 
vertical 0-100 VAS. This can be used as a quantitative measure of health outcome that reflects the 
subject’s own judgment. 
10.3.1.8 Ectropion Severity Score 
The ESS, has a maximum score of 8 points. A higher score indicates a worse ectropion. The score 
takes the severity of ectropion in terms of lateral and medial apposition, scleral show, conjunctival 
show, and roundness of the eye into account and gives an indication of the functional aspects 
involved in ectropion by scoring redness, excess tear film, and the position of the lacrimal 
punctum.14 
Table 10-1: 
Ectropion Severity Score 
 
Points per Item 
0 
0.5 
1 
Lateral apposition 
Nonaffected 
— 
Affected 
Medial apposition 
Nonaffected 
— 
Affected 
Scleral show 
No 
≤1 mm 
>1 mm 
Conjunctival show 
No 
— 
Yes 
Excess tear film 
No 
— 
Yes 
Redness of the eye 
No 
— 
Yes 
Round canthus 
No 
— 
Yes 
Punctum lacrimale 
Invisible 
Emerging 
Visible 
Maximum score 
 
 
8 points 
Source: Korteweg SFS, Stenekes MW, van Zyl FE, Werker PMN. Paralytic Ectropion treatment with lateral 
periosteal flap canthoplasty and introduction of the ectropion severity score. Plast Reconstr Surg Glob Open. 
2014;2(5):e151. 
10.3.1.9 Photography Substudy 
All sites that have photographic capability will take photographs as source data to support scoring 
at Baseline, Day 30, and Day 90. A central reader who will not be an investigator in the study will 
review the photographs to assess consistency of investigator scoring of LI severity as a quality 
check. Photographs may also be used for scientific publication purposes. Subjects will sign a 
separate, optional photographic informed consent form (ICF). 
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10.3.2 Clinical Pharmacology 
10.3.2.1 Pharmacokinetic Analysis Methods 
The pharmacokinetic characterization of drug concentrations for each dose to be profiled will use 
noncompartmental analysis (NCA). 
10.3.2.2 Pharmacokinetic Parameters 
Samples for PK will be drawn from all subjects at Baseline and at each clinic visit for trough 
values. 
Subjects who provide written informed consent to participate in the optional PK substudy will 
provide blood samples for PK analysis predose on Day 1 and at 1, 2, 4, 8, 12, and 24 hours postdose 
on Day 1 and Day 30. 
The PK parameter estimates will be completed using WinNonlin (Pharsight Corporation) software 
using the actual elapsed times from dose administration to sample collection (i.e., not nominal 
time). 
Standard PK parameters assessed will include measures of the extent of absorption using estimates 
of the area-under-the-curve (AUC) and rate-of-absorption using the maximum concentration 
(Cmax) and the time of Cmax (Tmax). Additional details of the parameters and their calculation and 
evaluation will be included in the statistical analysis plan (SAP). 
Table 10-2 shows the PK parameters that will be computed for each subject for samples obtained 
over the planned sampling intervals. 
Table 10-2: 
Pharmacokinetic Parameters 
Parameter 
Description of Parameter 
Cmax 
Maximum (or peak) serum concentration  
Tmax 
Time at which Cmax is observed 
AUC(0-t) 
Area under the plasma concentration-time curve from time 0 to the time of the last 
quantifiable plasma concentration 
AUC(0-inf) 
Area under the plasma concentration-time curve from time 0 to infinity (if data permits) 
t1/2 
Apparent first order terminal elimination half-life 
λz 
Apparent terminal phase rate constant (if data permits) 
10.3.3 Sample Collection 
Samples will be collected at the time points specified in the Schedule of Events (Section 2.2). 
Specimen preparation, handling, shipment, and storage for the complete blood count, chemistry, 
and urinalysis are described in the study laboratory manual. Finding veins in subjects with this 
disease can be challenging. Blood draws will be done at the corresponding study visits before 
application of the IP and should be 24 hours after IP application. Subjects must not apply the IP to 
the area where blood will be drawn within 24 hours before their next study visit to avoid 
contamination of the blood by IP that remained in the skin. For subjects in the PK substudy, a 
cannula should be placed before IP application and the cannula site may be occluded to prevent 
contamination with IP. 
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Actual PK sample times for subjects in the PK substudy will be recorded in the eCRF. 
Blood 
For subjects not in PK substudy: 
The expected amount of blood to be drawn at each visit varies from approximately 6 mL to a 
maximum of 21 mL (Screening Visit only). The total amount of blood drawn for the study will be 
about 123 mL per subject, unless the subject takes part in the PK substudy. 
 
For subjects in PK substudy: 
For subjects who opt to participate in the PK substudy, extra blood samples will be drawn at Visit 2 
and at Visit 4 for PK analysis. The amount of blood to be drawn per subject at each of these visits 
will be approximately 54 mL. For subjects taking part in the substudy, the total amount of blood 
drawn for the entire study will be approximately 195 mL. 
Urine 
Urinalysis will be performed at central laboratory. Dipstick and urine pregnancy tests will be 
conducted on site. 
10.3.4 Safety Variables 
Safety assessments will include the evaluation of AEs, including local tolerability 
(stinging/burning, pruritus, and erythema), clinical laboratory assessments, vital signs, 12-lead 
ECGs, and physical examinations. 
10.3.4.1 Clinical Laboratory Safety Assessments 
10.3.4.1.1 Clinical Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points specified in the 
Schedule of Events (Section 2.2). 
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Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
platelet count (or estimate), white blood cell count including differential 
Serum Chemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, 
creatinine, glucose, sodium, potassium, chloride, bicarbonate, lactate 
dehydrogenase, uric acid, total cholesterol, high-density lipoprotein, low-
density lipoprotein, triglycerides 
Coagulation Panel: prothrombin time, partial thromboplastin time, fibrinogen 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones 
Pregnancy Test: 
for women of childbearing potential only; serum at Screening, urine at 
each other visit. 
Serology 
Hepatitis B surface antigen, and hepatitis C 
 
All blood samples for the clinical laboratory tests must be taken in a fasting state, at least 8 hours 
after the previous drug application. 
Blood and urine samples for hematology, and serum chemistry will be sent to a central laboratory 
for analysis. Urine pregnancy tests and dipstick will be conducted at the study sites. 
10.3.4.1.2 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens in 
both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
In addition to appropriate handling of subject samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples. Procedures and regulations for the packaging and shipping 
of infectious samples are outlined in the study laboratory manual. The investigator is responsible 
for ensuring that all study samples that are to be transported to another location are packed and 
shipped appropriately according to the applicable regulations. 
Samples for assessment of clinical laboratory tests will be transported to the Clinical Reference 
Laboratory (see the study laboratory manual for addresses). 
10.3.4.1.3 Evaluation of Clinical Laboratory Values 
The normal ranges of values for the clinical laboratory assessments in this study will be provided 
by the responsible laboratory and submitted to Mayne Pharma LLC prior to beginning the study. 
They will be regarded as the reference ranges on which decisions will be made. 
If a laboratory value is out of the reference range, it is not necessarily clinically significant. The 
investigator must evaluate the out-of-range values and record his or her assessment of the clinical 
significance in the appropriate eCRF. 
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All clinical laboratory values that in the investigator’s opinion show clinically significant or 
pathological changes during or after termination of treatment must be reported as AEs and 
followed, as described in Section 11.2.5. 
All measurements described in this section are recognized standard methods. 
10.3.4.2 Clinical Examinations 
10.3.4.2.1 Vital Signs 
Vital signs, including height and weight (only assessed at Screening), blood pressure, and pulse 
will be measured. 
10.3.4.2.2 Twelve-lead Electrocardiogram 
A standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes. 
All ECG recordings will be identified with the subject number, date, and time of the recording. 
Gel ECG electrodes may be used for ECGs because they are more conductive and cause less 
trauma on compromised skin. Efficacy assessments should be conducted before ECGs to avoid 
possible artifact/changes from the ECG. 
For subjects in the PK substudy, additional ECGs will be performed postdose during serial blood 
sampling on Day 1 and Day 30. 
If there is a marked prolongation of the QT/QTc interval during treatment, a subject should be 
discontinued from the IP but remain in the study until full resolution of the event. The DSMB will 
be informed immediately of such an occurrence. 
10.3.4.2.3 Physical Examination 
A complete physical examination excluding the genitourinary examination will be performed at 
Screening, while limited physical examinations (to include HEENT, cardiorespiratory, abdomen, 
and range of motion) will be performed as indicated in the Schedule of Events (Section 2.2). 
10.3.4.2.4 Other Safety Variables 
Local tolerability will be assessed on a 0-3 scale (none, mild, moderate, severe). All application 
site reactions will be recorded as TEAEs in the diary. These should include the date and severity 
of the TEAE. 
10.3.4.3 Adverse Events 
The definitions and management of AEs, and any special considerations for AEs, are provided in 
Section 11. 
10.4. Procedural Adjustments Due to COVID-19 
The coronavirus (COVID-19) global pandemic has impacted the free movement of the world’s 
population, which has been restricted to control the spread of the disease. It is recommended that 
all sites and subjects comply with the applicable local and federal guidelines regarding the 
necessary and proper precautions regarding COVID-19. 
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Although it is preferable to conduct all necessary study assessments in person (onsite visits), this 
may not be possible as a result of COVID-19-related travel restrictions. To ensure the safety of 
subjects, investigators, and site staff, Visits 3-6 (Double-blind Period; Table 2-1), Visits 7-11 
(OLE Period; Table 2-2) and unscheduled visits may be conducted remotely. Screening and 
baseline visits must be performed onsite only, and must be postponed or scheduled for when onsite 
visits can be safely conducted. 
Appendix B details the procedures when it is inadvisable or not possible to conduct an onsite study 
visit. 
11. ADVERSE EVENTS
11.1. Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not related to the medicinal product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a 
pre-existing condition is considered an AE.) 
Events that occur in subjects treated with control product are also considered AEs. 
11.1.2 Adverse Drug Reaction 
All noxious and unintended responses to an investigational product related to any dose should be 
considered adverse drug reactions (ADRs). 
The phrase “responses to an investigational product” means that a causal relationship between an 
investigational product and an AE is at least a reasonable possibility, i.e., the relationship cannot 
be ruled out. All AEs judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship to an IP qualify as ADRs. 
All AEs for which the judgment of relationship to IP is “possible” or higher will be considered 
ADRs. If a relationship to IP is not provided, then the AE must be treated as if it were “possible.” 
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction 
An expected AE or ADR is one for which the nature or severity is consistent with the known AE 
profile of the product. For a preapproval test product, the known information is contained in the 
IB. For a marketed product, the known information is contained in the current package insert for 
the product. 
An unexpected adverse event (UAE) or unexpected adverse drug reaction (UADR) is one for 
which the nature or severity of which is not consistent with the applicable product information 
(e.g., Investigator’s Brochure [IB] for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product). For example, hepatic necrosis 
would be unexpected (greater severity) if the IB only listed elevated hepatic enzymes or hepatitis. 
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Likewise, cerebral thromboembolism and cerebral vasculitis would be unexpected (greater 
specificity) if the IB only listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction constitute unexpected events. 
11.1.4 Serious Adverse Events/Drug Reaction 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. 
An elective hospital admission to treat a condition present before exposure to the IP, or a 
hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or 
event as an SAE. Further, an overnight stay in the hospital that is only due to transportation, 
organization, or accommodation problems and without medical background does not need 
to be considered an SAE. 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the IP 
during pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject that has 
received an IP is not considered an SAE unless it is suspected that the IP(s) interacted with 
a contraceptive method and led to the pregnancy. 
• is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result 
in hospitalization, development of drug dependency, or drug abuse. The occurrence of 
malignant tumors is also to be considered serious. 
11.1.5 Significant Adverse Events 
Other significant AEs are defined as marked hematological and other laboratory abnormalities 
(other than those meeting the definition of serious) and any events that led to an intervention, 
including withdrawal of test drug, dose reduction, or significant additional concomitant therapy. 
11.1.6 Treatment-Emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening is after the first application 
of IP (trifarotene or vehicle) and not more than 14 days after the last application of IP. 
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11.2. Event Assessment and Follow-up of Adverse Events 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care or upon review by a study 
monitor. 
All reported AEs, including local and systemic AEs not meeting the criteria for SAEs, will be 
captured on the appropriate eCRF. Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event. 
All reported AEs occurring while on study must be documented appropriately regardless of 
relationship. All reported AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE. 
Changes in the severity of a reported AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
Study clinic personnel will record all reportable events with start dates occurring any time after 
informed consent is obtained until 14 (for nonserious AEs) or 30 days (for SAEs) after the last day 
of study participation. At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit. Events will be followed for outcome information until resolution or 
stabilization. 
11.2.1 Assessment 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. In addition, 
although local tolerability will be assessed on a 0-3 scale, all application site reactions should be 
recorded as AEs. 
The Tolerability Assessments Form at each visit collects a numeric severity score by body area for 
erythema, stinging/burning, and pruritus. 
In addition, if skin irritation is more than the expected erythema, stinging/burning, and pruritus 
with the application of this topical retinoid (i.e., clinically relevant), please enter the application 
site reactions in the Adverse Event description section. If a diagnosis is known, record the 
diagnosis. If a diagnosis is known and there are other signs/symptoms that are not generally part 
of the main diagnosis, record the diagnosis and each sign/symptom on a separate line. If a diagnosis 
is not known, record each sign/symptom on a separate line. Examples are allergic contact 
dermatitis, sunburn, skin erosion, and swelling. 
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11.2.2 Evaluation 
11.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as follows: 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.4. 
11.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.4. 
11.2.2.3 Action(s) Taken 
All AEs will be treated/managed according to standard practice. The following actions may be 
taken with regard to the IP. Section 9.4 describes dose adjustment and stopping rules for individual 
subjects. 
Action(s) taken may consist of the following: 
Dose not changed 
An indication that a medication schedule was maintained. 
Dose reduced 
An indication that a medication schedule was modified by reducing the 
frequency of application. 
Drug interrupted 
An indication that a medication schedule was modified by temporarily 
terminating a prescribed regimen of medication. 
Drug withdrawn 
An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
11.2.2.4 Outcome at the Time of Last Observation 
The outcome of an AE at the time of last observation will be classified as follows: 
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• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
*Only select fatal as an outcome when the AE results in death. If more than one AE is judged to 
be possibly related to the subject’s death, the outcome of death should be indicated for each such 
AE. Although “fatal” is usually an event outcome, events such as sudden death or unexplained 
death should be reported as SAEs. 
11.2.2.5 Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AE’s relationship to the IP. The categories for 
classifying the investigator’s opinion of the relationship are as follows: 
Not related 
An AE with sufficient evidence to accept that there is no causal 
relationship to IP administration (e.g., no temporal relationship to drug 
administration, because the drug was administered after onset of event; 
investigation shows that the drug was not administered; another cause 
was proven.) 
Unlikely related 
An AE, including laboratory test abnormality, with a temporal 
relationship to IP administration that makes a causal relationship 
improbable, and in which other drugs, events, or underlying disease 
provide plausible explanations. 
Possibly related 
An AE with a reasonable time sequence to administration of the IP, but 
that could also be explained by concurrent disease or other drugs or 
events. Information on drug withdrawal may be lacking or unclear. 
Related 
An AE occurring in a causal plausible time relationship to IP 
administration that cannot be attributed to a concurrent disease or other 
drugs, chemicals, or events. The AE relationship to the IP must be 
assessed separately by the investigator and Mayne Pharma LLC. 
 
11.2.3 Documentation 
Any AE that occurs during the Screening Period will be captured as on the AE page of the eCRF 
(not medical history). All AEs that occur within the period of observation for the study must be 
documented in the eCRF with the following information, where appropriate. (The period of 
observation for the study is described in Section 11.2.) 
• AE name or term 
• When the AE first occurred (start date and time) 
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• When the AE stopped (stop date and time or an indication of “ongoing”) 
• Severity of the AE 
• Seriousness (hospitalization, death, etc.) 
• Actions taken 
• Outcome 
• Investigator opinion regarding the AE relationship to the IP(s) 
11.2.4 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. If such treatment constitutes a deviation from the protocol, the subject may be withdrawn 
for treatment but continue to be followed for efficacy and safety in the study. The decision about 
whether the subject may continue in the study will be made by the sponsor after consultation with 
the investigator and/or medical monitor. 
If AEs occur in a subject that are not tolerable, the investigator must decide whether to stop the 
subject’s involvement in the study and/or treat the subject. Special procedures may be 
recommended for the specific IP, such as the collection of a serum sample for determining blood 
concentrations of IP, specific tapering procedures, or treatment regimens, as appropriate. 
It is not necessary to unblind a subject’s treatment assignment in most circumstances, even if an 
SAE has occurred. If unblinding is necessary, see Section 9.6 for a description of the unblinding 
procedures. 
11.2.5 Follow-up 
Any AE will be followed (up to a maximum of 14 days after the last dose of IP) to a satisfactory 
resolution, until it becomes stable, or until it can be explained by another known cause(s) (i.e., 
concurrent condition or medication) and clinical judgment indicates that further evaluation is not 
warranted. All findings relevant to the final outcome of an AE must be reported in the subject’s 
medical record and recorded on the eCRF page. 
11.2.6 Reporting 
11.2.6.1 Serious Adverse Events 
The investigator or designee must report all SAEs promptly to Premier Research within 24 hours 
of first becoming aware of the event by e.g., completing, signing and dating the Serious Adverse 
Event Report Form, verifying the accuracy of the information recorded in the form with the source 
documents and eCRF, and sending the SAE form to the Premier Research by one of the following 
methods: 
Email: globalPV-US@premier-research.com 
Email: PVDS-ROW@premier-research.com 
Fax number: +1 215 972 8765 
Fax number: +421 2 6820 3713 
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This written report should be submitted on the SAE form provided for this purpose. At the time of 
first notification, the investigator or designee should provide the following information, if 
available: 
• Protocol number 
• Reporter (study site and investigator) 
• Suspect IP 
• Subject’s study number 
• Subject’s year of birth 
• Subject’s gender 
• Date of first dose of IP(s) 
• Date of last dose of IP(s), if applicable 
• Adverse event term 
• Date of occurrence of the event 
• A brief description of the event, outcome to date, and any actions taken 
• The seriousness criteria(on) that were met 
• Concomitant medication at onset of the event 
• Relevant medical history information 
• Relevant laboratory test findings 
• Investigator’s opinion of the relationship to IP(s) (“Is there a reasonable possibility that 
the IP caused the SAE? Yes or No?”) 
• Whether and when the investigator was unblinded as to the subject’s treatment 
assignment 
Any missing or additional relevant follow-up information concerning the SAE should be sent to 
the sponsor/sponsor representative via the same contact details above as soon as possible on a 
follow-up SAE Report Form, together with the following minimal information (initial report, 
adverse event, date of occurrence, subject identification (ID), study ID, IP, and site number); this 
will allow the follow-up information to be linked to the initial SAE report. 
Specific information may be requested by the Premier Research Pharmacovigilance Department 
using a follow-up request form or via email communication. 
The investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his or her health authorities, institutional review board 
(IRB)/independent ethics committee (IEC), principal and coordinating investigators, study 
investigators, and institutions. Each investigator is obligated to learn about the reporting 
requirements for investigators in his/her country. The study monitor may be able to assist with 
this. 
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11.2.6.2 Adverse Drug Reactions 
All ADRs should be reported by the investigator in the eCRF. 
Suspected serious ADRs must be reported to the sponsor immediately, regardless of the time 
elapsed since the end of the observation period. 
11.2.6.3 Nonserious Adverse Events 
Nonserious AEs will be recorded in the eCRF and reported by Premier Research to Mayne Pharma 
LLC in aggregate monthly status reports. 
11.3. Special Considerations 
11.3.1 Adverse Events of Special Interest 
Since topical retinoids are associated with local application site AEs, particularly when beginning 
treatment, these events will be followed closely during the study and considered AEs of special 
interest (AESIs). 
11.3.2 Pregnancy 
All WOCBP who participate in the study should be counseled on the need to practice highly 
effective birth control and on the importance of avoiding pregnancy during study participation. 
Women should be instructed to contact the investigator or study staff immediately if pregnancy 
occurs or is suspected. 
Pregnancy testing will be conducted prior to administration of the IP on every woman of 
childbearing potential. A woman who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered to be a screening failure. 
A woman who becomes pregnant during IP treatment will be immediately discontinued from study 
treatment. The investigator must report the pregnancy of any woman who becomes pregnant 
during or within 30 days after discontinuing treatment as if it were an SAE within 24 hours of 
learning of the pregnancy, to Premier Research Pharmacovigilance using the Pregnancy Data 
Collection Form via the same fax number and/or email address as for SAE reporting. If a partner 
of a male study subject becomes pregnant, the investigator must report the pregnancy as soon as 
possible after learning of it to the Premier Research Pharmacovigilance using the Pregnancy Data 
Collection Form. A separate pregnant partner ICF will be required. 
Early Termination Visit assessments are required as soon as possible after learning of the 
pregnancy in a study subject. The investigator is also responsible for following the pregnancy until 
delivery or termination. These findings must be reported on the Pregnancy Data Collection Form 
and forwarded to Premier Research Pharmacovigilance. The event meets the SAE criterion only if 
it results in a spontaneous abortion or a congenital anomaly. In such case, an additional form 
(Serious Adverse Event Report Form) must be filled out by the investigator and provided to 
Premier Research Pharmacovigilance within 24 hours of knowledge of the pregnancy’s serious 
outcome. 
Among the clinical studies, 12 pregnancies were reported: 4 resulted in normal births; 5 resulted 
in spontaneous abortions (none of which was considered related to CD5789); 1 was electively 
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aborted, and 2 were lost to follow-up (Investigator’s Brochure for CD5789 Cutaneous 
Formulation). 
12. DATA SAFETY MONITORING BOARD 
Safety oversight will be under the direction of a DSMB composed of individuals with the 
appropriate expertise, including LI. Members of the DSMB should be independent from the study 
conduct and free of conflict of interest, or measures should be in place to minimize perceived 
conflict of interest. The DSMB will operate under a charter that will be finalized prior to the start 
of the study. The DSMB will meet at least 3 times during the conduct of the study: when the study 
begins, when 15 adult subjects have enrolled in Cohort A and have completed at least 28 days of 
treatment, and after 60 subjects have enrolled in the study. 
The DSMB will meet after 15 subjects in Cohort A have completed at least 28 days of double-
blind treatment to review aggregate safety and tolerability data (including PK and ECG results). 
The safety data will be unblinded to the DSMB. At that time, the DSMB will decide whether 
Cohort B (adults and subjects aged 12–17) may begin enrolling, or if additional adult safety data 
are required before allowing subjects aged 12 – 17 to participate in the study. The DSMB will have 
the authority to recommend to the sponsor that the study be modified, placed on hold, or stopped 
if serious safety issues are discovered. The DSMB will provide its input to Mayne Pharma LLC. 
Any protocol changes the DSMB may suggest will be submitted to all applicable regulatory bodies 
for review and approval. 
In case of significant toxicity, the DSMB may choose to review the available safety data and 
recommend stopping recruitment in a particular dose group. 
Stopping rules for individual subjects are in Section 8.4. The DSMB committee members are as 
follow: 
• Univ. Prof. Dr. med. Steffen Emmert, Director at Clinic and Polyclinic for Dermatology 
& Venereology University Medical Center Rostock 
• Jeffrey Louis Sugarman, M.D., Ph.D. Pediatric Dermatologist 
• Moise L. Levy, MD, Pediatric Dermatologist 
• Gabriele Accetta, Ph.D,. Biostatistician 
 
13. STATISTICS 
13.1. Statistical Analysis 
This section presents a summary of the planned statistical analyses. A SAP that describes the 
details of the analyses to be conducted will be written prior to database lock. 
Unless otherwise indicated, all testing of statistical significance will be two-sided, and a difference 
resulting in a P value of ≤ 0.05 will be considered statistically significant. 
Summary statistics will be provided for the variables described below. For continuous variables, 
these statistics will include the number of subjects, mean, standard deviation (SD), median, 
minimum, and maximum. For categorical variables, these statistics will include the number and 
percentage of subjects in each category. 
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The primary analysis period is the first 90 days of treatment (i.e., the Double-blind Period). Overall 
unblinding will take place at the end of the Double-blind Period of the study only after the database 
is locked. A second analysis will take place for endpoints assessed from Day 90 through the OLE 
Period. The baseline for the safety and efficacy parameters will be measured at Visit 1 or Visit 2, 
per the Schedule of Events for both the Double-blind Period (Table 2-1) and OLE (Table 2-2). 
13.1.1 Analysis Populations 
The following 5 analysis populations are planned for the Double-blind Period of this study: 
• Safety: all subjects who are randomized to treatment and receive at least 1 application of 
study drug in the Double-blind Period. This population will be the primary population for 
analyses of safety. 
• Intent-to-treat (ITT): all randomized subjects. This population will be used as the primary 
population for the analysis of efficacy for the Double-blind Period of the study. 
• Modified intent-to-treat (mITT): all subjects in the safety population with at least 
1 postbaseline assessment of efficacy in the Double-blind Period. 
• Per-protocol (PP): subjects in the mITT Population who met all inclusion criteria and no 
exclusion criteria, were compliant with study drug application, and who had no 
significant protocol deviations. 
• Pharmacokinetic: all subjects in the Safety Population who have at least 1 plasma sample 
with quantifiable concentration. This population will be used to summarize all PK 
endpoints. 
The following analysis populations are planned for the OLE of this study: 
• OLE Safety: all subjects who complete the 90-day Double-blind Treatment Period and 
receive at least 1 application of study drug in the OLE. 
• OLE ITT: all subjects who complete the 90-day Double-blind Treatment Period and sign 
the OLE informed consent. 
• OLE mITT: all subjects in the OLE safety population with at least 1 assessment of 
efficacy after Visit 6. 
• OLE PP: all subjects in the OLE mITT population who met all inclusion criteria and no 
exclusion criteria, were compliant with study drug application from baseline through 
EOT, and who had no significant protocol deviations throughout the study. 
Inclusion in the analysis populations will be determined prior to database lock. Deviations related 
to COVID-19 will also be evaluated in determining PP population eligibility. 
If a subject is randomized incorrectly or is administered the incorrect IP, analyses of the ITT and 
mITT populations will be based on the assigned treatment whereas all other analyses will be based 
on the actual treatment received. 
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13.1.2 Study Subjects and Demographics 
13.1.2.1 Disposition and Withdrawals 
For the Double-blind Period, the numbers of subjects randomized, completing Day 90 of the study, 
and withdrawing early from the Double-blind Period, along with reasons for withdrawal, will be 
tabulated overall and by randomized treatment group. The number of subjects in each analysis 
population will be reported. The number of subjects completing study milestones will also be 
tabulated by randomized treatment group. This analysis will be conducted for the ITT population. 
For the OLE, the number of subjects entering the OLE, completing the study, and withdrawing 
early, along with reasons for withdrawal, will be tabulated overall. The number of subjects in each 
analysis population will be reported. The number of subjects completing study milestones will also 
be tabulated. This analysis will be conducted for the OLE ITT population. 
13.1.2.2 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol or International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) requirements. The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions are 
to be developed by the site and implemented promptly. 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations promptly. All deviations must be addressed in study source documents, and reported to 
Premier Research or Mayne Pharma LLC. Protocol deviations must be sent to the reviewing IRB 
per their policies. The site investigator is responsible for knowing and adhering to the reviewing 
IRB requirements. Further details about the handling of protocol deviations will be included in the 
protocol deviation guidance plan. 
Subjects who taper to once-weekly application or who take a “drug holiday” will not be reported 
as having deviated from the protocol. 
13.1.2.3 Demographics and Other Baseline Characteristics 
These analyses will be conducted for the ITT and OLE ITT populations. 
Demographic variables will include age, sex, race, ethnicity, height, weight, and BMI. Baseline 
subject characteristics will include medical history, physical examination findings, and IGA score. 
Prior and concomitant medications will be summarized by randomized treatment group, by the 
number and percentage of subjects taking each medication, and classified using World Health 
Organization Drug Dictionary (WHO-DD) Anatomical Therapeutic Chemical (ATC) classes and 
preferred terms. 
13.1.3 Exposure and Compliance 
Investigational product administration will be summarized in terms of each subject’s dose, and in 
terms of duration of exposure for each period. Descriptive statistics for these quantities, including 
the mean, median, SD, minimum, maximum, and quartiles, will be provided by treatment group. 
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Additionally, the number of subjects who are compliant with investigational product will be 
presented by treatment group for the Double-blind Period and overall for the OLE. 
Subjects who taper to once-weekly application or who take a “drug holiday” will not be reported 
as having deviated from the protocol. 
13.1.4 Efficacy Analysis 
The ITT population will be used as the primary population for the primary analysis of efficacy at 
Day 90. Select efficacy analyses will be repeated as secondary analyses in the ITT and PP 
populations for the Double-blind Period. Efficacy analyses will also be repeated in the OLE using 
the OLE ITT, OLE mITT, and OLE PP populations. No formal inferential analyses will be 
conducted for efficacy variables in the OLE. 
Efficacy endpoints will be based on investigator assessment. 
13.1.4.1 Efficacy Endpoints 
Primary efficacy endpoint: The proportion of subjects in each treatment group who experience 
successful resolution of LI where “success” is defined as clear/almost clear overall and at least a 
2-grade change from Baseline at Day 90/EOT in the Double-blind Period on the 5-point IGA scale. 
Secondary: The secondary endpoints are as follow: 
• The difference in mean scores between the active trifarotene cream HE1 and 
vehicle groups in the following assessment indices from Baseline through Day 90: 
▪ 5-point VIIS scale for scaling 
▪ Individual score for roughness (Scale: 0–4) 
▪ Palm/sole Assessment (Scale: 0–4) 
▪ Quality of life per DLQI and cDLQI 
• The difference in proportion of subjects with presence of fissures on palm/soles 
(presence/absence, number of fissures, and pain associated with fissures [on a 
0-3 scale]) at Day 90 between the active trifarotene cream HE1 and vehicle 
groups 
Exploratory: The exploratory endpoints are as follow: 
• The difference in mean ectropion scores (ESS of 0–8) between the active trifarotene 
cream HE1 and vehicle groups from Baseline through Day 90 
• The difference in quality of life per EQ-5D-5L and EQ-5D-Y scores between the 
active trifarotene cream HE1 and vehicle groups from Baseline through Day 90 
13.1.4.2 Primary Analysis 
For the Double-blind Period only, the number and proportion of subjects in each treatment group 
with successful resolution of LI by Day 90/EOT will be presented. The primary efficacy endpoint 
will be analyzed using a logistic regression model with treatment and age group as factors. Other 
baseline characteristics and interactions may be included. The odds ratios and 95% CIs for the 
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odds ratios will be presented. The difference in proportions between the active trifarotene cream 
HEI and vehicle cream group, 95% CIs for the differences, and P-values for the differences in 
treatment will also be presented. 
Descriptive summaries (such as mean, standard error, median, minimum, and maximum) and the 
changes from baseline will be provided for IGA scores for both periods. 
13.1.4.3 Secondary Analyses 
Secondary and exploratory efficacy endpoints will be analyzed separately for each period 
(Double-blind and OLE) using descriptive statistics. 
Additionally, for the Double-blind Period only, change from Baseline in continuous secondary 
endpoints through Day 90 will be presented and analyzed using a mixed model for repeated 
measures (MMRM). The model will include the change from baseline score as the dependent 
variable, treatment group as a fixed effect, subject as a random effect, and baseline score value as 
a covariate. 
For subjects who report having fissures, descriptive summaries of the number of fissures and pain 
related to fissures will also be presented by treatment group and body area for each period. 
The DLQI scores will also be analyzed using descriptive statistics through Day 90. 
The proportion of subjects with at least a 50% reduction in IGA score from Baseline will be 
analyzed using the same logistic regression analysis described in Section 13.1.4.2. 
13.1.4.4 Exploratory Analyses 
Descriptive summaries and the changes from baseline will be provided for ectropion scores and 
EQ-5D-5L scores by visit for each period. No formal inferential analyses will be conducted for 
exploratory endpoints. 
13.1.4.5 Corroborative, Sensitivity, and Other Analyses 
To assess the effect of missing data on the primary efficacy analysis, a sensitivity analysis will be 
performed using multiple imputation (MI) for the Double-blind Period only. Multiple-imputations 
will be used to replace missing IGA outcomes using multiple draws from the posterior predictive 
distribution estimated from the treatment groups. IGA scores will be imputed and then categorized 
as treatment success according to Section 13.1.4.1. Imputation will not be performed for the OLE. 
Full details will be specified in the SAP. 
Thorough assessment on the extent of missing data and procedural adjustments due to COVID-19 
as it pertains to the primary and secondary efficacy endpoints will be conducted ahead of database 
lock, and additional sensitivity analyses may be performed. Full details will be documented in the 
SAP. 
The proportion of subjects who experience a 2-grade change from baseline to Day 90 in individual 
score for roughness and palm/sole assessment will also be explored using a logistic regression 
model with treatment and age group as factors. Other baseline characteristics and interactions may 
be included. The odds ratios and 95% CIs for the odds ratios will be presented. The difference in 
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proportions between the active trifarotene cream HEI and vehicle cream group and the 95% CIs 
for the differences will be presented. 
For analyses involving study site, if the number of subjects per site is small, sites may be pooled 
for safety and efficacy analysis or omitted from statistical models as the anticipated number of 
subjects per site is small, treatment is self-administered, and the sites are using standardized 
procedures for all assessments. If the distribution of enrollments at sites is such that one or few are 
enrolling a majority of subjects, a subgroup analysis by site may be performed. The final 
determination will be made prior to database lock. 
Details of these analyses will be further detailed in the SAP. 
13.1.5 Clinical Pharmacology Analyses 
13.1.5.1 Pharmacokinetics 
For noncompartmental analysis, plasma concentrations will be listed and summarized at each time 
point using descriptive statistics. Descriptive statistics reported will include the arithmetic mean, 
SD, CV%, geometric mean, minimum, maximum, and median. Only the range and the median will 
be reported for Tmax, as this is a categorical parameter. The PK parameters will also be summarized 
by treatment using descriptive statistics. 
Individual plasma concentration plots and mean data graphs will be produced using both linear 
and semi-logarithmic scales. Mean data graphs will show plasma concentration profiles by 
treatment group. 
Pharmacokinetic plasma parameter estimates and summaries will be completed for the subjects in 
the PK population. Testing of PK parameters will be outlined in the SAP. 
13.1.6 Safety and Tolerability Analyses 
Safety analyses through Day 90 of the Double-blind Period will be conducted using data from the 
Safety Population and safety analyses in the OLE will be conducted using the OLE Safety 
Population (as defined in Section 13.1.1). Safety variables include treatment-emergent AEs, 
clinical laboratory values, vital signs, ECG readings, and physical examination results. No formal 
inferential analyses will be conducted for safety variables in either period. 
13.1.6.1 Local Tolerability 
During all clinic visits, the investigator will assess local tolerability (stinging/burning, pruritus, or 
erythema on 0-3 scales [none, mild, moderate, severe]) for each treated body area (chest/abdomen, 
back, arms, legs, and face/neck). Descriptive summaries will be presented by period, treatment 
group, and visit. 
13.1.6.2 Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 20.1 or higher. 
Treatment-emergent AEs are defined as: 
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• AEs with onset at the time of or following the start of treatment with IP through the 
Follow-up Visit or Early Termination Visit, whichever occurs first, or 
• AEs starting prior to the start of treatment but increasing in severity or relationship at the 
time of, or following, the start of treatment with IP through the Follow-up Visit or Early 
Termination Visit, whichever occurs first. 
The number and percentage of subjects with AEs will be displayed by each treatment group in the 
Double-blind Period and overall in the OLE by system organ class and preferred term. Summaries 
of AEs by severity and relationship to IP will also be provided. Serious adverse events and AEs 
resulting in discontinuation of IP will be summarized separately in a similar manner. Subject 
listings of AEs, SAEs, and AEs causing discontinuation of IP will be produced. 
13.1.6.3 Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from baseline values will be presented for clinical laboratory values for each treatment 
group at each time point in each period. 
The number of subjects with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from baseline (shift tables) for each clinical 
laboratory parameter by treatment group and by study visit in each period. 
Laboratory values that are outside the normal range will also be flagged in the data listings and 
presented with the corresponding normal ranges. Any out-of-range values that are identified by 
the investigator as being clinically significant will also be shown in a data listing. 
13.1.6.4 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for SBP, DBP, and pulse for each period. 
The number of subjects with vital signs values categorized as below, within, or above normal 
ranges will be tabulated showing change from baseline (shift tables) for each parameter by period, 
by treatment group and by study visit. Pre and post-treatment values may also be presented with 
an analysis of mean changes from baseline. 
13.1.6.5 Twelve-lead Electrocardiograms 
The number and percentage of subjects with normal and abnormal ECG findings will be 
summarized for each treatment group at each time point in each period. Abnormal results will be 
grouped as clinically significant and not clinically significant. 
A comparison of QT results will be presented. Summary statistics will be displayed by period, by 
treatment group, and by visit for QT and the QT interval corrected for heart rate (QTc) calculated 
using Fridericia’s QT correction methods. 
Descriptive summaries (mean, SD, median, minimum, and maximum) will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTcF interval (Fredericia’s correction 
methods), and HR for each treatment group at each time point in each period. 
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13.1.6.6 Physical Examination Findings 
The number and percentage of subjects with normal and abnormal findings in the complete 
physical examination will be displayed for each treatment group in each period. 
13.1.7 Interim Analysis 
No interim analyses are planned. 
13.2. Sample Size Determination 
Accounting for a 20% drop-out/nonevaluable rate, a total sample size of 120 subjects randomized 
in a 1:1:1 ratio to 2 active trifarotene cream HE1 arms and a vehicle cream arm will provide 
>80% power to detect a difference between each separate trifarotene cream HE1 arm (32 evaluable 
subjects) and the vehicle cream arm (32 evaluable subjects) 2-sided Fisher’s Exact Test assuming 
a 70% success rate and a 40% success rate, respectively. This study is not powered to detect a 
difference between the 2 active arms. 
14. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
14.1. Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 16). The sponsor reserves the right to withdraw a subject from the study (Section 8.3), to 
terminate participation of a study site at any time (Section 14.7), and/or to discontinue the study 
(Section 14.6). 
Mayne Pharma LLC agrees to provide the investigator with sufficient material and support to 
permit the investigator to conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 18.1), the investigator indicates that he or she 
has read the protocol carefully, fully understands the requirements, and agrees to conduct the study 
in accordance with the procedures and requirements described in this protocol. 
The trial will be conducted in accordance with ICH GCP, and the applicable United States (US) 
Code of Federal Regulations (CFR). The principal investigator will assure that no deviation from, 
or changes to, the protocol will take place without prior agreement from the Investigational New 
Drug (IND) sponsor, funding agency and documented approval from the IRB, except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection and ICH GCP training. 
Investigators should ensure that all persons who are delegated study-related responsibilities are 
adequately qualified and informed about the protocol, the IP(s), and their specific duties within the 
context of the study. Investigators are responsible for providing Mayne Pharma LLC with 
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documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
14.1.3 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying study product may inspect all 
documents and records required to be maintained by the investigator, including, but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. 
The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at Premier Research. This will not include the participant’s contact 
or identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by clinical sites and by Premier Research staff will be secured and password protected. At the end 
of the study, all study databases will be de-identified and archived at Premier Research. 
14.2. Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from the sponsor or its designee that the study can be initiated at the study site. The study site will 
not be authorized for study initiation until: 
1. The study site has received the appropriate IRB/IEC approval for the protocol and the 
appropriate ICF. 
2. All regulatory/GCP documents have been submitted to and approved by the sponsor or its 
designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
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14.3. Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study. Subjects may 
only be rescreened once 30 days or more after the original Screening Visit. If a subject is eligible 
to enter the study after having previously failed screening, the subject will be assigned a new 
subject identification number. 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
14.4. Study Documents 
All documentation and material provided by Mayne Pharma LLC for this study are to be retained 
in a secure location and treated as confidential material. 
14.4.1 Informed Consent 
Consent and assent forms describing in detail the study intervention, study procedures, and risks 
are given to the participant and written documentation of informed consent is required prior to 
starting intervention/administering study intervention. The informed consent and assent forms are 
submitted with this protocol. 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent and assent forms will 
be IRB-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may 
arise. A verbal explanation will be provided in terms suited to the participant’s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research participants. 
Participants will have the opportunity to carefully review the written consent and assent forms and 
ask questions before signing. The participants should have the opportunity to discuss the study 
with their family or surrogates or think about it before agreeing to participate. The participant will 
sign the informed consent or assent document prior to any procedures being done specifically for 
the study. Participants must be informed that participation is voluntary and that they may withdraw 
from the study at any time, without prejudice. A copy of the informed consent and assent document 
will be given to the participants for their records. The informed consent process will be conducted 
and documented in the source document (including the date) and the form signed before the 
participant undergoes any study-specific procedures. The rights and welfare of the participants will 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
14.4.2 Investigator’s Regulatory/Good Clinical Practice Documents 
The regulatory/GCP documents are listed below. 
• Signed original protocol (i.e., Investigator’s Agreement) 
• Curricula vitae of all investigators and subinvestigators 
• Name and address of the laboratories 
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• List of laboratory reference ranges, and if available, a quality certificate 
• Form Signature Log/Delegation of Study-related Duties 
• Approved ICF and subject materials 
• FDA1572 and financial disclosure forms, as applicable (US sites) 
• Any other relevant GCP documents 
The regulatory/GCP documents must be received from the investigator and reviewed and approved 
by Mayne Pharma LLC or its designee before the study site can initiate the study and before Mayne 
Pharma LLC will authorize shipment of IP to the study site. Copies of the investigator’s 
regulatory/GCP documents must be retained at the study site in a secure location. Additional 
documents, including a copy of the protocol and applicable amendment(s), the trifarotene 
(CD5789) Cream IB, eCRF completion guidelines, copies of regulatory references, copies of 
IRB/IEC correspondence, and IP accountability records should also be retained as part of the 
investigator’s regulatory/GCP documents. It is the investigator’s responsibility to ensure that 
copies of all required regulatory/GCP documents are organized, current, and available for 
inspection. 
14.4.3 Case Report Forms 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign an 
ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the study to ensure that the study information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered in the electronic data capture 
(EDC) system according to the completion guidelines provided by the sponsor or its designee. 
The eCRFs must be signed by the investigator or a subinvestigator. These signatures serve to attest 
that the information contained in the eCRF is accurate and true. 
14.4.4 Source Documents 
Information recorded in the EDC system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
Clinical laboratory data required by the protocol will be electronically transferred from the 
central/local laboratory to the sponsor or its designee. A paper copy of the laboratory results will 
be provided to the study site and should be retained with each subject’s source data. 
14.5. Data Quality Control 
Mayne Pharma LLC and its designees will perform quality control checks on this clinical study. 
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14.5.1 Monitoring Procedures 
Mayne Pharma LLC and/or its designee will conduct site visits to monitor the study and ensure 
compliance with the protocol, GCP, and applicable regulations and guidelines. The assigned 
clinical research associate(s) (CRA[s]) will visit the investigator and study site at periodic intervals 
and maintain periodic communication. The investigator agrees to allow the CRA(s) and other 
authorized Mayne Pharma LLC personnel access. The CRA(s) will maintain current personal 
knowledge of the study through observation, review of study records and source documentation, 
and discussion of the conduct of the study with the investigator and staff. While on site, the CRA(s) 
will review 
• regulatory documents, directly comparing entries in the EDC system with the source 
documents 
• consenting procedures 
• AE procedures 
• storage and accountability of IP and study materials 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRF will be provided to the sites. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow Mayne Pharma LLC or designee auditors or inspectors from regulatory agencies 
to review records and to assist the inspectors in their duties, if requested. 
For additional information, please refer to the clinical monitoring plan (CMP). 
14.5.2 Data Management 
Mayne Pharma LLC or designee will be responsible for activities associated with the data 
management of this study. The standard procedures for handling and processing records will be 
followed per GCP and Premier Research’s standard operating procedures. A comprehensive data 
management plan (DMP) will be developed, including a data management overview, description 
of database contents, annotated CRF, pre-entry review list, self-evident correction conventions, 
query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries will be provided to the sites. 
14.5.3 Quality Assurance/Audit 
This study will be subject to audit by Mayne Pharma LLC or its designee. Audits may be performed 
to check compliance with GCP guidelines and can include: 
• site audits 
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• Trial Master File audits 
• database audits 
• document audits (e.g., protocol and/or clinical study report [CSR]) 
Mayne Pharma LLC or its designee may conduct additional audits on a selection of study sites, 
requiring access to subject notes, study documentation, and facilities or laboratories used for the 
study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB/IEC or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify Mayne Pharma LLC immediately. 
14.6. Study Termination 
The study may be terminated at Mayne Pharma LLC’s discretion at any time and for any reason. 
The DSMB may recommend discontinuation of the study if they find evidence of unacceptable 
risk to subjects. 
14.6.1 Regular Study Termination 
The end of this study is defined as the date of the last visit of the last subject (last subject out or 
last subject last visit) participating in the study. Within 90 days of the end of the clinical study, 
Mayne Pharma LLC or designee will notify the IECs and regulatory authorities about the regular 
termination of the study as required according to national laws and regulations. 
14.6.2 Premature Study Termination 
The study may be temporarily suspended or terminated prematurely if there is sufficient reasonable 
cause at any time by Mayne Pharma LLC, IECs, regulatory authorities, respective steering 
committees, or the coordinating investigator. A decision to prematurely terminate the study is 
binding to all investigators of all study sites. 
Within 15 days of premature termination of a clinical study, Mayne Pharma LLC or its designee 
will notify the IECs and regulatory authorities about the premature termination as required 
according to national laws and regulations. Mayne Pharma LLC or its designee must clearly 
explain the reasons for premature termination. 
Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigator, funding agency, the IND 
or IDE sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the 
PI will promptly inform study participants, the IRB, and sponsor and will provide the reason(s) for 
the termination or suspension. Study participants will be contacted, as applicable, and be informed 
of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
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• Demonstration of efficacy that would warrant stopping 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
If the study is terminated prematurely, all investigators have to inform their subjects and take care 
of appropriate follow-up and further treatment of the subjects to ensure protection of the subjects’ 
interests. Study sites may be asked to have all subjects currently participating in the study complete 
all of the assessments for the Follow-up Visit. 
The study might resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB/IEC and/or FDA. 
14.7. Study Site Closure 
At the end of the study, all study sites will be closed. Mayne Pharma LLC may terminate 
participation of a study site at any time. Examples of conditions that may require premature 
termination of a study site include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate subject enrollment 
14.7.1 Record Retention 
For sites in the US, the investigator shall retain and preserve 1 copy of all data generated in the 
course of the study, specifically including, but not limited to, those defined by GCP as essential 
until 1 of the following occurs: 
• At least 2 years after the last marketing authorization for the IP has been approved or the 
sponsor has discontinued its research with the IP, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development of 
the IP. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor has 30 days to respond to the investigator’s notice, and the 
sponsor has further opportunity to retain such materials at the sponsor’s expense. 
Outside of the US, after completing the study, Mayne Pharma LLC will receive the original eCRFs 
or at least a legible copy and retain the documents for at least 5 years after the completion of the 
study. 
One copy will remain with the investigator. The investigator shall arrange for the retention of the 
subject identification codes, subject files and other source data until at least 5 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or until at least 2 years have elapsed since 
the formal discontinuation of the clinical development of the product. These documents need to be 
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retained for a longer period of time if required by applicable regulatory authorities or by agreement 
with the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor shall have 30 days to respond to the investigator’s notice, 
and the sponsor shall have a further opportunity to retain such materials at the sponsor’s expense. 
Copies of these study records (and all study-related documents, including source data) shall be 
kept by the investigator for the maximum period of time permitted by the hospital, institution, or 
private practice. 
14.7.2 Sample Retention 
Blood samples will be used for purposes related to this study only, and will not be stored for future 
research. The samples will be stored until they are no longer needed, and the decision has been 
made that none of the samples needs to be reanalyzed. In addition, identifiable samples can be 
destroyed at any time at the request of the subject. 
Data collected for this study will be analyzed and stored at Premier Research. 
14.8. Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Mayne Pharma LLC. The protocol amendment must be signed by 
the investigator and approved by the IRB or IEC before it may be implemented. Protocol 
amendments will be filed with the appropriate regulatory agency(s) having jurisdiction over the 
conduct of the study. 
14.9. Use of Information and Publication 
All information concerning trifarotene (CD5789) cream HE1, Mayne Pharma LLC’s operations, 
patent applications, formula, manufacturing processes, basic scientific data, and formulation 
information supplied by Mayne Pharma LLC or its designee to the investigator, and not previously 
published, is considered confidential and remains the sole property of Mayne Pharma LLC. Case 
report forms also remain the property of Mayne Pharma LLC. The investigator agrees to use this 
information for purposes of study execution through finalization and will not use it for other 
purposes without the written consent of the sponsor. 
The information developed in this study will be used by Mayne Pharma LLC in connection with 
the continued development of trifarotene (CD5789) cream HE1 and thus, may be disclosed as 
required to other clinical investigators or government regulatory agencies. 
The information generated by this study is the property of Mayne Pharma LLC. Publication or 
other public presentation of trifarotene (CD5789) cream HE1 data resulting from this study 
requires prior review and written approval of Mayne Pharma LLC. Abstracts, manuscripts, and 
presentation materials should be provided to Mayne Pharma LLC for review and approval at least 
30 days prior to the relevant submission deadline. Data from individual study sites must not be 
published separately. 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition, or publication by the investigator until Mayne Pharma LLC has reviewed and 
commented on such a presentation or manuscript for publication. If applicable, this study will be 
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registered at ClinicalTrials.gov, and results information from this study will be submitted to 
ClinicalTrials.gov. 
15. FINAL CLINICAL STUDY REPORT 
Mayne Pharma LLC will retain ownership of the data. 
The final CSR will be written within 6 months of completion of the study. This report will include 
a summary of the study results based on a statistical evaluation and clinical assessment of the 
protocol-defined endpoints. 
The final CSR may be submitted to the regulatory authorities. 
16. ETHICAL AND LEGAL CONSIDERATIONS 
16.1. Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry GCP 
E6 (including archiving of essential study documents), the Integrated Addendum to ICH E6 (R2) 
of November 2016, the Declaration of Helsinki, the applicable regulations of the country(ies) in 
which the study is conducted, and with the Commission Directives 2001/20/EC and 2005/28/EC. 
16.2. Subject Information and Informed Consent and/or Assent 
A properly constituted, valid IRB or IEC must review and approve the protocol, the investigator’s 
ICF, and related subject information and recruitment materials before the start of the study. 
It is the responsibility of the investigator to ensure that written informed consent and/or assent is 
obtained from the subject before any activity or procedure is undertaken that is not part of routine 
care. 
According to the Declaration of Helsinki and ICH GCP, subjects must provide their written 
informed assent or consent prior to enrollment in a clinical study and before any protocol-specified 
procedures are performed. Subjects must declare their consent by personally signing and dating 
the ICF. The written ICF will embody the elements of informed consent and/or assent as described 
in the Declaration of Helsinki and will also comply with local regulations. 
Each subject should be made aware by the investigator of the nature of the study (objectives, 
methods, and potential hazards and benefits) and the procedures involved, using the information 
on the ICF. Information should be given in both oral and written form whenever possible and 
deemed appropriate by the IRB/IEC. Subjects, their relatives, or, if necessary, legal representatives 
must be given ample opportunity to inquire about details of the study. 
Subject information and the ICF must be in a language fully comprehensible to the prospective 
subject. The written information must be provided to the subject to give him or her sufficient time 
to understand the information and to prepare questions before being asked for his or her consent. 
The investigator must confirm that the text was understood by the subject. The subject will then 
sign and date the IRB/IEC-approved consent form indicating that he or she has given his or her 
consent to participate in the study. The signature confirms that the consent is based on information 
that has been understood. The form will also be signed by the investigator obtaining the consent 
and annotated with the study subject number. Each subject’s signed ICF must be kept on file by 
the investigator for possible inspection by regulatory authorities, Mayne Pharma LLC, and/or the 
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sponsor’s designee. Collection of informed consent and/or assent has to be documented in the 
eCRF. 
Furthermore, the subject will be informed that if he or she wishes to drop out or withdraw (see 
Section 8.3) at any time during the study, this will not have any negative consequences. Subjects 
may be withdrawn by the investigator if any change related to safety or ethics precludes further 
participation in the study. Subjects will be asked to agree to a final assessment in the event of an 
early termination of the study. 
Subjects will be informed that data from their case may be stored in a computer without inclusion 
of their name and that such data will not be revealed to any unauthorized third party. Data will be 
reviewed by the monitor, an independent auditor, and possibly by representatives of regulatory 
authorities and/or IRBs/IECs. The terms of the local data protection legislation will be applied as 
appropriate. 
16.3. Approval by Institutional Review Board and Independent Ethics Committee 
A valid IRB/IEC must review and approve this protocol before study initiation. Written 
notification of approval is to be provided by the investigator to the sponsor’s or the sponsor’s 
representative before shipment of investigational drug supplies, and will include the date of the 
committee’s approval and the chairperson’s signature. This written approval must follow local 
country requirements. 
Until written approval by the IRB/IEC has been received by the investigator, no subject may 
undergo any procedure not part of routine care for the subject’s condition. 
Protocol amendments must also be reviewed and approved by the IRB/IEC. Written approval from 
the IRB/IEC, or a designee, must be received by Mayne Pharma LLC before implementation. 
16.4. Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator 
and the sponsor. 
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17. REFERENCES 
1. Vahlquist A, Blockhuys S, Steijlen P, 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 Derm. 2014;170(1):173-181. 
2. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited 
ichthyoses: results of the first ichthyosis consensus conference in sorèze 2009. J Am Acad 
Dermatol. 2010;63(4):607–-641. 
3. Vahlquist A, Gånemo A, Virtanen M. Congenital ichthyosis: an overview of current and 
emerging therapies. Acta Derm Venereol. 2008;88(1):4–14. 
4. Blanchet-Bardon C, Nazzaro V, Rognin C, Geiger JM, Puissant A. Acitretin in the 
treatment of severe disorders of keratinization. J Am Acad Dermatol. 1991;24(6):982–986. 
5. Kullavanijaya P and Kulthanan K. Clinical efficacy and side effects of acitretin on the 
disorders of keratinization: a one-year study. J Dermatol. 1993;20:501–506. 
6. Lacour M, Nikhar-Mehta B, Atherton DJ, Harper JI. An appraisal of acitretin therapy in 
children with inherited disorders of keratinization. Br J Dermatol. 1996;134:1023–1029. 
7. Steijlen PM, Van Dooren-Greebe RJ, Van De Kerkhof PCM. Acitretin in the treatment of 
lamellar ichthyosis. Br J Dermatol. 1994;130(2):211–214. 
8. Katugampola RP, Finlay AY. Oral retinoid therapy for disorders of keratinization: single-
centre retrospective 25 years’ experience on 23 patients. Br J Dermatol. 
2006;154(2):267-276. 
9. Gånemo A, Virtanen M, Vahlquist A. Improved topical treatment of lamellar ichthyosis: a 
double‐blind study of four different cream formulations. Br J Derm. 1999;141(6):1027–
1032. 
10. Kiistala R, Lauharanta J, Kanerva L. Transepidermal water loss and sweat gland response 
in lamellar ichthyosis before and during treatment with etretinate: report of three cases. 
Acta Derm Venereol. 1982;62(3):268–270. 
11. Ramirez ME, Youseef WF, Romero RG. Acute percutaneous lactic acid poisoning in a 
child. Pediatr Dermatol. 2006;23(3):282–285. 
12. Chiaretti A, Wismayer DS, Tortorolo L, Piastra M, Polidori G. Salicylate intoxication using 
a skin ointment. Acta Paediatr. 1997;86(3):330-331. 
13. Marukian NV, Deng Y, Gan G, et al. Establishing and validating an ichthyosis severity 
index. J Invest Dermatol. 2017;137(9):1834-1841. 
14. Korteweg SFS, Stenekes MW, van Zyl FE, Werker PMN. Paralytic ectropion treatment 
with lateral periosteal flap canthoplasty and introduction of the ectropion severity score. 
Plast Reconstr Surg Glob Open. 2014;2(5):e151. 
 
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18. ATTACHMENTS 
18.1. Investigator’s Agreement 
 
PROTOCOL NUMBER: 
18-ICH-001 
PROTOCOL TITLE: 
A Phase 2 Randomized, Multicenter, Double-blind, 
Vehicle-controlled, 90-Day, Safety, Efficacy, and Systemic 
Exposure Study followed by a 90-Day Open-label Extension of 
Trifarotene (CD5789) Cream HE1 in Adults and Adolescents with 
Autosomal Recessive Ichthyosis with Lamellar Scale 
AMENDMENT 2 DATE: 
28-Oct-2020 
The undersigned acknowledges possession of and has read the product information 
(e.g., investigator’s brochure) on the IP and has discussed these data with the study monitor. 
Having considered fully all the available information, the undersigned considers that it is ethically 
justifiable to give the IP to selected subjects in his/her care, according to the study protocol. 
He or she agrees to use the study material, including IP, only as specified in the protocol. He or 
she understands that changes cannot be made to the protocol without prior written approval of 
Mayne Pharma LLC. 
He or she understands that any deviation from the protocol may lead to early termination of the 
study. 
He or she agrees to report to Mayne Pharma LLC within time any clinical AE or abnormal 
laboratory value that is serious, whether or not considered related to the administration of IP. 
He or she agrees to comply with Mayne Pharma LLC and regulatory requirements for the 
monitoring and auditing of this study. In addition, he or she agrees that the study will be carried 
out in accordance ICH, the Declaration of Helsinki, and the local laws and regulations relevant to 
the use of new therapeutic agents. 
I, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the study. 
Principal Investigator: 
 
Printed Name: 
 
 
 
Signature: 
 
 
 
Date: 
 
 
 
Investigator’s name and address (stamp) 
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APPENDICES 
A. Regulations and Good Clinical Practice Guidelines 
B. Procedural Adjustments Due to COVID-19 
 
 
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A. Regulations and Good Clinical Practice Guidelines 
1. Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
Refer to the following European Directives (and applicable regulations/guidances): 
• European Directive 2001/20/EC and related guidance documents 
• European Directive 2005/28/EC and related guidance documents> 
2. Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URLs: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf 
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B. Procedural Adjustments Due to COVID-19 
The coronavirus (COVID-19) global pandemic has impacted the free movement of the world’s 
population, which has been restricted to control the spread of the disease. It is recommended that 
all sites and subjects comply with the applicable local and federal guidelines regarding the 
necessary and proper precautions regarding COVID-19. 
Trifarotene cream HE1 does not increase the risk for contracting COVID-19. 
Although it is preferable to conduct all necessary study assessments in person (on -site visits), this 
may not be possible as a result of COVID-19 -related travel restrictions site closures, or subject 
confinement. If the subject becomes infected with COVID-19, the investigator or the treating 
physician will decide on continuation of the study treatment; note that topical trifarotene does not 
modify immunity. 
The skin of individuals with LI is thick, scaly, and often dry, tight, and inelastic. This rigidity may 
produce major discomfort through formation of painful cracks in the skin and open areas. Extreme 
thickening of the skin on the soles of the feet can make walking difficult for many patients, and 
cracks and fissures on the fingers can make even simple tasks difficult or painful. Tight skin can 
interfere with joint mobility, and over time, lead to decreased joint mobility. Some individuals may 
be unable to close their eyes completely (ectropion) because of the tightness of the skin around the 
eyes and eyelids and may seem to "sleep with their eyes open." In addition, the general aspect of 
this chronic and difficult to manage skin disease often causes depression. For these reasons, as 
well as the lack of treatment options for individuals with LI, Mayne Pharma thinks it is important 
for this patient population to continue having access to the treatment offered in this study. 
The best way to ensure the reliability of the data collected is to follow the Study Protocol. 
However, the subjects’ safety and wellbeing is a top priority. Therefore, in extraordinary situations 
when it is inadvisable or not possible to conduct an onsite study visit, please follow these 
procedures. 
 
❑ Subject visits: 
Visits 3 to 6 of the Double-blind Period, Visits 7 to 11 of the OLE Period, and unscheduled visits 
may be conducted remotely (i.e., via telephone or video call). Screening and Baseline Visits must 
be performed onsite only and must be postponed or scheduled for when onsite visits can be safely 
conducted. The schedule of telephone visits will continue as indicated in the study protocol 
(Table 2-1 and Table 2-2); however, onsite visits will be postponed or rescheduled as possible. 
When it is not possible to postpone or reschedule the onsite visit, and to ensure the safety of the 
subjects and to not jeopardize the study procedures and the scientific value of the trial, onsite visits 
will be changed into telephone visits. As soon as the COVID-19 situation that triggered the use of 
these procedural adjustments is resolved, the schedule of onsite visits will resume. Information 
collected during the telephone visits will focus on safety data and primary objective endpoints. 
The following information is expected to be collected by the PI/study staff during the telephone 
visits, as applicable per protocol: 
 
• Ask/remind the subject about any required study procedure considered necessary 
and according to the protocol. For example: 
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o Ask the subject about study drug application 
o Remind the subject to complete the subject diary 
o Advise subjects regarding permitted emollient(s) and/or sunscreen for use 
on nontreatment days 
• Record concomitant medications and concomitant therapies 
• Record Adverse Events and information reported in the subject diary 
• Record the subject’s general health status 
• Assess local tolerance at the application sites 
• For efficacy assessments, use videoconference for precise scoring; if this is not 
possible, ask subject if status is the better, worse, or unchanged for the following 
assessments and enter the outcome for reference in the source data: 
o Investigator’s Global Assessment (IGA) 
o Visual Index for Ichthyosis Severity (VIIS) 
o Roughness 
o Palm/sole 
o Palm/sole fissuring 
o Ectropion 
• Record urine pregnancy test result for female subjects 
• Evaluate treatment compliance, including frequency of application and check if 
there is cream left in the tubes after application and approximately how much in 
conjunction with the subject’s diary 
• Adjust the treatment if necessary, as per study protocol, according to application 
site tolerance and treatment compliance 
 
Remote visits are not possible in the following instances: 
• Baseline visits will be canceled if the subject is unable to go to the site. If this 
occurs, rescreening may be necessary when the COVID-19 outbreak is resolved. 
• End-of-Treatment visits are recommended to occur onsite. Therefore, the telephone 
visit will be completed, followed by an onsite visit when the COVID-19 outbreak 
is resolved. 
 
❑ Pregnancy Tests 
Retinoids are potentially teratogenic and, therefore, monthly pregnancy tests for women of 
childbearing potential (WOCBP) are considered critical for subject safety. Consequently, urine 
pregnancy tests, along with the instructions on how to use them, will be sent to the subject’s home. 
The study staff will instruct the subjects how to properly perform the test during the telephone 
visits and will document it and the result. 
 
❑ Supply of Study Medication 
For all randomized subjects who have already attended the baseline visit (Day 1) and, have had 
study staff apply the first administration of the study drug in the clinic and instructed the subject, 
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should continue their treatments to ensure the reliability of the study data and the scientific value 
of the trial. Therefore, if the subject is not able to travel to the site, the site will ship the study drug 
and to the subject’s home using their preferred local courier service. Patient diaries may be sent to 
subjects electronically or via postal service. Completed diaries may be returned to the site in the 
same manner. 
Investigators/site staff will properly record that the subject has been told their study medication 
will be sent to their home, and when the study medication was received. Subjects should retain 
any unused IP and return them to the study site at the next onsite visit, when the study staff will 
weigh the kits (tubes and boxes, but not leaflets). 
 
❑ Quality of life per Dermatology Life Quality Index (DLQI) and EQ-5D Quality of Life 
Questionnaire 
Quality of Life questionnaires should be completed on the day of the remote visit and prior to 
applying treatment (if the remote visit falls on a treatment day). Questionnaires may be sent to 
subjects electronically or via postal service, and completed questionnaires may be returned to the 
site in the same manner. If subjects are unable to send completed questionnaires to the site, 
investigators should ask and record the subject’s responses during the remote visit. 
However, questions relative to social interaction might not be relevant due to social distancing 
and/or quarantining. This will be captured in the questionnaires and can be differentiated in the 
analysis. 
 
❑ Monitoring visits: 
If onsite monitoring visits are not possible as a consequence of COVID-19 outbreak, remote visits 
(via telephone) will be arranged in agreement with the study sites to assist the study progression 
and to ensure study compliance, without reducing the level of monitoring. 
 
❑ Participant Information 
Participating subjects must be promptly informed about changes in the study conduct during 
COVID-19 outbreak. Information about the changes should first be communicated to subjects via 
a telephone conversation. 
In addition, a Subject Information Sheet has been created to inform subjects about how the above-
mentioned changes might impact their usual participation in the study. The investigators/study 
staff will send this information sheet to the subject by the appropriate means (for example, via 
email or via courier). Investigators/study staff will confirm and document in the medical history 
the date the patient was informed via telephone and the date the Subject Information Sheet was 
mailed to and received by the subjects. 
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❑ Informed consent and/or assent process recommendations 
Where country regulation requires that the COVID-19 Information Sheet is signed by the subjects 
to express their consent to the changes in the study procedures due to COVID-19 or a subject is 
completing the double-blind part of the study and needs to consent to continue in the open label 
extension part, the process will be as follows: 
1) First option is to collect face-to-face written consent with the investigator according to ICH 
E6 (R2) and local regulation. 
2) When face-to-face written consent is not possible trial participants can be contacted via 
phone or video call to obtain remote consents as follows: 
a. Informed consent document/assent, if applicable, is emailed, faxed, or sent via 
courier or regular mail by site staff to subject prior to remote visit. 
• If document is emailed, subject should print document prior to visit. 
b. Subject will be contacted via phone or video call by the investigator/designee. 
Informed consent/assent discussion with the subject will be facilitated by the 
Investigator or staff delegated to perform this task 
• Investigator/designee will document details of the remote informed consent 
process in the trial participant’s medical records. 
c. Subject will sign and date informed consent/assent while on phone or video call 
with Investigator/designee 
• Investigator/designee will document the time and date that they witness the 
signing of the informed consent/assent via phone or video call in the trial 
participant’s medical records. 
d. Investigator/designee will sign and date copy of the Informed consent/assent 
documenting that they witnessed the signature of the subject via phone or video call 
e. Subject will send signed and dated informed consent by email or courier back to 
investigational site to be included in the subject file. 
• If sent by email, subject should save the original copy and bring it to his/her 
next onsite visit. 
f. Investigator/designee will attach the subject signed Informed consent/assent to the 
copy signed and dated by Investigator/designee upon receipt. 
g. When subject returns to the site, consent will occur face-to-face with site staff 
according to ICH E6 (R2) and local requirements. 
 
 
 
 
Video call will be used only if allowed per country regulation. If you have doubts on whether 
video call can be used in your country, please contact your CRA.  
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AD-PR-62.04 20-Jul-2012 
Page 1 of 1 
Note: Retain a word version of this file note to permit later updates/additions.  All updates/additions must be 
resigned.  Date each entry for updates. 
TYPE 
Protocol 
PROTOCOL 
Mayne 18-ICH-001 Amendment 2.0 
EFFECTIVE 
03-Nov-2020
 Tick here if Permanent 
TITLE 
Date change in protocol amendment 2.0 
FUNCTIONS AFFECTED 
Medical Writing/Clinical/SSU 
PURPOSE AND DETAILS
Provide 
all 
necessary 
information, being clear and 
concise. 
For 
file 
notes 
resulting from audits, DO 
NOT refer to the audit, state 
only the facts. 
File notes 
must not contain identifying 
information 
e.g., 
patient 
names. 
Date in footer on p. 2 was incorrect (27-Oct-2020) and was updated 
after signature to 28-Oct-2020. 
ACTIONS /IMPACTS 
Provide any corrective 
and preventative action 
(CAPA) plan, if 
applicable. 
Summarise any actions or impacts on general or study specific activities as a result of 
the reason for this file note. 
This note to file records the change of the protocol amendment date 
for p 2 to make consistent throughout the document. No further 
action is required. 
Note: Approval is ALWAYS required for file notes written on behalf of an Investigator. 
For all other file notes, if in doubt, check with your Supervisor/Department Head/Project Manager whether 
approval is required. 
AUTHOR: 
 
Kristen T. Drake 
Date 
Dir, Medical Writing 
APPROVER: 
Laura Tran-Viet 
Date 
Project Manager 
03-Nov-2020 | 12:20:41 EST
03-Nov-2020 | 12:23:01 EST
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Page 251 of 703 
FILE NOTE 


 
AD-MW-08.04 15-Apr-2016 
Page 1 of 133 
PROTOCOL/CLINICAL INVESTIGATION PLAN AMENDMENT 
 
PRODUCT NAME/NUMBER: 
Trifarotene (CD5789) Cream HE1 
PROTOCOL NUMBER: 
18-ICH-001 
IND NUMBER: 
140538 
NCT NUMBER:  
NCT03738800 
EUDRACT NUMBER: 
2018-003272-12 
DEVELOPMENT PHASE: 
2 
PROTOCOL TITLE: 
A Phase 2 Randomized, Multicenter, Double-blind, 
Vehicle-controlled, 12-Week, Safety, Efficacy, and 
Systemic Exposure Study followed by a 12-Week 
Open-label Extension of Trifarotene (CD5789) Cream 
HE1 in Subjects with Autosomal Recessive Ichthyosis 
with Lamellar Scale  
PROTOCOL DATE: 
Original: 28-Nov-2018 
AMENDMENT 1 DATE: 
Final v2.0, 21-Oct-2019 
AMENDMENT 2 DATE: 
Final v3.0 for Ukraine, 21-Nov-2019 
COORDINATING/PRINCIPAL 
INVESTIGATOR: 
Keith A. Choate, MD 
Department of Dermatology, Yale University School of 
Medicine,  
PO Box 208059 
333 Cedar Street 
New Haven, CT 06520, USA 
+1 203 789 1249 
SPONSORED BY: 
Mayne Pharma LLC 
1240 Sugg Parkway   
Greenville, NC 27834, USA  
+1 984 242 1400 
CONTRACT RESEARCH 
ORGANIZATION: 
Premier Research  
One Park Drive, Suite 150 
Durham, NC 27709, USA 
+1 919 627 9100 
This study will be performed in compliance with ICH Good Clinical Practices and applicable 
regulatory requirements, including the archiving of essential documents. Information contained in 
this protocol is confidential in nature and may not be used, divulged, published, or otherwise 
disclosed to others except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. Persons to whom this information 
· pharma 
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Page 2 of 133 
is disclosed should be informed that it is confidential and may not be further disclosed without the 
express permission of Mayne Pharma LLC. 
 
 
 
 
 
 
 
 
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1. APPROVAL SIGNATURES 
PROTOCOL NUMBER: 
18-ICH-001 
PROTOCOL TITLE: 
 
A Phase 2 Randomized, Multicenter, Double-blind, 
Vehicle-controlled, 12-Week, Safety, Efficacy, and Systemic 
Exposure Study followed by a 12-Week Open-label Extension of 
Trifarotene (CD5789) Cream HE1 in Subjects with Autosomal 
Recessive Ichthyosis with Lamellar Scale 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge, it 
accurately describes the planned conduct of the study. 
SIGNATURE 
 
DATE: 
 
 
 
 
 
 
Ilana Stancovski, PhD  
Chief Scientific Officer  
Mayne Pharma LLC 
 
 
 
 
 
 
Phoevos Hughes, JD 
Associate Director, Clinical Operations 
Mayne Pharma LLC 
 
 
 
 
 
 
Marlis Sarkany, MD 
Senior Medical Director 
Premier Research 
 
 
 
 
 
 
Adrienne Kuxhausen, MS 
Senior Biostatistician 
Premier Research 
 
 
27 Nov 2019
02-Dec-2019 | 10:50:55 EST
02-Dec-2019 | 09:55:42 EST
02-Dec-2019 | 07:35:16 PST
(
DocuSigned by: 
I r""'.,.,,,. *~ 
V 
Signer Name: Phoevos Hughes 
L
Signing R_eason: I approve this document 
S1gn1ng Time: 02-Dec-2019 I 07:35:12 PST 
2D 1 DC 1 CA65A848718371307 AF875E4CE 
(
DocuSigned by: 
I -,,,-~ 
V 
Signer Name: Marlis Sarkany 
L
Signing Reason: I have reviewed this document 
Signing Time: 02-Dec-2019 I 09:55:35 EST 
16E1 C8AEDC854CDC86688C1 FD466E26F 
(
DocuSigned by: 
I ~ •• """-~ 
V 
Signer Name: Adrienne Kuxhausen 
L
Signing R_eason: I approve this document 
Signing Time: 02-Dec-2019 I 10:50:53 EST 
6E6B87C6B98740819F26B8D5A7D662CF 
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2. PROTOCOL SUMMARY 
2.1. Synopsis 
PRODUCT 
NAME/NUMBER 
Trifarotene (CD5789) Cream HE1 
PROTOCOL 
NUMBER 
18-ICH-001 
EUDRACT 
NUMBER 
2018-003272-12 
DEVELOPMENT 
PHASE 
2 
PROTOCOL TITLE 
A Phase 2 Randomized, Multicenter, Double-blind, Vehicle-controlled, 12-Week, Safety, 
and Efficacy, and Systemic Exposure Study followed by a 12-Week Open-label Extension 
of Trifarotene (CD5789) Cream HE1 in Subjects with Autosomal Recessive Ichthyosis 
with Lamellar Scale  
INDICATION 
Lamellar ichthyosis 
OBJECTIVES 
Primary: To compare the safety and efficacy of 2 concentrations of trifarotene cream HE1 
versus vehicle in subjects with moderate to severe autosomal recessive ichthyosis with 
lamellar scale, also known as lamellar ichthyosis (LI) after 12 weeks of treatment. 
Secondary:  
• 
To assess systemic exposure to trifarotene and its major metabolites after topical 
application of the investigational product (IP) on up to 90% body surface area (BSA) 
twice weekly. 
• 
To assess safety for up to 24 weeks of dosing with open-label trifarotene cream HE1 
200 µg/g. 
STUDY DESIGN 
 
This is a 2-cohort, multicenter study in subjects with moderate to severe LI (i.e., 3–4 on 
a 5-point Investigator’s Global Assessment [IGA] where 0 = clear; 1 = almost clear; 
2 = mild; 3 = moderate; and 4 = severe). Subjects in Cohort A and Cohort B will be 
randomized in a double-blind fashion to 1 of 2 doses of trifarotene cream HE1 or vehicle 
and treated twice weekly for 12 weeks. Subjects who complete the randomized, Double-
blind Period of the study will be eligible to enter a 12-week, Open-label Extension (OLE) 
in which additional PK, safety, and efficacy data will be collected. 
Approximately 15 subjects will be randomized into the first cohort of subjects (Cohort A) 
in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or 
vehicle and treated twice weekly for up to 12 weeks. After the initial 15 subjects complete 
at least 28 days of treatment, an independent data safety monitoring board (DSMB) will 
review aggregate safety and tolerability data (including PK and electrocardiogram [ECG] 
data). If no safety issues are identified, an additional group of approximately 105 subjects 
will be allowed to enroll in Cohort B. Subjects in Cohort B will be randomized 1:1:1 to 
trifarotene cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle and treated 
twice weekly for up to 12 weeks in the same manner as subjects in Cohort A.  
All subjects (Cohort A and Cohort B) who complete the 12-week Double-blind Treatment 
Period will be eligible to enroll in the 12-week OLE. Subjects in the OLE will receive 
open-label trifarotene cream HE1 200 µg/g twice weekly for up to 12 weeks.  
Upon signing informed consent and entering the Screening Period, subjects may begin 
washout, during which they will stop using physical and medical treatments for LI, 
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including balneotherapy and the following prohibited medications, as applicable. 
Washout may be up to 3 months, as necessary.  
a. 
Topical treatments 
Medication 
Washout  
Corticosteroids (except inhaled and ophthalmic corticoids) 
2 weeks 
Retinoids (e.g., tretinoin, tazarotene) 
4 weeks 
Vitamin D analogues 
2 weeks 
Immunosuppressants (e.g., tacrolimus) 
2 weeks 
Antracen derivatives, tar and salicylic preparations 
2 weeks 
Keratolytics (such as urea, lactic acid, propylene glycol, 
salicylic acid) except keratolytic shampoo 
2 weeks 
b. Systemic treatments 
Medication 
Washout  
Retinoids 
8 weeks 
Oral Vitamin A supplementation more than 3500 IU per day 
2 weeks 
Medication interfering with bone activity, e.g., corticosteroids, 
thyroid hormones, cytotoxics, bisphosphonates, calcitonins, 
tetracyclines, quinolones, thiazides, salicylates in long-term 
course, heparin, theophylline, barbiturates, colchicines (except 
Vitamin D analogues taken at stable dose since at least 1 month) 
8 weeks 
QT prolonging drugs 
5 half lives 
Enzymatic inductors (such as rifampicine, phenytoin, 
carbamazepine, phenobarbital, St. John’s Wort) 
3 months 
CYP2C9 and 2C8 inhibitors (not all inclusive: gemfibrozil, 
fluconazole, fluvoxamine, sulfaphenazole, miconazole, 
amiodarone, sertraline, sulfamethoxazole, valproic acid, 
voriconazole, trimethoprim, rosiglitazone, pioglitazone) 
5 half lives 
Monoclonal antibody treatment (e.g., anti-IL17) 
5 half lives 
During washout, subjects may continue taking usual care of visible skin (face and scalp) 
for cosmetic reasons and of extremities (hands and feet) to avoid functional consequences 
on walking or moving their fingers. Subjects may shower, but not bathe or swim during 
the Screening Period.  
After completing any necessary washout of prohibited medications, subjects will return 
to the site to complete the study eligibility requirements. 
Study drug will be packaged in 50-g tubes from which up to 36 g of investigational 
product (IP) may be dispensed per application, i.e., the maximum dose per application. 
Study staff will apply the first dose of study drug to each subject in the clinic on Day 1 
after Baseline measurements, and will record the amount of study drug applied. If the 
product will be applied at home by someone other than the study subject, it is 
recommended that this person assist with application at the first visit to learn how the IP 
is applied. 
Thereafter, each subject will apply approximately the same amount (up to 36 g) of study 
drug as for the first dose on up to 90% of BSA twice weekly, sparing the scalp, inguinal, 
and axillary areas. Subjects will receive an adequate number of tubes to use 1 tube per 
application and will use a new tube for each treatment day. Subjects may use less than the 
full amount of product in a tube. Subjects will record the date and time of study treatment 
administration in the subject diary. 
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Local tolerability may differ in subjects with LI compared to healthy subjects, as their 
skin is drier and may be more sensitive. Local tolerability will be followed very carefully 
during the study. Subjects will receive information on study drug use and stopping rules 
and will be instructed to contact the site with any safety/tolerability issues. Study 
personnel will telephone subjects in between scheduled visits (i.e., at Day 7 and Day 45 
in the Double-blind Period; at Day 97 and 134 in the OLE) to assess safety; an 
unscheduled clinic visit may be performed, if necessary. If the treatment causes 
application site reactions, the frequency of application will be reduced or interrupted only 
on the area of concern, as indicated herein. During all clinic visits, the investigator will 
assess local tolerability (Scale: 0-3 [none, mild, moderate, severe]) for stinging/burning, 
pruritus, erythema) for each body area (chest/abdomen, back, arms, legs, and face/neck), 
and the following procedures will be followed: 
- 
If a score of 2 (moderate) is recorded on a local tolerability assessment scale 
(stinging/burning, pruritus, erythema) on any treated area, the study drug will be 
applied on that area only once weekly, until the score is back to <2. Continue to 
treat all other areas twice weekly provided the score is <2 on those areas. 
- 
If a score of 3 (severe) is recorded on a local tolerability assessment scale 
(stinging/burning, pruritus, erythema) on any treated area, the study drug will not 
be applied on that area until the score is back to <3 (i.e., “drug holiday”). Continue 
to treat all other areas twice weekly provided the score is <2 on those areas. 
Stopping rules and treatment modification will be defined at the subject level based on 
local tolerability, selected laboratory parameters, and adverse events (AEs). Any changes 
in dosing must be documented in the subject diary and the electronic case report form. 
All subjects will be provided with diaries in which to record study drug application 
(days/times and any areas of skin not treated [e.g., due to local reactions]) and any AEs, 
including application site reactions and concomitant medications used. Subjects will also 
be advised on permitted emollient(s) use on nontreatment days during the study; use of 
emollient(s) and/or sunscreen(s) on study drug treatment days within 4 hours before or 
after study drug application is prohibited. 
At all sites with photographic capability, photographs will be taken as source data to 
support scoring at Baseline, Day 30, and Day 90. A central reader who will not be an 
investigator in the study will review the photographs to assess consistency of investigator 
scoring of LI severity as a quality check. Photographs may also be used for scientific 
publication purposes. Subjects will sign a separate, optional photographic informed 
consent form (ICF). 
Samples for pharmacokinetic (PK) analysis will be drawn from all subjects at Baseline 
and at each clinic visit. Visits for PK must occur at least 24 hours after the last application 
of the IP to avoid contamination of the blood samples with any IP that may have remained 
on the skin after the last application. Subjects should not apply IP on visit days until after 
the visit. 
In addition, a PK substudy will be conducted on Days 1 and 30 at sites with the capability 
to conduct it. Participation in the PK substudy will be optional and will include at least 
30 subjects. Subjects who participate in the PK substudy will come from both study 
cohorts and will undergo serial blood sampling predose and at 1, 2, 4, 8, 12, and 24 hours 
postdose on Day 1 and Day 30. Trough levels will be drawn for these subjects at each of 
the other clinic visits. For the subjects in the PK substudy, postdose ECGs will be 
performed at each serial blood draw on Day 1 and Day 30. 
Subjects who complete the Double-blind Treatment Period will have the option to 
continue into the OLE to assess safety for an additional 12-weeks with trifarotene cream 
HE1 200 µg/g twice weekly, on up to 90% of BSA, sparing the scalp, inguinal, and 
axillary areas. Subjects with heavy facial hair should not apply IP to hair-bearing areas. 
During the OLE, subjects will return to the site at Weeks 14, 16, 20, 24, and 26 for safety, 
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tolerability, and efficacy assessments. Blood samples will be drawn for clinical laboratory 
safety tests and PK at Weeks 16 and 24. Study personnel will telephone subjects in 
between scheduled visits (i.e., at Day 97 and Day 134) to assess safety; an unscheduled 
clinic visit may be performed, if necessary.  
PLANNED 
NUMBER OF 
SUBJECTS 
Approximately 120 total subjects; 15 subjects in Cohort A and 105 subjects in Cohort B. 
STUDY ENTRY 
CRITERIA 
Inclusion criteria:  
1. Subject is ≥18 years old.  
2. Subject has known diagnosis of LI.  
3. Subject has moderate to severe (IGA 3-4) LI on the IGA of LI severity.  
4. Subject has signed an ICF at Screening before any investigational procedures.  
5. Subject who is participating in photography has signed a photography ICF. 
6. Subject who is participating in the optional PK substudy has signed a PK ICF. 
7. Subject is not of childbearing potential, i.e., a female who is postmenopausal 
(absence of menstrual bleeding for 1 year before Baseline, without any other 
medical reason, hysterectomy or bilateral oophorectomy),  
OR  
Subject is a woman of childbearing potential (WOCBP) or a male subject with sexual 
partners capable of reproduction who agrees to use 2 effective forms of contraception 
during the study and for at least 1 month after the last study drug application. The 
2 authorized forms of contraception are condom used with 1 of the following 
methods of contraception: 
• bilateral tubal ligation 
• combined oral contraceptives (estrogens and progesterone) or implanted or 
injectable contraceptives with a stable dose for at least 1 month before Baseline; 
hormonal contraceptives must inhibit ovulation 
• hormonal intrauterine device (IUD) inserted at least 1 month before Baseline 
OR 
Agrees to abstain from heterosexual intercourse during study participation and for 
1 month after the last application of study drug and to use a highly effective 
contraceptive as backup if he or she becomes sexually active during the study. 
Abstinence is only acceptable if this is the subject’s usual lifestyle. Periodic 
abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception. 
AND 
Male subjects may not donate sperm during the study and for at least 1 month after 
the last study drug application. 
8. Women of childbearing potential must be nonlactating and have negative pregnancy 
test results at Screening (serum) and on Day 1 before study drug administration 
(urine). 
9. Subject is reliable and capable of adhering to the protocol and visit schedule, in the 
investigator’s judgment, and has signed informed consent. 
10. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin). 
 
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Exclusion criteria: 
1. Subject has any variant of ichthyosis other than LI or another disorder of 
keratinization, including syndromic ichthyoses.  
2. Subject has current moderate or severe stinging/burning at Screening. 
3. Subject has an ongoing cutaneous infection or any other significant concomitant skin 
disease (other than the LI) which, in the investigator’s opinion, may interfere with 
the study assessments. 
4. Subject with a known lipid disorder (hypertriglyceridemia >200 mg/dL, 
hypercholesterolemia >250 mg/dL) unless well controlled by stable doses of 
lipid-lowering agents for at least 6 months. 
5. Subject was previously treated with trifarotene/CD5789 in an acne or ichthyosis 
study.  
6. Subject has any other significant concomitant disease, or poorly controlled medical 
condition other than LI that in the investigator’s opinion may put him or her at risk if 
he or she takes part in the study, and/or that may interfere with the study assessments. 
7. Subject has a medical condition that potentially alters bone metabolism 
(e.g., osteoporosis, thyroid dysfunction, Cushing syndrome, Crohn’s disease, or 
ulcerative colitis). 
8. Subject is being treated for major depression disorder and/or has a history of major 
depression or suicide attempt requiring hospitalization, medications, and close 
psychiatric surveillance to prevent suicide attempts.  
9. Subject with positive serology for hepatitis B surface antigen, hepatitis C, or are 
known to be HIV positive or to have AIDS at Screening. 
10. Subject with any of the following laboratory values at Screening: 
a. 
Aspartate aminotransferase or alanine aminotransferase >1.5 × upper limit 
of normal defined by the laboratory 
b. Total bilirubin >1.1 mg/dL or, in case of Gilbert’s syndrome, total bilirubin 
>3 mg/dL 
c. 
Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women 
d. Platelets <150 × 109/L or >400 × 109/L 
11. Subject has any clinically other significant abnormal laboratory value (hematology, 
chemistry, or urinalysis) at Screening that, in the investigator’s opinion, may put the 
subject at risk if he or she takes part in the study, and/or that may interfere with the 
study assessments. 
12. Subject has had recent systemic malignancy (e.g., within 5 years) with exception of 
nonmelanoma skin cancer or cervical intraepithelial neoplasia of Grade 1 who are 
>6 months post-treatment. 
13. Subject has a history of long QT syndrome or clinically significant electrocardiogram 
(ECG) abnormalities, including clinically significant conduction disorders or 
significant arrhythmias, QTcF interval >450 ms, PR interval is not between 120 and 
220 ms (inclusive), HR >100 bpm or <50 bpm, QRS interval >110 ms, or 
QT intervals that cannot be consistently analyzed. 
14. Subject has a known allergy or sensitivity to any of the components of the 
investigational products.  
15. Subject has been exposed to excessive ultraviolet (UV) radiations on the treated 
zones within 1 month before Baseline visit or is planning intensive UV exposure 
during the study (e.g., occupational exposure to the sun, sunbathing, phototherapy, 
etc.). 
16. Subject is inherently sensitive to sunlight. 
17. Subject is unable or unwilling to stop use of topical or systemic retinoids. 
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18. Subject is presumed to be abusing drugs or alcohol at Screening or Baseline Visits 
based on medical history or current clinical symptoms. 
19. Subject is participating in another interventional clinical trial. 
20. Subject is institutionalized. 
21. Subject is in any way related to the sponsor, investigator, or site personnel. 
INVESTIGATIONAL 
PRODUCT 
Name: Trifarotene (CD5789) cream HE1  
Double-blind Period dose, route, frequency: A fixed dose (up to 36 g per dose, determined 
at Visit 2) of 100 µg/g or 200 µg/g applied topically twice weekly on up to 90% BSA  
Open-label Extension dose, route, frequency: A fixed dose (up to 36 g per dose, 
determined at Visit 2) of 200 µg/g applied topically twice weekly on up to 90% BSA 
REFERENCE 
PRODUCT 
Name: Vehicle cream 
Double-blind Period dose, route, frequency: A fixed dose (up to 36 g per dose, determined 
at Visit 2) applied topically twice weekly on up to 90% BSA  
TREATMENT 
REGIMENS 
Topical application twice weekly to all affected skin except the scalp, axillae, and inguinal 
area.   
COORDINATING/ 
PRINCIPAL 
INVESTIGATOR 
Keith A. Choate, MD 
Department of Dermatology, Yale University School of Medicine 
New Haven, CT 06520, USA 
PLANNED STUDY 
SITES 
Approximately 40 sites across North America, Europe, Israel, and Australia 
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CRITERIA FOR 
EVALUATION 
Primary efficacy endpoint: The proportion of subjects in each treatment group who 
experience successful resolution of LI where “success” is defined as clear/almost clear on 
treated areas and at least a 2-grade change from Baseline at Week 12/end-of-treatment 
(EOT) in the Double-blind Period on the 5-point IGA full body scale.  
Secondary endpoints:  
− 
The difference in mean scores between the active trifarotene cream HE1 and 
vehicle groups in the following assessment indices from Baseline through Week 12: 
− 
5-point Visual Index for Ichthyosis Severity (VIIS) for scaling from 
Baseline through Week 12 (overall 16 points for scaling, i.e., 0-4 points for 
4 body areas: chest/abdomen, back, arms, and legs) 
− 
Individual score for roughness (Scale: 0–4) overall 
− 
Palm/sole Assessment (Scale: 0–4)  
• 
Quality of life per Dermatology Life Quality Index (DLQI)  
− 
The difference in proportion of subjects with presence of fissures on palms/soles 
(presence/absence, number of fissures, and pain associated with fissures on a 
0-3 scale) at Week 12 between the active trifarotene cream HE1 and vehicle groups 
Exploratory endpoints:  
− 
The difference in mean ectropion (Ectropion Severity Score [ESS] of 0–8) scores 
between the active trifarotene cream HE1 and vehicle groups from Baseline through 
Week 12 
− 
The difference in quality of life per EQ-5D-5L score between the active trifarotene 
cream HE1 and vehicle groups from Baseline through Week 12 
Safety endpoints:  
− 
Reported serious adverse events (SAEs), treatment-emergent AEs (TEAEs), and 
changes in clinical laboratory tests, vital signs, physical examinations, and 12-lead 
ECGs  
− 
Local tolerability (Scale: 0-3 [none, mild, moderate, severe], determined by the 
investigator) for each body area (chest/abdomen, back, legs, arms, and face/neck). 
Pharmacokinetic endpoints: Plasma concentrations of CD5789 and its major metabolites 
will be measured. 
STATISTICAL 
METHODS 
Analysis Populations:  
The following are planned for the Double-blind Period of the study: 
The Safety population will be the primary population for analyses of safety and 
tolerability and will comprise all subjects who are randomized to treatment and receive at 
least 1 application of study drug.  
The intent-to-treat (ITT) population will comprise all randomized subjects. This 
population will be used as the primary population for the analysis of efficacy for the 
Double-blind Period of the study. 
The modified intent-to-treat (mITT) population comprises all subjects in the safety 
population with at least 1 postbaseline assessment of efficacy in the Double-blind Period. 
This population will be used as the primary population for the analysis of efficacy for the 
Double-blind Period of the study. 
The per protocol (PP) population will be defined prior to database lock and will comprise 
subjects in the mITT population who met all inclusion criteria and no exclusion criteria, 
were compliant with study drug application, and who had no significant protocol 
deviations.  
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The PK population includes all subjects in the Safety Population who have at least 
1 plasma sample with quantifiable concentration. The PK population will be used to 
summarize all PK endpoints. 
The following populations are planned for the OLE of this study: 
The OLE Safety population: all subjects who complete the 12-week Double-blind 
Treatment Period and receive at least 1 application of study drug in the OLE. 
OLE ITT population: all subjects who complete the 12-week Double-blind Period and 
who sign the OLE informed consent. 
The OLE mITT population: all subjects in the OLE safety population with at least 
1 assessment of efficacy after Visit 6. 
The OLE PP population: all subjects in the OLE mITT population who met all inclusion 
criteria and no exclusion criteria, were compliant with study drug application from 
baseline through EOT, and who had no significant protocol deviations throughout the 
study. 
Subject Characteristics and Disposition: Descriptive statistics will be used to summarize 
demographic characteristics (age, sex, ethnicity, and race) and baseline characteristics for 
all enrolled subjects. Medical history, physical examination findings, and vital sign 
measurements for all randomized subjects will be presented in listings. 
Efficacy Analyses: The number and proportion of subjects in each treatment group with 
successful resolution of LI by Week 12/EOT in the Double-blind Period will be presented. 
The primary efficacy endpoint will be analyzed using a logistic regression model with 
treatment and age group as factors. Other baseline characteristics and interactions may be 
included. The odds ratios and 95% CIs for the odds ratios will be presented. The difference 
in proportions between the active trifarotene cream HEI and vehicle cream groups, 
95% CIs for the differences, and P-values for the differences in treatment will also be 
presented. 
The IGA scores as well as secondary and exploratory efficacy endpoints will be analyzed 
by visit using descriptive statistics through Week 24. Change from Baseline through 
Week 12 will be presented and analyzed using a mixed model for repeated measures 
(MMRM). The model will include the change from Baseline score as the dependent 
variable, treatment group as a fixed effect, subject as a random effect, and Baseline score 
value as a covariate. Frequencies of results and 95% confidence intervals will also be 
reported, and scores will be analyzed as categorical variables using the Cochran-Mantel-
Haenszel test. For subjects who report having fissures, the number of fissures and pain 
related to fissures will also be presented on a scale of 0-3 (none, mild, moderate, severe). 
Clinical Pharmacology Analyses: Noncompartmental PK analysis will be performed for 
the PK subset of subjects, as data permit. Plasma concentrations of CD5789 and its major 
metabolites will be measured and will be listed by subject. 
Safety Analyses: Safety and tolerability will be assessed based on the incidence of 
reported TEAEs, and SAEs, including relationship to study drug and severity, as well as 
physical examination findings, vital sign measurements (supine systolic blood pressure 
[SBP] and diastolic blood pressure [DBP] and pulse), clinical laboratory results 
(hematology, including serum aminotransferases and serum lipids, coagulation, clinical 
chemistry, and urinalysis) and 12-lead ECGs. Descriptive statistics for observed values 
and change from Baseline will be calculated at each visit within each study period and by 
treatment group within cohort. 
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SAMPLE SIZE 
DETERMINATION 
The first cohort of 15 subjects is a reasonable sample size to assess safety and tolerability 
before enrolling additional subjects in Cohort B. Accounting for a 20% drop-
out/nonevaluable rate, a total sample size of 120 subjects randomized in a 1:1:1 ratio to 
2 active trifarotene cream HE1 arms and a vehicle cream arm will provide >80% power 
to detect a difference between each separate trifarotene cream HE1 arm (32 evaluable 
subjects) and the vehicle cream arm (32 evaluable subjects) 2-sided Fisher’s Exact Test 
assuming a 70% success rate and a 40% success rate, respectively. This study is not 
powered to detect a difference between the 2 active arms. 
STUDY AND 
TREATMENT 
DURATION 
The sequence and maximum duration of the study will be as follows:  
1. Screening: Up to 35 days (after signing informed consent, if necessary, washout may 
be up to 3 months, and subjects should return to the site after washout to complete 
the study eligibility requirements). 
2. Double-blind study drug application: Twice weekly for up to 12 weeks.  
3. Optional Open-label Extension: Twice weekly for up to 12 weeks. 
4. Follow-up: 14 days after last study drug application. 
The maximum study duration for each subject is approximately 229 days 
(33 weeks).  
The maximum treatment duration for each subject is 24 weeks. 
 
 
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2.2. Schedule of Events  
Table 2-1: 
Schedule of Events for Double-blind Period 
 
 
Double-blind Treatment Period 
 
Screening 
(-35 days to -1 day) 
Washout up to 3 monthsa 
 
 
Baseline  
(Day 1) 
Telephone 
Visit 
(Day 7) 
Day 14  
± 5 days 
Day 30  
± 7 days 
Telephone 
Visit 
(Day 45) 
Day 60  
± 7 days 
Day 90b,c 
± 7 days 
(ET) 
Visit 
1 
2 
 
3 
4 
 
5 
6 
Week 
 
1 
 
2 
4 
 
8 
12 
Written informed consent  
X 
 
 
 
 
 
 
Xa 
Assign screening number 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
Physical examination  
X 
X d 
 
 
 
 
 
X c 
Vital signs (blood pressure and pulse)  
X 
X 
 
X 
X 
 
X 
X 
Height, weight, and BMI  
X 
 
 
 
 
 
 
X 
IGA assessmente 
X 
X 
 
X 
X 
 
X 
X 
VIISf assessment 
X 
X 
 
X 
X 
 
X 
X 
Roughness assessmentg 
X 
X 
 
X 
X 
 
X 
X 
Palm/sole assessment  
X 
X 
 
X 
X 
 
X 
X 
Palm/sole fissuring assessmenth 
X 
X 
 
X 
X 
 
X 
X 
Ectropion score  
X 
X 
 
X 
X 
 
X 
X 
Photographsi 
 
X 
 
 
X 
 
 
X 
Quality of life per Dermatology Life 
Quality Index (DLQI) 
 
X 
 
X 
X 
 
X 
X 
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Double-blind Treatment Period 
 
Screening 
(-35 days to -1 day) 
Washout up to 3 monthsa 
 
 
Baseline  
(Day 1) 
Telephone 
Visit 
(Day 7) 
Day 14  
± 5 days 
Day 30  
± 7 days 
Telephone 
Visit 
(Day 45) 
Day 60  
± 7 days 
Day 90b,c 
± 7 days 
(ET) 
Visit 
1 
2 
 
3 
4 
 
5 
6 
Week 
 
1 
 
2 
4 
 
8 
12 
EQ-5D Quality of Life Questionnaire 
 
X 
 
X 
X 
 
X 
X 
12-lead ECGj 
X 
X 
 
 
X 
 
 
X 
Clinical laboratory tests (hematology, 
chemistry, urinalysis)k 
X 
X 
 
 
X 
 
 
X 
Serology (hepatitis B surface antigen, 
hepatitis C) 
X 
 
 
 
 
 
 
 
Pregnancy test for female subjects 
(serum at Screening; urine 
subsequently) 
X 
X 
 
 
X 
 
X 
X 
Randomization via IWRS 
 
X 
 
 
 
 
 
 
PK blood sample collectionl 
 
X 
 
X 
X 
 
X 
X 
Initial study drug application by clinic 
staff and measurementm 
 
X 
 
 
 
 
 
 
Application instructions, advice on 
emollient and sunscreen use 
 
X 
X 
X 
X 
X 
 
 
Dispense study drug and diariesn 
 
Xn 
 
X 
X 
 
X 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
Tolerability assessment  
 
X 
 
X 
X 
 
X 
X 
Adverse events (and review diaries) 
 
X 
X 
X 
X 
X 
X 
X 
Collect all used/unused study drugo 
 
 
 
X 
X 
 
X 
X 
Provide information about OLE option 
 
 
 
 
X 
X 
X 
 
Abbreviations: BMI = body mass index; DLQI = Dermatology Life Quality Index; ECG = electrocardiogram; ET = early termination; HEENT = head, eyes, ears, 
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nose, throat; ICF = informed consent form; IGA = Investigator’s Global Assessment; IWRS = interactive web response system; OLE = open-label extension; 
PK = pharmacokinetic; WOCBP = women of childbearing potential; VIIS = Visual Index for Ichthyosis Severity 
a. 
Upon signing informed consent and entering the Screening Period, subjects will stop using physical and medical treatments for LI, including balneotherapy, 
and may begin to washout prohibited topical and systemic treatments with designated washout periods, as applicable. Washout may be up to 3 months, as 
necessary. During washout, subjects may continue taking usual care of visible skin (face and scalp) for cosmetic reasons and of extremities (hands and feet) 
to avoid functional consequences on walking or moving their fingers. Subjects may shower, but not bathe or swim during the Screening Period. After 
completing any necessary washout of prohibited medications, subjects will return to the site to complete the study eligibility requirements. 
b. Day 90 procedures should be conducted for subjects who terminate the study early. If a subject discontinues IP, but continues to attend clinic visits, Day 90 
will occur as scheduled. Day 90/Week 12 will be the first visit of the OLE for subjects who choose to continue (subjects will have up to 7 days to decide to 
sign the ICF and begin the OLE). Subjects who decide to continue into the OLE will have the following additional procedures: 1) sign informed consent; 2) 
will be weighed; 3) will be instructed on study drug application; 4) will be given new diaries, and 5) will be provided with study drug. 
c. 
A Follow-up telephone call will be made within 14 days after Day 90 to subjects who choose not to continue into the OLE. 
d. Limited physical examination to include HEENT, cardiorespiratory, abdomen, range of motion.  
e. 
IGA: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe. 
f. 
VIIS scale for each body area: chest/abdomen, back, legs, and arms, for a possible overall score = 16. 
g. Roughness (0-4 scale);  
h. Palm/sole fissuring assessment: present/absent/number/pain (0-3 scale). 
i. 
Photography will be performed at sites with the capability for subjects who sign a photographic ICF. A central reader who will not be an investigator in the 
study will review the photographs to assess consistency of investigator scoring of LI severity as a quality check. 
j. 
ECG to be conducted at Screening, Baseline, Day 30, and Day 90 for all subjects. Subjects in the PK substudy will also have postdose ECGs at each serial 
blood draw on Day 1 and Day 30. 
k. Subjects must be fasting (i.e., at least 8 hours) 
l. 
Samples for PK will be drawn from all subjects at Baseline and at each clinic visit. At selected sites among subjects who consent to participate in the PK 
substudy, samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1. On Day 30, IP will be applied in the clinic for PK substudy 
subjects, and PK samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose. Trough levels will be drawn when the subjects are in the clinic 
for other study visits (i.e., Day 14, Day 60, and Day 90). Visits for PK must occur at least 24 hours after the last application of the IP to avoid contamination 
of the blood samples with any IP that may have remained in the skin after the last application. 
m. Study staff will apply initial dose of study drug in the clinic after Baseline measurements, and the amount of study drug used will be measured (i.e., 
36-g tube will be measured before and after application to determine amount used) to determine fixed dose. 
n. Study drug provided in 50-g tubes (maximum single application is 36 g). Measure study drug tubes before dispensing; subjects must record days/times of 
study drug application in the diaries and any areas of skin not treated, e.g., due to local reactions). Dispense enough additional study drug until next visit 
(except at Day 90, unless subject consents to continue into OLE). 
o. Confirm study drug compliance by measuring tube weight and reviewing diary.  
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Table 2-2: 
Schedule of Events for Open-label Extension  
 
Open-label Treatment Period 
Follow-up 
 
 
Telephone 
Visit 
(Day 97)a 
Day 104  
± 5 days 
Day 120  
± 7 days 
Telephone 
Visit 
(Day 134) 
Day 150 
± 7 days 
Day 180  
± 7 
days/ET 
Day 194 or 14 days after End of 
Open-label Treatment 
Visit 
 
7 
8 
 
9 
10 
11 
Week 
 
14 
16 
 
20 
24 
26 
Informed consenta 
 
 
 
 
 
 
 
Physical examinationb 
 
 
 
 
 
X 
X 
Vital signs (blood pressure and 
pulse)  
 
 
X 
X 
 
X 
X 
Weight 
X 
 
 
 
 
 
 
Record IGAc  
 
X 
X 
 
X 
X 
X 
VIISd assessment 
 
X 
X 
 
X 
X 
X 
Roughness assessmente 
 
X 
X 
 
X 
X 
X 
Palm/sole assessment 
 
X 
X 
 
X 
X 
X 
Palm/sole fissuring assessment 
 
X 
X 
 
X 
X 
X 
Ectropion score  
 
 
X 
X 
 
X 
X 
Clinical laboratory tests 
(hematology, chemistry, 
urinalysis),f 
 
 
X 
 
 
X 
 
Pregnancy test for female 
subjects (urine) 
 
 
X 
 
X 
X 
X 
ECG 
 
 
X 
 
 
X 
 
PK blood sample collectiong 
 
 
X 
 
 
X 
 
Application instructions, advice 
on emollient and sunscreen useh 
X 
X 
X 
X 
 
 
 
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Open-label Treatment Period 
Follow-up 
 
 
Telephone 
Visit 
(Day 97)a 
Day 104  
± 5 days 
Day 120  
± 7 days 
Telephone 
Visit 
(Day 134) 
Day 150 
± 7 days 
Day 180  
± 7 
days/ET 
Day 194 or 14 days after End of 
Open-label Treatment 
Visit 
 
7 
8 
 
9 
10 
11 
Week 
 
14 
16 
 
20 
24 
26 
Dispense study drug and 
diariesi 
 
X 
X 
 
X 
 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
Tolerability assessment  
 
X 
X 
 
X 
X 
 
Adverse events (and review 
diaries) 
X 
X 
X 
X 
X 
X 
X 
Collect all used/unused study 
drugj  
 
X 
X 
 
X 
X 
 
Abbreviations: ECG = electrocardiogram; ET = early termination; HEENT = head, eyes, ears, nose, throat; ICF = informed consent form; IGA = Investigator’s 
Global Assessment; PK = pharmacokinetic; OLE = open-label extension; VIIS = Visual Index for Ichthyosis Severity; WOCBP = women of childbearing 
potential 
a. Subjects will sign the OLE ICF at the Double-blind Day 90/Week 12 Visit or within 7 days thereafter. All efficacy assessments, safety/tolerability 
assessments, including clinical laboratory testing and PK from Day 90/Week 12 will be carried over for the OLE and will not be repeated.  
b. Limited physical examination to include HEENT, cardiorespiratory, abdomen, range of motion.  
c. IGA: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe  
d. VIIS scale for each body area: chest/abdomen, back, legs, and arms, for a possible overall score = 16. 
e. Roughness (0-4 scale); fissuring assessment on palms/soles: present/absent/number/pain (0-3 scale). 
f. Subjects must be fasting (at least 8 hours) 
g. Samples for PK will be drawn from all subjects at Day 120 and Day 180. Visits for PK must occur at least 24 hours after the last application of the IP to avoid 
contamination of the blood samples with any IP that may have remained in the skin after the last application. 
h. Subjects must record days/times of study drug application in the diaries and any areas of skin not treated (e.g., due to local reactions).  
i. All subjects in the OLE will receive trifarotene 200 µg/g. Study drug provided in 50-g tubes (maximum single application is 36 g). Measure study drug tubes 
before dispensing. Dispense enough additional study drug until the next visit (except at Day 180). 
j. Confirm study drug compliance by measuring tube weight and reviewing diary. 
 
 
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3. TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES ...................................................................................................3 
2. 
PROTOCOL SUMMARY ........................................................................................................4 
2.1. Synopsis ..........................................................................................................................4 
2.2. Schedule of Events ........................................................................................................13 
3. 
TABLE OF CONTENTS .......................................................................................................18 
3.1. List of In-Text Tables ...................................................................................................22 
3.2. List of In-Text Figures ..................................................................................................23 
REASONS FOR AMENDMENT ..................................................................................................24 
SUMMARY OF AMENDED SECTIONS ....................................................................................26 
AMENDED PROTOCOL .............................................................................................................57 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...........................................58 
5. 
INTRODUCTION ..................................................................................................................60 
5.1. Background and Rationale ............................................................................................60 
5.1.1 CD5789 (Trifarotene) ........................................................................................61 
5.2. Clinical Experience .......................................................................................................61 
5.3. Summary of Potential Risks and Benefits .....................................................................62 
6. 
OBJECTIVES .........................................................................................................................64 
6.1. Primary Objective .........................................................................................................64 
6.2. Secondary Objectives ....................................................................................................64 
7. 
STUDY DESIGN ...................................................................................................................65 
7.1. Overall Study Design and Plan .....................................................................................65 
7.2. Rationale and Discussion of Study Design ...................................................................70 
7.3. Selection of Doses in the Study ....................................................................................70 
7.4. Study Sites .....................................................................................................................70 
7.5. Point of Contact ............................................................................................................71 
7.6. End of Study Definition ................................................................................................71 
8. 
SUBJECT POPULATION .....................................................................................................72 
8.1. Selection of Study Population and Diagnosis ...............................................................72 
8.2. Study Entry Criteria ......................................................................................................72 
8.2.1 Inclusion Criteria ...............................................................................................72 
8.2.2 Exclusion Criteria ..............................................................................................73 
8.3. Premature Subject Withdrawal .....................................................................................74 
8.4. Discontinuation of Study Intervention ..........................................................................74 
8.5. Subject Replacement Criteria ........................................................................................75 
9. 
TREATMENTS ......................................................................................................................76 
9.1. Identification of Investigational Product(s) ..................................................................76 
9.2. Treatments Administered ..............................................................................................76 
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9.3. Selection of Timing of Dose for Each Subject..............................................................77 
9.4. Dose Adjustment Criteria ..............................................................................................77 
9.4.1 Stopping Rules ..................................................................................................78 
9.5. Treatment Compliance ..................................................................................................78 
9.6. Method of Assigning Subjects to Treatment Groups ....................................................78 
9.7. Blinding and Unblinding Treatment Assignment .........................................................79 
9.8. Permitted and Prohibited Therapies ..............................................................................79 
9.8.1 Permitted Therapies ...........................................................................................80 
9.8.2 Prohibited Therapies ..........................................................................................81 
9.8.3 Restrictions ........................................................................................................81 
9.9. Treatment after End of Study ........................................................................................81 
9.10. Dispensing and Storage .................................................................................................81 
9.11. Drug Accountability ......................................................................................................82 
9.12. Labeling and Packaging ................................................................................................82 
9.12.1 Labeling .............................................................................................................83 
9.12.2 Packaging ..........................................................................................................83 
10. STUDY PROCEDURES ........................................................................................................84 
10.1. Study Duration ..............................................................................................................84 
10.1.1 Overall Study Schedule .....................................................................................84 
10.2. Study Periods and Visits ...............................................................................................84 
10.2.1 Screening and Washout .....................................................................................84 
10.2.1.1 Screening Visit (Visit 1) .......................................................................84 
10.2.1.2 Washout ................................................................................................85 
10.2.2 Double-blind Treatment Period .........................................................................85 
10.2.2.1 Baseline Visit (Visit 2, Day 1) ..............................................................85 
10.2.2.2 Telephone Visit (Day 7) ........................................................................87 
10.2.2.3 Visit 3 (Day 14 ±5 days) .......................................................................87 
10.2.2.4 Visit 4 (Day 30 ±7 days) .......................................................................87 
10.2.2.5 Telephone Visit (Day 45) ......................................................................89 
10.2.2.6 Visit 5 (Day 60 ±7 days) .......................................................................89 
10.2.2.7 Visit 6 (90 ±7 days) or Early Termination ............................................90 
10.2.3 Follow-up Telephone Call (±14 days after Day 90) – Only Subjects Who Do Not 
Continue into Open-label Extension .................................................................91 
10.2.4 Open-label Extension ........................................................................................91 
10.2.4.1 Telephone Visit (Day 97) ......................................................................91 
10.2.4.2 Visit 7 (Week 14; Day 104 ±5 days) .....................................................91 
10.2.4.3 Visit 8 (Week 16; Day 120 ±7 days) .....................................................92 
10.2.4.4 Telephone Visit (Day 134) ....................................................................92 
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10.2.4.5 Visit 9 (Week 20; Day 150 ±7 days) .....................................................93 
10.2.4.6 Visit 10 (Week 24; Day 180 ±7 days) or Early Termination ................93 
10.2.4.7 Follow-up Evaluation – Open-Label Extension (Week 26/Visit 11) ....94 
10.3. Assessments ..................................................................................................................94 
10.3.1 Efficacy Variables .............................................................................................94 
10.3.1.1 Investigator’s Global Assessment .........................................................94 
10.3.1.2 Visual Index for Ichthyosis Severity – Scaling .....................................95 
10.3.1.3 Individual Score for Roughness ............................................................95 
10.3.1.4 Palm/Sole Assessment ..........................................................................96 
10.3.1.5 Fissuring Assessment ............................................................................96 
10.3.1.6 Dermatology Life Quality Index ...........................................................96 
10.3.1.7 EQ-5D Quality of Life Questionnaire ...................................................96 
10.3.1.8 Ectropion Severity Score ......................................................................96 
10.3.1.9 Photography Substudy ..........................................................................97 
10.3.2 Clinical Pharmacology ......................................................................................97 
10.3.2.1 Pharmacokinetic Analysis Methods ......................................................97 
10.3.2.2 Pharmacokinetic Parameters .................................................................97 
10.3.3 Sample Collection .............................................................................................98 
10.3.4 Safety Variables ................................................................................................99 
10.3.4.1 Clinical Laboratory Safety Assessments ...............................................99 
10.3.4.2 Clinical Examinations .........................................................................100 
10.3.4.3 Adverse Events ...................................................................................101 
11. ADVERSE EVENTS ............................................................................................................102 
11.1. Definitions ...................................................................................................................102 
11.1.1 Adverse Events ................................................................................................102 
11.1.2 Adverse Drug Reaction ...................................................................................102 
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction ......................................102 
11.1.4 Serious Adverse Events/Drug Reaction ..........................................................103 
11.1.5 Significant Adverse Events .............................................................................103 
11.1.6 Treatment-Emergent Adverse Events .............................................................103 
11.2. Event Assessment and Follow-up of Adverse Events ................................................103 
11.2.1 Assessment ......................................................................................................104 
11.2.2 Evaluation ........................................................................................................105 
11.2.2.1 Severity of Adverse Events .................................................................105 
11.2.2.2 Seriousness ..........................................................................................105 
11.2.2.3 Action(s) Taken ...................................................................................105 
11.2.2.4 Outcome at the Time of Last Observation ..........................................106 
11.2.2.5 Adverse Event Relationship to Investigational Product......................106 
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11.2.3 Documentation ................................................................................................107 
11.2.4 Treatment of Adverse Events ..........................................................................107 
11.2.5 Follow-up ........................................................................................................107 
11.2.6 Reporting .........................................................................................................108 
11.2.6.1 Serious Adverse Events.......................................................................108 
11.2.6.2 Adverse Drug Reactions .....................................................................109 
11.2.6.3 Nonserious Adverse Events ................................................................109 
11.3. Special Considerations ................................................................................................109 
11.3.1 Adverse Events of Special Interest ..................................................................109 
11.3.2 Pregnancy ........................................................................................................109 
12. DATA SAFETY MONITORING BOARD .........................................................................111 
13. STATISTICS ........................................................................................................................112 
13.1. Statistical Analysis ......................................................................................................112 
13.1.1 Analysis Populations .......................................................................................112 
13.1.2 Study Subjects and Demographics ..................................................................113 
13.1.2.1 Disposition and Withdrawals ..............................................................113 
13.1.2.2 Protocol Deviations .............................................................................113 
13.1.2.3 Demographics and Other Baseline Characteristics .............................113 
13.1.3 Exposure and Compliance ...............................................................................114 
13.1.4 Efficacy Analysis ............................................................................................114 
13.1.4.1 Efficacy Endpoints ..............................................................................114 
13.1.4.2 Primary Analysis .................................................................................115 
13.1.4.3 Secondary Analyses ............................................................................115 
13.1.4.4 Exploratory Analyses ..........................................................................115 
13.1.4.5 Corroborative, Sensitivity, and Other Analyses ..................................115 
13.1.5 Clinical Pharmacology Analyses .....................................................................116 
13.1.5.1 Pharmacokinetics ................................................................................116 
13.1.6 Safety and Tolerability Analyses ....................................................................116 
13.1.6.1 Local Tolerability ................................................................................116 
13.1.6.2 Adverse Events ...................................................................................117 
13.1.6.3 Clinical Laboratory Evaluations .........................................................117 
13.1.6.4 Vital Signs ...........................................................................................117 
13.1.6.5 Twelve-lead Electrocardiograms ........................................................117 
13.1.6.6 Physical Examination Findings ...........................................................118 
13.1.7 Interim Analysis ..............................................................................................118 
13.2. Sample Size Determination .........................................................................................118 
14. STUDY CONDUCT .............................................................................................................119 
14.1. Sponsor and Investigator Responsibilities ..................................................................119 
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14.1.1 Sponsor Responsibilities .................................................................................119 
14.1.2 Investigator Responsibilities ...........................................................................119 
14.1.3 Confidentiality and Privacy .............................................................................119 
14.2. Site Initiation ...............................................................................................................120 
14.3. Screen Failures ............................................................................................................120 
14.4. Study Documents ........................................................................................................120 
14.4.1 Informed Consent ............................................................................................121 
14.4.2 Investigator’s Regulatory/Good Clinical Practice Documents .......................121 
14.4.3 Case Report Forms ..........................................................................................122 
14.4.4 Source Documents ...........................................................................................122 
14.5. Data Quality Control ...................................................................................................122 
14.5.1 Monitoring Procedures ....................................................................................122 
14.5.2 Data Management ............................................................................................123 
14.5.3 Quality Assurance/Audit .................................................................................123 
14.6. Study Termination .......................................................................................................124 
14.6.1 Regular Study Termination .............................................................................124 
14.6.2 Premature Study Termination .........................................................................124 
14.7. Study Site Closure .......................................................................................................125 
14.7.1 Record Retention .............................................................................................125 
14.7.2 Sample Retention ............................................................................................125 
14.8. Changes to the Protocol ..............................................................................................126 
14.9. Use of Information and Publication ............................................................................126 
15. FINAL CLINICAL STUDY REPORT ................................................................................127 
16. ETHICAL AND LEGAL CONSIDERATIONS ..................................................................128 
16.1. Declaration of Helsinki and Good Clinical Practice ...................................................128 
16.2. Subject Information and Informed Consent ................................................................128 
16.3. Approval by Institutional Review Board and Independent Ethics Committee ...........129 
16.4. Finance and Insurance .................................................................................................129 
17. REFERENCES .....................................................................................................................130 
18. ATTACHMENTS .................................................................................................................131 
18.1. Investigator’s Agreement ............................................................................................131 
APPENDICES .............................................................................................................................132 
A. 
Regulations and Good Clinical Practice Guidelines ...................................................133 
 
 
3.1. List of In-Text Tables 
Table 2-1: 
Schedule of Events for Double-blind Period .....................................................13 
Table 2-2: 
Schedule of Events for Open-label Extension ...................................................16 
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Table 9-1: 
Washout Periods for Prohibited Medications ....................................................80 
Table 9-2: 
Amount of Study Drug Needed Per Visit ..........................................................82 
Table 10-1: 
Pharmacokinetic Parameters .............................................................................98 
 
3.2. List of In-Text Figures 
Figure 7-1: 
Double-blind Study Design ...............................................................................68 
Figure 7-2: 
Open-label Study Design ...................................................................................69 
Figure 10-1: 
Ectropion Severity Score ...................................................................................97 
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REASONS FOR AMENDMENT 
Protocol Amendment 2 is a major amendment that addresses feedback from the Regulatory 
Agencies, Competent Authorities, Central Ethics Committees, and investigators. The following 
changes were made: 
1. Changed the primary endpoint to the Investigator’s Global Assessment (IGA) and made the 
Visual Index for Ichthyosis Severity (VIIS) a secondary endpoint. 
2. Aligned power calculation and parameter assumptions with the new primary endpoint. 
3. Added optional photography evaluation of scoring by a central reader who is not a study 
investigator as a quality check. 
4. Clarified body areas that should be excluded from treatment and/or assessment, and clarified 
dose adjustment for local tolerability and documentation thereof. 
5. Clarified inclusion and exclusion criteria, and added that subjects with recent systemic 
malignancy (e.g., within 5 years) are excluded, with exceptions for those with nonmelanoma 
skin cancer or cervical intraepithelial neoplasia Grade 1 who are >6 months post-treatment. 
6. Added exclusion criteria for subjects unable or unwilling to stop use of topical or systemic 
retinoids; institutionalized subjects, and subjects in any way related to the sponsor, 
investigator, or site personnel. 
7. Specified when the data safety monitoring board (DSMB) will meet and what data will be 
reviewed. 
8. Added characterization of the investigational product. 
9. Added background information about Study RD.03.SRE.40181E with CD5789 in subjects 
with ichthyosis. 
10. Added rationale for 200 µg/g dose in OLE. 
11. Added risk of absorption. 
12. Added protective measures for risk of photosensitivity. 
13. Specified that a tool will be supplied to apply investigational product to the back, and that if 
the investigational product (IP) is applied to the subject by someone other than the study 
subject, they should attend the first visit to learn how to apply it, and that hands must be 
washed immediately afterward or vinyl gloves should be used. 
14. Specified windows and procedures for preventing blood draw contamination by the IP. 
15. Specified that fissuring assessment is limited to palms/soles. 
16. Added washout durations for keratolytics and monoclonal antibody medications, specified 
that washout includes physical treatments such as balneotherapy, and clarified that washout 
must be completed before study treatment begins. 
17. Clarified that subjects may continue taking usual care of visible skin (face and scalp) for 
cosmetic reasons and of extremities (hands and feet) to avoid functional consequences on 
walking or moving their fingers. 
18. Clarified that hormonal contraceptives must inhibit ovulation, and that abstinence relates to 
heterosexual intercourse and must be evaluated in relation to the duration of the clinical trial 
and the preferred and usual lifestyle of the subject. 
19. Revised the statistical analyses to reflect the change in endpoints. 
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20. Clarified permitted and prohibited therapies and medications, and use of standard of care 
treatment and timing thereof. 
21. Specified that lamellar ichthyosis (LI) assessments must be done in order of presentation. 
22. Revised descriptions of LI assessment tools scores (IGA and VIIS). 
23. Defined fissures. 
24. Clarified that investigators should use their judgment as to which quality-of-life tools should 
be used based on the subject’s maturity. 
25. Added a new section describing the photographic substudy. 
26. Added electrocardiogram (ECG) for subjects in the PK substudy during serial blood draws 
on Days 1 and 30. 
27. Clarified eligibility for OLE. 
28. Reordered sections to put assessments in order of performance and renumbered all sections 
and lists accordingly. 
29. Corrected duplicate endnote reference and typographical errors. 
 
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SUMMARY OF AMENDED SECTIONS 
Section 
Previous Text 
Revision 
Rationale 
Synopsis and 
Section 7.1 
This is a 2-cohort, multicenter 
study in subjects with 
moderate to severe LI (i.e., 3-4 
on a 5-point Visual Index for 
Ichthyosis Severity (VIIS) for 
scaling where 0 = clear and 4 = 
severe on at least 2 areas of the 
4 body areas assessed 
(chest/abdomen, back, arms, 
and legs). 
This is a 2-cohort, multicenter 
study in subjects with 
moderate to severe LI (i.e., 3–4 
on a 5-point Investigator 
Global Assessment [IGA)] 
scale where 0 = clear; 
1 = almost clear; 2 = mild; 
3 = moderate; and 
4 = severe). 
To follow FDA 
recommendation to use 
IGA as primary endpoint 
Synopsis and 
Section 7.1 
After the initial 15 subjects 
complete at least 28 days of 
treatment, an independent Data 
Safety Monitoring Board 
(DSMB) will review aggregate 
safety and tolerability data. 
After the initial 15 subjects 
complete at least 28 days of 
treatment, an independent Data 
Safety Monitoring Board 
(DSMB) will review aggregate 
safety and tolerability data 
(including PK and 
electrocardiogram [ECG] 
data). 
To clarify what data the 
DSMB will review 
Synopsis and 
Section 7.1 
All subjects who complete the 
12-week Double-blind 
Treatment Period will be 
eligible to enroll in the 
12-week OLE Period.  
All subjects (Cohort A and 
Cohort B) who complete the 
12-week Double-blind 
Treatment Period will be 
eligible to enroll in the 
12-week OLE.  
To specify that subjects 
from both double-blind 
cohorts will be eligible to 
continue into the Open-
label Extension (OLE).  
Synopsis, 
Table 2-1, 
Sections 7.1, 
Section 9.8, and 
10.2.1.2 
After Screening, eligible 
subjects for Cohort A and B 
will enter a Washout Period of 
up to 35 days, during which 
they must stop using the 
following prohibited 
medications 
Upon signing informed 
consent and entering the 
Screening Period, subjects 
will stop using physical and 
medical treatments for LI, 
including balneotherapy, and 
may begin to washout 
prohibited topical and 
systemic treatments with 
designated washout periods, 
as applicable. Washout may 
be up to 3 months, as 
necessary 
To allow for full washout 
of any prohibited 
medications before 
randomization. 
Therapeutic baths can 
substantially improve 
scaling and affect the 
IGA evaluation. 
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Section 
Previous Text 
Revision 
Rationale 
 
 
Added: During washout, 
subjects may continue taking 
usual care of visible skin 
(face and scalp) for cosmetic 
reasons and of extremities 
(hands and feet) to avoid 
functional consequences on 
walking or moving their 
fingers. Subjects may shower 
but not bathe or swim. The 
IGA will be evaluated on the 
rest of the body at Baseline. 
After completing any 
necessary washout of 
prohibited medications, 
subjects will return to the 
site to complete the study 
eligibility requirements. 
For psychosocial and 
functional reasons, and 
to not deter them from 
entering the study, allow 
subjects to use usual care 
on visible skin and on 
hands and feet.  
To exclude bathing to 
better assess moderate to 
severe LI and evaluate 
IGA on rest of body. 
To ensure subjects 
complete screening and 
eligibility within 35 days 
of randomization after 
any necessary washout. 
Synopsis and 
Table 9-1 
 
Added a washout period of 
2 weeks for topical 
keratolytics (e.g., urea, lactic 
acid, propylene glycol, 
salicylic acid) except 
keratolytic shampoo. 
Added a washout period for 
monoclonal antibody 
treatment (e.g., anti-IL17) of 
5 half-lives. 
To clarify length of the 
washout periods for 
these treatments. 
Synopsis, 
Section 7.1, and 
Section 9.2 
Thereafter, each subject will 
apply approximately the same 
amount (up to 36 g) of study 
drug as for the first dose on up 
to 90% of BSA twice weekly, 
sparing the scalp, inguinal, and 
axillary areas. Subjects will 
receive an adequate number of 
tubes to use 1 tube per 
application and will use a new 
tube for each treatment day. 
Subjects may use less than the 
full amount of product in a 
tube. Subjects will record the 
date and time of study 
treatment administration in the 
subject diary. 
Added: If the product will be 
applied at home by someone 
other than the study subject, 
it is recommended that 
person assist with application 
at the first visit to learn how 
the IP is applied. 
Subjects with heavy facial 
hair should not apply IP to 
hair-bearing areas. 
To specify areas not to 
be treated. 
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Rationale 
Synopsis 
 
Added: If the treatment 
causes application site 
reactions, the frequency of 
application will be reduced 
or interrupted only on the 
area concerned, as indicated 
herein.  
To clarify dose 
adjustment and 
evaluation. 
Synopsis, 
Table 2-1 
footnote, and 
Section 9.4 
During all clinic visits, the 
investigator will assess local 
tolerability (Scale: 0-3 [none, 
mild, moderate, severe]) for 
stinging/burning, pruritus, 
erythema) and the following 
procedures will be followed: 
During all clinic visits, the 
investigator will assess local 
tolerability (Scale: 0-3 [none, 
mild, moderate, severe]) for 
stinging/burning, pruritus, 
erythema) for each body area 
(chest/abdomen, back, arms, 
legs, and face/neck) and the 
following procedures will be 
followed: 
To clarify areas to be 
assessed for local 
tolerability. 
Synopsis and 
Section 9.4 
− If a score of 2 (moderate) 
is recorded on a local 
tolerability assessment 
scale (stinging/burning, 
pruritus, erythema) on any 
treated area, the study drug 
will be applied on this area 
only once weekly, until the 
score is back to <2. 
− If a score of 3 (severe) is 
recorded on a local 
tolerability assessment 
scale (stinging/burning, 
pruritus, erythema) on any 
treated area, the study drug 
will not be applied on that 
area until the score is back 
to <3. 
− If a score of 2 (moderate) 
is recorded on a local 
tolerability assessment 
scale (stinging/burning, 
pruritus, erythema) on any 
treated area (e.g., the 
face), the study drug will 
be applied on this area 
only once weekly, until 
the score returns to <2. 
Continue to treat all 
other areas twice weekly 
provided the score is <2 
on those areas. 
− If a score of 3 (severe) is 
recorded on a local 
tolerability assessment 
scale (stinging/burning, 
pruritus, erythema) on any 
treated area, the study 
drug will not be applied 
on that area until the score 
is back to <3 (i.e., “drug 
holiday”). Continue to 
treat all other areas 
twice weekly provided 
the score is <2 on those 
areas. 
Any changes in dosing must 
be documented in the 
subject diary and the eCRF. 
To clarify dose 
adjustment for local 
tolerability, and how it 
should be documented. 
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Synopsis and 
Section 7.1, and 
Section 10.3.1.9 
Photographs will be taken at 
Baseline, Day 30 and Day 90 
at selected sites with 
photographic capability for 
subjects who sign a separate 
photographic informed consent 
form (ICF). 
At all sites with photographic 
capability photographs will be 
taken as source data to 
support scoring at Baseline, 
Day 30, and Day 90. A central 
reader who will not be an 
investigator in the study will 
review the photographs to 
assess consistency of 
investigator scoring of LI 
severity as a quality check. 
Photographs may also be 
used for scientific publication 
purposes. Subjects will sign a 
separate, optional 
photographic informed consent 
form (ICF). 
To obtain photographic 
evidence, where 
possible, for 
confirmation of scoring 
consistency, as assessed 
by a central reader. 
Synopsis and 
Section 7.1 
 
Added: Visits for PK must 
occur at least 24 hours after 
the last application of the 
study drug, to avoid 
contamination of the blood 
samples with any IP that 
may have remained in the 
skin after the last 
application.  
To ensure 
pharmacokinetic (PK) 
blood draws are not 
contaminated with IP. 
Synopsis and 
Section 7.1 
In addition, a PK substudy will 
be conducted at specific sites 
with the capability to conduct 
it. 
In addition, a PK substudy will 
be conducted on Days 1 and 
30 at sites with the capability 
to conduct it. 
Added: For the subjects in 
the PK substudy, postdose 
ECGs will be performed at 
each serial blood draw on 
Day 1 and Day 30. 
To clarify on which days 
the PK substudy will be 
performed, and that 
postdose ECGs will be 
performed during serial 
sampling on those days 
(per MHRA request). 
Synopsis and 
Section 8.2.1 
Inclusion criterion #3: 
Subject has moderate to severe 
(VIIS 3-4) LI on at least 2 of 
the 4 body areas assessed 
(chest/abdomen, back, arms, 
and legs). 
Inclusion criterion #3: 
Subject has moderate to severe 
(IGA 3-4) LI on the IGA of LI 
severity. 
To follow FDA 
recommendation to 
change primary endpoint 
to IGA.  
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Synopsis and 
Section 8.2.1 
Inclusion criterion #7: 
• combined oral 
contraceptives (estrogens 
and progesterone) or 
implanted or injectable 
contraceptives with a stable 
dose for at least 1 month 
before Baseline 
• hormonal intrauterine device 
(IUD) inserted at least 
1 month before Baseline 
OR 
Agrees to abstain from sex 
during study participation 
and for 1 month after the 
last application of study 
drug and to use a highly 
effective contraceptive as 
backup if he or she becomes 
sexually active during the 
study. 
Inclusion criterion #7: 
• combined oral 
contraceptives (estrogens 
and progesterone) or 
implanted or injectable 
contraceptives with a stable 
dose for at least 1 month 
before Baseline; hormonal 
contraceptives must 
inhibit ovulation 
• hormonal intrauterine device 
(IUD) inserted at least 
1 month before Baseline 
OR 
Agrees to abstain from 
heterosexual intercourse 
during study participation 
and for 1 month after the 
last application of study 
drug and to use a highly 
effective contraceptive as 
backup if he or she becomes 
sexually active during the 
study. Abstinence is only 
acceptable if this is the 
subject’s usual lifestyle. 
Periodic abstinence 
(calendar, symptothermal, 
postovulation methods), 
withdrawal (coitus 
interruptus), spermicides 
only, and lactational 
amenorrhoea method are 
not acceptable methods of 
contraception. 
To align with Clinical 
Trial Facilitation Group 
(CTFG) 
recommendations related 
to contraception and 
pregnancy testing in 
clinical trials, per 
MHRA. 
Synopsis and 
Section 8.2.2 
Exclusion criterion #2: 
Subject has a history of or 
current moderate or severe 
stinging/burning at Screening. 
Exclusion criterion #2: 
Subject has a history of or 
current moderate or severe 
stinging/burning at Screening. 
To clarify that history of 
stinging/burning does not 
prevent enrollment. 
Synopsis and 
Section 8.2.2 
Exclusion criterion #4: 
Subject with a known lipid 
disorder unless well controlled 
by stable doses of 
lipid-lowering agents for at 
least 6 months. 
 
Exclusion criterion #4: 
Subject with a known lipid 
disorder 
(hypertriglyceridemia 
>200 mg/dL, 
hypercholesterolemia 
>250 mg/dL) unless well 
controlled by stable doses of 
lipid-lowering agents for at 
least 6 months. 
To group all lipidema 
criteria together. 
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Synopsis and 
Section 8.2.2 
Exclusion criterion #5: 
Subject was previously treated 
with trifarotene/CD5789, 
including the acne formulation, 
or participated in previous 
studies for ichthyosis. 
Exclusion criterion #5: 
Subject was previously treated 
with trifarotene/CD5789 in an 
acne or ichthyosis study. 
To avoid restricting 
enrollment. 
Synopsis and 
Section 8.2.2 
Exclusion criterion #6: 
Subject has known skeletal 
disease, hypertriglyceridemia, 
hypercholesterolemia, liver 
disease, or other poorly 
controlled medical conditions. 
Exclusion criterion #6: 
Subject has any other 
significant concomitant 
disease, or poorly controlled 
medical condition other than 
LI that, in the investigator’s 
opinion, may put him or her 
at risk if he or she takes part 
in the study, and/or that may 
interfere with the study 
assessments. 
To add 
hypertriglyceridemia and 
hypercholesterolemia as 
exclusion criteria and 
combine Exclusion 
Criterion #4 and 
Exclusion Criterion #7 to 
avoid restricting 
enrollment 
Synopsis and 
Section 8.2.2 
Exclusion criterion #7: 
Subject has a medical 
condition that potentially alters 
bone metabolism (e.g., 
osteoporosis, thyroid 
dysfunction, Cushing 
syndrome), Crohn’s disease, or  
any other significant 
concomitant disease other than 
LI that, in the investigator’s 
opinion, may put him or her at 
risk if he or she takes part in 
the study, and/or that may 
interfere with the study 
assessments 
Exclusion criterion #7: 
Subject has a medical 
condition that potentially alters 
bone metabolism (e.g., 
osteoporosis, thyroid 
dysfunction, Cushing 
syndrome, Crohn’s disease, 
or ulcerative colitis).any other 
significant concomitant disease 
other than LI that, in the 
investigator’s opinion, may put 
him or her at risk if he or she 
takes part in the study, and/or 
that may interfere with the 
study assessments 
To exclude subjects with 
conditions that may 
affect skeletal integrity. 
Synopsis and 
Section 8.2.2 
Exclusion criterion #8: 
Subject is being treated for 
major depression disorder  
Exclusion criterion #8: 
Subject is being treated for 
major depression disorder 
and/or has a history of major 
depression or suicide attempt 
requiring hospitalization, 
medications, and close 
psychiatric surveillance to 
prevent suicide attempts.  
To define major 
depressive disorder and 
to allow subjects with 
treated mild depression 
to be enrolled. 
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Synopsis and 
Section 8.2.2 
Exclusion criterion #10: 
Subject with any of the 
following laboratory values at 
Screening: 
a. Aspartate aminotransferase 
or alanine aminotransferase 
>1.5 × upper limit of normal 
defined by the laboratory 
b. Triglycerides >200 mg/dL 
c. Total cholesterol 
>250 mg/dL 
d. Hemoglobin <12.5 g/dL for 
men and <11.5 g/dL for 
women 
e. Platelets <150 × 109/L or 
>400 × 109/L 
Exclusion criterion #10: 
Subject with any of the 
following laboratory values at 
Screening: 
a. Aspartate aminotransferase 
or alanine aminotransferase 
>1.5 × upper limit of 
normal defined by the 
laboratory 
b. Total bilirubin 
>1.1 mg/dL or, in case of 
Gilbert’s syndrome, total 
bilirubin >3 mg/dL 
c. Hemoglobin <12.5 g/dL for 
men and <11.5 g/dL for 
women 
d. Platelets <150 × 109/L or 
>400 × 109/L 
Moved triglycerides and 
total cholesterol to 
Exclusion Criterion #4 
and add total bilirubin 
and Gilbert’s syndrome 
(per MHRA request). 
Synopsis and 
Section 8.2.2 
 
Added: 
Exclusion criterion #12: 
Subject has had recent 
systemic malignancy (e.g., 
within 5 years) with 
exception of nonmelanoma 
skin cancer or cervical 
intraepithelial neoplasia of 
Grade 1 who are >6 months 
post-treatment. 
To exclude subjects with 
recent systemic 
malignancies. 
Synopsis and 
Section 8.2.2 
 
Added: 
Exclusion criterion #17: 
Subject is unable or 
unwilling to stop use of 
topical or systemic retinoids. 
To exclude subjects 
using topical or systemic 
retinoids, per MHRA 
request. 
Synopsis and 
Section 8.2.2 
 
Added: Exclusion criterion 
#20: 
Subject is institutionalized 
Added: Exclusion criterion 
#21: 
Subject is in any way related 
to the sponsor, investigator, 
or site personnel. 
To exclude vulnerable or 
biased subjects 
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Synopsis, 
Section 7.1, and 
Section 10.3 
Primary efficacy endpoint: The 
number of subjects in each 
treatment group who 
experience successful 
resolution of LI where 
“success” is defined as 
clear/almost clear overall and 
at least a 50% reduction from 
Baseline at Week 12/end-of-
treatment (EOT) in the 
Double-blind Period on the 
overall 16-point VIIS for 
scaling (i.e., 0-4 points on each 
of the 4 body areas: 
chest/abdomen, back, arms, 
and legs). 
Primary efficacy endpoint:  
The number of subjects in each 
treatment group who 
experience successful 
resolution of LI where 
“success” is defined as 
clear/almost clear on treated 
areas and at least a 2-grade 
change from Baseline at 
Week 12/end-of-treatment 
(EOT) in the Double-blind 
Period on the 5-point IGA 
full body scale. 
To follow FDA 
recommendation to 
change primary endpoint 
from VIIS to IGA. 
Synopsis and 
Section 13.1.4.1 
 
The number of subjects in each 
treatment group who 
experience successful 
resolution of LI where 
“success” is defined as 
clear/almost clear on treated 
areas and at least a 2-grade 
change from Baseline at Week 
12/end-of-treatment (EOT) in 
the Double-blind Period on the 
5-point IGA full body scale. 
The number of subjects in each 
treatment group who 
experience successful 
resolution of LI where 
“success” is defined as 
clear/almost clear overall and 
at least a 50% reduction from 
Baseline at Week 12/end-of-
treatment (EOT) in the 
Double-blind Period on the 
overall 16-point VIIS for 
scaling (i.e., 0 4 points on each 
of the 4 body areas: 
chest/abdomen, back, arms, 
and legs). 
 
Secondary endpoints: 
• 
The difference in mean 
scores between the active 
trifarotene cream HE1 and 
vehicle groups in the 
following assessment 
indices: 
The proportion of subjects in 
each treatment group who 
experience successful 
resolution of LI where 
“success” is defined as 
clear/almost clear on treated 
areas and at least a 2-grade 
change from Baseline at 
Week 12/end-of-treatment 
(EOT) in the Double-blind 
Period on the 5-point IGA full 
body scale.  
 
Secondary endpoints: 
• The difference in mean 
scores between the active 
trifarotene cream HE1 and 
vehicle groups in the 
following assessment 
indices from baseline 
through Week 12: 
− 
5-point Visual Index for 
Ichthyosis Severity 
(VIIS) scale for scaling 
from Baseline through 
Week 12 (overall 16 
points for scaling, i.e. 0-4 
points for 4 body areas: 
chest/abdomen, back, 
arms and legs) 
− Individual score for 
roughness (Scale: 0–4) 
overall 
− Palm/sole Assessment 
(Scale: 0–4)  
To reflect change in 
endpoints; IGA is now 
primary endpoint (and 
thus, no individual 
scaling score is needed), 
and VIIS is a secondary 
endpoint.  
To limit fissure 
evaluation to the 
palms/soles. 
To clarify endpoints for 
statistical analysis. 
 
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− Palm/sole Assessment 
(Scale: 0–4)  
− Individual score of 
scaling (Scale: 0–4)  
− Individual score for 
roughness (Scale: 0–4) 
overall 
• 
The difference in 
proportion of subjects 
with presence of fissures 
(presence/absence, 
number of fissures, and 
pain associated with 
fissures on a 0-3 scale) 
between the active 
trifarotene cream HE1 and 
vehicle groups. 
• 
Quality of life per 
EQ-5D-5L  
• 
The difference in mean 
ectropion (Ectropion 
Severity Score [ESS] of 
0–8) scores between the 
active trifarotene cream 
HE1 and vehicle groups 
• 
Quality of life per DLQI  
 
− Quality of life per 
DLQI  
 
• 
The difference in 
proportion of subjects 
with presence of fissures 
on palms/soles 
(presence/absence, 
number of fissures, and 
pain associated with 
fissures on a 0-3 scale) at 
Week 12 between the 
active trifarotene cream 
HE1 and vehicle groups. 
• 
The difference in mean 
ectropion (Ectropion 
Severity Score [ESS] of 
0–8) scores between the 
active trifarotene cream 
HE1 and vehicle groups 
from Baseline through 
Week 12 
• 
The difference in quality 
of life per EQ-5D-5L 
scores between the active 
trifarotene cream HE1 
and vehicle groups from 
Baseline through 
Week 12 
Synopsis  
Safety endpoints:  
• Reported serious adverse 
events (SAEs), treatment-
emergent AEs (TEAEs), 
and changes in clinical 
laboratory tests, vital signs, 
physical examinations, and 
12-lead ECGs  
• Local tolerability (Scale: 
0-3 [none, mild, moderate, 
severe], determined by the 
investigator)  
 
Safety endpoints:  
• Reported serious adverse 
events (SAEs), treatment-
emergent AEs (TEAEs), 
and changes in clinical 
laboratory tests, vital signs, 
physical examinations, and 
12-lead ECGs  
• Local tolerability (Scale: 
0-3 [none, mild, moderate, 
severe], determined by the 
investigator) for each body 
area (chest/abdomen, 
back, legs, arms, and 
face/neck). 
To clarify that 
tolerability will be 
assessed on all body 
areas where the 
treatment is applied. 
Synopsis and 
Section 13.1.4.2 
The intent-to-treat (ITT) 
population will comprise all 
randomized subjects.  
The modified intent-to-treat 
(mITT) population comprises 
all subjects in the safety 
The intent-to-treat (ITT) 
population will comprise all 
randomized subjects. This 
population will be used as the 
primary population for the 
analysis of efficacy for the 
To clarify that the intent-
to-treat population will 
be used for the primary 
analyses of efficacy for 
the double-blind period. 
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population with at least 1 
postbaseline assessment of 
efficacy in the Double-blind 
Period. This population will be 
used as the primary population 
for the analysis of efficacy for 
the Double-blind Period of the 
study. 
 
The number and proportion of 
subjects in each treatment 
group with successful 
resolution of LI by Week 
12/EOT in the Double-blind 
Period will be presented. 
Generalized estimating 
equations (GEE) for binary 
response will be used to model 
the odds of successful 
resolution of LI with treatment 
group as a predictor. Other 
covariates, such as baseline 
IGAVIIS scores, baseline 
characteristics, and interactions 
may be included. Various 
correlation matrix structures 
will be explored to model the 
within subject correlation. 
Additionally, the difference in 
mean VIIS score at Week 
12/EOT between the active 
trifarotene cream HE1 groups 
and vehicle group will be 
analyzed using a 2-sided, 2-
sample Wilcoxon rank-sum 
test at the 5% significance 
level; 95% confidence 
intervals will be presented.  
The VIIS scores as well as 
secondary and exploratory 
efficacy endpoints will be 
analyzed by visit using 
descriptive statistics through 
Week 24.   
Double-blind Period of the 
study. 
The modified intent-to-treat 
(mITT) population comprises 
all subjects in the safety 
population with at least 1 
postbaseline assessment of 
efficacy in the Double-blind 
Period. 
The number and proportion of 
subjects in each treatment 
group with successful 
resolution of LI by Week 
12/EOT in the Double-blind 
Period will be presented. The 
primary efficacy endpoint 
will be analyzed using a 
logistic regression model 
with treatment and age 
group as factors. Other 
baseline characteristics and 
interactions may be included. 
The odds ratios and 95% CIs 
for the odds ratios will be 
presented. The difference in 
proportions between the 
active trifarotene cream HEI 
and vehicle cream group, 
95% CIs for the differences, 
and P-values for the 
differences in treatment will 
also be presented. 
 
The IGA scores as well as 
continuous secondary and 
exploratory efficacy endpoints 
will be analyzed by visit using 
descriptive statistics through 
Week 24. 
Deleted: Frequencies of results 
and 95% confidence intervals 
will also be reported, and 
scores will be analyzed as 
categorical variables using the 
Cochran-Mantel-Haenszel test. 
To follow change in 
primary endpoint and 
addition of secondary 
endpoints. 
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Synopsis and 
Section 10.1.1 
Screening and washout: Up to 
35 days 
Screening: Up to 35 days 
(after signing informed 
consent, if necessary, 
washout may be up to 3 
months, and subjects should 
return to the site after 
washout to complete the 
study eligibility 
requirements) 
To allow for full washout 
of any prohibited 
medications before 
randomization. 
Synopsis and 
Section 13.2 
Accounting for a 20% drop-
out/nonevaluable rate, a total 
sample size of 120 subjects 
randomized in a 1:1:1 ratio to 
2 active trifarotene cream HE1 
arms and a vehicle cream arm 
will provide >80% power to 
detect a difference between 
each separate trifarotene cream 
HE1 arm (32 evaluable 
subjects) and the vehicle cream 
arm (32 evaluable subjects) 
using a 2-sample t-test 
assuming a mean difference of 
at least 1.0 and a standard 
deviation of 1.4 or lower. 
Accounting for a 20% drop-
out/nonevaluable rate, a total 
sample size of 120 subjects 
randomized in a 1:1:1 ratio to 
2 active trifarotene cream HE1 
arms and a vehicle cream arm 
will provide >80% power to 
detect a difference between 
each separate trifarotene cream 
HE1 arm (32 evaluable 
subjects) and the vehicle cream 
arm (32 evaluable subjects) 
using a 2-sided Fisher’s 
Exact Test assuming a 70% 
success rate and a 40% 
success rate, respectively. 
To align power 
calculation and 
parameter assumptions 
with the new primary 
endpoint. 
Table 2-1 
Screening (-35 days to -1 day) 
Screening (-35 days to -1 day) 
Washout up to 3 months 
Added footnote a: Upon 
signing informed consent and 
entering the Screening 
Period, subjects will stop 
using physical and medical 
treatments for LI, including 
balneotherapy, and may 
begin to washout prohibited 
topical and systemic 
treatments with designated 
washout periods, as 
applicable. Washout may be 
up to 3 months, as necessary. 
During washout, subjects 
may continue taking usual 
care of visible skin (face and 
scalp) for cosmetic reasons 
and of extremities (hands 
and feet) to avoid functional 
consequences on walking or 
moving their fingers. 
Subjects may shower but not 
bathe or swim during the 
Screening Period. After 
completing any necessary 
To allow for full washout 
of any prohibited 
medications before 
randomization. 
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washout of prohibited 
medications, subjects will 
return to the site to complete 
the study eligibility 
requirements. 
Table 2-1  
Schedule of Events for 
Double-blind Period 
Reordered assessments of 
IGA, VIIS, and roughness to 
be in order of conduct. 
Added “palm/sole” to 
fissuring assessment. 
Changed “assign 
randomization number” to 
“Randomization via IWRS.” 
Added “and sunscreen” to 
advice on emollient use. 
Changed complete physical 
examination to be done at 
Screening and limited physical 
examinations at other time 
points as indicated. 
Changed height, weight, and 
BMI to be done at Screening 
instead of Baseline. 
Added abbreviation IWRS and 
definition. 
Added to footnote: 
Photography will be performed 
at sites with the capability for 
subjects who sign a 
photographic ICF. A central 
reader who will not be an 
investigator in the study will 
review the photographs to 
assess consistency of 
investigator scoring of LI 
severity as a quality check. 
Added to footnote subjects in 
PK substudy will have 
postdose ECG at each serial 
blood draw on Day 1 and 
Day 30. 
Added to footnote: Visits for 
PK must occur at least 
24 hours after the last 
application of the IP to avoid 
contamination of the blood 
samples with any IP that 
may have remained in the 
To clarify that IGA 
should be performed first 
and all efficacy 
assessments should be 
performed in the order in 
which they are listed 
within the protocol. 
To limit fissure 
evaluation to the 
palms/soles. 
To specify that 
randomization will be 
conducted via IWRS to 
avoid confusing site 
personnel. 
To include sunscreen to 
instructions regarding 
emollient use. 
To clarify when physical 
examinations and height, 
weight, and BMI are 
performed. 
To specify that a central 
reader will assess the 
photographs as a quality 
check of scoring 
consistency from Days 
30 and 90. 
To ensure postdose 
ECGs are collected (per 
MHRA advice) for 
subjects in PK substudy 
during serial sampling. 
To ensure PK samples 
are not contaminated by 
recent application of 
study drug. 
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skin after the last 
application. 
Table 2-2 
Schedule of Events for Open-
label Extension 
Revised footnote to IGA 
criteria. 
Reordered and revised 
assessments 
To specify order of 
assessment performance 
and that assessment of 
scaling is no longer 
done, and to clarify that 
fissuring only applies to 
palms/soles. 
Section 5.2 
 
Added: One study was 
conducted with CD5789 
50 μg/g, 100 μg/g, and 
placebo in subjects with 
icthyosis (Study 
RD.03.SRE.40181E). Among 
31 subjects treated in this 
study, 17 were treated with 
CD5789 100 μg/g, and 14 
were treated with 50 μg/g (all 
subjects received placebo 
[vehicle] on the contralateral 
zone). Mean (SD) baseline 
IGA score was 5.7 ± 1.6 
among the 31 subjects. 
Improvement in the 
investigator’s global 
assessment (IGA) of scaling 
and roughness was observed 
by Day 8 with both doses. 
The primary efficacy 
criterion was the change in 
IGA from the Baseline Visit 
(Day 1) to the Final Visit 
(Day 43). At Endpoint 
(intent-to-treat population, 
last observation carried 
forward [LOCF]), the 
CD5789 100 μg/g group had 
a statistically significant 
decrease from Baseline in 
IGA compared with Vehicle 
(-1.4±2.2; p=0.018) 
(Investigator’s Brochure for 
CD5789 Cutaneous 
Formulation). 
Added: However, it is 
possible that absorption in 
subjects with LI may be 
greater than in healthy 
To add experience with 
CD5789 in subjects with 
ichthyosis and to clarify 
that systemic absorption 
may differ in subjects 
with ichthyosis. 
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volunteers, due to the skin 
being compromised. 
Based on these data, both the 
100 µg/g and 200 µg/g doses 
showed an acceptable safety 
profile and will be used in 
this phase 2 LI study, to 
determine which of the 2 
doses is most effective. The 
open-label extension (OLE) 
will evaluate the long-term 
safety of the higher dose in 
this patient population. 
Section 5.3 
The potential risks of study 
participation include those 
associated with exposure to 
tifarotene (CD5789) cream 
HE1 and the risks of medical 
evaluation, including 
venipuncture. 
The potential risks of study 
participation for all subjects 
include those associated with 
exposure to trifarotene 
(CD5789) cream HE1 and the 
risks of medical evaluation, 
including venipuncture.  
Added: In addition, subjects 
should take protective 
measures such as applying 
sunscreen (except within 
4 hours before and/or 
4 hours after study drug 
application), and/or wearing 
protective clothing (e.g., long 
sleeves, hats, and covering 
legs and feet), and/or seeking 
shade or shelter from the 
sun. 
Added: No clinically 
significant systemic risks 
associated with CD5789 have 
been identified. Given the 
mechanism of action for 
CD5789 Cream HE1, it is 
assumed that efficacy will 
increase as the dose is 
increased. As such, the 
200 µg/g dose was selected 
for the OLE based on its 
previously established safety 
profile, expected superiority 
to placebo and 100 µg/g. 
However the Data Safety 
Monitoring Board (DSMB), 
who will routinely review 
aggregate safety and 
tolerability data, as well as 
any safety concerns brought 
To specify protective 
measures for avoiding 
sunlight/UV light (per 
MHRA request). 
To include systemic 
risks, and to add that the 
DSMB applies to both 
parts of the study and 
that if the 200 µg/g dose 
causes safety issues, the 
protocol will be amended 
if necessary. 
 
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to the their attention by the 
study investigators or 
medical monitor, may 
determine that the study 
should be modified, placed 
on hold, or stopped if serious 
safety issues are discovered. 
This is applicable for both 
the double-blind portion and 
OLE. If the 200 µg/g dose in 
raises any safety concerns, 
the protocol will be amended 
and the dose will be reduced. 
Section 7.1 
During all clinic visits, the 
investigator will assess local 
tolerability (Scale: 0-3 [none, 
mild, moderate, severe]) 
averaged over the BSA and 
will follow the procedures 
detailed in Section 9.4 
During all clinic visits, the 
investigator will assess local 
tolerability (Scale: 0-3 [none, 
mild, moderate, severe]) for 
each treated body area 
(chest/abdomen, back, legs, 
arms, and face/neck) and will 
follow the procedures detailed 
in Section 9.4 
To clarify that local 
tolerability assessments 
will be performed on all 
treated areas. 
Figure 7-1 
Redrawn 
Removed extraneous 
arrows; improved layout 
Section 8.4 
An investigator may 
discontinue a participant’s 
study treatment for any of the 
following reasons 
•
If any clinical AE,
laboratory abnormality, or
other medical condition or
situation occurs such that
continued participation in
the study would not be in
the best interest of the
participant
An investigator must 
discontinue a participant’s 
study treatment for any of the 
following reasons 
•
If any clinical AE,
laboratory abnormality, or
other medical condition or
situation occurs such that
continued participation in
the study would result in a
significant burden to the
participant
To clarify that this is 
mandatory. 
To clarify that these 
would be burdensome to 
the participant. 
Section 9.1 
Added: It is a potent RARγ 
agonist characterized by its 
high specificity to this 
receptor. 
To further characterize 
the investigational 
product. 
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Section 9.2 
 
Added: The IP should be 
applied thinly and gently 
rubbed in. 
Added: If the product will be 
applied at home by someone 
other than the study subject, 
it is recommended that 
person assist with application 
at the first visit to learn how 
the IP is applied. 
To clarify how IP should 
be administered. 
To clarify that anyone 
other than the study 
subject, who may apply 
the IP to the subject, is 
trained on application of 
IP. 
 
Subjects should not apply IP 
on visit days until after the 
visit. 
Added: Persons other than 
the study subject applying 
the study drug must wash 
their hands after application 
or use disposable vinyl 
gloves. In addition, a long-
handled applicator will be 
provided for application on 
the back. The applicator 
must be washed with warm 
water and soap after every 
application.  
Trifarotene cream should not 
come into contact with the 
eyes, mouth, angles of the 
nose, or mucous membranes. 
For the ectropion treatment, 
Q-tips are recommended for 
precise application on 
eyelids, without contact to 
the eye or conjunctiva. If the 
IP gets into the eye, it must 
be flushed immediately with 
warm water. In case of eye 
irritation, the subject must 
be seen by an 
ophthalmologist.  
To specify areas not to 
be treated. 
To ensure the safety of 
others who may apply 
the IP to the study 
subject and to improve 
application. 
To ensure PK blood 
draws are not 
contaminated with IP. 
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At least 24 hours must have 
elapsed since last IP 
administration before PK 
blood draws are performed. 
Subjects should not apply IP 
to the area where blood will 
be drawn for at least 24 
hours before the next PK 
sample draw. Subjects should 
not apply IP on visit days until 
after the visit, unless they are 
participating in the PK 
substudy, in which case the 
IP will be applied in the 
clinic on Day 30 after the 
blood draw. Among subjects 
participating in the PK 
substudy, ensure the PK line 
is inserted before study drug 
application to prevent 
contamination with the IP 
and protect the skin around 
the needle insertion point 
from study drug application. 
 
Section 9.3 
 
Added: Visits for PK must 
occur at least 24 hours after 
the last application of the IP 
to avoid contamination of the 
blood samples with any IP 
that may have remained in 
the skin after the last 
application. Subjects should 
not apply the IP on visit days 
until after the visit, unless 
they participate in the PK 
substudy, in which case the 
IP will be applied in the 
clinic on Day 30 after the PK 
blood draw. 
To ensure PK blood 
draws are not 
contaminated with IP. 
Section 9.4.1 
 
Added: Any changes in 
dosing must be documented 
in the subject diary and the 
eCRF. 
To ensure documentation 
of any dosing changes. 
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Section 9.5 
 
Added: Subjects who taper to 
once weekly application or 
who take a “drug holiday” 
for tolerability will not be 
reported as having deviated 
from the protocol (see 
Section 9.4 for dose 
adjustment and stopping 
rules); any changes in dosing 
must be documented in the 
subject diary and the eCRF. 
To clarify that subjects 
who require dose 
adjustment because of 
local tolerability will not 
be counted as having 
deviated from the 
protocol. 
Section 9.7 
Unblinding should be 
discussed in advance with the 
medical monitor, if possible.  
The investigator may discuss 
with the medical monitor in 
advance of unblinding a 
subject, if possible, if it is not 
deemed as an emergency. 
However, the investigator 
has the ultimate decision for 
unblinding a subject for 
medical treatment and no 
procedures will prevent or 
delay necessary unblinding 
in an emergency for the 
subject’s safety. 
To clarify that the 
investigator has the 
authority to make 
decisions about 
unblinding a subject (per 
MHRA 
recommendation). 
Section 9.8.1 
Subjects will be advised on 
permitted emollient(s) for use 
on nontreatment days during 
the study; use of emollient(s) 
on study drug treatment days 
within 4 hours of study drug 
application is prohibited. 
Subjects will be advised on 
permitted emollient(s) for use 
as often as needed on 
nontreatment days during the 
study; on treatment days, the 
use of emollient(s) is 
permitted except within 
4 hours before or after study 
drug application. Similarly, 
protective sunscreen should 
be applied as often as 
needed, except within 
4 hours before or after study 
drug application. Subjects 
may use their standard of 
care treatment on their faces 
and/or palms/soles after the 
Week 4 assessment if they 
experience a worsening of 
IGA in those areas. In the 
US/EU, this may include 
compounded emollients with 
keratolytics (alpha or beta 
hydroxyl acids) and/or urea. 
These standard of care 
treatments should be 
approved by the investigator 
and documented in the 
eCRF.  
To clarify when use of 
emollients and protective 
sunscreen is permitted.  
To add sunscreen as 
protection from 
sunlight/UV light. 
To allow subjects who 
experience worsening of 
IGA to return to standard 
of care treatment, as 
approved by the 
investigator, after 
Day 30. 
To avoid combination 
treatment during the 
OLE (no washout is 
necessary). Standard of 
care is permitted after the 
OLE Week 16 visit, as 
long as it does not 
contain prohibited 
medications, 
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Subjects who enter the OLE 
must stop standard of care 
treatment. If they experience 
a worsening of IGA they may 
use standard of care 
treatment on their faces 
and/or palms/soles after the 
Week 16 visit if the standard 
of care does not contain 
prohibited medications. If 
those standard of care 
treatments include 
prohibited medications, the 
subject should be 
discontinued from the study. 
Section 9.8.2 
 
The therapies listed in Table 
9-1 are prohibited during the 
study. 
The medications listed in 
Table 9 1 are prohibited during 
the study. 
Added: Balneotherapy is also 
prohibited during the 
Screening Period and during 
the study. 
Added: Use of benzoyl 
peroxide is permitted on 
non-treatment days for 
subjects with concomitant 
acne only; it must not be 
applied on treatment days 
due to risk of inactivation of 
trifarotene by benzoyl 
peroxide. 
Added: For enrolled subjects 
who require prescription of a 
systemic azole, the principal 
investigator should discuss 
with the medical monitor 
whether the subject may 
continue in the study. 
To allow subjects with 
acne to use benzoyl 
peroxide on 
nontreatment days. 
To specify that physical 
treatments such as 
balneotherapy are also 
prohibited. 
To specify that if 
subjects are prescribed 
an azole after study 
enrollment, their 
continued participation 
must be discussed with 
the medical monitor.  
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Section 9.8.3 
Subjects should not shower, 
bathe, or swim within 4 hours 
of after study drug application. 
No occlusive dressings should 
be applied to areas where study 
drug was applied.  
Subjects should only use 
investigator-approved 
emollients, and should not use 
them on treatment days within 
4 hours of study drug 
application. 
Subjects should not shower, 
bathe, or swim for at least 
4 hours after study drug 
application. No occlusive 
dressings should be applied to 
areas where study drug was 
applied.  
Subjects should only use 
investigator-approved 
emollients, and should not use 
them on treatment days for at 
least 4 hours before and after 
study drug application. 
Added: In addition, subjects 
should take protective 
measures to avoid exposure 
of treated areas to sunlight, 
such as applying sunscreen 
(except within 4 hours before 
and/or 4 hours after study 
drug application), and/or 
wearing protective clothing 
(e.g., long sleeves, hats, and 
covering legs and feet), 
and/or seeking shade or 
shelter from the sun.  
To clarify the window 
for showering or bathing 
and use of emollients on 
treatment days. 
To improve safety with 
regard to exposure to 
sunlight/UV light. 
Section 10.2 
 
Added: It is suggested that 
quality of life assessments be 
conducted first to avoid any 
bias, and that the IGA be 
recorded as the first LI 
assessment at every visit. 
To clarify order of 
assessment and to ensure 
IGA is recorded first as 
primary efficacy 
endpoint. 
Section 10.2.1.1 
Subjects must be screened 
within 35 days before 
randomization in the study. 
The following procedures will 
be performed at Screening 
The subject must complete 
eligibility screening within 35 
days before randomization in 
the study. The following 
procedures will be performed 
during Screening 
Reordered assessments to be in 
order of performance.  
Revised assessments to 
exclude individual scaling, to 
limit fissuring to palms/soles, 
and to add photographs as 
source documents. 
To reflect that subjects 
who require washout 
may return to the site to 
complete eligibility 
assessments within 
35 days of 
randomization. 
To reflect the changes in 
primary and secondary 
endpoints, the limit of 
fissuring to palms/soles, 
and the addition of 
photographs as source 
documents, and to ensure 
the order of assessments 
is correct. 
Section 10.2.2.1 
 
Reordered assessments to be in 
order of performance.  
To specify order of 
assessments; to specify 
that randomization is via 
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Revised assessments to 
exclude individual scaling, to 
limit fissuring to palms/soles, 
and to add cross-reference to 
Sections 10.3.1.5 and 10.3.1.6. 
Specified randomization to be 
done via IWRS. 
Added caution to ensure that 
PK lines are placed before IP 
application.  
Added instructions if the 
product will be applied at 
home by someone other than 
the study subject. 
Added sunscreen(s) use on 
nontreatment days and time 
frame for use on treatment 
days. 
Added: Among subjects in 
the PK study, perform an 
additional ECGs at times of 
serial sampling. 
the IWRS,; to specify 
that fissuring is only to 
be assessed on 
palms/soles, to provide 
location of specific 
quality of life scales, to 
specify procedures and 
times for PK serial blood 
draws to prevent 
contamination with IP, to 
ensure persons other than 
the study subject who 
may apply IP to the 
study subject are trained 
in IP application 
procedure; and to specify 
when emollients and 
protective sunscreen may 
be used on treatment 
days. 
Section 10.2.2.2 
and 
Section 10.2.2.5 
Staff will instruct subject on 
study drug application, advise 
subjects regarding permitted 
emollient(s) for use on 
nontreatment days (use of 
emollient(s) on study drug 
treatment days within 4 hours 
of study drug application is 
prohibited), and remind 
subjects not to apply IP on 
visit days until after the visit.  
Staff will instruct subject on 
study drug application, advise 
subjects regarding permitted 
emollient(s) for use on 
nontreatment days (use of 
emollient(s) and/or 
sunscreen(s) on study drug 
treatment days within 4 hours 
before or after study drug 
application is prohibited), and 
remind subjects that 24 hours 
must have elapsed since IP 
application before the 
subject’s next visit. Subjects 
should not apply IP on visit 
days until after the visit.  
To specify when 
emollients and protective 
sunscreen may be used 
on treatment days, and to 
add a window for IP 
application before next 
visit to prevent 
IP-contamination of PK 
blood samples. 
Sections 
10.2.2.3, 10.2.2.4, 
10.2.2.6, and 
10.2.2.7 
 
 
Reordered assessments to be in 
order of performance. Revised 
assessments to exclude 
individual scaling, to limit 
fissuring to palms/soles, and 
to add cross-reference to 
Sections 10.3.1.5 and 10.3.1.6. 
Added sunscreen(s) use on 
nontreatment days and time 
frame for use on treatment 
days. 
To specify order of 
assessments; to specify 
that fissuring is only to 
be assessed on 
palms/soles; to provide 
location of specific 
quality of life scales; to 
specify when emollients 
and protective sunscreen 
may be used on 
treatment days, and to 
add a window for IP 
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Added reminder that 24 hours 
must have elapsed since IP 
application before the 
subject’s next visit. Subjects 
should not apply IP on visit 
days until after the visit. 
application before next 
visit to prevent 
IP-contamination of PK 
blood samples. 
10.2.2.4  
 
Added caution to ensure that 
PK lines are placed before IP 
application.  
Added: Among subjects in 
the PK study, perform an 
additional ECGs at times of 
serial sampling. 
 
To specify order of 
assessments; to specify 
that fissuring is only to 
be assessed on 
palms/soles; to provide 
location of specific 
quality of life scales; to 
specify procedures and 
times for PK serial blood 
draws to prevent 
contamination with IP; to 
add postdose ECGs for 
subjects in PK substudy; 
and to specify when 
emollients and protective 
sunscreen may be used 
on treatment days. 
Section 10.2.2.7 
For subjects who successfully 
complete the initial 12 weeks 
of double-blind treatment and 
choose to continue into the 
OLE, this visit will be the first 
visit of that portion of the 
study.  
 
For subjects who successfully 
complete (i.e., have reliable 
visit attendance and 
compliance with IP 
application, in the 
investigator’s opinion) the 
initial 12 weeks of double-
blind treatment and choose to 
continue into the OLE, this 
visit will be the first visit of 
that portion of the study.  
To define “successful 
completion” of the 
Double-blind Period and 
to clarify eligibility for 
OLE. 
Section 10.2.4 
Subjects who complete the 
12-week Double-blind 
Treatment Period of the study 
may choose to continue into an 
optional 12-week Open-label 
Extension with trifarotene 
cream HE1 200 µg/g. 
Subjects who successfully 
complete (i.e., have reliable 
visit attendance and 
compliance with IP 
application, in the 
investigator’s opinion) the 
initial 12 weeks of double-
blind treatment may choose 
to continue into an optional 
12-week OLE with trifarotene 
cream HE1 200 µg/g. 
To clarify eligibility for 
OLE. 
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Section 10.2.4.2 
– 10.4.2.7 
 
Reordered assessments to be in 
order of performance, and 
revised assessments to limit 
fissuring to palms/soles. 
Added sunscreen(s) use on 
nontreatment days and time 
frame for use on treatment 
days. 
Added reminder that at least 
24 hours must have elapsed 
since IP application before 
the subject’s next PK blood 
draw. 
To specify order of 
assessments; to specify 
that fissuring is only to 
be assessed on 
palms/soles. 
To specify when 
emollients and protective 
sunscreen may be used 
on treatment days. 
To add a window for IP 
application before next 
visit to prevent 
IP-contamination of PK 
blood samples. 
Section 10.3 
The 5-point VIIS is a valid 
measure of disease severity 
and meets the need for a 
clinically meaningful measure 
of success for ichthyosis 
studies. The VIIS scale was 
developed to generate a 
reliable method to assess 
ichthyosis clinical severity 
using solely scale and 
erythema, which are the only 
findings present in ichthyosis 
of every genetic cause, and 
occur either upon skin of 
normal thickness (lamellar 
subtypes) or upon thickened 
skin (keratoderma subtypes).13 
The VIIS uses a 5 point index 
to assess the level of severity 
of scale and erythema in each 
of 4 body areas: 
chest/abdomen, back, legs, and 
arms, for a possible overall 
total of 16 points 
(Section 10.3.1.1).  
The 5-point IGA is a valid 
measure of disease severity 
and meets the need for a 
clinically meaningful measure 
of success for ichthyosis 
studies. The IGA scale was 
developed with the support 
of experts from academic 
reference centers for the 
treatment of ichthyosis. Each 
level of severity will consider 
both the severity of scaling 
and the severity of roughness 
(Section 10.3.1.1).  
To reflect the change in 
primary endpoint to IGA. 
Section 10.3.1.1 
10.3.1.1 Visual Index for 
Ichthyosis Severity – Scaling 
The primary endpoint is the 
number of subjects in each 
treatment group who 
experience successful 
resolution of LI where 
“success” is defined as 
clear/almost clear overall and 
at least a 50% reduction from 
Baseline at Week 12/EOT on 
10.3.1.1 Investigator’s 
Global Assessment 
The primary endpoint is the 
number of subjects in each 
treatment group who 
experience successful 
resolution of LI where 
“success” is defined as 
clear/almost clear and at least 
a 2-grade change from 
Baseline at Week 12/EOT in 
the Double-blind Period on 
To reflect the change in 
primary endpoint to IGA 
and that fissuring will 
only be assessed on 
palms/soles. 
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the overall 16-point VIIS for 
scaling. 
The investigator will rate the 
subject’s condition using the 
5-point VIIS for each body 
area (chest/abdomen, back, 
legs, and arms) and an overall 
score at each time point shown 
in the Schedule of Events 
(Section 2.2): 
0 Clear  
Normal skin; no perceptible 
scale or smoothening 
1 Almost clear 
Areas of normal skin 
intermixed with areas 
showing smoothening 
(diminished fine skin 
markings; shininess; 
waxiness) or small scales 
(visibly separated/fractured 
stratum corneum) 
2 Mild 
Confluent smoothening 
(diminished fine skin 
markings; shininess; 
waxiness) or small scales 
(visibly separated/fractured 
stratum corneum) 
3 Moderate 
Confluent scales (visibly 
separated/fractured stratum 
corneum) including some 
large (>1cm), thick scales 
4 Severe 
Confluent, primarily large, 
thick scales 
the 5-point IGA full body 
scale. 
The investigator will rate the 
subject’s condition using the 
5-point IGA at each time point 
shown in the Schedule of 
Events (Section 2.2).  
The IGA will be measured on 
a 5-point scale, excluding the 
following areas: knees, 
elbows, neck, palms, soles, 
axillae, groin, and scalp: 
0 Clear 
No scaling and no 
roughness 
1 Almost Clear 
Occasional fine scales; 
hardly palpable 
roughness (mostly 
smooth) 
2 Mild  
Small and fine scales 
predominate; no more 
than a few large scales; 
mild roughness on 
palpation 
3 Moderate 
Some large scales that 
may be thick; coarse 
roughness on palpation 
4 Severe 
Confluent, primarily 
large (>1 cm), thick scales 
with plate-like 
hyperkeratosis  
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Section 10.3.1.2 
10.3.1.2 Investigator’s Global 
Assessment 
 
Changed to : 
10.3.1.2 Visual Index for 
Ichthyosis Severity – Scaling 
The primary secondary 
endpoint is the number of 
subjects in each treatment 
group who experience a 
severity score of 0 or 1 and at 
least a 50% reduction from 
Baseline at Week 12/EOT on 
the overall 16 point VIIS for 
scaling. 
The investigator will rate the 
subject’s condition using the 
5-point VIIS for each body 
area (chest/abdomen, back, 
legs, and arms) and an overall 
score at each time point shown 
in the Schedule of Events 
(Section 2.2). 
Deleted clear/almost 
clear/mild/moderate/severe 
from scoring scale. 
To reflect the change in 
primary endpoint to IGA. 
Section 10.3.1.3 
Individual Score of Scaling 
(Scale: 0-4) 
 
Changed to: 
Individual Score for 
Roughness 
 
No individual score for 
scaling is needed now 
that IGA is primary 
endpoint. 
Section 10.3.1.5 
 
Added: A fissure is a 
longitudinal and deep crack 
that separates the stratum 
corneum and may penetrate 
down to the dermis, causing 
pain and sometimes bleeding.  
To clarify the definition 
of a fissure. 
Section 10.3.1.8 
 
Added: Figure 10-1 
Ectropion Severity Score 
(from reference #14)  
To show how the 
ectropion score should 
be calculated. 
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Section 10.3.3 
Sample Collection: 
Blood: 
Each blood sample will be 
3 mL/kg in volume. The total 
amount of blood to be drawn 
for serial PK assessments will 
be a maximum of 5 mL/kg per 
subject over a 24-hour period. 
 
Added: Finding veins in 
subjects with this disease can 
be challenging. Blood draws 
will be done at the 
corresponding study visits 
before application of the IP 
and should be 24 hours after 
IP application. Subjects must 
not apply the IP to the area 
where blood will be drawn 
within 24 hours before their 
next study visit to avoid 
contamination of the blood 
by IP that remained in the 
skin. For subjects in the PK 
substudy, a cannula should 
be placed before IP 
application and the cannula 
site may be occluded to 
prevent contamination with 
IP. 
Actual PK sample times for 
subjects in the PK substudy 
will be recorded in the eCRF. 
Blood: 
For subjects not in PK 
substudy: 
The expected amount of 
blood to be drawn at each 
visit varies from 
approximately 6 mL to a 
maximum of 21 mL 
(Screening Visit only). The 
total amount of blood drawn 
for the study will be about 
123 mL per subject, unless 
the subject takes part in the 
PK substudy. 
For subjects in PK substudy: 
For subjects who opt to 
participate in the PK 
substudy, extra blood 
samples will be drawn at 
Visit 2 and at Visit 4 for PK 
analysis. The amount of 
blood to be drawn per 
subject at each of these visits 
will be approximately 54 mL. 
For subjects taking part in 
the substudy, the total 
amount of blood drawn for 
To clarify how blood 
draws should be 
performed to prevent 
contamination with IP. 
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Section 
Previous Text 
Revision 
Rationale 
the entire study will be 
approximately 195 mL. 
Section 
10.3.4.2.2 
 
Added: Gel ECG electrodes 
may be used for ECGs 
because they are more 
conductive and cause less 
trauma on compromised 
skin. Efficacy assessments 
should be conducted before 
ECGs to avoid possible 
artefact/changes from the 
ECG.  
For subjects in the PK 
substudy, additional ECGs 
will be performed postdose 
during serial blood sampling 
on Day 1 and Day 30. 
If there is a marked 
prolongation of the QT/QTc 
interval during treatment, a 
subject should be 
discontinued from the IP, but 
remain in the study until full 
resolution of the event. The 
DSMB will be informed 
immediately of such an 
occurrence. 
To ensure the most 
comfortable method is 
used; to address order of 
assessments; to add 
ECGs postdose at Day 1 
and Day 30 (per MHRA 
request) among subjects 
in the PK substudy; and 
to address procedures 
should QT/QTc 
prolongation occur. 
10.3.4.2.3 
A complete physical 
examination excluding the 
genitourinary examination will 
be performed as indicated in 
the Schedule of Events 
(Section 2.2). 
A complete physical 
examination excluding the 
genitourinary examination will 
be performed at Screening, 
while limited physical 
examinations (to include 
HEENT, cardiorespiratory, 
abdomen, and range of 
motion) will be performed as 
indicated in the Schedule of 
Events (Section 2.2). 
To clarify when 
complete and limited 
physical examinations 
are to be performed. 
Section 
10.3.4.2.4 
All application site reactions 
will be recorded as AEs. 
All application site reactions 
will be recorded as TEAEs in 
the diary. These should 
include the date and severity 
of the TEAE. 
To specify that all 
application site reactions 
should be recorded in the 
subjects’ diaries in detail.  
Section 11.2.3 
 
Added: Any AE that occurs 
during the Screening Period 
will be captured as such on 
the AE page of the eCRF 
(not medical history).  
To clarify that any AE 
that occurs after signing 
of the ICF is to be 
captured as such and not 
as medical history. 
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Revision 
Rationale 
Section 11.3.2 
All WOCBP who participate in 
the study should be counseled 
on the need to practice 
adequate birth control and on 
the importance of avoiding 
pregnancy during study 
participation.  
All WOCBP who participate in 
the study should be counseled 
on the need to practice highly 
effective birth control and on 
the importance of avoiding 
pregnancy during study 
participation.  
Added: Among the clinical 
studies, 12 pregnancies were 
reported: 4 resulted in 
normal births; 5 resulted in 
spontaneous abortions (none 
of which was considered 
related to CD5789); 1 was 
electively aborted, and 2 
were lost to follow-up 
(Investigator’s Brochure for 
CD5789 Cutaneous 
Formulation). 
To clarify that birth 
control must be “highly 
effective” (per MHRA).  
To add data on 
pregnancy from clinical 
studies with CD5789. 
Section 12 
The DSMB will meet after 
subjects in Cohort A have 
completed at least 28 days of 
double-blind treatment to 
review aggregate safety and 
tolerability data. The data will 
remain blinded unless an issue 
or trend arises that requires 
unblinding. At that time, the 
DSMB will decide whether 
Cohort B (adults and subjects 
aged 12–17) may begin 
enrolling. The DSMB will 
have the authority to 
recommend to the sponsor that 
the study be placed on hold, or 
discontinued if serious safety 
issues are discovered.  
The DSMB will meet after 
15 subjects in Cohort A have 
completed at least 28 days of 
double-blind treatment to 
review aggregate safety and 
tolerability data (including PK 
and ECG results). The safety 
data will be unblinded. At that 
time, the DSMB will decide 
whether Cohort B (adults and 
subjects aged 12–17) may 
begin enrolling, or if additional 
adult safety data are required 
before allowing subjects aged 
12 – 17 to participate in the 
study. The DSMB will have 
the authority to recommend to 
the sponsor that the study be 
modified, placed on hold, or 
stopped if serious safety issues 
are discovered.  
Added: Any protocol changes 
the DSMB may suggest will 
be submitted to all applicable 
regulatory bodies for review 
and approval. 
To clarify when the 
DSMB will meet, and 
what data they will 
review. 
 
Section 13.1.2.2 
and 
Section 13.1.3 
 
Added: Subjects who taper to 
once-weekly application or 
who take a “drug holiday” 
will not be reported as 
having deviated from the 
protocol. 
Clarified that subjects 
requiring dose 
adjustment or temporary 
interruption are not 
protocol deviators. 
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Section 13.1.2.3 
Baseline subject characteristics 
will include medical history, 
physical examination findings, 
and VIIS score. 
Baseline subject characteristics 
will include medical history, 
physical examination findings, 
and IGA score. 
To reflect change in 
primary endpoint to IGA. 
Section 13.1.4 
The mITT population will be 
used as the primary population 
for the primary analysis of 
efficacy at Week 12. All 
efficacy analyses will be 
repeated as secondary analyses 
in the ITT and PP populations 
for the Double-blind Period. 
Efficacy analyses will also be 
repeated in the OLE using the 
OLE mITT and OLE PP 
populations. No formal 
inferential analyses will be 
conducted for efficacy 
variables in the OLE. 
The ITT population will be 
used as the primary population 
for the primary analysis of 
efficacy at Week 12. Select 
efficacy analyses will be 
repeated as secondary analyses 
in the ITT and PP populations 
for the Double-blind Period. 
Efficacy analyses will also be 
repeated in the OLE using the 
OLE ITT, OLE mITT, and 
OLE PP populations. No 
formal inferential analyses will 
be conducted for efficacy 
variables in the OLE 
 
Section 13.1.4.2 
Descriptive summaries (such 
as mean, standard error, 
median, minimum, and 
maximum) and the changes 
from baseline will be provided 
for VIIS scores for both 
periods. 
Descriptive summaries (such 
as mean, standard error, 
median, minimum, and 
maximum) and the changes 
from baseline will be provided 
for IGA scores for both 
periods. 
To reflect the change in 
primary endpoint to IGA. 
Section 13.1.4.3 
Additionally, for the Double-
blind Period only, change from 
Baseline endpoints through 
Week 12 will be presented and 
analyzed using a mixed model 
for repeated measures 
(MMRM). The model will 
include the change from 
baseline score as the dependent 
variable, treatment group as a 
fixed effect, subject as a 
random effect, and baseline 
score value as a covariate. 
Frequencies of results and 95% 
CIs will also be reported and 
scores will be analyzed as 
categorical variables using the 
Cochran-Mantel-Haenszel test. 
Additionally, for the Double-
blind Period only, change from 
Baseline in continuous 
secondary endpoints through 
Week 12 will be presented and 
analyzed using a mixed model 
for repeated measures 
(MMRM). The model will 
include the change from 
baseline score as the dependent 
variable, treatment group as a 
fixed effect, subject as a 
random effect, and baseline 
score value as a covariate.  
Added: The proportion of 
subjects with at least a 50% 
reduction in IGA score from 
Baseline will be analyzed 
using the same logistic 
regression analysis described 
in Section 13.1.4.2. 
To reflect and clarify 
changes in secondary 
endpoints. 
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Section 
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Section 13.1.4.5 
To assess the effect of missing 
data on the primary efficacy 
analysis, a sensitivity analysis 
will be performed using LOCF 
for the Double-blind Period 
only. Imputation will not be 
performed in the OLD period.  
 
To assess the effect of missing 
data on the primary efficacy 
analysis, a sensitivity analysis 
will be performed using 
multiple imputation (MI) for 
the Double-blind Period only. 
Multiple-imputations will be 
used to replace missing IGA 
outcomes using multiple 
draws from the posterior 
predictive distribution 
estimated from the treatment 
groups. IGA scores will be 
imputed and then 
categorized as treatment 
success according to Section 
13.1.4.1. Imputation will not 
be performed in the OLE 
period. Full details will be 
specified in the Statistical 
Analysis Plan (SAP).  
Added: The proportion of 
subjects who experience a 
2-grade change from baseline 
to Week 12 in individual 
score for roughness and 
palm/sole assessment will 
also be explored using a 
logistic regression model 
with treatment and age 
group as factors. Other 
baseline characteristics and 
interactions may be included. 
The odds ratios and 95% CIs 
for the odds ratios will be 
presented. The difference in 
proportions between the 
active trifarotene cream HEI 
and vehicle cream group and 
the 95% CIs for the 
differences will be presented. 
To align with current 
FDA thinking. Single 
imputation does not 
consider all missingness 
patterns. 
To explore a defined 
threshold for a clinically 
meaningful endpoint for 
phase 3. 
Section 13.1.6.1 
During all clinic visits, the 
investigator will assess local 
tolerability (Scale: 0-3 [none, 
mild, moderate, severe]) 
averaged over the BSA.  
During all clinic visits, the 
investigator will assess local 
tolerability (Scale: 0-3 [none, 
mild, moderate, severe]) for 
each treated body area 
(chest/abdomen, back, arms, 
legs, and face/neck). 
To clarify that all treated 
areas are included in the 
local tolerability 
assessment. 
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Section 14.7.2 
Blood samples will be used for 
purposes related to this 
research. The samples will be 
stored until the sponsor has 
determined that specimens are 
no longer needed, and the 
decision has been made that 
none of the samples needs to 
be reanalyzed 
Blood samples will be used for 
purposes related to this study 
only, and will not be stored 
for future research. The 
samples will be stored until 
they are no longer needed, 
and the decision has been 
made that none of the samples 
needs to be reanalyzed.  
To clarify that no 
samples will be stored 
for future research 
 
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AMENDED PROTOCOL 
The following are the amended protocol and appendices, including all revisions specified above. 
 
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4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABBREVIATION 
EXPLANATION 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse events of special interest 
ATC 
anatomical therapeutic chemical 
AUC 
area-under-the-curve 
BMI 
body mass index 
BSA 
body surface area 
CFR 
code of federal regulations 
CI 
confidence interval 
Cmax 
maximum concentration 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
DBP 
diastolic blood pressure 
DLQI 
dermatology life quality index 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end-of-treatment 
ESS 
ectropion severity score 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GEE 
generalized estimating equations 
HR 
heart rate 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification 
IEC 
independent ethics committee 
IGA  
Investigator’s Global Assessment 
IND 
investigational new drug 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent-to-treat 
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ABBREVIATION 
EXPLANATION 
IUD 
intrauterine device 
IWRS 
interactive web response system 
LI 
lamellar ichthyosis 
MedDRA 
medical dictionary for regulatory activities 
mITT 
modified intent-to-treat 
MMRM 
mixed model of repeated measures 
NCA 
noncompartmental analysis 
OC 
observed case 
OLE 
open-label extension 
PG 
propylene glycol 
PK 
Pharmacokinetic(s) 
PoC 
proof-of-concept 
PP 
per-protocol 
QTc 
QT interval corrected for heart rate 
RARγ 
retinoid acid receptor γ  
RBC 
red blood count 
RR 
respiratory rate 
RXR 
retinoid X receptor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
Tmax 
time of Cmax 
UAE 
unexpected adverse event 
UADR 
unexpected adverse drug reaction 
US 
United States 
UV 
ultraviolet 
VIIS 
Visual Index for Ichthyosis Severity 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
women of childbearing potential 
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5. INTRODUCTION 
5.1. Background and Rationale 
The ichthyoses comprise a large group of skin scaling disorders with diverse etiology. The 
stereotypic pathophysiology is epidermal hyperplasia and the formation of excess stratum corneum 
accompanied by abnormal (delayed and/or disordered) desquamation, with visible accumulation 
of squames (scales) on the skin’s surface – the clinical hallmark of all the ichthyoses. 
Lamellar ichthyosis (LI) is recognized as a severe form of ichthyosis that persists throughout life. 
During the first postnatal weeks, the hyperkeratotic membrane patients are typically born with is 
gradually shed, and is replaced by scaling and lichenification that involves the entire body 
including the intertriginous areas, palms, soles, and scalp. While usually not life threatening, LI 
can result in disability, partial deafness, poor adaptation to environmental conditions (due to 
hypohydrosis), severe discomfort (pruritus, fissuring of the skin) and significant psychosocial 
impact. 
Lamellar ichthyosis, a member of the nonsyndromic autosomal recessive congenital ichthyosis 
group of ichthyoses, has an incidence of 1 per 100,000-300,000 live births.1 Lamellar ichthyosis 
is undoubtedly a rare disease. 
Therapeutic approaches for LI are mainly based on the use of topical emollients, keratolytic agents 
(urea, lactic acid, salicylic acid), topical retinoids and, in severe cases, oral retinoids.2,3 
Oral retinoid usage in LI is mainly based on case reports and case series.4,5,6,7,8 The mechanism of 
retinoid action involves modulation of keratinocyte differentiation, keratinocyte hyperproliferation 
and tissue infiltration by inflammatory cells. Systemic retinoids (such as acitretin, etretinate, or 
isotretinoin) have been found to be efficacious in the treatment of severe ichthyoses, especially in 
LI.6 
Vahlquist, et al (2008)3 report that by combining 2 or more keratolytic agents and moisturizers in 
the same lipophilic cream base, it is often possible to achieve additive or even synergistic effects 
in LI without the need to use irritating concentrations of either agent alone. In a double-blind trial 
of 4 different cream mixtures in 20 patients with LI, a mixture of 5% lactic acid and 20% propylene 
glycol (PG) in a semi-occlusive cream for 4 weeks twice daily was significantly more effective 
than 20% PG or 5% urea alone in the same vehicle.9 Although the treatments were well tolerated, 
an efficient removal of hyperkeratosis without correcting the underlying biochemical defect in LI 
is likely to deteriorate the patient’s intrinsic barrier problem, because an excessive production of 
corneocytes probably represents a homeostatic response to an ineffective barrier. Indeed, 
transepidermal water loss increased after successful treatment of LI with either topical 
keratolytics9 or oral retinoid.10 Although this may not be noticeable by the patient, even minor 
deteriorations in the barrier function can enhance transcutaneous penetration of active cream 
ingredients or other topically applied chemicals, which is a matter of special concern in children. 
Accordingly, α-hydroxy acids and salicylic acid should not be used at all in babies and only with 
great caution when treating large, eroded skin areas in adult patients.11,12 
Many patients with LI use pumice, foot files, or gentle rubbing of the skin after a hot bath or a 
shower to remove scales and hyperkeratosis. Overnight occlusion of problematic skin areas with 
plastic sheets after applying a thick layer of emollient or keratolytic agents is another way of 
potentiating therapy, especially on the scalp, which is notoriously difficult to treat. Although 
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usually effective, all these remedies may further damage the skin barrier and lead to exaggerated 
epidermal proliferation, erythema, painful erosions and increased transcutaneous penetration.3 
Based on this information, LI has significant unmet medical need for safer and more effective 
therapies. 
5.1.1 CD5789 (Trifarotene) 
CD5789 is a new chemical entity discovered by Galderma R&D SNC and formulated for topical 
application. It is a novel retinoid acid receptor γ (RARγ) agonist, characterized by its high 
specificity to this receptor. CD5789 is selective for RARγ over RARα and RARβ (approximately 
50- and 8-fold, respectively), with no retinoid X receptor (RXR) activity. CD5789 is currently 
under clinical development for the topical treatment of various dermatoses, including acne vulgaris 
and LI. 
The pharmacological retinoid-like properties of CD5789 were confirmed in in vitro and in vivo 
models, showing its interest for its development in the treatment of LI. Therefore, it may have an 
effect on the differentiation and hyperproliferation of keratinocytes, and consequently improve 
hyperkeratotic skin of patients with lamellar ichthyosis. 
Within the overall acne development program at Galderma, CD5789 has been tested in different 
pharmaceutical forms for topical administration. As of 15-Jan-2018, 6 different formulations have 
been evaluated: a solution, a gel and 4 creams (CD5789 cream A, CD5789 cream B, 
CD5789 cream HE1 concept and its optimized version, cream HE1), with different concentrations 
(up to 400 µg/g). Therefore, several formulations at different CD5789 concentrations have been 
tested in nonclinical and clinical development programs. 
Galderma decided to develop a new cream formulation that might better address the issue of skin 
dryness in patients with LI. This formulation was named “Cream HE1 concept.” It has been 
preliminarily investigated in an exploratory trial in psoriasis at concentrations up to 400 μg/g 
(RD.03.SRE.40204E). In a proof-of-concept study (RD.03.SRE.40181E), positive results were 
also obtained in patients with LI with CD5789 cream (up to 100 µg/g) that was effective in 
decreasing scaling and roughness. Based on these results, a new CD5789 formulation (cream HE1) 
was developed for further clinical investigations in LI. The formulation cream HE1 was developed 
with the objective to obtain a formulation with appropriate stability of the active ingredient and in 
which CD5789 would be homogeneously dissolved in the oily phase at a higher concentration 
compared to the cream formulation used in the acne program. Cream HE1 contains 100, 200, or 
400 μg/g (0.01% [w/w], 0.02% [w/w], 0.04% [w/w], respectively) of CD5789. 
Galderma has granted Mayne Pharma LLC an exclusive license to develop and commercialize 
CD5789 (trifarotene) for LI and other orphan diseases; therefore, the LI indication is no longer 
pursued by Galderma. 
5.2. Clinical Experience 
The cream HE1 differs from the CD5789 cream used to treat acne vulgaris in that it contains fewer 
excipients with drying effects and therefore may be better suited for patients with LI. 
Throughout the 30 clinical studies that comprise the clinical development program for CD5789 
topical products, 1976 subjects were exposed to CD5789. No systemic safety concerns related to 
CD5789 gel or creams, or cream HE1 at doses up to 400 μg/g were reported. The subjects were 
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exposed to a maximal total CD5789 dose of 36 g/day (Investigator’s Brochure for CD5789 
Cutaneous Formulation). 
One study was conducted with CD5789 50 μg/g, 100 μg/g, and placebo in subjects with ichthyosis 
(Study RD.03.SRE.40181E). Among 31 subjects treated in this study, 17 were treated with 
CD5789 100 μg/g, and 14 were treated with 50 μg/g (all subjects received placebo [vehicle] on the 
contralateral zone). Mean (SD) baseline IGA score was 5.7 ± 1.6 among the 31 subjects. 
Improvement in the investigator’s global assessment (IGA) of scaling and roughness was observed 
by Day 8 with both doses. The primary efficacy criterion was the change in IGA from the Baseline 
Visit (Day 1) to the Final Visit (Day 43). At Endpoint (intent-to-treat population, last observation 
carried forward [LOCF]), the CD5789 100 μg/g group had a statistically significant decrease from 
Baseline in IGA compared with Vehicle (-1.4±2.2; p=0.018) (Investigator’s Brochure for CD5789 
Cutaneous Formulation). 
The CD5789 PK profile was also investigated using cream HE1 (Study GD.03.SRE.103813) in 
36 healthy volunteers of Japanese and non-Japanese origin. Subjects were treated daily on up to 
90% of body surface area (BSA) for 29 days with up to 36 g of cream formulation. Both CD5789 
100 μg/g and 200 μg/g cream HE1 were investigated. Plasma PK assessment demonstrated that 
repeated topical applications of CD5789 cream HE1 resulted in low and similar CD5789 systemic 
levels in all treatment groups. In addition, no systemic safety concerns were raised from this 
healthy volunteer study in which cream HE1 200 μg/g was applied daily under maximal-use 
conditions on almost the full body. In this study, however, the level of irritation resulted in the 
need to decrease the frequency of application to twice weekly (Investigator’s Brochure for CD5789 
Cutaneous Formulation). However, it is possible that absorption in subjects with LI may be greater 
than in healthy volunteers, due to the skin being compromised. 
Based on these data, both the 100 µg/g and 200 µg/g doses showed an acceptable safety profile 
and will be used in this phase 2 LI study, to determine which of the 2 doses is most effective. The 
open-label extension (OLE) will evaluate the long-term safety of the higher dose in this patient 
population.  
5.3. Summary of Potential Risks and Benefits 
Although the primary objective of this study is safety in the patient population with LI, the 
potential benefits of study participation are that subjects with LI may experience a reduction in 
their LI symptoms as a result of treatment with trifarotene (CD5789) cream HE1. No other benefits 
of participation are anticipated. 
The potential risks of study participation include those associated with exposure to trifarotene 
(CD5789) cream HE1 and the risks of medical evaluation, including venipuncture.  
Animal studies with CD5789 have shown reproductive toxicity in the embryo-fetal studies. 
Despite low systemic levels with the CD5789 concentration of 50 μg/g used in patients with acne, 
CD5789 must not be administered during pregnancy. 
When CD5789 is used in the other formulations and/or for other indications and/or with higher 
concentrations or higher application surface areas, the potential risk of teratogenicity needs to be 
considered as the safety margin may be lower. Depending on the study population and conditions 
mentioned above, or other specific requirements, the appropriate contraception method is 
described in this protocol. 
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It is unknown whether CD5789 or its metabolites are excreted in human milk. A risk to the 
newborns/infants cannot be excluded. Lactating women are not eligible for the clinical study. 
Certain cutaneous signs and symptoms of irritation and localized reactions at the application site 
such as erythema, scaling, dryness, stinging/burning, and pruritus may be experienced with use of 
CD5789. Depending upon the severity of these side effects, subjects may be instructed to reduce 
the frequency of application or to discontinue use.  
Trifarotene cream contains propylene glycol that is mildly irritant to the skin, eyes, and mucous 
membranes. Trifarotene (CD5789) cream HE1 also contains butylated hydroxytoluene that may 
cause local skin reactions (e.g., contact dermatitis), or irritation to the eyes and mucous membranes 
and sodium benzoate that is mildly irritant to the skin, eyes, and mucous membranes. 
CD 5789 is mildly irritant to the skin, eyes, and mucous membranes. Therefore, it should not come 
into contact with the eyes, mouth, or mucous membranes.  
There is a potential risk of skin sensitization. If a reaction suggesting sensitivity to trifarotene 
(CD5789) cream HE1 occurs, the use of the trifarotene cream HE1 must be discontinued. 
There is a potential risk of photosensitivity disorder (sunburn). Excessive exposure to sunlight or 
ultraviolet (UV) radiation (i.e., occupational exposure to the sun, planned holidays in the sun 
during the study, phototherapy, tanning salon) must be avoided during the studies. In addition, 
subjects should take protective measures such as applying sunscreen (except within 4 hours before 
and/or 4 hours after study drug application), and/or wearing protective clothing (e.g., long sleeves, 
hats, and covering legs and feet) and/or seeking shade or shelter from the sun. 
As reported with other topical retinoids, there is a potential risk of pigmentation disorders. 
No clinically significant systemic risks associated with CD5789 have been identified. Given the 
mechanism of action for CD5789 Cream HE1, it is assumed that efficacy will increase as the dose 
is increased. As such, the 200 µg/g dose was selected for the OLE based on its previously 
established safety profile, expected superiority to placebo and 100 µg/g. However the Data Safety 
Monitoring Board (DSMB), who will routinely review aggregate safety and tolerability data, as 
well as any safety concerns brought to the their attention by the study investigators or medical 
monitor, may determine that the study should be modified, placed on hold, or stopped if serious 
safety issues are discovered. This is applicable for both the double-blind portion and OLE. If the 
200 µg/g dose in raises any safety concerns, the protocol will be amended and the dose will be 
reduced. 
A summary of the pharmaceutical properties and known potential risks of trifarotene (CD5789) 
cream HE1 is provided in the current version of the investigator’s brochure (IB). The investigator 
must become familiar with all sections of the trifarotene (CD5789) cream IB before the start of the 
study. 
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6. OBJECTIVES 
6.1. Primary Objective 
The primary objective is to compare the safety and efficacy of 2 concentrations of trifarotene cream 
HE1 versus vehicle in subjects with moderate to severe autosomal recessive ichthyosis with 
lamellar scale, also known as lamellar ichthyosis (LI) after 12 weeks of treatment. 
6.2. Secondary Objectives 
The secondary objectives are as follows: 
• To assess systemic exposure to trifarotene and its major metabolites after topical 
application of the investigational product (IP) on up to 90% BSA twice weekly. 
• To assess safety for up to 24 weeks of dosing with open-label trifarotene cream HE1 
200 µg/g. 
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7. STUDY DESIGN 
7.1. Overall Study Design and Plan 
The first part of this study is a phase 2, randomized, 2-cohort, double-blind, vehicle-controlled, 
multicenter study of the safety, tolerability, PK, and efficacy study of trifarotene cream HE1 
100 µg/g and 200 µg/g in subjects with LI. Subjects who complete the randomized, double-blind, 
vehicle-controlled period of the study will be eligible to continue into an open-label extension 
(OLE) and be treated with trifarotene cream HE1 200 µg/g for an additional 12 weeks. 
The randomized, double-blind, vehicle-controlled period of the study in subjects with moderate to 
severe LI (i.e., 3–4 on a 5-point Investigator Global Assessment [IGA] scale where 0 = clear; 1 = 
almost clear; 2 = mild; 3 = moderate; and 4 = severe, is designed to compare the safety of 2 doses 
of trifarotene cream HE1 with that of vehicle in the treatment of LI.  
Upon signing informed consent and entering the Screening Period, subjects will stop using 
physical and medical treatments for LI, including balneotherapy, and may begin to washout 
prohibited topical and systemic treatments with designated washout periods (Table 9-1), as 
applicable. Washout may be up to 3 months, as necessary. 
During washout, subjects may continue taking usual care of visible skin (face and scalp) for 
cosmetic reasons and of extremities (hands and feet) to avoid functional consequences on walking 
or moving their fingers. Subjects may shower, but not bathe or swim. The IGA will be evaluated 
on the rest of the body at Baseline. After completing any necessary washout of prohibited 
medications, subjects will return to the site to complete the study eligibility requirements. 
The first cohort of subjects (Cohort A) will randomize approximately 15 subjects in a 1:1:1 ratio 
to trifarotene (CD5789) cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle.  
Study drug will be packaged in 50-g tubes from which up to 36 g of IP may be dispensed per 
application, i.e., the maximum dose per application. Study staff will apply the first dose of study 
drug to each subject in the clinic on Day 1 after Baseline measurements, and will record the amount 
of study drug applied (i.e., study staff will measure the 50-g tube before and after the first 
application to determine the fixed dose amount for each subject). If the product will be applied at 
home by someone other than the study subject, it is recommended that this person assist with 
application at the first visit to learn how the IP is applied. 
Thereafter, subjects will apply approximately the same amount (up to 36 g) of study drug as for 
the first dose on up to 90% of BSA twice weekly, sparing the scalp, inguinal, and axillary areas. 
Subjects with heavy facial hair should not apply IP to hair-bearing areas. Subjects will receive an 
adequate number of tubes to use 1 tube per application and will use a new tube for each treatment 
day. Subjects may use less than the full amount of IP in a tube. 
Subjects enrolled in Cohort A will continue treatment for up to 12 weeks.  
After the initial 15 subjects complete at least 28 days of treatment, an independent DSMB will 
review aggregate safety and tolerability data (including PK and electrocardiogram [ECG] data). If 
no safety issues are identified, additional subjects will be allowed to enroll in Cohort B (up to 
approximately 105 subjects). Subjects in Cohort B will be randomized 1:1:1 to trifarotene cream 
HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle and similarly treated twice weekly for 
up to 12 weeks in the same manner as subjects in Cohort A.  
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All subjects will be provided with diaries in which to record study drug application (days/times 
and any areas of skin not treated [e.g., due to local reactions]), any application site reactions, 
adverse events (AEs), and concomitant medications used. Subjects will also be advised on 
permitted emollient(s) and/or sunscreen(s) use on nontreatment days during the study; use of 
emollient(s) and/or sunscreen on study drug treatment days within 4 hours before or after study 
drug application is prohibited. 
At all sites with photographic capability, photographs will be taken as source data to support 
scoring at Baseline, Day 30, and Day 90. A central reader who will not be an investigator in the 
study will review the photographs to assess consistency of investigator scoring of LI severity as a 
quality check. Photographs may also be used for scientific publication purposes. Subjects will sign 
a separate, optional, photographic informed consent form (ICF).  
Samples for PK will be drawn from all subjects at Baseline and at each clinic visit, as indicated in 
the Schedule of Events (Table 2-1). Visits for PK must occur at least 24 hours after the last 
application of the IP to avoid contamination of the blood samples with any IP that may have 
remained in the skin after the last application. Subjects should not apply IP on visit days until after 
the visit. 
In addition, a PK substudy will be conducted on Days 1 and 30 at sites with the capability to 
conduct it. Participation in the PK substudy will be optional and will include at least 30 subjects. 
Subjects who participate in the PK substudy will come from both study cohorts and will undergo 
serial blood sampling predose and at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1 and Day 30. 
Trough levels will be drawn for all subjects at specified time points. For the subjects in the PK 
substudy, postdose ECGs will be performed at each serial blood draw on Day 1 and Day 30. 
Efficacy will be assessed by the number of subjects in each treatment group who achieve “success” 
defined as clear/almost clear overall and at least a 50% reduction from Baseline at 
Week 12/end-of-treatment (EOT) in the Double-blind Period on the 5-point IGA scale (i.e., 0 = 
clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe). In addition, efficacy criteria include 
assessment scales for palm/sole, scaling, roughness, fissuring, and the Dermatology Life Quality 
Index (DLQI), and the EQ-5D Quality of Life (QoL) Questionnaire. Ectropion Severity Scores 
(ESS) between the active trifarotene cream HE1 and vehicle groups will be an exploratory 
endpoint. 
Plasma concentrations of CD5789 and its major metabolites will be measured. 
Safety will be assessed by evaluating reported adverse events (AEs), changes in clinical laboratory 
test results, vital sign measurements, physical examinations, 12-lead ECGs, and local tolerability. 
All AEs observed by the study personnel or reported by the subject during the study (from the time 
of the signing of the informed consent through the post-treatment visit) will be documented. 
Topical trifarotene cream HE1 was generally well tolerated in recently completed phase 3 pivotal 
and long-term safety studies in subjects aged 9 years and older with acne vulgaris. The local 
tolerability of the trifarotene cream HE1 formulation in subjects with LI is unknown and will be 
monitored during the study. Subjects will receive information on study drug use and stopping rules 
and will be instructed to contact the site with any safety/tolerability issues. Study personnel will 
telephone subjects in between scheduled visits (i.e., at Day 7 and Day 45) to assess safety; an 
unscheduled clinic visit may be performed, if necessary. During all clinic visits, the investigator 
will assess local tolerability (Scale: 0-3 [none, mild, moderate, severe]) on each treated body area 
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(chest/abdomen, back, legs, arms, and face/neck) and will follow the procedures detailed in Section 
9.4. 
All subjects (Cohort A and Cohort B) who complete the 12-week Double-blind Treatment Period 
will be eligible to enroll in the 12-week OLE. Subjects in the OLE will receive open-label 
trifarotene cream HE1 200 µg/g twice weekly for up to 12 weeks. During the OLE, subjects will 
return to the site at Weeks 14, 16, 20, 24, and 26. Additional PK samples will be drawn at Week 
16 and Week 24 from all subjects who continue into the OLE (Table 2-2).  
Stopping rules and treatment modification will be defined at the subject level based on local 
tolerability, selected laboratory parameters, and AEs; see Section 9.4. 
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Figure 7-1: 
Double-blind Study Design 
 
 
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DSMB reviews safety data 
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Figure 7-2: 
Open-label Study Design 
 
 
Double-blind Treatment Period 
Study Day 90/Week 12 (- 7 days) 
= first visit of 
Open-label Extension Period with 
trifarotene 200 µg/g 
Continue through 12 weeks of treatment 
Follow-up Day 192 or 14 days after 
End of Treatment 
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7.2. Rationale and Discussion of Study Design 
The first part of this study is a randomized, double-blind, placebo-controlled study of the safety, 
tolerability, PK, and efficacy study of trifarotene cream HE1 100 µg/g and 200 µg/g in subjects 
with LI.  
In a previous proof-of-concept study (RD.03.SRE.40181E), subjects with LI applied trifarotene 
50 and 100 µg/g cream to limited areas and results demonstrated a decrease in scaling with good 
safety and tolerance. In a phase 1 study in healthy Japanese and non-Japanese subjects 
(RD.03.SPR.103813), repeated topical applications of trifarotene (CD5789 cream HE1) 100 µg/g 
and 200 µg/g resulted in low and similar CD5789 systemic levels in all the cohorts. These studies 
are fully described in the current IB. 
To ensure safety, this phase 2 study will begin with an initial cohort (Cohort A) of 15 subjects 
randomized 1:1:1 to trifarotene cream HE1 100 µg/g, 200 µg/g, or vehicle to be applied twice 
weekly. An independent DSMB will review aggregate safety and tolerability data from the initial 
15 subjects’ first 28 days of treatment. If no safety issues are identified, 105  additional subjects 
will be allowed to enroll in Cohort B and randomized to trifarotene cream HE1 100 µg/g, 
trifarotene cream HE1 200 µg/g, or vehicle and treated twice weekly in the same manner as 
subjects in Cohort A. All subjects in the randomized, double-blind portion of the study will be 
treated for up to 12 weeks and data on safety, tolerability, PK, and efficacy collected.  
Subjects who successfully complete the initial 12 weeks of double-blind treatment will have the 
option to enter an OLE with trifarotene cream HE1 200 ug/g twice weekly for up to 12 weeks.  
The OLE will collect additional safety, tolerability, PK, and efficacy data. As designed, this study 
will provide important information on safety, tolerability, and PK with dosing of subjects with LI 
for up to 6 months.  
The protocol includes appropriate monitoring for safety and tolerability. If subjects develop 
significant local application site reactions or tolerability issues, the protocol includes language for 
reducing the frequency of application or halting study drug application until the symptoms abate. 
7.3. Selection of Doses in the Study 
Based on the results from Study RD.03.SRE.40181E and Study SRE.103813, the doses of 
100 µg/g and 200 µg/g were selected for further investigation in subjects with moderate to severe 
LI to determine which of the 2 doses is most effective. The PoC study demonstrated efficacious 
treatment with 100 µg/g in adults. The PK and tolerability study showed that, when the frequency 
of application was reduced from daily to twice weekly, the 200 µg/g cream HE1 had good local 
tolerability. 
Therefore, the current study will use these doses compared with vehicle, applied twice weekly on 
up to approximately 90% BSA in subjects with LI. The OLE will evaluate the long-term safety of 
the higher dose in this patient population. 
7.4. Study Sites 
The study will take place at approximately 40 sites in North America, Europe, Israel, and Australia.  
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7.5. Point of Contact 
A point of contact will be identified to provide information to subjects about where to obtain 
information on the study, the rights of subjects, and whom to contact in case of a study-related 
injury. This information will be provided in the subject information and informed consent form 
(ICF). 
7.6. End of Study Definition 
A clinical trial is considered completed when the last participant’s last study visit has occurred. 
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8. SUBJECT POPULATION 
8.1. Selection of Study Population and Diagnosis 
Diagnosis of LI for the purposes of this study will be a clinical diagnosis. Although some younger 
subjects may have had genetic testing, older subjects may not.  
While LI is a rare disease and subject enrollment may be challenging, due to possible bias 
introduced by including household members in the same study, it is recommended that only 
1 household member be included in the study to maintain the blind and ensure all assessments are 
independent. 
8.2. Study Entry Criteria 
8.2.1 Inclusion Criteria 
A subject will be eligible for study participation if he or she meets all of the following criteria: 
1. Subject is ≥18 years old.  
2. Subject has known diagnosis of LI.  
3. Subject has moderate to severe (IGA 3–4) LI on the IGA of LI severity.  
4. Subject has signed an ICF at Screening before any investigational procedures.  
5. Subject who is participating in optional photography has signed a photography ICF. 
6. Subject who is participating in the optional PK substudy has signed a PK ICF. 
7. Subject is not of childbearing potential, i.e., a female who is postmenopausal (absence of 
menstrual bleeding for 1 year before Baseline, without any other medical reason, 
hysterectomy or bilateral oophorectomy),  
OR  
• Subject is a woman of childbearing potential (WOCBP) or a male subject with sexual partners 
capable of reproduction who agrees to use 2 effective forms of contraception during the study 
and for at least 1 month after the last study drug application. The 2 authorized forms of 
contraception are condom used with 1 of the following methods of contraception: 
• bilateral tubal ligation 
• combined oral contraceptives (estrogens and progesterone) or implanted or injectable 
contraceptives with a stable dose for at least 1 month before Baseline; hormonal 
contraceptives must inhibit ovulation 
• hormonal intrauterine device (IUD) inserted at least 1 month before Baseline 
OR 
Agrees to abstain from heterosexual intercourse during study participation and for 1 month 
after the last application of study drug and to use a highly effective contraceptive as backup if 
he or she becomes sexually active during the study. Abstinence is only acceptable if this is the 
subject’s usual lifestyle. Periodic abstinence (calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method are not acceptable methods of contraception. 
AND 
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Male subjects may not donate sperm during the study and for at least 1 month after the last 
study drug application. 
8. Women of childbearing potential must be nonlactating and have negative pregnancy test results 
at Screening (serum) and on Day 1 before study drug administration (urine). 
9. Subject is reliable and capable of adhering to the protocol and visit schedule, in the 
investigator’s judgment, and has signed informed consent. 
10. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin). 
8.2.2 Exclusion Criteria 
A subject will be excluded from the study if he or she meets any of the following criteria: 
1. Subject has any variant of ichthyosis other than LI or another disorder of keratinization, 
including syndromic ichthyoses.  
2. Subject has current moderate or severe stinging/burning at Screening. 
3. Subject has an ongoing cutaneous infection or any other significant concomitant skin disease 
(other than the LI) which, in the investigator’s opinion, may interfere with the study 
assessments. 
4. Subject with a known lipid disorder (hypertriglyceridemia >200 mg/dL, hypercholesterolemia 
>250 mg/dL) unless well controlled by stable doses of lipid-lowering agents for at least 
6 months. 
5. Subject was previously treated with trifarotene/CD5789 in an acne or ichthyosis study.  
6. Subject has any other significant concomitant disease, or poorly controlled medical condition 
other than LI that in the investigator’s opinion may put him or her at risk if he or she takes part 
in the study, and/or that may interfere with the study assessments. 
7. Subject has a medical condition that potentially alters bone metabolism (e.g., osteoporosis, 
thyroid dysfunction, Cushing syndrome, Crohn’s disease, or ulcerative colitis). 
8. Subject is being treated for major depression disorder and/or has a history of major depression 
or suicide attempt requiring hospitalization, medications, and close psychiatric surveillance to 
prevent suicide attempts.   
9. Subject with positive serology for hepatitis B surface antigen, hepatitis C, or are known to be 
HIV positive or to have AIDS at Screening. 
10. Subject with any of the following laboratory values at Screening: 
a. Aspartate aminotransferase or alanine aminotransferase >1.5 × upper limit of normal 
defined by the laboratory 
b. Total bilirubin >1.1 mg/dL or, in case of Gilbert’s syndrome, total bilirubin >3 mg/dL 
c. Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women 
d. Platelets <150 × 109/L or >400 × 109/L. 
11. Subject has any clinically other significant abnormal laboratory value (hematology, chemistry, 
or urinalysis) at Screening that, in the investigator’s opinion, may put the subject at risk if he 
or she takes part in the study, and/or that may interfere with the study assessments. 
12. Subject has had recent systemic malignancy (e.g., within 5 years) with exception of 
nonmelanoma skin cancer or cervical intraepithelial neoplasia of Grade 1 who are >6 months 
post-treatment. 
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13. Subject has a history of long QT syndrome or clinically significant ECG abnormalities, 
including clinically significant conduction disorders or significant arrhythmias, QTcF interval 
>450 ms, PR interval is not between 120 and 220 ms (inclusive), HR >100 bpm or <50 bpm, 
QRS interval >110 ms, or QT intervals that cannot be consistently analyzed. 
14. Subject has a known allergy or sensitivity to any of the components of the investigational 
products.  
15. Subject has been exposed to excessive UV radiations on the treated zones within 1 month 
before Baseline visit or is planning intensive UV exposure during the study (e.g., occupational 
exposure to the sun, sunbathing, phototherapy, etc.). 
16. Subject is inherently sensitive to sunlight. 
17. Subject is unable or unwilling to stop use of topical or systemic retinoids. 
18. Subject is presumed to be abusing drug or alcohol at Screening or Baseline Visits based on 
medical history or current clinical symptoms. 
19. Subject is participating in another interventional clinical trial. 
20. Subject is institutionalized. 
21. Subject is in any way related to the sponsor, investigator, or site personnel. 
8.3. Premature Subject Withdrawal 
All subjects will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. The investigator should make every reasonable 
attempt to keep subjects in the study; however, subjects must be withdrawn from the study if they 
withdraw consent to participate. Investigators must attempt to contact subjects who fail to attend 
scheduled visits by telephone or other means to exclude the possibility of an AE being the cause 
of withdrawal. Should this be the cause, the AE must be documented, reported, and followed as 
described in Section 11.2. 
The sponsor reserves the right to request the withdrawal of a subject due to protocol deviations or 
other reasons. 
The investigator also has the right to withdraw subjects from the study at any time for lack of 
therapeutic effect that is intolerable or otherwise unacceptable to the subject, for intolerable or 
unacceptable AEs, intercurrent illness, noncompliance with study procedures, administrative 
reasons, or in the investigator’s opinion, to protect the subject’s best interest. 
If a subject is withdrawn before completing the study, the reason for withdrawal and the date of 
discontinuation will be recorded on the appropriate page of the electronic case report form (eCRF). 
Whenever possible and reasonable, the evaluations that were to be conducted at the completion of 
the study should be performed at the time of premature discontinuation. 
8.4. Discontinuation of Study Intervention 
Discontinuation from study treatment does not mean withdrawal from the study, and the remaining 
study procedures should be completed as indicated in the study protocol (see Section 10.2.4.5). If 
a clinically significant finding is identified (including, but not limited to changes from Baseline) 
after enrollment, the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an AE. 
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An investigator must discontinue a participant’s study treatment for any of the following reasons: 
• Pregnancy 
• Significant study intervention noncompliance  
• If any clinical AE, laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would result in a significant burden to the 
participant 
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for discontinuation of study treatment will be recorded on the eCRF. Subjects who sign 
the informed consent form and are randomized but do not receive the study intervention may be 
replaced. Subjects who sign the informed consent form, are randomized, and receive the study 
intervention, and subsequently discontinue study treatment, or are withdrawn from the study will 
not be replaced. 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site will attempt to contact the participant and reschedule the missed visit and counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
8.5. Subject Replacement Criteria 
Withdrawn subjects will not be replaced. If a substantial number of subjects are withdrawn from 
the study, the sponsor will evaluate the need for developing replacement criteria. 
Randomized subjects withdrawn from the study may not reenter. The subject number for a 
withdrawn subject will not be reassigned to another subject. 
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9. TREATMENTS 
9.1. Identification of Investigational Product(s) 
Trifarotene cream HE1 is a cream containing 100 or 200 μg/g (0.01% [w/w] or 0.02% [w/w], 
respectively) of CD5789 and the following excipients: purified water, propylene glycol, allantoin, 
glycerin, medium-chain triglycerides, polypropylene glycol 15 stearyl ether, cyclomethicone, 
phenoxyethanol, copolymer of acrylamide and sodium acryloyldimethyltaurate, dispersion 40% in 
isohexadecane (simulgel 600 PHA), sodium benzoate, butylated hydroxytoluene, and 
gluconolactone. It is an RARγ agonist characterized by its high specificity to this receptor. 
Vehicle contains the same ingredients, without the CD5789. 
Trifarotene cream HE1 and vehicle will be provided in cream form for topical application and will 
be supplied in 50-g tubes from which a maximum of 36 g of IP may be extracted. 
Trifarotene cream HE1 and vehicle will be supplied by G. Production, Inc. (Galderma) in 
Baie-D'Urfé, QC, Canada. 
9.2. Treatments Administered  
For the Double-blind Treatment Period, a fixed dose (determined at Visit 2) of trifarotene cream 
HE1 100 µg/g or 200 µg/g or vehicle cream will be applied topically twice weekly on up to 90% 
BSA of each subject. The IP should be applied thinly and gently rubbed in. 
Study staff will apply the first administration of IP in the clinic on Day 1 after Baseline 
measurements, and the amount of IP used will be measured (i.e., 50-g tube will be measured before 
and after application to determine amount used). If the product will be applied at home by someone 
other than the study subject, it is recommended that this person assist with application at the first 
visit to learn how the IP is applied. 
The maximum dose per application is 36 g (i.e., 1 tube). Subjects will receive an adequate number 
of tubes to use 1 tube per application and will use a new tube for each treatment day. Subjects may 
use less than full amount of product in a tube. Subjects will continue treatment for up to 12 weeks. 
After the Day 1 visit, subjects will apply approximately the same amount (up to 36 g) of study 
drug as for the first dose on up to 90% of BSA twice weekly, sparing the scalp, inguinal, and 
axillary areas. Subjects with heavy facial hair should not apply IP to hair-bearing areas. Persons 
other than the study subject applying the study drug must wash their hands after application or use 
disposable vinyl gloves. In addition, a long-handled applicator will be provided for application on 
the back. The applicator must be washed with warm water and soap after every application.  
Trifarotene cream should not come into contact with the eyes, mouth, angles of the nose, or mucous 
membranes. For the ectropion treatment, Q-tips are recommended for precise application on 
eyelids, without contact to the eye or conjunctiva. If the IP gets into the eye, it must be flushed 
immediately with warm water. In case of eye irritation, the subject must be seen by an 
ophthalmologist.  
For the OLE, all subjects will receive trifarotene cream HE1 200 µg/g and apply the same fixed 
dose in the same manner as in the Double-blind Period for an additional 12 weeks. 
Visits for PK must occur at least 24 hours after the last application of the IP to avoid contamination 
of the blood samples with any IP that may have remained in the skin after the last application. 
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Subjects should not apply IP on visit days until after the visit, unless they are participating in the 
PK substudy, in which case the IP will be applied in the clinic on Day 30 after the blood draw. 
Among subjects participating in the PK substudy, ensure the PK line is inserted before study drug 
application to prevent contamination with the IP and to protect the skin around the needle insertion 
point from study drug application. 
9.3. Selection of Timing of Dose for Each Subject 
Subjects will be randomized in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g or 200 µg/g or 
vehicle cream. After Day 1, on which the study staff will apply the first administration of IP in the 
clinic, each subject will apply approximately the same amount of IP on up to 90% of their BSA 
twice weekly. It is suggested that each subject choose 2 specific days per week at least 3 days apart 
on which to apply their IP (e.g., Tuesday and Friday), and maintain that regimen throughout the 
study. Visits for PK must occur at least 24 hours after the last application of the IP to avoid 
contamination of the blood samples with any IP that may have remained on the skin after the last 
application. Subjects should not apply the IP on visit days until after the visit, unless they 
participate in the PK substudy, in which case the IP will be applied in the clinic on Day 30 after 
the PK blood draw.  
All subjects will be provided with diaries in which to record study drug application (days/times) 
and any areas of skin not treated (e.g., due to local reactions). 
If a subject misses an IP application, they should apply the IP as soon as they remember and record 
the date/time in the subject diary, then wait at least 3 days and continue their regimen. 
Subjects should not shower, bathe, or swim for at least 4 hours after IP application. No occlusive 
dressings should be used on areas to which IP is applied. 
Subjects who continue into the Open-label Extension will receive trifarotene cream HE1 200 µg/g 
and apply the same fixed dose in the same manner as in the Double-blind Period for an additional 
12 weeks. 
9.4. Dose Adjustment Criteria 
Local tolerance will be followed very carefully during the study. Subjects will receive information 
on study drug use and stopping rules and will be instructed to contact the site with any 
safety/tolerability issues. Study personnel will telephone subjects in between scheduled visits (i.e., 
at Day 7 and Day 45) to assess safety; an unscheduled clinic visit may be performed, if necessary. 
During all clinic visits, the investigator will assess local tolerability on a 0-3 scale (0 = none, 1 = 
mild, 2 = moderate, 3 = severe) for each treated body area (chest/abdomen, back, arms, legs, and 
face/neck), and the following procedures will be followed: 
− If a score of 2 (moderate) is recorded on a local tolerability assessment scale 
(stinging/burning, pruritus, erythema) on any treated area (e.g., the face), the study drug 
will be applied on this area only once weekly, until the score returns to <2. Continue to 
treat all other areas twice weekly provided the score is <2 on those areas. 
− If a score of 3 (severe) is recorded on a local tolerability assessment scale (stinging/burning, 
pruritus, erythema) on any treated area, the study drug will not be applied on that area until 
the score is back to <3 (i.e., “drug holiday”). Continue to treat all other areas twice weekly 
provided the score is <2 on those areas. 
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Any changes in dosing must be documented in the subject diary and the eCRF. 
9.4.1 Stopping Rules 
A subject’s treatment in either the Double-blind Period or the Open-label Extension must be 
stopped if any of the following occur: 
• Subject becomes pregnant or suspects they are pregnant 
• Subject has severe (score of 3) local application site AEs that do not abate with “drug 
holiday” and reintroduction of IP.  
• Subject has clinically significant changes in laboratory values (liver function tests, 
cholesterol/triglycerides – which may occur with systemic retinoid use) 
Any changes in dosing must be documented in the subject diary and the eCRF. 
9.5. Treatment Compliance 
Subjects will be asked to record their twice-weekly applications of IP in the diary during both the 
Double-blind Period and the OLE. Deviations from the planned doses (missed dose or timing) will 
be recorded on the subject’s eCRF. Study personnel will review diaries at each visit and diaries 
will be collected as source documents. Information from subject diaries will be transcribed on the 
appropriate eCRF pages for documentation of subject compliance with the IP. 
Study personnel will assess treatment compliance with IP regimens by weighing IP tubes before 
dispensing and upon return and by questioning the subject, at every postrandomization visit. A 
participant is compliant with study product if he or she takes at least 80% of the scheduled doses 
as assessed by diary entries, supplemented by tube weight. A subject who is not compliant (used 
80–120% of IP tubes) will be counseled at each visit on the importance of using the IP as 
instructed.  
Subjects who taper to once-weekly application or who take a “drug holiday” for tolerability will 
not be reported as having deviated from the protocol (see Section 9.4 for dose adjustment and 
stopping rules); any changes in dosing must be documented in the subject diary and the eCRF. 
9.6. Method of Assigning Subjects to Treatment Groups 
In the double-blind, parallel-group, randomized period of the study, subjects who meet study entry 
criteria will be randomly assigned in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g or 200 µg/g 
or vehicle cream. The randomization schedule will be computer generated using a permuted block 
algorithm and will randomly allocate IP to randomization numbers. The randomization numbers 
will be assigned sequentially through a central interactive web response system (IWRS) as subjects 
are entered into the study. Study center will not be a blocking factor in the randomization schedule. 
Premier Research will prepare the randomization schedule before the start of the study. No one 
involved in the study performance will have access to the randomization schedule before the 
official unblinding of treatment assignments. No subject will be randomized into this study more 
than once. 
In the OLE, all subjects will receive trifarotene cream HE1 200 µg/g. 
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9.7. Blinding and Unblinding Treatment Assignment 
All subjects, investigators, and study personnel involved in the conduct of the Double-blind Period 
of the study, including data management, will be blinded to treatment assignment with the 
exception of a specified unblinded statistician and programmer from Premier Research who will 
have access to the randomization code. The statistician will have access to unblinded data if there 
is an unblinded DSMB review.  
Study personnel will make every effort to safeguard the integrity of the study blind to minimize 
bias in the conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
subject’s treatment assignment. 
The investigator may discuss with the medical monitor in advance of unblinding a subject, if 
possible, if it is not deemed an emergency. However, the investigator has the ultimate decision for 
unblinding a subject for medical treatment and no procedures will prevent or delay necessary 
unblinding in an emergency for the subject’s safety. For emergency unblinding, study personnel 
will use the IWRS code. If the investigator is not able to discuss treatment unblinding in advance, 
then he/she must notify the medical monitor as soon as possible about the unblinding incident 
without revealing the subject’s treatment assignment.  
The investigator or designee must record the date and reason for treatment unblinding on the 
appropriate eCRF for that subject. In all cases that are not emergencies, the investigator must 
discuss the event with the medical monitor prior to unblinding the subject’s treatment assignment. 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
that subject’s treatment assignment without unblinding the treatment assignments for the 
remaining subjects in the study. Thus, the overall study blind will not be compromised. If a 
subject’s treatment assignment is unblinded, he/she may or may not be asked to withdraw from 
the study. The investigator will make this decision after consultation with the medical monitor. 
The primary analysis period is the first 12 weeks of treatment (i.e., the Double-blind Period). 
Overall unblinding will take place at the end of the Double-blind Period of the study only after 
database lock has been achieved. A second analysis will take place for endpoints assessed from 
Week 12 through the OLE. 
9.8. Permitted and Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate eCRF. 
Upon signing informed consent and entering the Screening Period, subjects will stop using 
physical and medical treatments for LI, including balneotherapy, and may begin to washout 
prohibited topical and systemic treatments with designated washout periods (Table 9-1), as 
applicable. Washout may be up to 3 months, as necessary. 
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Table 9-1: 
Washout Periods for Prohibited Medications 
Medication 
Washout Period 
Topical Treatments 
Corticosteroids (except inhaled and ophthalmic corticoids) 
2 weeks 
Retinoids (e.g., tretinoin, tazarotene) 
4 weeks 
Vitamin D analogues 
2 weeks 
Immunosuppressants (e.g., tacrolimus) 
2 weeks 
Antracen derivatives, tar and salicylic preparations 
2 weeks 
Keratolytics (such as urea, lactic acid, propylene glycol, salicylic acid) except keratolytic 
shampoo 
2 weeks 
Systemic treatments 
Retinoids 
8 weeks 
Oral Vitamin A supplementation more than 3500 IU per day 
2 weeks 
Medication interfering with bone activity, e.g., corticosteroids, thyroid hormones, cytotoxics, 
bisphosphonates, calcitonins, tetracyclines, quinolones, thiazides, salicylates in long-term 
course, heparin, theophylline, barbiturates, colchicines (except Vitamin D analogues taken at 
stable dose since at least 1 month) 
8 weeks 
QT prolonging drugs 
5 half lives 
Enzymatic inductors (such as rifampicine, phenytoin, carbamazepine, phenobarbital, 
St. John’s Wort) 
3 months 
CYP2C9 and 2C8 inhibitors (not all inclusive: gemfibrozil, fluconazole, fluvoxamine, 
sulfaphenazole, miconazole, amiodarone, sertraline, sulfamethoxazole, valproic acid, 
voriconazole, trimethoprim, rosiglitazone, pioglitazone) 
5 half lives 
Monoclonal antibodies (e.g., anti-IL17) 
5 half lives 
 
During washout, subjects may continue taking usual care of visible skin (face and scalp) for 
cosmetic reasons and of extremities (hands and feet) to avoid functional consequences on walking 
or moving their fingers. Subjects may shower, but not bathe or swim. The IGA will be evaluated 
on the rest of the body at Baseline.  
After completing any necessary washout of prohibited medications, subjects will return to the site 
to complete the study eligibility requirements. 
9.8.1 Permitted Therapies 
Subjects will be advised on permitted emollient(s) for use as often as needed on nontreatment days 
during the study; on treatment days, the use of emollient(s) is permitted except within 4 hours 
before or after study drug application. Similarly, protective sunscreen should be applied as often 
as needed, except within 4 hours before or after study drug application. Subjects may use their 
standard of care treatment on their faces and/or palms/soles after the Week 4 assessment if they 
experience a worsening of IGA in those areas. In the US/EU, this may include compounded 
emollients with keratolytics (alpha or beta hydroxyl acids) and/or urea. These standard of care 
treatments should be approved by the investigator and documented in the eCRF.  
Subjects who enter the OLE must stop standard of care treatment. If they experience a worsening 
of IGA they may use standard of care treatment on their faces and/or palms/soles after the Week 16 
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visit if the standard of care does not contain prohibited medications. If those standard of care 
treatments include prohibited medications, the subject should be discontinued from the study. 
Other concomitant medications are allowed (e.g., analgesics, antihistamines), but should be limited 
to those medications considered necessary. All concomitant medications, both prescribed and 
over-the-counter, should be recorded in the eCRF. 
9.8.2 Prohibited Therapies 
The medications listed in Table 9-1 are prohibited during the study. Balneotherapy is also 
prohibited during the Screening Period and during the study. 
Subjects may not use concomitant keratolytics such as urea, salicylic acid, alpha, or beta 
hydroxyacids. Subjects may not use topical or systemic retinoids. Subjects may not take more than 
3500 IU/day Vitamin A (e.g., as in a multivitamin). Use of benzoyl peroxide is permitted on 
nontreatment days for subjects with concomitant acne only); it must not be applied on treatment 
days due to risk of inactivation of trifarotene by benzoyl peroxide. 
Subjects receiving excluded therapies will be ineligible for study enrollment or for continued 
treatment in the study, at the investigator’s discretion with consultation with Mayne Pharma LLC 
and the medical monitor. For enrolled subjects who require prescription of a systemic azole, the 
principal investigator should discuss with the medical monitor whether the subject may continue 
in the study.  
9.8.3 Restrictions 
Subjects should not shower, bathe, or swim for at least 4 hours after study drug application. No 
occlusive dressings should be applied to areas where study drug was applied.  
Subjects should only use investigator-approved emollients, and should not use them on treatment 
days within at least 4 hours before and after study drug application.  
In addition, subjects should take protective measures to avoid exposure of treated areas to sunlight, 
such as applying sunscreen (except within 4 hours before and/or 4 hours after study drug 
application), and/or wearing protective clothing (e.g., long sleeves, hats, and covering legs and 
feet), and/or seeking shade or shelter from the sun. 
9.9. Treatment after End of Study 
After the end of the study, each subject will be treated according to standard clinical practice. 
9.10. Dispensing and Storage 
The test product supplied by Mayne Pharma LLC is to be used exclusively in the clinical study 
according to the instructions of this protocol. The investigator is responsible for dispensing the IP 
according to the dosage scheme and for ensuring proper storage of the IP. 
The investigator must confirm the receipt of the IP with his or her signature. A copy of this receipt 
must be kept by the investigator and another copy will be stored at Premier Research. Until the IP 
is dispensed to the subjects, it must be stored at 20–25°C (68–77°F), with excursions permitted to 
15–30°C (59–86°F); do not freeze and with the tube kept tightly closed in a securely locked area 
that is not generally accessible. 
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The key to the storage area is to be kept by the investigator or designee responsible for the IP. The 
store will be accessible only to those persons authorized by the investigator to dispense the IP. 
9.11. Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the IPs, including the date, quantity, batch or code number, and identification of 
subjects (subject number) who received the IP. The investigator will not supply the IP to any 
person except those named as subinvestigators on the Form Food and Drug Administration 
(FDA) 1572, designated study personnel, and subjects in this study. The investigator will not 
dispense the IP from any study sites other than those listed on the Form FDA 1572. Investigational 
product(s) may not be relabeled or reassigned for use by other subjects. If any of the IP is not 
dispensed, is lost, stolen, spilled, unusable, or is received in a damaged container, this information 
must be documented and reported to the sponsor and appropriate regulatory agencies, as required. 
Each subject will be given enough tubes of study drug to apply up to 1 tube-full (approximately 
36 g of clinical trial material) per treatment day until the next study visit. Tubes will be packed 
2 to a carton, and each subject will receive enough cartons to have the maximum number of tubes 
needed until the next study visit. The number of study drug tubes the subject needs to provide 
enough IP until the next visit is shown in Table 9-2.  
Table 9-2: 
Amount of Study Drug Needed Per Visit 
Treatment Period 
Number of Cartons 
Number of Tubes 
Double-blind Treatment Period 
Baseline 
3 
6 
Day 14 
4 
8 
Day 30 
6 
12 
Day 60 
6 
12 
OLE  
Day 90 
3 
6 
Day 104 
4 
8 
Day 120 
6 
12 
Day 150 
6 
12 
 
Each carton will be weighed before dispensing and subjects are to bring all cartons and tubes back 
at each study visit, whereupon study staff will weigh them again to estimate study drug use and 
compliance. 
Upon completion of the study, the IP (partly used, unused, and empty tubes) must be left in the 
original packaging and returned to the sponsor or designee for destruction. 
9.12. Labeling and Packaging 
Labeling and packaging of IP will be performed by Catalent Pharma Solutions, Philadelphia, PA, 
USA.  
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Tubes will be packaged in cartons comprising 2 tubes each. Tubes will be labeled with inner and 
outer booklet labels, and carton number. Each carton will also be labeled with inner and outer 
booklet labels and numbered.  
9.12.1 Labeling 
The tubes will have a label affixed that meets the applicable regulatory requirements and may 
include, but is not limited to, the following: subject identifier, IP name, lot number, protocol 
number, carton number, caution statement, storage, and sponsor identification. 
Save all empty packaging or packaging containing unused tubes for final disposition by the 
sponsor or contract pharmacy. 
Final labeling will comply with the regulatory requirements of each country where the study will 
be conducted. 
9.12.2 Packaging 
Investigational products will be packaged in high-density polyethylene, 35×100 mm tubes 
weighing 50 g from which a maximum of 36 g of IP can be extracted. Trifarotene cream HE1 and 
vehicle will be packaged so as to be blinded to the investigator, the study clinic personnel, and the 
subjects. 
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10. STUDY PROCEDURES 
Subjects must provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
Subjects who agree to participate in the photography and/or PK substudies must provide written 
informed consent before photographs or serial blood samples are collected. 
For the timing of assessments and procedures throughout the study, refer to the Schedule of 
Events (Section 2.2). Throughout the study, every reasonable effort should be made by study 
personnel to follow the timing of assessments and procedures in the Schedule of Events for each 
subject. If a subject misses a study visit for any reason, the visit should be rescheduled as soon as 
possible. 
10.1. Study Duration 
10.1.1 Overall Study Schedule 
The overall study duration is expected to be approximately 19 months. 
The planned sequence and maximum duration of the study periods will be as follows: 
1. Screening: up to 35 days (after signing informed consent, if necessary, washout may be up 
to 3 months, and subjects should return to the site after washout to complete the study 
eligibility requirements).  
2. Double-blind treatment: Twice weekly for 12 weeks. 
3. Optional Open-label Extension treatment: Twice weekly for 12 weeks. 
4. Follow-up: 14 days after last study drug application. 
The maximum treatment duration for each subject is approximately 12 weeks for subjects who 
choose not to continue into the OLE, and 24 weeks for those who choose to continue.  
The maximum study duration for each subject is approximately 229 days (33 weeks). 
10.2. Study Periods and Visits 
It is suggested that quality of life assessments be conducted first to avoid any bias, and that the 
IGA be recorded as the first LI assessment at every visit. 
10.2.1 Screening and Washout 
10.2.1.1 Screening Visit (Visit 1) 
The subject must complete eligibility screening within 35 days before randomization in the study. 
The following procedures will be performed during Screening: 
1. Obtain written informed consent. 
2. Assign a screening number when a subject begins screening. 
3. Assess inclusion/exclusion criteria. 
4. Collect demographic information. 
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5. Record medical history, including current therapies (e.g., prescription and nonprescription
medications).
6. Perform a physical examination.
7. Measure vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and
pulse).
8. Measure height, weight, and calculate body mass index (BMI).
9. Record IGA.
10. Record VIIS.
11. Record roughness assessment.
12. Record palm/sole assessment.
13. Record palm/sole assessment of fissuring.
14. Record ectropion score.
15. Perform a 12-lead ECG.
16. Collect blood and urine for laboratory tests.
17. Perform serum pregnancy test for WOCBP.
Procedures for rescreening subjects who initially fail to meet study entry criteria are described in 
Section 14.3. 
10.2.1.2 Washout 
Upon signing informed consent and entering the Screening Period, subjects will stop using 
physical and medical treatments for LI, including balneotherapy, and may begin to washout the 
prohibited topical and systemic treatments with designated washout periods, as applicable (Table 
9-1). Washout may be up to 3 months, as necessary.
During washout, subjects may continue taking usual care of visible skin (face and scalp) for 
cosmetic reasons and of extremities (hands and feet) to avoid functional consequences on walking 
or moving their fingers. Subjects may shower but not bathe or swim. The IGA will be evaluated 
on the rest of the body at Baseline. 
After completing any necessary washout of prohibited medications, subjects will return to the site 
to complete the study eligibility requirements (Section 10.2.1.1). 
10.2.2 Double-blind Treatment Period 
Eligible subjects who have washed out prohibited medications will be randomized to double-blind 
study drug. 
10.2.2.1 Baseline Visit (Visit 2, Day 1) 
The following procedures will be performed on Day 1 in the study clinic: 
1. Review inclusion/exclusion criteria.
2. Record responses to DLQI and EQ-5D Quality of Life Questionnaires
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3. Perform physical examination.  
4. Record vital signs (blood pressure and pulse).  
5. Record concomitant medications and concomitant therapies. 
6. Record IGA.  
7. Record VIIS.  
8. Record roughness assessment.  
9. Record palm/sole assessment. 
10. Record palm/sole assessment of fissuring. 
11. Record ectropion score.  
12. At sites where the photographic substudy is conducted, take photographs of subjects who 
have provided informed consent for the photography. 
13. Perform a 12-lead ECG. 
14. Perform urine pregnancy test for WOCBP. 
15. Collect blood and urine for routine laboratory tests (subject must be fasting; i.e., at least 
8 hours). 
16. Randomize via IWRS. 
17. Collect a predose PK blood sample (all subjects).  
18. Among subjects who consent to participate in the PK substudy, ensure that PK lines are 
placed before IP application. The IP will be applied in the clinic at this visit, and samples 
for PK will be taken at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1.  
19. Among subjects in the PK study, perform additional ECGs at times of serial sampling. 
20. Clinic staff instructs subject on study drug application, applies initial study drug dose and 
measures amount used (i.e., study staff will weigh the 50-g tube before and after the first 
application to determine the fixed dose amount for each subject). If the product will be 
applied at home by someone other than the study subject, it is recommended that this person 
assist with application at this visit to learn how the IP is applied. 
21. Assess and record local tolerance/AEs. 
22. Dispense study drug and diaries. 
23. Advise subjects regarding permitted emollient(s) for use on nontreatment days; use of 
emollient(s) and/or sunscreen on study drug treatment days within 4 hours before or after 
study drug application is prohibited. Remind subjects that at least 24 hours must have 
elapsed since IP application before their next visit. Subjects should not to apply IP on visit 
days until after the visit. 
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10.2.2.2 Telephone Visit (Day 7) 
Clinic staff will telephone subject to assess safety and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient(s) and/or 
sunscreen on study drug treatment days within 4 hours before or after study drug application is 
prohibited), and remind subjects that at least 24 hours must have elapsed since IP application 
before their next visit. Subjects should not apply IP on visit days until after the visit. An 
unscheduled clinic visit may be performed, if necessary. 
10.2.2.3 Visit 3 (Day 14 ±5 days) 
The following procedures will be performed on Day 14 in the study clinic: 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires.  
2. Record concomitant medications and concomitant therapies. 
3. Record vital signs (blood pressure and pulse). 
4. Record IGA.   
5. Record VIISIGA. 
6. Record roughness assessment.  
7. Record palm/sole assessment. 
8. Record palm/sole assessment of fissuring 
9. Record ectropion score. 
10. Assess local tolerance. 
11. Record AEs and review diary. 
12. Collect a PK blood sample (all subjects). 
13. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
14. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
Remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit. Subjects should not apply IP on visit days until after the visit.  
15. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
10.2.2.4 Visit 4 (Day 30 ±7 days) 
The following procedures will be performed on Day 30 in the study clinic: 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires. 
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2. Record concomitant medications and concomitant therapies. 
3. Record vital signs (blood pressure and pulse). 
4. Record IGA. 
5. Record VIIS. 
6. Record roughness assessment.  
7. Record palm/sole assessment. 
8. Record palm/sole assessment of fissuring 
9. Record ectropion score.  
10. At sites where the optional photographic substudy is conducted, take photographs of 
subjects who have provided informed consent for the substudy. 
11. Assess local tolerance. 
12. Record AEs and review diary. 
16. Perform a 12-lead ECG 
17. Perform a urine pregnancy test for WOCBP. 
18. Collect blood and urine for routine laboratory tests (subject must be fasting at least 
8 hours). 
19. Collect a PK blood sample (all subjects). 
20. Among subjects who consent to participate in the PK substudy, ensure that PK lines are 
placed before IP application. The IP will be applied in the clinic at this visit, and samples 
will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose. 
21. Among subjects in the PK study, perform an additional ECGs at times of serial sampling. 
22. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
23. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) on study 
drug treatment days within 4 hours before and after study drug application is prohibited. 
Remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit. Subjects should not apply IP on visit days until after the visit.  
24. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
25. Provide information about OLE option to study subject. 
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10.2.2.5 Telephone Visit (Day 45) 
Clinic staff will telephone subject to assess safety and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) and/or sunscreen for use on nontreatment days (use of 
emollient(s) on study drug treatment days within 4 hours before or after study drug application is 
prohibited), and remind subjects that 24 hours must have elapsed since IP application before the 
subject’s next visit. Subjects should not to apply IP on visit days until after the visit. An 
unscheduled clinic visit may be performed, if necessary. Staff will remind subject about OLE 
option. 
10.2.2.6 Visit 5 (Day 60 ±7 days) 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires. 
2. Record concomitant medications and concomitant therapies. 
3. Record vital signs (blood pressure and pulse).  
4. Perform a urine pregnancy test for WOCBP. 
5. Record IGA.  
6. Record VIIS.   
7. Record roughness assessment.  
8. Record palm/sole assessment. 
9. Record palm/sole assessment of fissuring 
10. Record ectropion score.  
11. Assess local tolerance.  
12. Record AEs and review diary. 
13. Collect a PK blood sample (all subjects). 
14. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
15. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
16. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) and/or 
sunscreen on study drug treatment days within 4 hours before and after study drug 
application is prohibited. Remind subjects that 24 hours must have elapsed since IP 
application before the subject’s next visit. Subjects should not apply IP on visit days until 
after the visit. 
17. 
Provide information about OLE option. 
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10.2.2.7 Visit 6 (90 ±7 days) or Early Termination 
The following procedures will be performed on Day 90 in the study clinic: 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires. 
2. Perform a physical examination. 
3. Record vital signs (blood pressure and pulse). 
4. Record concomitant medications and concomitant therapies. 
5. Record IGA. 
6. Record VIIS. 
7. Record roughness assessment.  
8. Record palm/sole assessment. 
9. Record palm/sole assessment of fissuring. 
10. Record ectropion score.  
11. At sites where the optional photographic substudy is conducted, take photographs of 
subjects who have provided informed consent for the substudy. 
12. Assess local tolerance. 
13. Record AEs and review diary. 
14. Perform a 12-lead ECG. 
15.  Perform a urine pregnancy test for WOCBP. 
16. Collect blood and urine for routine laboratory tests (subject must be fasting at least 
8 hours). 
17. Collect a PK blood sample (all subjects). 
18. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
For subjects who successfully complete (i.e., have reliable visit attendance and compliance with 
IP application, in the investigator’s opinion) the initial 12 weeks of double-blind treatment and 
choose to continue into the OLE, this visit will be the first visit of that portion of the study. All 
efficacy assessments, safety/tolerability assessments, including clinical laboratory testing, PK 
from Day 90/Week 12 will be carried over to the OLE and will not be repeated. Subjects will have 
up to 7 days to decide to enter the OLE; if the subject chooses to continue into OLE, the following 
additional procedures will be done: 
1. Have the subject sign OLE-specific informed consent.  
2. Measure subject’s weight. 
3. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
Remind subjects that at least 24 hours must have elapsed since IP application before the 
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PK draws at the Week 16 and Week 24 Visits, and not to apply IP on visit days until after 
the visits. 
4. Weigh new study drug tubes and dispense enough additional study drug until next visit 
(only for subjects who choose to continue into the OLE). 
5. Dispense study diary. 
10.2.3 Follow-up Telephone Call (±14 days after Day 90) – Only Subjects Who Do Not 
Continue into Open-label Extension 
Clinic staff will telephone subjects who choose not to continue into the Open-label Extension 
within 14 days after Day 90 to assess any ongoing AEs.  
10.2.4 Open-label Extension  
Subjects who successfully complete (i.e., have reliable visit attendance and compliance with IP 
application, in the investigator’s opinion) the initial 12 weeks of double-blind treatment may 
choose to continue into an optional 12-week OLE with trifarotene cream HE1 200 µg/g. During 
the OLE, subjects will return to the site at Weeks 14, 16, 20, 24, and 26. Additional PK samples 
will be drawn at Week 16 and 24 from all subjects who continue into the OLE.  
10.2.4.1 Telephone Visit (Day 97) 
Clinic staff will telephone subject to assess safety (AEs) and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient(s) on study drug 
treatment days within 4 hours of study drug application is prohibited), and remind subjects not to 
apply IP on visit days until after the visit. An unscheduled clinic visit may be performed, if 
necessary. 
10.2.4.2 Visit 7 (Week 14; Day 104 ±5 days) 
The following procedures will be performed at this study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Record IGA.   
4. Record VIIS. 
5. Record assessment of roughness. 
6. Record palm/sole assessment. 
7. Record palm/sole assessment of fissuring. 
8. Record ectropion score. 
9. Assess and record local tolerance/AEs and review diary. 
10. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
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11. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
12. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) and/or sunscreen on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
Remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit. Subjects should not apply IP on visit days until after the visit.at the Week 16 and 
Week 24 Visits, and not to apply IP on visit days until after the visit. 
10.2.4.3 Visit 8 (Week 16; Day 120 ±7 days) 
The following procedures will be performed at this study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Record IGA. 
4. Record VIIS.   
5. Record assessment of roughness. 
6. Record palm/sole assessment.  
7. Record palm/sole assessment of fissuring. 
8. Record ectropion score. 
9. Assess and record local tolerance/AEs and review diary. 
10. Perform a 12-lead ECG. 
11. Perform a urine pregnancy test for WOCBP. 
12. Collect blood and urine for routine laboratory tests (subject must be fasting at least 
8 hours). 
13. Collect a PK blood sample (all subjects) 
14. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
15. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
16. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) and/or sunscreen on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
Remind subjects not to apply IP on visit days until after the visit. 
10.2.4.4 Telephone Visit (Day 134) 
Clinic staff will telephone subject to assess safety (AEs) and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) and/or sunscreen for use on nontreatment days (use of 
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emollient(s) on study drug treatment days within 4 hours of study drug application is prohibited), 
and remind subjects that 24 hours must have elapsed since IP application before the subject’s next 
visit. Subjects should not apply IP on visit days until after the visit. An unscheduled clinic visit 
may be performed, if necessary. 
10.2.4.5 Visit 9 (Week 20; Day 150 ±7 days) 
The following procedures will be performed at each study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Record IGA. 
4. Record VIIS.   
5. Record assessment of roughness. 
6. Record palm/sole assessment.  
7. Record palm/sole assessment of fissuring. 
8. Record ectropion score. 
9. Assess and record local tolerance/AEs and review diary. 
10. Perform a urine pregnancy test for WOCBP. 
11. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
12. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
10.2.4.6 Visit 10 (Week 24; Day 180 ±7 days) or Early Termination 
The following procedures will be performed at Week 24 in the study clinic: 
1. Perform a physical examination. 
2. Record vital signs (blood pressure and pulse). 
3. Record concomitant medications and concomitant therapies. 
4. Record IGA. 
5. Record VIIS. 
6. Assess roughness. 
7. Record palm/sole assessment.  
8. Record palm/sole assessment of fissuring. 
9. Record ectropion score.  
10. Assess local tolerance 
11. Record AEs and review diary. 
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12. Perform a 12-lead ECG. 
13. Perform a urine pregnancy test for WOCBP. 
14. Collect blood and urine for routine laboratory tests (subject must be fasting at least 
8 hours). 
15. Collect a PK blood sample (all subjects) 
16. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
10.2.4.7 Follow-up Evaluation – Open-Label Extension (Week 26/Visit 11) 
At 14 days after the last administration of the IP, the following procedures will be performed: 
1. Perform a physical examination. 
2. Record vital signs (blood pressure and pulse). 
3. Record any concomitant medications/therapies. 
4. Record IGA. 
5. Record VIIS.   
6. Assess roughness. 
7. Record palm/sole assessment.  
8. Record palm/sole assessment of fissuring. 
9. Record ectropion score.  
10. Assess and record AEs occurring since the last evaluation and review diary.  
11. Perform a urine pregnancy test for WOCBP. 
10.3. Assessments 
The 5-point IGA is a valid measure of disease severity and meets the need for a clinically 
meaningful measure of success for ichthyosis studies. The IGA scale was developed with the 
support of experts from academic reference centers for the treatment of ichthyosis. Each level of 
severity will consider both the severity of scaling and the severity of roughness (Section 10.3.1.2). 
While retinoid treatment is expected to reduce scale, it may increase erythema; therefore, in this 
study, erythema will be evaluated as part of local tolerability. 
10.3.1 Efficacy Variables 
All efficacy measurements will use scales previously used for dermatological studies or as defined 
in the following sections. 
10.3.1.1 Investigator’s Global Assessment 
The primary endpoint is the number of subjects in each treatment group who experience successful 
resolution of LI where “success” is defined as clear/almost clear and at least a 2-grade change from 
Baseline at Week 12/EOT in the Double-blind Period on a 5-point IGA full body scale. 
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The investigator will rate the subject’s condition using the 5-point IGA at each time point shown 
in the Schedule of Events (Section 2.2).  
The IGA will be measured on a 5-point scale, excluding the following areas: knees, elbows, neck, 
palms, soles, axillae, groin, and scalp: 
0 
Clear 
No scaling and no roughness 
1 
Almost Clear 
Occasional fine scales; hardly palpable roughness 
(mostly smooth) 
2 
Mild 
Small and fine scales predominate; no more than a few 
large scales; mild roughness on palpation 
3 
Moderate 
Some large scales that may be thick; coarse roughness 
on palpation 
4 
Severe 
Confluent, primarily large (>1 cm), thick scales with 
plate-like hyperkeratosis  
10.3.1.2 Visual Index for Ichthyosis Severity – Scaling 
The secondary endpoint is the number of subjects in each treatment group who experience a 
severity score of 0 or 1 at Week 12/EOT on the overall 16-point VIIS for scaling. 
The investigator will rate the subject’s condition using the 5-point VIIS for each body area 
(chest/abdomen, back, legs, and arms) and an overall score at each time point shown in the 
Schedule of Events (Section 2.2): 
0 
Normal skin; no perceptible scale or smoothening 
1 
Areas of normal skin intermixed with areas showing smoothening (diminished fine skin 
markings, shininess, waxiness) or small scales (visibly separated/fractured stratum 
corneum) 
2 
Confluent smoothening (diminished fine skin markings, shininess, waxiness) or small 
scales (visibly separated/fractured stratum corneum) 
3 
Confluent scales (visibly separated/fractured stratum corneum) including some large 
(>1 cm), thick scales 
4 
Confluent, primarily large, thick scales 
 
10.3.1.3 Individual Score for Roughness 
The amount of roughness of the skin overall will be measured on a 5-point scale. 
0 Clear 
Smooth skin 
1 Almost Clear 
Hardly palpable roughness 
2 Mild 
Mild roughness (fine sand paper-like) 
3 Moderate 
Moderate, coarse roughness (coarse sand paper-like) 
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4 Severe 
Very coarse skin (broken cornflakes-like) 
10.3.1.4 Palm/Sole Assessment 
Thickening of the skin on the palms and soles will be measured on a 5-point scale. 
0 Clear 
No thickening, no roughness, no fissure 
1 Almost Clear 
Only slight thickening, minimal to no roughness, no 
fissures 
2 Mild 
Some thickening, mild roughness on palpation, few 
fissures may be present 
3 Moderate 
Substantial and diffuse thickening, coarse roughness on 
palpation may be present, fissures may be present 
4 Severe 
Very thickened and rough skin, numerous fissures 
10.3.1.5 Palm/Sole Fissuring Assessment 
Fissuring will be assessed by recording the presence or absence of fissures, the number of fissures 
present, and the pain associated with each fissure. A fissure is a longitudinal and deep crack that 
separates the stratum corneum and may penetrate down to the dermis, causing pain and sometimes 
bleeding. The subject will assess pain associated with fissures as ranging from 0-3 (none, mild, 
moderate, severe).  
10.3.1.6 Dermatology Life Quality Index 
The DLQI is a dermatology-specific Quality of Life instrument. It is a simple 10-question validated 
questionnaire with 6 domains (symptoms and feelings, daily activities, leisure, work and school, 
personal relationships, and treatment); higher scores indicate poorer quality of life. The DLQI is 
the most frequently used instrument in studies of randomized controlled trials in dermatology.  
10.3.1.7 EQ-5D Quality of Life Questionnaire 
The EQ-5D is a standardized instrument developed by the EuroQol Group as a measure of health-
related quality of life used in a wide range of health conditions and treatments. The EQ-5D consists 
of a descriptive system and the EQ visual analog scale (VAS).   
The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. The EQ VAS records the subject’s self-rated health on a 
vertical 0-100 VAS. This can be used as a quantitative measure of health outcome that reflects the 
subject’s own judgment. 
10.3.1.8 Ectropion Severity Score  
The Ectropion Severity Score (ESS), has a maximum score of 8 points. A higher score indicates a 
worse ectropion. The score takes the severity of ectropion in terms of lateral and medial apposition, 
scleral show, conjunctival show, and roundness of the eye into account and gives an indication of 
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the functional aspects involved in ectropion by scoring redness, excess tear film, and the position 
of the lacrimal punctum.14 
 
Figure 10-1: Ectropion Severity Score 
Source: Korteweg SFS, Stenekes MW, van Zyl FE, Werker PMN. Paralytic Ectropion treatment with lateral periosteal 
flap canthoplasty and introduction of the ectropion severity score. Plast Reconstr Surg Glob Open. 2014;2(5):e151. 
10.3.1.9 Photography Substudy 
All sites that have photographic capability will take photographs as source data to support scoring 
at Baseline, Day 30, and Day 90. A central reader who will not be an investigator in the study will 
review the photographs to assess consistency of investigator scoring of LI severity as a quality 
check. Photographs may also be used for scientific publication purposes. Subjects will sign a 
separate, optional photographic informed consent form (ICF). 
10.3.2 Clinical Pharmacology 
10.3.2.1 Pharmacokinetic Analysis Methods  
The pharmacokinetic characterization of drug concentrations for each dose to be profiled will use 
noncompartmental analysis (NCA).  
10.3.2.2 Pharmacokinetic Parameters 
Samples for PK will be drawn from all subjects at Baseline and at each clinic visit for trough 
values.  
Subjects who provide written informed consent to participate in the optional PK substudy will 
provide blood samples for PK analysis predose on Day 1 and at 1, 2, 4, 8, 12, and 24 hours postdose 
on Day 1 and Day 30. 
Lateral appo ition 
1edial appo ition 
ceral ho\v 
onjunctival how 
Exce 
t ar film. 
Redne of the e e 
Round anthus 
Punctum lacrin1ale 
iaxin11u11 core 
Points per Item 
0 
onaffect d 
onaffec ed 
0 
0 
0 
0 
0 
Invi ible 
0.5 
::;;;1 1nm 
E1nerging 
1 
A££ cted 
Affected 
> 1 min 
e 
Visible 
8 point 
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The PK parameter estimates will be completed using WinNonlin (Pharsight Corporation) software 
using the actual elapsed times from dose administration to sample collection (i.e., not nominal 
time). 
Standard PK parameters assessed will include measures of the extent of absorption using estimates 
of the area-under-the-curve (AUC) and rate-of-absorption using the maximum concentration 
(Cmax) and the time of Cmax (Tmax). Additional details of the parameters and their calculation and 
evaluation will be included in the statistical analysis plan (SAP). 
Table 10-1 shows the PK parameters that will be computed for each subject for samples obtained 
over the planned sampling intervals. 
Table 10-1: 
Pharmacokinetic Parameters 
Parameter 
Description of Parameter 
Cmax 
Maximum (or peak) serum concentration  
Tmax 
Time at which Cmax is observed 
AUC(0-t) 
Area under the plasma concentration-time curve from time 0 to the time of the last 
quantifiable plasma concentration 
AUC(0-inf) 
Area under the plasma concentration-time curve from time 0 to infinity (if data permit) 
t1/2 
Apparent first order terminal elimination half-life 
λz 
Apparent terminal phase rate constant (if data permit) 
10.3.3 Sample Collection 
Samples will be collected at the time points specified in the Schedule of Events (Section 2.2). 
Specimen preparation, handling, shipment, and storage for the complete blood count, chemistry, 
and urinalysis are described in the study laboratory manual. Finding veins in subjects with this 
disease can be challenging. Blood draws will be done at the corresponding study visits before 
application of the IP and should be 24 hours after IP application. Subjects must not apply the IP to 
the area where blood will be drawn within 24 hours before their next study visit to avoid 
contamination of the blood by IP that remained in the skin. For subjects in the PK substudy, a 
cannula should be placed before IP application and the cannula site may be occluded to prevent 
contamination with IP.  
Actual PK sample times for subjects in the PK substudy will be recorded in the eCRF. 
Blood 
For subjects not in PK substudy: 
The expected amount of blood to be drawn at each visit varies from approximately 6 mL to a 
maximum of 21 mL (Screening Visit only). The total amount of blood drawn for the study will be 
about 123 mL per subject, unless the subject takes part in the PK substudy. 
 
For subjects in PK substudy: 
For subjects who opt to participate in the PK substudy, extra blood samples will be drawn at Visit 2 
and at Visit 4 for PK analysis. The amount of blood to be drawn per subject at each of these visits 
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will be approximately 54 mL. For subjects taking part in the substudy, the total amount of blood 
drawn for the entire study will be approximately 195 mL. 
Urine 
Urinalysis will be performed at central laboratory. Dipstick and urine pregnancy tests will be 
conducted on site.  
10.3.4 Safety Variables 
Safety assessments will include the evaluation of AEs, including local tolerability 
(stinging/burning, pruritus, and erythema), clinical laboratory assessments, vital signs, 12-lead 
ECGs, and physical examinations. 
10.3.4.1 Clinical Laboratory Safety Assessments 
10.3.4.1.1 Clinical Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points specified in the 
Schedule of Events (Section 2.2). 
Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
platelet count (or estimate), white blood cell count including differential 
Serum Chemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, 
creatinine, glucose, sodium, potassium, chloride, bicarbonate, lactate 
dehydrogenase, uric acid, total cholesterol, high-density lipoprotein, low-
density lipoprotein, triglycerides 
Coagulation Panel: prothrombin time, partial thromboplastin time, fibrinogen 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones 
Pregnancy Test: 
for women of childbearing potential only; serum at Screening, urine at 
each other visit. 
Serology 
Hepatitis B surface antigen, and hepatitis C 
 
All blood samples for the clinical laboratory tests must be taken in a fasting state, at least 8 hours 
after the previous drug application.  
Blood and urine samples for hematology, and serum chemistry will be sent to a central laboratory 
for analysis. Urine pregnancy tests and dipstick will be conducted at the study sites. 
10.3.4.1.2 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens in 
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both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
In addition to appropriate handling of subject samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples. Procedures and regulations for the packaging and shipping 
of infectious samples are outlined in the study laboratory manual. The investigator is responsible 
for ensuring that all study samples that are to be transported to another location are packed and 
shipped appropriately according to the applicable regulations.  
Samples for assessment of clinical laboratory tests will be transported to the Clinical Reference 
Laboratory (see the study laboratory manual for addresses). 
10.3.4.1.3 Evaluation of Clinical Laboratory Values 
The normal ranges of values for the clinical laboratory assessments in this study will be provided 
by the responsible laboratory and submitted to Mayne Pharma LLC prior to beginning the study. 
They will be regarded as the reference ranges on which decisions will be made. 
If a laboratory value is out of the reference range, it is not necessarily clinically significant. The 
investigator must evaluate the out-of-range values and record his or her assessment of the clinical 
significance in the appropriate eCRF. 
All clinical laboratory values that in the investigator’s opinion show clinically significant or 
pathological changes during or after termination of treatment must be reported as AEs and 
followed, as described in Section 11.2.5. 
All measurements described in this section are recognized standard methods. 
10.3.4.2 Clinical Examinations 
10.3.4.2.1 Vital Signs 
Vital signs, including height and weight (only assessed at Screening), blood pressure, and pulse 
will be measured.  
10.3.4.2.2 Twelve-lead Electrocardiogram 
A standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes. 
All ECG recordings will be identified with the subject number, date, and time of the recording. 
Gel ECG electrodes may be used for ECGs because they are more conductive and cause less 
trauma on compromised skin. Efficacy assessments should be conducted before ECGs to avoid 
possible artefact/changes from the ECG.  
For subjects in the PK substudy, additional ECGs will be performed postdose during serial blood 
sampling on Day 1 and Day 30. 
If there is a marked prolongation of the QT/QTc interval during treatment, a subject should be 
discontinued from the IP but remain in the study until full resolution of the event. The DSMB will 
be informed immediately of such an occurrence. 
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10.3.4.2.3 Physical Examination 
A complete physical examination excluding the genitourinary examination will be performed at 
Screening, while limited physical examinations (to include HEENT, cardiorespiratory, abdomen, 
and range of motion) will be performed as indicated in the Schedule of Events (Section 2.2). 
10.3.4.2.4 Other Safety Variables 
Local tolerability will be assessed on a 0-3 scale (none, mild, moderate, severe). All application 
site reactions will be recorded as TEAEs in the diary. These should include the date and severity 
of the TEAE. 
10.3.4.3 Adverse Events 
The definitions and management of AEs, and any special considerations for AEs, are provided in 
Section 11. 
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11. ADVERSE EVENTS 
11.1. Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not related to the medicinal product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a 
pre-existing condition is considered an AE.) 
Events that occur in subjects treated with control product are also considered AEs. 
11.1.2 Adverse Drug Reaction 
All noxious and unintended responses to an investigational product related to any dose should be 
considered adverse drug reactions (ADRs). 
The phrase “responses to an investigational product” means that a causal relationship between an 
investigational product and an AE is at least a reasonable possibility, i.e., the relationship cannot 
be ruled out. All AEs judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship to an IP qualify as ADRs. 
All AEs for which the judgment of relationship to IP is “possible” or higher will be considered 
ADRs. If a relationship to IP is not provided, then the AE must be treated as if it were “possible.”  
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction 
An expected AE or ADR is one for which the nature or severity is consistent with the known AE 
profile of the product. For a preapproval test product, the known information is contained in the 
IB. For a marketed product, the known information is contained in the current package insert for 
the product. 
An unexpected adverse event (UAE) or unexpected adverse drug reaction (UADR) is one for 
which the nature or severity of which is not consistent with the applicable product information 
(e.g., IB for an unapproved investigational product or package insert/summary of product 
characteristics for an approved product). For example, hepatic necrosis would be unexpected 
(greater severity) if the IB only listed elevated hepatic enzymes or hepatitis. Likewise, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (greater specificity) if the IB only 
listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction constitute unexpected events.  
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11.1.4 Serious Adverse Events/Drug Reaction 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. 
An elective hospital admission to treat a condition present before exposure to the IP, or a 
hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or 
event as an SAE. Further, an overnight stay in the hospital that is only due to transportation, 
organization, or accommodation problems and without medical background does not need 
to be considered an SAE. 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the IP 
during pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject that has 
received an IP is not considered an SAE unless it is suspected that the IP(s) interacted with 
a contraceptive method and led to the pregnancy.  
• is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result 
in hospitalization, development of drug dependency, or drug abuse. The occurrence of 
malignant tumors is also to be considered serious.  
11.1.5 Significant Adverse Events 
Other significant AEs are defined as marked hematological and other laboratory abnormalities 
(other than those meeting the definition of serious) and any events that led to an intervention, 
including withdrawal of test drug, dose reduction, or significant additional concomitant therapy. 
11.1.6 Treatment-Emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening is after the first application 
of IP (trifarotene or vehicle) and not more than 14 days after the last application of IP. 
11.2. Event Assessment and Follow-up of Adverse Events 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care or upon review by a study 
monitor. 
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All reported AEs, including local and systemic AEs not meeting the criteria for SAEs, will be 
captured on the appropriate eCRF. Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event. 
All reported AEs occurring while on study must be documented appropriately regardless of 
relationship. All reported AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
Changes in the severity of a reported AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
Study clinic personnel will record all reportable events with start dates occurring any time after 
informed consent is obtained until 14 (for nonserious AEs) or 30 days (for SAEs) after the last day 
of study participation. At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit. Events will be followed for outcome information until resolution or 
stabilization. 
11.2.1 Assessment 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. In addition, 
although local tolerability will be assessed on a 0-3 scale, all application site reactions should be 
recorded as AEs. 
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11.2.2 Evaluation 
11.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as follows: 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.4. 
11.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.4. 
11.2.2.3 Action(s) Taken 
All AEs will be treated/managed according to standard practice. The following actions may be 
taken with regard to the IP. Section 9.4 describes dose adjustment and stopping rules for individual 
subjects. 
Action(s) taken may consist of the following: 
Dose not changed 
An indication that a medication schedule was maintained. 
Dose reduced 
An indication that a medication schedule was modified by subtraction, 
either by changing the frequency, strength, or amount. 
Drug interrupted 
An indication that a medication schedule was modified by temporarily 
terminating a prescribed regimen of medication. 
Drug withdrawn 
An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
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11.2.2.4 Outcome at the Time of Last Observation 
The outcome of an AE at the time of last observation will be classified as follows: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
*Only select fatal as an outcome when the AE results in death. If more than one AE is judged to 
be possibly related to the subject’s death, the outcome of death should be indicated for each such 
AE. Although “fatal” is usually an event outcome, events such as sudden death or unexplained 
death should be reported as SAEs. 
11.2.2.5 Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AE’s relationship to the IP. The categories for 
classifying the investigator’s opinion of the relationship are as follows: 
Not related 
An AE with sufficient evidence to accept that there is no causal relationship 
to IP administration (e.g., no temporal relationship to drug administration, 
because the drug was administered after onset of event; investigation shows 
that the drug was not administered; another cause was proven.) 
Unlikely 
related 
An AE, including laboratory test abnormality, with a temporal relationship to 
IP administration that makes a causal relationship improbable, and in which 
other drugs, events, or underlying disease provide plausible explanations. 
Possibly related An AE with a reasonable time sequence to administration of the IP, but that 
could also be explained by concurrent disease or other drugs or events. 
Information on drug withdrawal may be lacking or unclear. 
Related 
An AE occurring in a causal plausible time relationship to IP administration 
that cannot be attributed to a concurrent disease or other drugs, chemicals, or 
events. The AE relationship to the IP must be assessed separately by the 
investigator and Mayne Pharma LLC. 
 
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11.2.3 Documentation 
Any AE that occurs during the Screening Period will be captured as on the AE page of the eCRF 
(not medical history). All AEs that occur within the period of observation for the study must be 
documented in the eCRF with the following information, where appropriate. (The period of 
observation for the study is described in Section 11.2.) 
• AE name or term 
• When the AE first occurred (start date and time) 
• When the AE stopped (stop date and time or an indication of “ongoing”) 
• Severity of the AE 
• Seriousness (hospitalization, death, etc.) 
• Actions taken 
• Outcome 
• Investigator opinion regarding the AE relationship to the IP(s) 
11.2.4 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. If such treatment constitutes a deviation from the protocol, the subject may be withdrawn 
for treatment but continue to be followed for efficacy and safety in the study. The decision about 
whether the subject may continue in the study will be made by the sponsor after consultation with 
the investigator and/or medical monitor. 
If AEs occur in a subject that are not tolerable, the investigator must decide whether to stop the 
subject’s involvement in the study and/or treat the subject. Special procedures may be 
recommended for the specific IP, such as the collection of a serum sample for determining blood 
concentrations of IP, specific tapering procedures, or treatment regimens, as appropriate. 
It is not necessary to unblind a subject’s treatment assignment in most circumstances, even if an 
SAE has occurred. If unblinding is necessary, see Section 9.6 for a description of the unblinding 
procedures. 
11.2.5 Follow-up 
Any AE will be followed (up to a maximum of 14 days after the last dose of IP) to a satisfactory 
resolution, until it becomes stable, or until it can be explained by another known cause(s) (i.e., 
concurrent condition or medication) and clinical judgment indicates that further evaluation is not 
warranted. All findings relevant to the final outcome of an AE must be reported in the subject’s 
medical record and recorded on the eCRF page.  
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11.2.6 Reporting 
11.2.6.1 Serious Adverse Events 
The investigator or designee must report all SAEs promptly to Premier Research within 24 hours 
of first becoming aware of the event by e.g., completing, signing and dating the Serious Adverse 
Event Report Form, verifying the accuracy of the information recorded in the form with the source 
documents and eCRF, and sending the SAE form to the Premier Research by one of the following 
methods:  
Email: globalPV-US@premier-research.com 
Email: PVDS-ROW@premier-research.com 
Fax number: +1 215 972 8765 
Fax number: +421 2 6820 3713 
This written report should be submitted on the SAE form provided for this purpose. At the time of 
first notification, the investigator or designee should provide the following information, if 
available: 
• Protocol number 
• Reporter (study site and investigator) 
• Suspect IP 
• Subject’s study number 
• Subject’s year of birth 
• Subject’s gender 
• Date of first dose of IP(s) 
• Date of last dose of IP(s), if applicable 
• Adverse event term 
• Date of occurrence of the event 
• A brief description of the event, outcome to date, and any actions taken 
• The seriousness criteria(on) that were met 
• Concomitant medication at onset of the event 
• Relevant medical history information 
• Relevant laboratory test findings 
• Investigator’s opinion of the relationship to IP(s) (“Is there a reasonable possibility that 
the IP caused the SAE? Yes or No?”) 
• Whether and when the investigator was unblinded as to the subject’s treatment 
assignment  
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Any missing or additional relevant follow-up information concerning the SAE should be sent to 
the sponsor/sponsor representative via the same contact details above as soon as possible on a 
follow-up SAE Report Form, together with the following minimal information (initial report, 
adverse event, date of occurrence, subject identification (ID), study ID, IP, and site number); this 
will allow the follow-up information to be linked to the initial SAE report.  
Specific information may be requested by the Premier Research Pharmacovigilance Department 
using a follow-up request form or via email communication. 
The investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his or her health authorities, institutional review board 
(IRB)/independent ethics committee (IEC), principal and coordinating investigators, study 
investigators, and institutions. Each investigator is obligated to learn about the reporting 
requirements for investigators in his/her country. The study monitor may be able to assist with 
this. 
11.2.6.2 Adverse Drug Reactions 
All ADRs should be reported by the investigator in the eCRF.  
Suspected serious ADRs must be reported to the sponsor immediately, regardless of the time 
elapsed since the end of the observation period. 
11.2.6.3 Nonserious Adverse Events 
Nonserious AEs will be recorded in the eCRF and reported by Premier Research to Mayne Pharma 
LLC in aggregate monthly status reports. 
11.3. Special Considerations 
11.3.1 Adverse Events of Special Interest 
Since topical retinoids are associated with local application site AEs, particularly when beginning 
treatment, these events will be followed closely during the study and considered AEs of special 
interest (AESIs). 
11.3.2 Pregnancy 
All WOCBP who participate in the study should be counseled on the need to practice highly 
effective birth control and on the importance of avoiding pregnancy during study participation. 
Women should be instructed to contact the investigator or study staff immediately if pregnancy 
occurs or is suspected. 
Pregnancy testing will be conducted prior to administration of the IP on every woman of 
childbearing potential. A woman who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered to be a screening failure. 
A woman who becomes pregnant during IP treatment will be immediately discontinued from study 
treatment. The investigator must report the pregnancy of any woman who becomes pregnant 
during or within 30 days after discontinuing treatment as if it were an SAE within 24 hours of 
learning of the pregnancy, to Premier Research Pharmacovigilance using the Pregnancy Data 
Collection Form via the same fax number and/or email address as for SAE reporting. The 
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investigator should contact the designated individual(s) who receive SAE notification and record 
information related to the pregnancy on an SAE and AE form (entering the event temporarily as 
nonserious on both forms) provided by the sponsor or its designee. If a partner of a male study 
subject becomes pregnant, the investigator must report the pregnancy as soon as possible after 
learning of it to the Premier Research Pharmacovigilance using the Pregnancy Data Collection 
Form. A separate pregnant partner ICF will be required. 
Early Termination Visit assessments are required as soon as possible after learning of the 
pregnancy in a study subject. The investigator is also responsible for following the pregnancy until 
delivery or termination. These findings must be reported on the Exposure in Utero form and 
forwarded to the designated individual(s). The event meets the SAE criterion only if it results in a 
spontaneous abortion or a congenital anomaly. 
Among the clinical studies, 12 pregnancies were reported: 4 resulted in normal births; 5 resulted 
in spontaneous abortions (none of which was considered related to CD5789); 1 was electively 
aborted, and 2 were lost to follow-up (IB for CD5789 Cutaneous Formulation). 
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12. DATA SAFETY MONITORING BOARD 
Safety oversight will be under the direction of a DSMB composed of individuals with the 
appropriate expertise, including LI. Members of the DSMB should be independent from the study 
conduct and free of conflict of interest, or measures should be in place to minimize perceived 
conflict of interest. The DSMB will operate under a charter that will be finalized prior to the start 
of the study. The DSMB will meet at least 3 times during the conduct of the study: when the study 
begins, when 15 subjects have enrolled in Cohort A and have completed at least 28 days of 
treatment, and after 60 subjects have enrolled in the study. 
The DSMB will meet after 15 subjects in Cohort A have completed at least 28 days of double-
blind treatment to review aggregate safety and tolerability data (including PK and ECG results). 
The safety data will be unblinded. At that time, the DSMB will decide whether Cohort B may 
begin enrolling. The DSMB will have the authority to recommend to the sponsor that the study be 
modified, placed on hold, or stopped if serious safety issues are discovered. The DSMB will 
provide its input to Mayne Pharma LLC. Any protocol changes the DSMB may suggest will be 
submitted to all applicable regulatory bodies for review and approval. 
In case of significant toxicity, the DSMB may choose to review the available safety data and 
recommend stopping recruitment in a particular dose group. 
Stopping rules for individual subjects are in Section 9.4.1. 
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13. STATISTICS
13.1. Statistical Analysis 
This section presents a summary of the planned statistical analyses. A SAP that describes the 
details of the analyses to be conducted will be written prior to database lock.  
Unless otherwise indicated, all testing of statistical significance will be two-sided, and a difference 
resulting in a P value of ≤ 0.05 will be considered statistically significant.  
Summary statistics will be provided for the variables described below. For continuous variables, 
these statistics will include the number of subjects, mean, standard deviation (SD), median, 
minimum, and maximum. For categorical variables, these statistics will include the number and 
percentage of subjects in each category. 
The primary analysis period is the first 12 weeks of treatment (i.e., the Double-blind Period). 
Overall unblinding will take place at the end of the Double-blind Period of the study only after the 
database is locked. A second analysis will take place for endpoints assessed from Week 12 through 
the OLE Period. The baseline for the safety and efficacy parameters will be measured at Visit 1 or 
Visit 2, per the Schedule of Events for both the Double-blind Period (Table 2-1) and OLE (Table 
2-2).
13.1.1 Analysis Populations 
The following 5 analysis populations are planned for the Double-blind Period of this study: 
•
Safety: all subjects who are randomized to treatment and receive at least 1 application of
study drug in the Double-blind Period. This population will be the primary population for
analyses of safety.
•
Intent-to-treat (ITT): all randomized subjects. This population will be used as the primary
population for the analysis of efficacy for the Double-blind Period of the study.
•
Modified intent-to-treat (mITT): all subjects in the safety population with at least
1 postbaseline assessment of efficacy in the Double-blind Period.
•
Per-protocol (PP): subjects in the mITT Population who met all inclusion criteria and no
exclusion criteria, were compliant with study drug application, and who had no
significant protocol deviations.
•
Pharmacokinetic: all subjects in the Safety Population who have at least 1 plasma sample
with quantifiable concentration. This population will be used to summarize all PK
endpoints.
The following analysis populations are planned for the OLE of this study: 
•
OLE Safety: all subjects who complete the 12-week Double-blind Treatment Period and
receive at least 1 application of study drug in the OLE.
•
OLE ITT: all subjects who complete the 12-week Double-blind Treatment Period and
sign the OLE informed consent.
•
OLE mITT: all subjects in the OLE safety population with at least 1 assessment of
efficacy after Visit 6.
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• OLE PP: all subjects in the OLE mITT population who met all inclusion criteria and no 
exclusion criteria, were compliant with study drug application from baseline through 
EOT, and who had no significant protocol deviations throughout the study. 
Inclusion in the analysis populations will be determined prior to database lock. 
If a subject is randomized incorrectly or is administered the incorrect IP, analyses of the ITT and 
mITT populations will be based on the assigned treatment whereas all other analyses will be based 
on the actual treatment received. 
13.1.2 Study Subjects and Demographics 
13.1.2.1 Disposition and Withdrawals 
For the Double-blind Period, the numbers of subjects randomized, completing Week 12 of the 
study, and withdrawing early from the Double-blind Period, along with reasons for withdrawal, 
will be tabulated overall and by randomized treatment group. The number of subjects in each 
analysis population will be reported. The number of subjects completing study milestones will also 
be tabulated by randomized treatment group. This analysis will be conducted for the ITT 
population. 
For the OLE, the number of subjects entering the OLE, completing the study, and withdrawing 
early, along with reasons for withdrawal, will be tabulated overall. The number of subjects in each 
analysis population will be reported. The number of subjects completing study milestones will also 
be tabulated. This analysis will be conducted for the OLE ITT population. 
13.1.2.2 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol or International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) requirements. The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions are 
to be developed by the site and implemented promptly.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations promptly. All deviations must be addressed in study source documents, and reported to 
Premier Research or Mayne Pharma LLC. Protocol deviations must be sent to the reviewing IRB 
per their policies. The site investigator is responsible for knowing and adhering to the reviewing 
IRB requirements. Further details about the handling of protocol deviations will be included in the 
protocol deviation guidance plan. 
Subjects who taper to once-weekly application or who take a “drug holiday” will not be reported 
as having deviated from the protocol. 
13.1.2.3 Demographics and Other Baseline Characteristics 
These analyses will be conducted for the ITT and OLE ITT populations.  
Demographic variables will include age, sex, race, ethnicity, height, weight, and BMI. Baseline 
subject characteristics will include medical history, physical examination findings, and IGA score. 
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Prior and concomitant medications will be summarized by randomized treatment group, by the 
number and percentage of subjects taking each medication, and classified using World Health 
Organization Drug Dictionary (WHO-DD) Anatomical Therapeutic Chemical (ATC) classes and 
preferred terms. 
13.1.3 Exposure and Compliance 
Investigational product administration will be summarized in terms of each subject’s dose, and in 
terms of duration of exposure for each period. Descriptive statistics for these quantities, including 
the mean, median, SD, minimum, maximum, and quartiles, will be provided by treatment group. 
Additionally, the number of subjects who are compliant with investigational product will be 
presented by treatment group for the Double-blind Period and overall for the OLE.  
Subjects who taper to once-weekly application or who take a “drug holiday” will not be reported 
as having deviated from the protocol. 
13.1.4 Efficacy Analysis 
The ITT population will be used as the primary population for the primary analysis of efficacy at 
Week 12. Select efficacy analyses will be repeated as secondary analyses in the ITT and PP 
populations for the Double-blind Period. Efficacy analyses will also be repeated in the OLE using 
the OLE ITT, OLE mITT, and OLE PP populations. No formal inferential analyses will be 
conducted for efficacy variables in the OLE. 
13.1.4.1 Efficacy Endpoints 
Primary efficacy endpoint: The proportion of subjects in each treatment group who experience 
successful resolution of LI where “success” is defined as clear/almost clear overall and at least a 
2-grade change from Baseline at Week 12/EOT in the Double-blind Period on the 5-point IGA 
scale.  
Secondary: The secondary endpoints are as follow: 
• The difference in mean scores between the active trifarotene cream HE1 and 
vehicle groups in the following assessment indices from Baseline through 
Week 12: 
▪ 5-point VIIS scale for scaling from Baseline through Week 12 
▪ Individual score for roughness (Scale: 0–4) overall 
▪ Palm/sole Assessment (Scale: 0–4)  
▪ Quality of life per DLQI  
• The difference in proportion of subjects with presence of fissures on palm/soles 
(presence/absence, number of fissures, and pain associated with fissures [on a 
0-3 scale]) at Week 12 between the active trifarotene cream HE1 and vehicle 
groups  
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Exploratory: The exploratory endpoints are as follow: 
• The difference in mean ectropion scores (ESS of 0–8) between the active trifarotene 
cream HE1 and vehicle groups from Baseline through Week 12 
• The difference in quality of life per EQ-5D-5L  scores between the active trifarotene 
cream HE1 and vehicle groups from Baseline through Week 12 
13.1.4.2 Primary Analysis 
For the Double-blind Period only, the number and proportion of subjects in each treatment group 
with successful resolution of LI by Week 12/EOT will be presented. The primary efficacy endpoint 
will be analyzed using a logistic regression model with treatment and age group as factors. Other 
baseline characteristics and interactions may be included. The odds ratios and 95% CIs for the 
odds ratios will be presented. The difference in proportions between the active trifarotene cream 
HEI and vehicle cream group, 95% CIs for the differences, and P-values for the differences in 
treatment will also be presented. 
Descriptive summaries (such as mean, standard error, median, minimum, and maximum) and the 
changes from baseline will be provided for IGA scores for both periods.  
13.1.4.3 Secondary Analyses 
Secondary and exploratory efficacy endpoints will be analyzed separately for each period 
(Double-blind and OLE) using descriptive statistics.  
Additionally, for the Double-blind Period only, change from Baseline in continuous secondary 
endpoints through Week 12 will be presented and analyzed using a mixed model for repeated 
measures (MMRM). The model will include the change from baseline score as the dependent 
variable, treatment group as a fixed effect, subject as a random effect, and baseline score value as 
a covariate.  
For subjects who report having fissures, descriptive summaries of the number of fissures and pain 
related to fissures will also be presented by treatment group and body area for each period. 
The DLQI scores will also be analyzed using descriptive statistics through Week 12. 
The proportion of subjects with at least a 50% reduction in IGA score from Baseline will be 
analyzed using the same logistic regression analysis described in Section 13.1.4.2. 
13.1.4.4 Exploratory Analyses 
Descriptive summaries and the changes from  will be provided for ectropion scores and EQ-5D-
5L scores by visit for each period. No formal inferential analyses will be conducted for exploratory 
endpoints. 
13.1.4.5 Corroborative, Sensitivity, and Other Analyses 
To assess the effect of missing data on the primary efficacy analysis, a sensitivity analysis will be 
performed using multiple imputation (MI) for the Double-blind Period only. Multiple-imputations 
will be used to replace missing IGA outcomes using multiple draws from the posterior predictive 
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distribution estimated from the treatment groups. IGA scores will be imputed and then categorized 
as treatment success according to Section 13.1.4.1. Imputation will not be performed for the OLE. 
Full details will be specified in the SAP. 
The proportion of subjects who experience a 2-grade change from baseline to Week 12 in 
individual score for roughness and palm/sole assessment will also be explored using a logistic 
regression model with treatment and age group as factors. Other baseline characteristics and 
interactions may be included. The odds ratios and 95% CIs for the odds ratios will be presented. 
The difference in proportions between the active trifarotene cream HEI and vehicle cream group 
and the 95% CIs for the differences will be presented. 
For analyses involving study site, if the number of subjects per site is small, sites may be pooled 
for safety and efficacy analysis or omitted from statistical models as the anticipated number of 
subjects per site is small, treatment is self-administered, and the sites are using standardized 
procedures for all assessments. If the distribution of enrollments at sites is such that one or few are 
enrolling a majority of subjects, a subgroup analysis by site may be performed. The final 
determination will be made prior to database lock.  
Details of these analyses will be further detailed in the SAP. 
13.1.5 Clinical Pharmacology Analyses 
13.1.5.1 Pharmacokinetics 
For noncompartmental analysis, plasma concentrations will be listed and summarized at each time 
point using descriptive statistics. Descriptive statistics reported will include the arithmetic mean, 
SD, CV%, geometric mean, minimum, maximum, and median. Only the range and the median will 
be reported for Tmax, as this is a categorical parameter. The PK parameters will also be summarized 
by treatment using descriptive statistics.  
Individual plasma concentration plots and mean data graphs will be produced using both linear 
and semi-logarithmic scales. Mean data graphs will show plasma concentration profiles by 
treatment group. 
Pharmacokinetic plasma parameter estimates and summaries will be completed for the subjects in 
the PK population. Testing of PK parameters will be outlined in the SAP. 
13.1.6 Safety and Tolerability Analyses 
Safety analyses through Week 12 of the Double-blind Period will be conducted using data from 
the Safety Population and safety analyses in the OLE will be conducted using the OLE Safety 
Population (as defined in Section 13.1.1). Safety variables include treatment-emergent AEs, 
clinical laboratory values, vital signs, ECG readings, and physical examination results. No formal 
inferential analyses will be conducted for safety variables in either period. 
13.1.6.1 Local Tolerability 
During all clinic visits, the investigator will assess local tolerability (Scale: 0-3 [none, mild, 
moderate, severe]) for each treated body area (chest/abdomen, back, arms, legs, and face/neck). 
Descriptive summaries will be presented by period, treatment group, and visit. 
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13.1.6.2 Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 20.1 or higher.  
Treatment-emergent AEs are defined as: 
• AEs with onset at the time of or following the start of treatment with IP through the 
Follow-up Visit or Early Termination Visit, whichever occurs first, or 
• AEs starting prior to the start of treatment but increasing in severity or relationship at the 
time of, or following, the start of treatment with IP through the Follow-up Visit or Early 
Termination Visit, whichever occurs first. 
The number and percentage of subjects with AEs will be displayed by each treatment group in the 
Double-blind Period and overall in the OLE by system organ class and preferred term. Summaries 
of AEs by severity and relationship to IP will also be provided. Serious adverse events and AEs 
resulting in discontinuation of IP will be summarized separately in a similar manner. Subject 
listings of AEs, SAEs, and AEs causing discontinuation of IP will be produced. 
13.1.6.3 Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from baseline values will be presented for clinical laboratory values for each treatment 
group at each time point in each period. 
The number of subjects with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from baseline (shift tables) for each clinical 
laboratory parameter by treatment group and by study visit in each period.  
Laboratory values that are outside the normal range will also be flagged in the data listings and 
presented with the corresponding normal ranges. Any out-of-range values that are identified by 
the investigator as being clinically significant will also be shown in a data listing. 
13.1.6.4 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for systolic blood pressure (SBP), diastolic blood pressure 
(DBP), and pulse for each period. 
The number of subjects with vital signs values categorized as below, within, or above normal 
ranges will be tabulated showing change from baseline (shift tables) for each parameter by period, 
by treatment group and by study visit. Pre- and post-treatment values may also be presented with 
an analysis of mean changes from baseline. 
13.1.6.5 Twelve-lead Electrocardiograms 
The number and percentage of subjects with normal and abnormal ECG findings will be 
summarized for each treatment group at each time point in each period. Abnormal results will be 
grouped as clinically significant and not clinically significant. 
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A comparison of QT results will be presented. Summary statistics will be displayed by period, by 
treatment group, and by visit for QT and the QT interval corrected for heart rate (QTc) calculated 
using Fridericia’s QT correction methods.  
Descriptive summaries (mean, SD, median, minimum, and maximum) will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTcF interval (Fredericia’s correction 
methods), and HR for each treatment group at each time point in each period. 
13.1.6.6 Physical Examination Findings 
The number and percentage of subjects with normal and abnormal findings in the complete 
physical examination will be displayed for each treatment group in each period. 
13.1.7 Interim Analysis 
No interim analyses are planned.  
13.2. Sample Size Determination 
Accounting for a 20% drop-out/nonevaluable rate, a total sample size of 120 subjects randomized 
in a 1:1:1 ratio to 2 active trifarotene cream HE1 arms and a vehicle cream arm will provide 
>80% power to detect a difference between each separate trifarotene cream HE1 arm (32 evaluable 
subjects) and the vehicle cream arm (32 evaluable subjects) 2-sided Fisher’s Exact Test assuming 
a 70% success rate and a 40% success rate, respectively. This study is not powered to detect a 
difference between the 2 active arms. 
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14. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
14.1. Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 16). The sponsor reserves the right to withdraw a subject from the study (Section 8.3), to 
terminate participation of a study site at any time (Section 14.7), and/or to discontinue the study 
(Section 14.6). 
Mayne Pharma LLC agrees to provide the investigator with sufficient material and support to 
permit the investigator to conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 18.1), the investigator indicates that he or she 
has read the protocol carefully, fully understands the requirements, and agrees to conduct the study 
in accordance with the procedures and requirements described in this protocol.  
The trial will be conducted in accordance with ICH GCP, and the applicable United States (US) 
Code of Federal Regulations (CFR). The principal investigator will assure that no deviation from, 
or changes to, the protocol will take place without prior agreement from the Investigational New 
Drug (IND) sponsor, funding agency and documented approval from the IRB, except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection and ICH GCP training. 
Investigators should ensure that all persons who are delegated study-related responsibilities are 
adequately qualified and informed about the protocol, the IP(s), and their specific duties within the 
context of the study. Investigators are responsible for providing Mayne Pharma LLC with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
14.1.3 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying study product may inspect all 
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documents and records required to be maintained by the investigator, including, but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. 
The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at Premier Research. This will not include the participant’s contact 
or identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by clinical sites and by Premier Research staff will be secured and password protected. At the end 
of the study, all study databases will be de-identified and archived at the Premier Research 
14.2. Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from the sponsor or its designee that the study can be initiated at the study site. The study site will 
not be authorized for study initiation until: 
1. The study site has received the appropriate IRB/IEC approval for the protocol and the 
appropriate ICF. 
2. All regulatory/GCP documents have been submitted to and approved by the sponsor or its 
designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
14.3. Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study. Subjects may 
only be rescreened once 30 days or more after the original Screening Visit. If a subject is eligible 
to enter the study after having previously failed screening, the subject will be assigned a new 
subject identification number. 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
14.4. Study Documents 
All documentation and material provided by Mayne Pharma LLC for this study are to be retained 
in a secure location and treated as confidential material. 
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14.4.1 Informed Consent 
Consent forms describing in detail the study intervention, study procedures, and risks are given to 
the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. The informed consent forms are submitted with this 
protocol. 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be 
IRB-approved and the participant will be asked to read and review the document. The investigator 
will explain the research study to the participant and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants. Participants 
will have the opportunity to carefully review the written consent forms and ask questions before 
signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it before agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must 
be informed that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. A copy of the informed consent document will be given to the participants for 
their records. The informed consent process will be conducted and documented in the source 
document (including the date) and the form signed before the participant undergoes any 
study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
14.4.2 Investigator’s Regulatory/Good Clinical Practice Documents 
The regulatory/GCP documents are listed below. 
• Signed original protocol (i.e., Investigator’s Agreement) 
• Curricula vitae of all investigators and subinvestigators 
• Name and address of the laboratories 
• List of laboratory reference ranges, and if available, a quality certificate 
• Form Signature Log/Delegation of Study-related Duties 
• Approved ICF and subject materials 
• FDA1572 and financial disclosure forms, as applicable (US sites) 
• Any other relevant GCP documents 
The regulatory/GCP documents must be received from the investigator and reviewed and approved 
by Mayne Pharma LLC or its designee before the study site can initiate the study and before Mayne 
Pharma LLC will authorize shipment of IP to the study site. Copies of the investigator’s 
regulatory/GCP documents must be retained at the study site in a secure location. Additional 
documents, including a copy of the protocol and applicable amendment(s), the trifarotene 
(CD5789) Cream IB, eCRF completion guidelines, copies of regulatory references, copies of 
IRB/IEC correspondence, and IP accountability records should also be retained as part of the 
investigator’s regulatory/GCP documents. It is the investigator’s responsibility to ensure that 
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copies of all required regulatory/GCP documents are organized, current, and available for 
inspection. 
14.4.3 Case Report Forms 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign an 
ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the study to ensure that the study information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered in the electronic data capture 
(EDC) system according to the completion guidelines provided by the sponsor or its designee. 
The eCRFs must be signed by the investigator or a subinvestigator. These signatures serve to attest 
that the information contained in the eCRF is accurate and true. 
14.4.4 Source Documents 
Information recorded in the EDC system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
Clinical laboratory data required by the protocol will be electronically transferred from the 
central/local laboratory to the sponsor or its designee. A paper copy of the laboratory results will 
be provided to the study site and should be retained with each subject’s source data. 
14.5. Data Quality Control 
Mayne Pharma LLC and its designees will perform quality control checks on this clinical study. 
14.5.1 Monitoring Procedures 
Mayne Pharma LLC and/or its designee will conduct site visits to monitor the study and ensure 
compliance with the protocol, GCP, and applicable regulations and guidelines. The assigned 
clinical research associate(s) (CRA[s]) will visit the investigator and study site at periodic intervals 
and maintain periodic communication. The investigator agrees to allow the CRA(s) and other 
authorized Mayne Pharma LLC personnel access. The CRA(s) will maintain current personal 
knowledge of the study through observation, review of study records and source documentation, 
and discussion of the conduct of the study with the investigator and staff. While on site, the CRA(s) 
will review 
• regulatory documents, directly comparing entries in the EDC system with the source 
documents 
• consenting procedures 
• AE procedures 
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• storage and accountability of IP and study materials 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRF will be provided to the sites. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow Mayne Pharma LLC or designee auditors or inspectors from regulatory agencies 
to review records and to assist the inspectors in their duties, if requested.  
For additional information, please refer to the clinical monitoring plan (CMP). 
14.5.2 Data Management 
Mayne Pharma LLC or designee will be responsible for activities associated with the data 
management of this study. The standard procedures for handling and processing records will be 
followed per GCP and Premier Research’s standard operating procedures. A comprehensive data 
management plan (DMP) will be developed, including a data management overview, description 
of database contents, annotated CRF, pre-entry review list, self-evident correction conventions, 
query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries will be provided to the sites. 
14.5.3 Quality Assurance/Audit 
This study will be subject to audit by Mayne Pharma LLC or its designee. Audits may be performed 
to check compliance with GCP guidelines and can include: 
• site audits 
• Trial Master File audits 
• database audits 
• document audits (e.g., protocol and/or clinical study report [CSR]) 
Mayne Pharma LLC or its designee may conduct additional audits on a selection of study sites, 
requiring access to subject notes, study documentation, and facilities or laboratories used for the 
study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB/IEC or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify Mayne Pharma LLC immediately. 
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14.6. Study Termination 
The study may be terminated at Mayne Pharma LLC’s discretion at any time and for any reason. 
The DSMB may recommend discontinuation of the study if they find evidence of unacceptable 
risk to subjects. 
14.6.1 Regular Study Termination 
The end of this study is defined as the date of the last visit of the last subject (last subject out or 
last subject last visit) participating in the study. Within 90 days of the end of the clinical study, 
Mayne Pharma LLC or designee will notify the IECs and regulatory authorities about the regular 
termination of the study as required according to national laws and regulations. 
14.6.2 Premature Study Termination 
The study may be temporarily suspended or terminated prematurely if there is sufficient reasonable 
cause at any time by Mayne Pharma LLC, IECs, regulatory authorities, respective steering 
committees, or the coordinating investigator. A decision to prematurely terminate the study is 
binding to all investigators of all study sites. 
Within 15 days of premature termination of a clinical study, Mayne Pharma LLC or its designee 
will notify the IECs and regulatory authorities about the premature termination as required 
according to national laws and regulations. Mayne Pharma LLC or its designee must clearly 
explain the reasons for premature termination. 
Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigator, funding agency, the IND 
or IDE sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the 
PI will promptly inform study participants, the IRB, and sponsor and will provide the reason(s) for 
the termination or suspension. Study participants will be contacted, as applicable, and be informed 
of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
If the study is terminated prematurely, all investigators have to inform their subjects and take care 
of appropriate follow-up and further treatment of the subjects to ensure protection of the subjects’ 
interests. Study sites may be asked to have all subjects currently participating in the study complete 
all of the assessments for the Follow-up Visit. 
The study might resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB/IEC and/or FDA. 
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14.7. Study Site Closure 
At the end of the study, all study sites will be closed. Mayne Pharma LLC may terminate 
participation of a study site at any time. Examples of conditions that may require premature 
termination of a study site include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate subject enrollment 
14.7.1 Record Retention 
For sites in the US, the investigator shall retain and preserve 1 copy of all data generated in the 
course of the study, specifically including, but not limited to, those defined by GCP as essential 
until 1 of the following occurs: 
• At least 2 years after the last marketing authorization for the IP has been approved or the 
sponsor has discontinued its research with the IP, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development of 
the IP. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor has 30 days to respond to the investigator’s notice, and the 
sponsor has further opportunity to retain such materials at the sponsor’s expense. 
Outside of the US, after completing the study, Mayne Pharma LLC will receive the original eCRFs 
or at least a legible copy and retain the documents for at least 5 years after the completion of the 
study. 
One copy will remain with the investigator. The investigator shall arrange for the retention of the 
subject identification codes, subject files and other source data until at least 5 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or until at least 2 years have elapsed since 
the formal discontinuation of the clinical development of the product. These documents need to be 
retained for a longer period of time if required by applicable regulatory authorities or by agreement 
with the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor shall have 30 days to respond to the investigator’s notice, 
and the sponsor shall have a further opportunity to retain such materials at the sponsor’s expense. 
Copies of these study records (and all study-related documents, including source data) shall be 
kept by the investigator for the maximum period of time permitted by the hospital, institution, or 
private practice. 
14.7.2 Sample Retention 
Blood samples will be used for purposes related to this study only, and will not be stored for future 
research. The samples will be stored until they are no longer needed, and the decision has been 
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made that none of the samples needs to be reanalyzed. In addition, identifiable samples can be 
destroyed at any time at the request of the subject. 
Data collected for this study will be analyzed and stored at Premier Research.  
14.8. Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Mayne Pharma LLC. The protocol amendment must be signed by 
the investigator and approved by the IRB or IEC before it may be implemented. Protocol 
amendments will be filed with the appropriate regulatory agency(s) having jurisdiction over the 
conduct of the study. 
14.9. Use of Information and Publication 
All information concerning trifarotene (CD5789) cream HE1, Mayne Pharma LLC’s operations, 
patent applications, formula, manufacturing processes, basic scientific data, and formulation 
information supplied by Mayne Pharma LLC or its designee to the investigator, and not previously 
published, is considered confidential and remains the sole property of Mayne Pharma LLC. Case 
report forms also remain the property of Mayne Pharma LLC. The investigator agrees to use this 
information for purposes of study execution through finalization and will not use it for other 
purposes without the written consent of the sponsor. 
The information developed in this study will be used by Mayne Pharma LLC in connection with 
the continued development of trifarotene (CD5789) cream HE1 and thus, may be disclosed as 
required to other clinical investigators or government regulatory agencies. 
The information generated by this study is the property of Mayne Pharma LLC. Publication or 
other public presentation of trifarotene (CD5789) cream HE1 data resulting from this study 
requires prior review and written approval of Mayne Pharma LLC. Abstracts, manuscripts, and 
presentation materials should be provided to Mayne Pharma LLC for review and approval at least 
30 days prior to the relevant submission deadline. Data from individual study sites must not be 
published separately. 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition, or publication by the investigator until Mayne Pharma LLC has reviewed and 
commented on such a presentation or manuscript for publication. If applicable, this study will be 
registered at ClinicalTrials.gov, and results information from this study will be submitted to 
ClinicalTrials.gov. 
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15. FINAL CLINICAL STUDY REPORT 
Mayne Pharma LLC will retain ownership of the data. 
The final CSR will be written within 1 year of completion of the clinical part of the study. This 
report will include a summary of the study results based on a statistical evaluation and clinical 
assessment of the protocol-defined endpoints. 
The final CSR may be submitted to the regulatory authorities.  
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16. ETHICAL AND LEGAL CONSIDERATIONS 
16.1. Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry GCP 
E6 (including archiving of essential study documents), the Integrated Addendum to ICH E6 (R2) 
of November 2016, the Declaration of Helsinki, the applicable regulations of the country(ies) in 
which the study is conducted, and with the Commission Directives 2001/20/EC and 2005/28/EC. 
16.2. Subject Information and Informed Consent 
A properly constituted, valid IRB or IEC must review and approve the protocol, the investigator’s 
ICF, and related subject information and recruitment materials before the start of the study. 
It is the responsibility of the investigator to ensure that written informed consent is obtained from 
the subject before any activity or procedure is undertaken that is not part of routine care. 
According to the Declaration of Helsinki and ICH GCP, subjects must provide their written 
informed consent prior to enrollment in a clinical study and before any protocol-specified 
procedures are performed. Subjects must declare their consent by personally signing and dating 
the ICF. The written ICF will embody the elements of informed consent as described in the 
Declaration of Helsinki and will also comply with local regulations.  
Each subject should be made aware by the investigator of the nature of the study (objectives, 
methods, and potential hazards and benefits) and the procedures involved, using the information 
on the ICF. Information should be given in both oral and written form whenever possible and 
deemed appropriate by the IRB/IEC. Subjects, their relatives, or, if necessary, legal representatives 
must be given ample opportunity to inquire about details of the study.  
Subject information and the ICF must be in a language fully comprehensible to the prospective 
subject. The written information must be provided to the subject to give him or her sufficient time 
to understand the information and to prepare questions before being asked for his or her consent. 
The investigator must confirm that the text was understood by the subject. The subject will then 
sign and date the IRB/IEC-approved consent form indicating that he or she has given his or her 
consent to participate in the study. The signature confirms that the consent is based on information 
that has been understood. The form will also be signed by the investigator obtaining the consent 
and annotated with the study subject number. Each subject’s signed ICF must be kept on file by 
the investigator for possible inspection by regulatory authorities, Mayne Pharma LLC, and/or the 
sponsor’s designee. Collection of informed consent has to be documented in the eCRF. 
Furthermore, the subject will be informed that if he or she wishes to drop out or withdraw (see 
Section 8.3) at any time during the study, this will not have any negative consequences. Subjects 
may be withdrawn by the investigator if any change related to safety or ethics precludes further 
participation in the study. Subjects will be asked to agree to a final assessment in the event of an 
early termination of the study. 
Subjects will be informed that data from their case may be stored in a computer without inclusion 
of their name and that such data will not be revealed to any unauthorized third party. Data will be 
reviewed by the monitor, an independent auditor, and possibly by representatives of regulatory 
authorities and/or IRBs/IECs. The terms of the local data protection legislation will be applied as 
appropriate. 
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16.3. Approval by Institutional Review Board and Independent Ethics Committee 
A valid IRB/IEC must review and approve this protocol before study initiation. Written 
notification of approval is to be provided by the investigator to the sponsor’s or the sponsor’s 
representative before shipment of investigational drug supplies, and will include the date of the 
committee’s approval and the chairperson’s signature. This written approval must follow local 
country requirements. 
Until written approval by the IRB/IEC has been received by the investigator, no subject may 
undergo any procedure not part of routine care for the subject’s condition. 
Protocol amendments must also be reviewed and approved by the IRB/IEC. Written approval from 
the IRB/IEC, or a designee, must be received by Mayne Pharma LLC before implementation.  
16.4. Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator 
and the sponsor. 
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17. REFERENCES 
1. Vahlquist A, Blockhuys S, Steijlen P, 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 Derm. 2014;170(1):173-181. 
2. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited 
ichthyoses: results of the first ichthyosis consensus conference in sorèze 2009. J Am Acad 
Dermatol. 2010;63(4):607–-641. 
3. Vahlquist A, Gånemo A, Virtanen M. Congenital ichthyosis: an overview of current and 
emerging therapies. Acta Derm Venereol. 2008;88(1):4–14. 
4. Blanchet-Bardon C, Nazzaro V, Rognin C, Geiger JM, Puissant A. Acitretin in the 
treatment of severe disorders of keratinization. J Am Acad Dermatol. 1991;24(6):982–986. 
5. Kullavanijaya P and Kulthanan K. Clinical efficacy and side effects of acitretin on the 
disorders of keratinization: a one-year study. J Dermatol. 1993;20:501–506. 
6. Lacour M, Nikhar-Mehta B, Atherton DJ, Harper JI. An appraisal of acitretin therapy in 
children with inherited disorders of keratinization. Br J Dermatol. 1996;134:1023–1029. 
7. Steijlen PM, Van Dooren-Greebe RJ, Van De Kerkhof PCM. Acitretin in the treatment of 
lamellar ichthyosis. Br J Dermatol. 1994;130(2):211–214. 
8. Katugampola RP, Finlay AY. Oral retinoid therapy for disorders of keratinization: single-
centre retrospective 25 years’ experience on 23 patients. Br J Dermatol. 
2006;154(2):267-276. 
9. Gånemo A, Virtanen M, Vahlquist A. Improved topical treatment of lamellar ichthyosis: a 
double‐blind study of four different cream formulations. Br J Derm. 1999;141(6):1027–
1032. 
10. Kiistala R, Lauharanta J, Kanerva L. Transepidermal water loss and sweat gland response 
in lamellar ichthyosis before and during treatment with etretinate: report of three cases. 
Acta Derm Venereol. 1982;62(3):268–270. 
11. Ramirez ME, Youseef WF, Romero RG. Acute percutaneous lactic acid poisoning in a 
child. Pediatr Dermatol. 2006;23(3):282–285. 
12. Chiaretti A, Wismayer DS, Tortorolo L, Piastra M, Polidori G. Salicylate intoxication using 
a skin ointment. Acta Paediatr. 1997;86(3):330-331. 
13. Marukian NV, Deng Y, Gan G, et al. Establishing and validating an ichthyosis severity 
index. J Invest Dermatol. 2017;137(9):1834-1841. 
14. Korteweg SFS, Stenekes MW, van Zyl FE, Werker PMN. Paralytic ectropion treatment 
with lateral periosteal flap canthoplasty and introduction of the ectropion severity score. 
Plast Reconstr Surg Glob Open. 2014;2(5):e151. 
 
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18. ATTACHMENTS 
18.1. Investigator’s Agreement 
 
PROTOCOL NUMBER: 
18-ICH-001 
PROTOCOL TITLE: 
A Phase 2 Randomized, Multicenter, Double-blind, 
Vehicle-controlled, 12-Week, Safety, Efficacy, and Systemic 
Exposure Study followed by a 12-Week Open-label Extension of 
Trifarotene (CD5789) Cream HE1 in Subjects with Autosomal 
Recessive Ichthyosis with Lamellar Scale 
FINAL PROTOCOL 
DATE: 
v3.0 for Ukraine, 21-Nov-2019 
The undersigned acknowledges possession of and has read the product information 
(e.g., investigator’s brochure) on the IP and has discussed these data with the study monitor. 
Having considered fully all the available information, the undersigned considers that it is ethically 
justifiable to give the IP to selected subjects in his/her care, according to the study protocol. 
He or she agrees to use the study material, including IP, only as specified in the protocol. He or 
she understands that changes cannot be made to the protocol without prior written approval of 
Mayne Pharma LLC. 
He or she understands that any deviation from the protocol may lead to early termination of the 
study. 
He or she agrees to report to Mayne Pharma LLC within time any clinical AE or abnormal 
laboratory value that is serious, whether or not considered related to the administration of IP. 
He or she agrees to comply with Mayne Pharma LLC and regulatory requirements for the 
monitoring and auditing of this study. In addition, he or she agrees that the study will be carried 
out in accordance ICH, the Declaration of Helsinki, and the local laws and regulations relevant to 
the use of new therapeutic agents. 
I, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the study. 
Principal Investigator: 
 
Printed Name: 
 
 
 
Signature: 
 
 
 
Date: 
 
 
 
Investigator’s name and address (stamp) 
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APPENDICES 
A. Regulations and Good Clinical Practice Guidelines 
 
 
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A. Regulations and Good Clinical Practice Guidelines
1. Regulations
Refer to the following United States Code of Federal Regulations (CFR): 
•
FDA Regulations 21 CFR, Parts 50.20 – 50.27
Subpart B – Informed Consent of Human Subjects
•
FDA Regulations 21 CFR, Parts 56.107 – 56.115
Part 56 – Institutional Review Boards
Subpart B – Organization and Personnel
Subpart C – IRB Functions and Operations
Subpart D – Records and Reports
•
FDA Regulations 21 CFR, Parts 312.50 – 312.70
Subpart D – Responsibilities of Sponsors and Investigators
Refer to the following European Directives (and applicable regulations/guidances): 
•
European Directive 2001/20/EC and related guidance documents
•
European Directive 2005/28/EC and related guidance documents>
2. Good Clinical Practice Guidelines
ICH GCP guidelines can be found at the following URLs: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf 
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Page 1 of 93 
PROTOCOL/CLINICAL INVESTIGATION PLAN 
PRODUCT NAME/NUMBER: 
Trifarotene (CD5789) Cream HE1 
PROTOCOL NUMBER: 
18-ICH-001
IND NUMBER: 
140538 
NCT NUMBER:  
NCT03738800 
EUDRACT NUMBER: 
2018-003272-12 
DEVELOPMENT PHASE: 
2 
PROTOCOL TITLE: 
A Phase 2 Randomized, Multicenter, Double-blind, 
Vehicle-controlled, 12-Week, Safety, Efficacy, and 
Systemic Exposure Study followed by a 12-Week 
Open-label Extension of Trifarotene (CD5789) Cream HE1 
in Subjects with Autosomal Recessive Ichthyosis with 
Lamellar Scale  
PROTOCOL DATE: 
AMENDMENT DATE: 
Final v1.0, 28-Nov-2018 
Final v2.0 for Ukraine, 21-Oct-2019 
COORDINATING/PRINCIPAL 
INVESTIGATOR: 
Keith A. Choate, MD 
Department of Dermatology, Yale University School of 
Medicine,  
PO Box 208059 
333 Cedar Street 
New Haven, CT 06520, USA 
Phone: +1 203 789 1249 
SPONSORED BY: 
Mayne Pharma LLC 
1240 Sugg Parkway  
Greenville, NC 27834, USA 
Phone: +1 984 242 1400 
CONTRACT RESEARCH 
ORGANIZATION: 
Premier Research 
One Park Drive, Suite 150 
Durham, NC 27709, USA 
Phone: +1 919 627 9100 
This study will be performed in compliance with ICH Good Clinical Practices and applicable 
regulatory requirements, including the archiving of essential documents. Information contained in 
this protocol is confidential in nature and may not be used, divulged, published, or otherwise 
disclosed to others except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. Persons to whom this information 
is disclosed should be informed that it is confidential and may not be further disclosed without the 
express permission of Mayne Pharma LLC. 
· pharma 
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22-Oct-2019 | 13:24:52 EDT
23-Oct-2019 | 07:38:15 EDT
22-Oct-2019 | 10:31:09 PDT
Mayne Pharma LLC 
Protocol 18-ICH-00 1 
1. 
APPROVAL SIGNATURES 
PROTOCOL NUMBER: 
18-ICH-001 
Confidential 
PROTOCOL TITLE: 
A Phase 2 Randomized, Multi-center, Double-blind, 
Vehicle-controlled, 12-Week, Safety, Efficacy, and Systemic 
Exposure Study followed by a 12-Week Open-label Extension of 
Trifarotene (CD5789) Cream HEl in Subjects with Autosomal 
Recessive Ichthyosis with Lamellar Scale 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge, it 
accurately describes the planned conduct of the study. 
SIGNATURE 
~J>j 
~
1Llv 
Ilana Stancovski, PhD 
Chief Scientific Officer 
Mayne Pharma LLC 
(, 
DocuSigned by: 
I Ro~ it<Lr 
IJ 
Signer Name: Phoevos Hughes 
Signing Reason: I approve this document 
Signing Time: 22-0ct-2019 110:31 :05 PDT 
Ph 
m1bfughe~aJm>T18371307 AF875E4CE 
Associate Director, Clinical Operations 
Mayne Pharma LLC 
r DocuSigned by: 
I m-~~ 
0 
Signer Name: Marlis Sarkany 
Signing Reason: I approve this document 
Signing Time: 23-0ct-2019 I 07:38:03 EDT 
M 
1 BE 1 G8AEDG854CDC86688C 1 FD466E26F 
ar 1s ~arKany, lVllJ 
Senior Medical Director 
Premier Research 
0 
Signer Name: Adrienne Kuxhausen 
b
Signing Reason: I approve this document 
Signing Time: 22-0ct-2019 113:24:50 EDT 
Adrien¥r88.te'frRi\a.~gg~~9:K?s38D5A7D662CF 
Senior Biostatistician 
Premier Research 
21-Oct-2019 
AD-MW-07.06 08-Dec-2017 
DATE: 
Final v2.0 for Ukraine 
Page 2 of93 
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2. PROTOCOL SUMMARY 
2.1. Synopsis 
PRODUCT 
NAME/NUMBER 
Trifarotene (CD5789) Cream HE1 
PROTOCOL 
NUMBER 
18-ICH-001 
EUDRACT 
NUMBER 
2018-003272-12 
DEVELOPMENT 
PHASE 
2 
PROTOCOL TITLE 
A Phase 2 Randomized, Multi-center, Double-blind, Vehicle-controlled, 12-Week, 
Safety, and Efficacy, and Systemic Exposure Study followed by a 12-Week Open-label 
Extension of Trifarotene (CD5789) Cream HE1 in Subjects with Autosomal Recessive 
Ichthyosis with Lamellar Scale  
INDICATION 
Lamellar ichthyosis 
OBJECTIVES 
Primary: To compare the safety and efficacy of 2 concentrations of trifarotene cream HE1 
versus vehicle in subjects with moderate to severe autosomal recessive ichthyosis with 
lamellar scale, also known as lamellar ichthyosis (LI) after 12 weeks of treatment. 
Secondary: 
• 
To assess systemic exposure to trifarotene and its major metabolites after topical 
application of the investigational product (IP) on up to 90% body surface area (BSA) 
twice weekly. 
• 
To assess safety for up to 24 weeks of dosing with open-label trifarotene cream HE1 
200 µg/g. 
STUDY DESIGN 
This is a 2-cohort, multicenter study in subjects with moderate to severe LI (i.e., 3–4 on 
a 5-point Visual Index for Ichthyosis Severity (VIIS) for scaling where 0 = clear and 4 = 
severe) on at least 2 areas of the 4 body areas assessed (chest/abdomen, back, arms, and 
legs). Subjects in Cohorts A and B will be subsequently randomized in a double-blind 
fashion to 1 of 2 doses of trifarotene cream HE1 or vehicle and treated twice weekly for 
12 weeks. Subjects who complete the randomized, Double-blind Period of the study will 
be eligible to enter a 12-week, Open-label Extension (OLE) Period in which additional 
PK, safety, and efficacy data will be collected. 
Approximately 15 subjects will be randomized into the first cohort of subjects (Cohort A) 
in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or 
vehicle and treated twice weekly for up to 12 weeks. After the initial 15 subjects complete 
at least 28 days of treatment, an independent Data Safety Monitoring Board (DSMB) will 
review aggregate safety and tolerability data. If no safety issues are identified, an 
additional group of about 105 subjects will be allowed to enroll in Cohort B. Subjects in 
Cohort B will be randomized 1:1:1 to trifarotene cream HE1 100 µg/g, trifarotene cream 
HE1 200 µg/g, or vehicle and treated twice weekly for up to 12 weeks in the same manner 
as subjects in Cohort A.  
All subjects who complete the 12-week Double-blind Treatment Period will be eligible 
to enroll in the 12-week OLE Period. Subjects in the OLE will receive open-label 
trifarotene cream HE1 200 µg/g twice weekly for up to 12 weeks. 
After Screening, eligible subjects for Cohort A and B will enter a washout period of up 
to 35 days, during which they must stop using the following prohibited medications: 
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a. 
Topical treatments 
Medication 
Washout Period 
Corticosteroids (except inhaled and ophthalmic corticoids) 
2 weeks 
Retinoids (e.g., tretinoin, tazarotene) 
4 weeks 
Vitamin D analogues 
2 weeks 
Immunosuppressants (e.g., tacrolimus) 
2 weeks 
Antracen derivatives, tar and salicylic preparations 
2 weeks 
Keratolytics (such as urea, lactic acid, propylene glycol, 
salicylic acid) except keratolytic shampoo 
- 
b. Systemic treatments 
Medication 
Washout Period 
Retinoids 
8 weeks 
Oral Vitamin A supplementation more than 3500 IU per day 
2 weeks 
Medication interfering with bone activity, e.g., corticosteroids, 
thyroid hormones, cytotoxics, bisphosphonates, calcitonins, 
tetracyclines, quinolones, thiazides, salicylates in long-term 
course, heparin, theophylline, barbiturates, colchicines (except 
Vitamin D analogues taken at stable dose since at least 1 month) 
8 weeks 
QT prolonging drugs 
5 half lives 
Enzymatic inductors (such as rifampicine, phenytoin, 
carbamazepine, phenobarbital, St. John’s Wort) 
3 months 
CYP2C9 and 2C8 inhibitors (not all inclusive: gemfibrozil, 
fluconazole, fluvoxamine, sulfaphenazole, miconazole, 
amiodarone, sertraline, sulfamethoxazole, valproic acid, 
voriconazole, trimethoprim, rosiglitazone, pioglitazone) 
5 half lives 
Study drug will be packaged in 50-g tubes from which up to 36 g of investigational 
product (IP) may be dispensed per application, i.e., the maximum dose per application. 
Study staff will apply the first dose of study drug to each subject in the clinic on Day 1 
after Baseline measurements, and will record the amount of study drug applied.  
Thereafter, each subject will apply approximately the same amount (up to 36 g) of study 
drug as for the first dose on up to 90% of BSA twice weekly, sparing the scalp, inguinal, 
and axillary areas. Subjects will receive an adequate number of tubes to use 1 tube per 
application and will use a new tube for each treatment day. Subjects may use less than the 
full amount of product in a tube. Subjects will record the date and time of study treatment 
administration in the subject diary. 
Local tolerability may differ in subjects with LI compared to healthy subjects, as their 
skin is drier and may be more sensitive. Local tolerability will be followed very carefully 
during the study. Subjects will receive information on study drug use and stopping rules 
and will be instructed to contact the site with any safety/tolerability issues. Study 
personnel will telephone subjects in between scheduled visits (i.e., on Day 7 and Day 45 
in the Double-blind Period; at Day 97 and 134 in the OLE Period) to assess safety; an 
unscheduled clinic visit may be performed, if necessary. During all clinic visits, the 
investigator will assess local tolerability (Scale: 0–3 [none, mild, moderate, severe] for 
stinging/burning, pruritus, erythema) on each body area (chest/abdomen, back, arms, and 
legs) and the following procedures will be followed: 
• 
If a score of 2 (moderate) is recorded on a local tolerability assessment scale 
(stinging/burning, pruritus, erythema) on any treated area, the study drug will be 
applied on that area only once weekly, until the score is back to <2; 
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• 
If a score of 3 (severe) is recorded on a local tolerability assessment scale 
(stinging/burning, pruritus, erythema) on any treated area, the study drug will not 
be applied on that area until the score is back to <3. 
Stopping rules and treatment modification will be defined at the subject level based on 
local tolerability, selected laboratory parameters, and adverse events (AEs). 
All subjects will be provided with diaries in which to record study drug application 
(days/times and any areas of skin not treated [e.g., due to local reactions]) and any AEs, 
including application site reactions and concomitant medications used. Subjects will also 
be advised on permitted emollient(s) use on nontreatment days during the study; use of 
emollient(s) on study drug treatment days within 4 hours of study drug application is 
prohibited. 
Photographs will be taken at Baseline, on Day 30 and Day 90 at selected sites with 
photographic capability for subjects who sign a separate photographic informed consent 
form (ICF). 
Samples for pharmacokinetic (PK) analysis will be drawn from all subjects at Baseline 
and at each clinic visit.   
In addition, a PK substudy is to be conducted at a limited number of sites. Participation 
in the PK substudy will be optional and will include at least 30 subjects. Subjects who 
participate in the PK substudy will come from both study cohorts and will undergo serial 
blood sampling predose and at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1 and Day 30. 
Trough levels will be drawn for these subjects at each of the other clinic visits.  
Subjects who complete the Double-blind Treatment Period will have the option to 
continue into the OLE to assess safety for an additional 12-weeks with trifarotene cream 
HE1 200 µg/g twice weekly, on up to 90% of BSA, sparing the scalp, inguinal, and 
axillary areas. During the OLE Period, subjects will return to the site at Weeks 14, 16, 20, 
24, and 26 for safety, tolerability, and efficacy assessments. Blood samples will be drawn 
for clinical laboratory safety tests and PK at Weeks 16 and 24. Study personnel will 
telephone subjects in between scheduled visits (i.e., at Day 97 and Day 134) to assess 
safety; an unscheduled clinic visit may be performed, if necessary.  
PLANNED 
NUMBER OF 
SUBJECTS 
Approximately 120 total subjects; 15 subjects in Cohort A and 105 subjects in Cohort B. 
STUDY ENTRY 
CRITERIA 
Inclusion criteria:  
1. Subject is ≥18 years old.  
2. Subject has known diagnosis of LI.  
3. Subject has moderate to severe (VIIS 3-4) LI on at least 2 of the 4 body areas 
assessed (chest/abdomen, back, arms, and legs).  
4. Subject has signed an ICF at Screening before any investigational procedures. 
5. Subject who is participating in photography has signed a photography ICF. 
6. Subject who is participating in the optional PK substudy has signed a PK ICF. 
7. Subject is not of childbearing potential, i.e., a female who is postmenopausal 
(absence of menstrual bleeding for 1 year before Baseline, without any other 
medical reason, hysterectomy or bilateral oophorectomy),  
OR  
• 
Subject is a woman of childbearing potential (WOCBP) or a male subject with sexual 
partners capable of reproduction who agrees to use 2 effective forms of contraception 
during the study and for at least 1 month after the last study drug application. The 
2 authorized forms of contraception are condom used with 1 of the following 
methods of contraception: 
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• bilateral tubal ligation 
• combined oral contraceptives (estrogens and progesterone) or implanted or 
injectable contraceptives with a stable dose for at least 1 month before Baseline 
• hormonal intrauterine device (IUD) inserted at least 1 month before Baseline 
OR 
Agrees to abstain from sex during study participation and for 1 month after the last 
application of study drug and to use a highly effective contraceptive as backup if he 
or she becomes sexually active during the study. 
AND 
Male subjects may not donate sperm during the study and for at least 1 month after 
the last study drug application. 
8. Women of child-bearing potential must be nonlactating and have negative pregnancy 
test results at Screening (serum) and on Day 1 before study drug administration 
(urine). 
9. Subject is reliable and capable of adhering to the protocol and visit schedule, in the 
investigator’s judgment, and has signed informed consent. 
10. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin). 
 
Exclusion criteria: 
1. Subject has any variant of ichthyosis other than LI or another disorder of 
keratinization including syndromic ichthyoses.  
2. Subject has a history of or current moderate or severe stinging/burning at Screening. 
3. Subject has an ongoing cutaneous infection or any other significant concomitant skin 
disease (other than the LI) which, in the investigator’s opinion, may interfere with 
the study assessments. 
4. Subject with a known lipid disorder unless well controlled by stable doses of 
lipid-lowering agents for at least 6 months. 
5. Subject was previously treated with trifarotene/CD5789, including the acne 
formulation, or participated in previous studies for ichthyosis.  
6. Subject has known skeletal disease, hypertriglyceridemia, hypercholesterolemia, 
liver disease, or other poorly controlled medical conditions.  
7. Subject has a medical condition that potentially alters bone metabolism (e.g., 
osteoporosis, thyroid dysfunction, Cushing syndrome), Crohn’s disease, or any other 
significant concomitant disease other than LI that, in the investigator’s opinion, may 
put him or her at risk if he or she takes part in the study, and/or that may interfere 
with the study assessments. 
8. Subject is being treated for major depression disorder. 
9. Subject with positive serology for hepatitis B surface antigen, hepatitis C, or are 
known to be HIV positive or to have AIDS at Screening. 
10. Subject with any of the following laboratory values at Screening: 
a. 
Aspartate aminotransferase or alanine aminotransferase >1.5 × upper limit 
of normal defined by the laboratory 
b. Triglycerides >200 mg/dL 
c. 
Total cholesterol >250 mg/dL 
d. Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women 
e. 
Platelets <150 × 109/L or >400 × 109/L. 
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11. Subject has any clinically other significant abnormal laboratory value (hematology, 
chemistry, or urinalysis) at Screening that, in the investigator’s opinion, may put the 
subject at risk if he or she takes part in the study, and/or that may interfere with the 
study assessments. 
12. Subject has a history of long QT syndrome or clinically significant electrocardiogram 
(ECG) abnormalities, including clinically significant conduction disorders or 
significant arrhythmias, QTcF interval >450 ms, PR interval is not between 120 and 
220 ms (inclusive), HR >100 bpm or <50 bpm, QRS interval >110 ms, or 
QT intervals that cannot be consistently analyzed. 
13. Subject has a known allergy or sensitivity to any of the components of the 
investigational products.  
14. Subject has been exposed to excessive ultraviolet (UV) radiations on the treated 
zones within 1 month before Baseline visit or who is planning intensive UV exposure 
during the study (e.g., occupational exposure to the sun, sunbathing, phototherapy, 
etc.). 
15. Subject is inherently sensitive to sunlight. 
16. Subject is presumed to be abusing drugs or alcohol at Screening or Baseline Visits 
based on medical history or current clinical symptoms. 
17. Subject is participating in another interventional clinical trial. 
INVESTIGATIONAL 
PRODUCT 
Name: Trifarotene (CD5789) cream HE1  
Double-blind Period dose, route, frequency: A fixed dose (up to 36 g per dose, determined 
at Visit 2) of 100 µg/g or 200 µg/g applied topically twice weekly on up to 90% BSA  
Open-label Period dose, route, frequency: A fixed dose (up to 36 g per dose, determined 
at Visit 2) of 200 µg/g applied topically twice weekly on up to 90% BSA 
REFERENCE 
PRODUCT 
Name: Vehicle cream 
Double-blind Period dose, route, frequency: A fixed dose (up to 36 g per dose, determined 
at Visit 2) applied topically twice weekly on up to 90% BSA  
TREATMENT 
REGIMENS 
Topical application twice weekly to all affected skin except the scalp, axillae, and inguinal 
area.   
COORDINATING/ 
PRINCIPAL 
INVESTIGATOR 
Keith A. Choate, MD 
Department of Dermatology, Yale University School of Medicine 
New Haven, CT 06520, USA 
PLANNED STUDY 
SITES 
Approximately 40 sites across North America, Europe, Israel, and Australia 
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CRITERIA FOR 
EVALUATION 
Primary efficacy endpoint: The number of subjects in each treatment group who 
experience successful resolution of LI where “success” is defined as clear/almost clear 
overall and at least a 50% reduction from Baseline at Week 12/end-of-treatment (EOT) 
in the Double-blind Period on the overall 16-point VIIS for scaling (i.e., 0-4 points on 
each of the 4 body areas: chest/abdomen, back, arms, and legs).  
Secondary endpoints:  
• 
The difference in mean scores between the active trifarotene cream HE1 and 
vehicle groups in the following assessment indices: 
− 
Investigator’s Global Assessment (0-4) for each body area 
− 
Palm/sole Assessment (Scale: 0–4)  
− 
Individual score for roughness (Scale: 0–4) overall 
• 
Quality of life per Dermatology Life Quality Index (DLQI) 
• 
The difference in proportion of subjects with presence of fissures 
(presence/absence, number of fissures, and pain associated with fissures on a 
0-3 scale) between the active trifarotene cream HE1 and vehicle groups 
Exploratory endpoints:  
• 
The difference in mean ectropion (Ectropion Severity Score [ESS] of 0–8) scores 
between the active trifarotene cream HE1 and vehicle groups 
• 
Quality of life per EQ-5D-5L 
Safety endpoints:  
• 
Reported serious adverse events (SAEs), treatment-emergent AEs (TEAEs), 
and changes in clinical laboratory tests, vital signs, physical examinations, and 
12-lead ECGs  
• 
Local tolerability (Scale: 0–3 [none, mild, moderate, severe], determined by 
the investigator) on each of the 4 body areas (chest/abdomen, back, legs, arms) 
Pharmacokinetic endpoints: Plasma concentrations of CD5789 and its major metabolites 
will be measured. 
STATISTICAL 
METHODS 
Analysis Populations:  
The following are planned for the Double-blind Period of the study: 
The Safety population will be the primary population for analyses of safety and 
tolerability and will comprise all subjects who are randomized to treatment and receive at 
least 1 application of study drug.  
The intent-to-treat (ITT) population will comprise all randomized subjects. 
The modified intent-to-treat (mITT) population comprises all subjects in the safety 
population with at least 1 postbaseline assessment of efficacy in the Double-blind Period. 
This population will be used as the primary population for the analysis of efficacy for the 
Double-blind Period of the study. 
The per-protocol (PP) population will be defined prior to database lock and will comprise 
subjects in the mITT population who met all inclusion criteria and no exclusion criteria, 
were compliant with study drug application, and who had no significant protocol 
deviations.  
The PK population includes all subjects in the Safety Population who have at least 
1 plasma sample with quantifiable concentration. The PK population will be used to 
summarize all PK endpoints. 
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The following populations are planned for the OLE period of this study: 
The OLE Safety population: all subjects who complete the 12-week Double-blind 
Treatment Period and receive at least 1 application of study drug in the OLE Period. 
OLE ITT population: all subjects who complete the 12-week Double-blind Period and 
who sign the OLE informed consent. 
The OLE mITT population: all subjects in the OLE safety population with at least 
1 assessment of efficacy after Visit 6. 
The OLE PP population: all subjects in the OLE mITT population who met all inclusion 
criteria and no exclusion criteria, were compliant with study drug application from 
baseline through EOT, and who had no significant protocol deviations throughout the 
study. 
Subject Characteristics and Disposition: Descriptive statistics will be used to summarize 
demographic characteristics (age, sex, ethnicity, and race) and baseline characteristics for 
all enrolled subjects. Medical history, physical examination findings, and vital sign 
measurements for all randomized subjects will be presented in listings. 
Efficacy Analyses: The number and proportion of subjects in each treatment group with 
successful resolution of LI by Week 12/EOT in the Double-blind Period will be presented. 
Generalized estimating equations (GEE) for binary response will be used to model the 
odds of successful resolution of LI with treatment group as a predictor. Other covariates, 
such as baseline VIIS scores, baseline characteristics, and interactions may be included. 
Various correlation matrix structures will be explored to model the within subject 
correlation. Additionally, the difference in mean VIIS score at Week 12/EOT between the 
active trifarotene cream HE1 groups and vehicle group will be analyzed using a 2-sided, 
2-sample Wilcoxon rank-sum test at the 5% significance level; 95% confidence intervals 
will be presented.  
The VIIS scores as well as secondary and exploratory efficacy endpoints will be analyzed 
by visit using descriptive statistics through Week 24. Change from Baseline through 
Week 12 will be presented and analyzed using a mixed model for repeated measures 
(MMRM). The model will include the change from Baseline score as the dependent 
variable, treatment group as a fixed effect, subject as a random effect, and Baseline score 
value as a covariate. Frequencies of results and 95% confidence intervals will also be 
reported, and scores will be analyzed as categorical variables using the Cochran-Mantel-
Haenszel test. For subjects who report having fissures, the number of fissures and pain 
related to fissures will also be presented on a scale of 0–3 (none, mild, moderate, severe). 
Clinical Pharmacology Analyses: Noncompartmental PK analysis will be performed for 
the PK subset of subjects, as data permit. Plasma concentrations of CD5789 and its major 
metabolites will be measured and will be listed by subject. 
Safety Analyses: Safety and tolerability will be assessed based on the incidence of 
reported TEAEs, and SAEs, including relationship to study drug and severity, as well as 
physical examination findings, vital sign measurements (supine systolic blood pressure 
[SBP] and diastolic blood pressure [DBP] and pulse), clinical laboratory results 
(hematology, including serum aminotransferases and serum lipids, coagulation, clinical 
chemistry, and urinalysis) and 12-lead ECGs. Descriptive statistics for observed values 
and change from Baseline will be calculated at each visit within each study period and by 
treatment group within cohort. 
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SAMPLE SIZE 
DETERMINATION 
The first cohort of 15 subjects is a reasonable sample size to assess safety and tolerability 
before enrolling additional subjects in Cohort B. Accounting for a 20% drop-
out/nonevaluable rate, a total sample size of 120 subjects randomized in a 1:1:1 ratio to 
2 active trifarotene cream HE1 arms and a vehicle cream arm will provide >80% power 
to detect a difference between each separate trifarotene cream HE1 arm (32 evaluable 
subjects) and the vehicle cream arm (32 evaluable subjects) using a 2-sample t-test, 
assuming a mean difference of at least 1.0 and a standard deviation of 1.4 or lower. This 
study is not powered to detect a difference between the 2 active arms. 
STUDY AND 
TREATMENT 
DURATION 
The sequence and maximum duration of the study will be as follows:  
1. Screening and Washout: Up to 35 days (≥2 weeks washout for topical keratolytics, 
including urea and salicylic acid, and any topical retinoid or retinol [Vitamin A 
derivative], and ≥4 weeks washout for oral Vitamin A). 
2. Double-blind study drug application: Twice weekly for up to 12 weeks.  
3. Optional Open-label Treatment: Twice weekly for up to 12 weeks. 
4. Follow-up: 14 days after last study drug application. 
The maximum study duration for each subject is approximately 229 days 
(33 weeks).  
The maximum treatment duration for each subject is 24 weeks. 
 
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2.2. Schedule of Events  
Table 2-1: 
Schedule of Events for Double-blind Period 
 
Screening 
(-35 days to -1 day) 
Double-blind Treatment Period 
Baseline  
(Day 1) 
Telephone 
Visit 
(Day 7) 
Day 14  
± 5 days 
Day 30  
± 7 days 
Telephone 
Visit 
(Day 45) 
Day 60  
± 7 days 
Day 90a,b 
± 7 days (ET) 
Visit 
1 
2 
 
3 
4 
 
5 
6 
Week 
 
1 
 
2 
4 
 
8 
12 
Written informed consent 
X 
 
 
 
 
 
 
Xa 
Assign screening number 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
Physical examinationc  
X 
X 
 
 
 
 
 
X 
VIISd assessment 
X 
X 
 
X 
X 
 
X 
X 
Assign randomization number 
 
X 
 
 
 
 
 
 
IGA assessment 
X 
X 
 
X 
X 
 
X 
X 
Palm/sole assessment 
X 
X 
 
X 
X 
 
X 
X 
Roughness, fissuring assessmente 
X 
X 
 
X 
X 
 
X 
X 
Ectropion score  
X 
X 
 
X 
X 
 
X 
X 
Photographsf 
 
X 
 
 
X 
 
 
X 
Quality of life per Dermatology Life 
Quality Index (DLQI) 
 
X 
 
X 
X 
 
X 
X 
EQ-5D-5L Quality of Life Questionnaire 
 
X 
 
X 
X 
 
X 
X 
Vital signs (blood pressure and pulse)  
X 
X 
 
X 
X 
 
X 
X 
Height, weight, and BMI  
 
X 
 
 
 
 
 
X 
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Screening 
(-35 days to -1 day) 
Double-blind Treatment Period 
Baseline  
(Day 1) 
Telephone 
Visit 
(Day 7) 
Day 14  
± 5 days 
Day 30  
± 7 days 
Telephone 
Visit 
(Day 45) 
Day 60  
± 7 days 
Day 90a,b 
± 7 days (ET) 
Visit 
1 
2 
 
3 
4 
 
5 
6 
Week 
 
1 
 
2 
4 
 
8 
12 
12-lead ECGg 
X 
X 
 
 
X 
 
 
X 
Clinical laboratory tests (hematology, 
chemistry, urinalysis)h 
X 
X 
 
 
X 
 
 
X 
Serology (hepatitis B surface antigen, 
hepatitis C) 
X 
 
 
 
 
 
 
 
Pregnancy test for female subjects 
(serum at Screening; urine subsequently) 
X 
X 
 
 
X 
 
X 
X 
Assign randomization number  
 
X 
 
 
 
 
 
 
PK blood sample collectioni 
 
X 
 
X 
X 
 
X 
X 
Initial study drug application by clinic 
staff and measurementj 
 
X 
 
 
 
 
 
 
Application instructions, advice on 
emollient use 
 
X 
X 
X 
X 
X 
 
 
Dispense study drug and diariesk 
 
X 
 
X 
X 
 
X 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
Tolerability assessment  
 
X 
 
X 
X 
 
X 
X 
Adverse events (and review diaries) 
 
X 
X 
X 
X 
X 
X 
X 
Collect all used/unused study drugl 
 
 
 
X 
X 
 
X 
X 
Provide information about OLE option 
 
 
 
 
X 
X 
X 
 
Abbreviations: BMI = body mass index; DLQI = Dermatology Life Quality Index; ECG = electrocardiogram; ET = early termination; HEENT = head, eyes, ears, 
nose, throat; ICF = informed consent form; IGA = Investigator Global Assessment; OLE = open-label extension; PK = pharmacokinetic; WOCBP = women 
of childbearing potential; VIIS = Visual Index for Ichthyosis Severity 
a. 
Day 90 procedures should be conducted for subjects who terminate the study early. If a subject discontinues IP, but continues to attend clinic visits, Day 90 
will occur as scheduled. Day 90/Week 12 will be the first visit of the OLE Period for subjects who choose to continue (subjects will have up to 7 days to 
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decide to sign the ICF and begin the OLE). Subjects who decide to continue into the OLE will have the following additional procedures: 1) sign informed 
consent; 2) will be weighed; 3) will be instructed on study drug application; 4) will be given new diaries, and 5) will be provided with study drug. 
b. A Follow-up telephone call will be made within 14 days after Day 90 to subjects who choose not to continue into the Open-label Extension. 
c. 
Limited physical examination to include HEENT, cardiorespiratory, abdomen, range of motion.  
d. VIIS: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe for each of 4 body areas: chest/abdomen, back, arms, and legs (possible overall score 
= 16). 
e. 
Roughness (0-4 scale); fissuring assessment: present/absent/number/pain (0-3 scale). 
f. 
Photography will be performed at sites with the capability among subjects who sign a photographic ICF. 
g. ECG to be conducted at Screening, Baseline, Day 30, and Day 90 for all subjects.  
h. Subjects must be fasting (i.e., at least 8 hours) 
i. 
Samples for PK will be drawn from all subjects at Baseline and at each clinic visit. At selected sites among subjects who consent to participate in the 
PK-substudy, samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1. On Day 30, IP will be applied in the clinic for 
PK substudy subjects, and PK samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose. Trough levels will be drawn when the subjects are 
in the clinic for other study visits (i.e., Day 14, Day 60, and Day 90). 
j. 
Study staff will apply initial dose of study drug in the clinic after Baseline measurements, and the amount of study drug used will be measured (i.e., 
36-g tube will be measured before and after application to determine amount used) to determine fixed dose. 
k. Study drug provided in 50-g tubes (maximum single application is 36 g). Measure study drug tubes before dispensing; subjects must record days/times of 
study drug application in the diaries and any areas of skin not treated, e.g., due to local reactions). Dispense enough additional study drug until next visit 
(except at Day 90, unless subject consents to continue into OLE). 
l. 
Confirm study drug compliance by measuring tube weight and reviewing diary.  
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Table 2-2: 
Schedule of Events for Open-label Extension  
 
Open-label Treatment Period 
Follow-up 
 
Telephone 
Visit 
(Day 97)a 
Day 104  
± 5 days 
Day 120  
± 7 days 
Telephone 
Visit 
(Day 134) 
Day 150 
± 7 days 
Day 180  
± 7 days/ET 
Day 194 or 14 days 
after End of 
Open-label Treatment 
Visit 
 
7 
8 
 
9 
10 
11 
Week 
 
14 
16 
 
20 
24 
26 
Informed consenta 
 
 
 
 
 
 
 
Physical examinationb 
 
 
 
 
 
X 
X 
ECG 
 
 
X 
 
 
X 
 
VIISc assessment 
 
X 
X 
 
X 
X 
X 
IGA assessment 
 
X 
X 
 
X 
X 
X 
Palm/sole assessment 
 
X 
X 
 
X 
X 
X 
Roughness, fissuring assessmentd 
 
X 
X 
 
X 
X 
X 
Ectropion score  
 
X 
X 
 
X 
X 
X 
Vital signs (blood pressure and 
pulse)  
 
X 
X 
 
X 
X 
X 
Clinical laboratory tests (hematology, 
chemistry, urinalysis)e 
 
 
X 
 
 
X 
 
Pregnancy test for female subjects 
(urine) 
 
 
X 
 
X 
X 
X 
PK blood sample collectionf 
 
 
X 
 
 
X 
 
Application instructions, advice on 
emollient useg 
X 
X 
X 
X 
 
 
 
Dispense study drug and diariesh 
 
X 
X 
 
X 
 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
Tolerability assessment  
 
X 
X 
 
X 
X 
 
Adverse events (and review diaries) 
X 
X 
X 
X 
X 
X 
X 
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Open-label Treatment Period 
Follow-up 
 
Telephone 
Visit 
(Day 97)a 
Day 104  
± 5 days 
Day 120  
± 7 days 
Telephone 
Visit 
(Day 134) 
Day 150 
± 7 days 
Day 180  
± 7 days/ET 
Day 194 or 14 days 
after End of 
Open-label Treatment 
Visit 
 
7 
8 
 
9 
10 
11 
Week 
 
14 
16 
 
20 
24 
26 
Collect all used/unused study drugi  
 
X 
X 
 
X 
X 
 
Abbreviations: ECG = electrocardiogram; ET = early termination; HEENT = head, eyes, ears, nose, throat; IGA = Investigator Global Assessment; PK = 
pharmacokinetic; VIIS = Visual Index for Ichthyosis Severity; WOCBP = women of childbearing potential 
a. Subjects will sign the OLE ICF at the Double-blind Day 90/Week 12 Visit or within 7 days thereafter. All efficacy assessments, safety/tolerability 
assessments, including clinical laboratory testing and PK from Day 90/Week 12 will be carried over for the OLE Period and will not be repeated.  
b. Limited physical examination to include HEENT, cardiorespiratory, abdomen, range of motion.  
c. VIIS: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe for each of 4 body areas: chest/abdomen, back, arms, and legs (possible total score = 16). 
d. Roughness (0-4 scale); fissuring assessment: present/absent/number/pain (0-3 scale). 
e. Subjects must be fasting (at least 8 hours) 
f. Samples for PK will be drawn from all subjects on Day 120 and Day 180. 
g. Subjects must record days/times of study drug application in the diaries and any areas of skin not treated (e.g., due to local reactions).  
h. All subjects in the open-label extension will receive trifarotene 200 µg/g. Study drug provided in 50-g tubes (maximum single application is 36 g). Measure 
study drug tubes before dispensing. Dispense enough additional study drug until the next visit (except on Day 180). 
i. Confirm study drug compliance by measuring tube weight and reviewing diary. 
 
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3.
TABLE OF CONTENTS
1.
APPROVAL SIGNATURES ...................................................................................................2 
2.
PROTOCOL SUMMARY ........................................................................................................3 
2.1. Synopsis ..........................................................................................................................3 
2.2. Schedule of Events ........................................................................................................11 
3.
TABLE OF CONTENTS .......................................................................................................16 
3.1. List of In-Text Tables ...................................................................................................20 
3.2. List of In-Text Figures ..................................................................................................21 
SUMMARY OF AMENDED SECTIONS ....................................................................................22 
4.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...........................................23 
5.
INTRODUCTION ..................................................................................................................25 
5.1. Background and Rationale ............................................................................................25 
5.1.1. CD5789 (Trifarotene) ........................................................................................26 
5.2. Clinical Experience .......................................................................................................26 
5.3. Summary of Potential Risks and Benefits .....................................................................27 
6.
OBJECTIVES .........................................................................................................................29 
6.1. Primary Objective .........................................................................................................29 
6.2. Secondary Objectives ....................................................................................................29 
7.
STUDY DESIGN ...................................................................................................................30 
7.1. Overall Study Design and Plan .....................................................................................30 
7.2. Rationale and Discussion of Study Design ...................................................................34 
7.3. Selection of Doses in the Study ....................................................................................34 
7.4. Study Sites .....................................................................................................................34 
7.5. Point of Contact ............................................................................................................34 
7.6. End of Study Definition ................................................................................................35 
8.
SUBJECT POPULATION .....................................................................................................36 
8.1. Selection of Study Population and Diagnosis ...............................................................36 
8.2. Study Entry Criteria ......................................................................................................36 
8.2.1. Inclusion Criteria ...............................................................................................36 
8.2.2. Exclusion Criteria ..............................................................................................37 
8.3. Premature Subject Withdrawal .....................................................................................38 
8.4. Discontinuation of Study Intervention ..........................................................................38 
8.5. Subject Replacement Criteria ........................................................................................39 
9.
TREATMENTS ......................................................................................................................40 
9.1. Identification of Investigational Products .....................................................................40 
9.2. Treatments Administered ..............................................................................................40 
9.3. Selection of Timing of Dose for Each Subject..............................................................40 
9.4. Dose Adjustment Criteria ..............................................................................................41 
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9.4.1. Stopping Rules ..................................................................................................41 
9.5. Treatment Compliance ..................................................................................................41 
9.6. Method of Assigning Subjects to Treatment Groups ....................................................42 
9.7. Blinding and Unblinding Treatment Assignment .........................................................42 
9.8. Permitted and Prohibited Therapies ..............................................................................43 
9.8.1. Permitted Therapies ...........................................................................................43 
9.8.2. Prohibited Therapies ..........................................................................................43 
9.8.3. Restrictions ........................................................................................................44 
9.9. Treatment After End of Study .......................................................................................44 
9.10. Dispensing and Storage .................................................................................................44 
9.11. Drug Accountability ......................................................................................................44 
9.12. Labeling and Packaging ................................................................................................45 
9.12.1. Labeling .............................................................................................................45 
9.12.2. Packaging ..........................................................................................................45 
10. STUDY PROCEDURES ........................................................................................................46 
10.1. Study Duration ..............................................................................................................46 
10.1.1. Overall Study Schedule .....................................................................................46 
10.2. Study Periods and Visits ...............................................................................................46 
10.2.1. Screening and Washout .....................................................................................46 
10.2.1.1. Screening Visit (Visit 1) .......................................................................46 
10.2.1.2. Washout Period .....................................................................................47 
10.2.2. Double-blind Treatment Period .........................................................................47 
10.2.2.1. Baseline Visit (Visit 2, Day 1) ..............................................................47 
10.2.2.2. Telephone Visit (Day 7) ........................................................................48 
10.2.2.3. Visit 3 (Day 14 ±5 days) .......................................................................48 
10.2.2.4. Visit 4 (Day 30 ±7 days) .......................................................................49 
10.2.2.5. Telephone Visit (Day 45) ......................................................................50 
10.2.2.6. Visit 5 (Day 60 ±7 days) .......................................................................50 
10.2.2.7. Visit 6 (90 ±7 days) or Early Termination ............................................51 
10.2.3. Follow-up Telephone Call (±14 days after Day 90) – Only Subjects Who Do 
Not Continue into Open-label Extension ..........................................................52 
10.2.4. Open-label Extension ........................................................................................52 
10.2.4.1. Telephone Visit (Day 97) ......................................................................52 
10.2.4.2. Visit 7 (Week 14; Day 104 ±5 days) .....................................................52 
10.2.4.3. Visit 8 (Week 16; Day 120 ±7 days) .....................................................53 
10.2.4.4. Telephone Visit (Day 134) ....................................................................53 
10.2.4.5. Visit 9 (Week 20; Day 150 ±7 days) .....................................................53 
10.2.4.6. Visit 10 (Week 24; Day 180 ±7 days) or Early Termination ................54 
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10.2.4.7. Follow-up Evaluation – Open-Label Period (Week 26/Visit 11) .........54 
10.3. Assessments ..................................................................................................................55 
10.3.1. Efficacy Variables .............................................................................................55 
10.3.1.1. Visual Index for Ichthyosis Severity – Scaling .....................................55 
10.3.1.2. Investigator’s Global Assessment .........................................................56 
10.3.1.3. Palm/Sole Assessment ..........................................................................57 
10.3.1.4. Individual Score for Roughness ............................................................57 
10.3.1.5. Fissuring Assessment ............................................................................57 
10.3.1.6. Dermatology Life Quality Index ...........................................................57 
10.3.1.7. EQ-5D Quality of Life Questionnaire ...................................................57 
10.3.1.8. Ectropion Severity Score ......................................................................58 
10.3.2. Clinical Pharmacology ......................................................................................58 
10.3.2.1. Pharmacokinetic Analysis Methods ......................................................58 
10.3.2.2. Pharmacokinetic Parameters .................................................................58 
10.3.3. Sample Collection .............................................................................................59 
10.3.4. Safety Variables ................................................................................................59 
10.3.4.1. Clinical Laboratory Safety Assessments ...............................................59 
10.3.4.2. Clinical Examinations ...........................................................................60 
10.3.4.3. Adverse Events .....................................................................................61 
11. ADVERSE EVENTS ..............................................................................................................62 
11.1. Definitions .....................................................................................................................62 
11.1.1. Adverse Events ..................................................................................................62 
11.1.2. Adverse Drug Reaction .....................................................................................62 
11.1.3. Unexpected Adverse Event/Adverse Drug Reaction ........................................62 
11.1.4. Serious Adverse Events/Drug Reaction ............................................................63 
11.1.5. Significant Adverse Events ...............................................................................63 
11.1.6. Treatment-Emergent Adverse Events ...............................................................63 
11.2. Event Assessment and Follow-up of Adverse Events ..................................................63 
11.2.1. Assessment ........................................................................................................64 
11.2.2. Evaluation ..........................................................................................................65 
11.2.2.1. Severity of Adverse Events ...................................................................65 
11.2.2.2. Seriousness ............................................................................................65 
11.2.2.3. Action(s) Taken .....................................................................................65 
11.2.2.4. Outcome at the Time of Last Observation ............................................66 
11.2.2.5. Adverse Event Relationship to Investigational Product........................66 
11.2.3. Documentation ..................................................................................................66 
11.2.4. Treatment of Adverse Events ............................................................................67 
11.2.5. Follow-up ..........................................................................................................67 
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11.2.6. Reporting ...........................................................................................................67 
11.2.6.1. Serious Adverse Events.........................................................................67 
11.2.6.2. Adverse Drug Reactions .......................................................................69 
11.2.6.3. Nonserious Adverse Events ..................................................................69 
11.3. Special Considerations ..................................................................................................69 
11.3.1. Adverse Events of Special Interest ....................................................................69 
11.3.2. Pregnancy ..........................................................................................................69 
12. DATA SAFETY MONITORING BOARD ...........................................................................70 
13. STATISTICS ..........................................................................................................................71 
13.1. Statistical Analysis ........................................................................................................71 
13.1.1. Analysis Populations .........................................................................................71 
13.1.2. Study Subjects and Demographics ....................................................................72 
13.1.2.1. Disposition and Withdrawals ................................................................72 
13.1.2.2. Protocol Deviations ...............................................................................72 
13.1.2.3. Demographics and Other Baseline Characteristics ...............................72 
13.1.3. Exposure and Compliance .................................................................................73 
13.1.4. Efficacy Analysis ..............................................................................................73 
13.1.4.1. Efficacy Endpoints ................................................................................73 
13.1.4.2. Primary Analysis ...................................................................................74 
13.1.4.3. Secondary Analyses ..............................................................................74 
13.1.4.4. Exploratory Analyses ............................................................................74 
13.1.4.5. Corroborative, Sensitivity, and Other Analyses ....................................74 
13.1.5. Clinical Pharmacology Analyses .......................................................................75 
13.1.5.1. Pharmacokinetics ..................................................................................75 
13.1.6. Safety and Tolerability Analyses ......................................................................75 
13.1.6.1. Local Tolerability ..................................................................................75 
13.1.6.2. Adverse Events .....................................................................................75 
13.1.6.3. Clinical Laboratory Evaluations ...........................................................76 
13.1.6.4. Vital Signs .............................................................................................76 
13.1.6.5. Twelve-lead Electrocardiograms ..........................................................76 
13.1.6.6. Physical Examination Findings .............................................................76 
13.1.7. Interim Analysis ................................................................................................77 
13.2. Sample Size Determination ...........................................................................................77 
14. STUDY CONDUCT ...............................................................................................................78 
14.1. Sponsor and Investigator Responsibilities ....................................................................78 
14.1.1. Sponsor Responsibilities ...................................................................................78 
14.1.2. Investigator Responsibilities .............................................................................78 
14.1.3. Confidentiality and Privacy ...............................................................................78 
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14.2. Site Initiation .................................................................................................................79 
14.3. Screen Failures ..............................................................................................................79 
14.4. Study Documents ..........................................................................................................79 
14.4.1. Informed Consent ..............................................................................................80 
14.4.2. Investigator’s Regulatory/Good Clinical Practice Documents .........................80 
14.4.3. Case Report Forms ............................................................................................81 
14.4.4. Source Documents .............................................................................................81 
14.5. Data Quality Control .....................................................................................................81 
14.5.1. Monitoring Procedures ......................................................................................81 
14.5.2. Data Management ..............................................................................................82 
14.5.3. Quality Assurance/Audit ...................................................................................82 
14.6. Study Termination .........................................................................................................83 
14.6.1. Regular Study Termination ...............................................................................83 
14.6.2. Premature Study Termination ...........................................................................83 
14.7. Study Site Closure .........................................................................................................84 
14.7.1. Record Retention ...............................................................................................84 
14.7.2. Sample Retention ..............................................................................................85 
14.8. Changes to the Protocol ................................................................................................85 
14.9. Use of Information and Publication ..............................................................................85 
15. FINAL CLINICAL STUDY REPORT ..................................................................................86 
16. ETHICAL AND LEGAL CONSIDERATIONS ....................................................................87 
16.1. Declaration of Helsinki and Good Clinical Practice .....................................................87 
16.2. Subject Information and Informed Consent ..................................................................87 
16.3. Approval by Institutional Review Board and Independent Ethics Committee .............88 
16.4. Finance and Insurance ...................................................................................................88 
17. REFERENCES .......................................................................................................................89 
18. ATTACHMENTS ...................................................................................................................90 
18.1. Investigator’s Agreement ..............................................................................................90 
APPENDICES ...............................................................................................................................92 
A. 
Regulations and Good Clinical Practice Guidelines .....................................................93 
 
 
3.1. List of In-Text Tables 
Table 2-1: 
Schedule of Events for Double-blind Period .......................................................1 
Table 2-2: 
Schedule of Events for Open-label Extension ...................................................14 
Table 9-1: 
Washout Periods for Prohibited Medications ....................................................43 
Table 9-2: 
Amount of Study Drug Needed Per Visit ..........................................................45 
Table 10-1: 
Pharmacokinetic Parameters .............................................................................59 
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3.2. List of In-Text Figures 
Figure 7-1: 
Double-blind Study Design ...............................................................................32 
Figure 7-2: 
Open-label Study Design ...................................................................................33 
 
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SUMMARY OF AMENDED SECTIONS 
All references to “adults/adolescents” have been changed to “subjects” throughout the protocol. 
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4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABBREVIATION 
EXPLANATION 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse events of special interest 
ATC 
anatomical therapeutic chemical 
AUC 
area-under-the-curve 
BMI 
body mass index 
BSA 
body surface area 
CFR 
code of federal regulations 
CI 
confidence interval 
Cmax 
maximum concentration 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
DBP 
diastolic blood pressure 
DLQI 
dermatology life quality index 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
ESS 
ectropion severity score 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GEE 
generalized estimating equations 
HR 
heart rate 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification 
IEC 
independent ethics committee 
IGA  
Investigator’s Global Assessment 
IND 
investigational new drug 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent-to-treat 
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ABBREVIATION 
EXPLANATION 
IUD 
intrauterine device 
IWRS 
interactive web response system 
LI 
lamellar ichthyosis 
MedDRA 
medical dictionary for regulatory activities 
mITT 
modified intent-to-treat 
MMRM 
mixed model of repeated measures 
NCA 
noncompartmental analysis 
OC 
observed case 
OLE 
open-label extension 
PG 
propylene glycol 
PK 
Pharmacokinetic(s) 
PoC 
proof-of-concept 
PP 
per-protocol 
QTc 
QT interval corrected for heart rate 
RARγ 
retinoid acid receptor γ  
RBC 
red blood count 
RR 
respiratory rate 
RXR 
retinoid X receptor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
Tmax 
time of Cmax 
UAE 
unexpected adverse event 
UADR 
unexpected adverse drug reaction 
US 
United States 
UV 
ultraviolet 
VIIS 
Visual Index for Ichthyosis Severity 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
women of child-bearing potential 
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5. INTRODUCTION 
5.1. Background and Rationale 
The ichthyoses comprise a large group of skin scaling disorders with diverse etiology. The 
stereotypic pathophysiology is epidermal hyperplasia and the formation of excess stratum corneum 
accompanied by abnormal (delayed and/or disordered) desquamation, with visible accumulation 
of squames (scales) on the skin’s surface – the clinical hallmark of all the ichthyoses. 
Lamellar ichthyosis (LI) is recognized as a severe form of ichthyosis that persists throughout life. 
During the first postnatal weeks, the hyperkeratotic membrane patients are typically born with is 
gradually shed, and is replaced by scaling and lichenification that involves the entire body 
including the intertriginous areas, palms, soles, and scalp. While usually not life threatening, LI 
can result in disability, partial deafness, poor adaptation to environmental conditions (due to 
hypohydrosis), severe discomfort (pruritus, fissuring of the skin) and significant psychosocial 
impact. 
Lamellar ichthyosis, a member of the nonsyndromic autosomal recessive congenital ichthyosis 
group of ichthyoses, has an incidence of 1 per 100,000–300,000 live births.1 Lamellar ichthyosis 
is undoubtedly a rare disease. 
Therapeutic approaches for LI are mainly based on the use of topical emollients, keratolytic agents 
(urea, lactic acid, salicylic acid), topical retinoids and, in severe cases, oral retinoids.2,3 
Oral retinoid usage in LI is mainly based on case reports and case series.4,5,6,7,8 The mechanism of 
retinoid action involves modulation of keratinocyte differentiation, keratinocyte hyperproliferation 
and tissue infiltration by inflammatory cells. Systemic retinoids (such as acitretin, etretinate, or 
isotretinoin) have been found to be efficacious in the treatment of severe ichthyoses, especially in 
LI.6 
Vahlquist, et al (2008)3 report that by combining 2 or more keratolytic agents and moisturizers in 
the same lipophilic cream base, it is often possible to achieve additive or even synergistic effects 
in LI without the need to use irritating concentrations of either agent alone. In a double-blind trial 
of 4 different cream mixtures in 20 patients with LI, a mixture of 5% lactic acid and 20% propylene 
glycol (PG) in a semi-occlusive cream for 4 weeks twice daily was significantly more effective 
than 20% PG or 5% urea alone in the same vehicle.9 Although the treatments were well tolerated, 
an efficient removal of hyperkeratosis without correcting the underlying biochemical defect in LI 
is likely to deteriorate the patient’s intrinsic barrier problem, because an excessive production of 
corneocytes probably represents a homeostatic response to an ineffective barrier. Indeed, 
transepidermal water loss increased after successful treatment of LI with either topical 
keratolytics9 or oral retinoid.10 Although this may not be noticeable by the patient, even minor 
deteriorations in the barrier function can enhance transcutaneous penetration of active cream 
ingredients or other topically applied chemicals, which is a matter of special concern in children. 
Accordingly, α-hydroxy acids and salicylic acid should not be used at all in babies and only with 
great caution when treating large, eroded skin areas in adult patients.11,12 
Many patients with LI use pumice, foot files, or gentle rubbing of the skin after a hot bath or a 
shower to remove scales and hyperkeratosis. Overnight occlusion of problematic skin areas with 
plastic sheets after applying a thick layer of emollient or keratolytic agents is another way of 
potentiating therapy, especially on the scalp, which is notoriously difficult to treat. Although 
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usually effective, all these remedies may further damage the skin barrier and lead to exaggerated 
epidermal proliferation, erythema, painful erosions and increased transcutaneous penetration.3 
Based on this information, LI has significant unmet medical need for safer and more effective 
therapies. 
5.1.1. CD5789 (Trifarotene) 
CD5789 is a new chemical entity discovered by Galderma R&D SNC and formulated for topical 
application. It is a novel retinoid acid receptor γ (RARγ) agonist, characterized by its high 
specificity to this receptor. CD5789 is selective for RARγ over RARα and RARβ (approximately 
50- and 8-fold, respectively), with no retinoid X receptor (RXR) activity. CD5789 is currently 
under clinical development for the topical treatment of various dermatoses, including acne vulgaris 
and LI. 
The pharmacological retinoid-like properties of CD5789 were confirmed in in vitro and in vivo 
models, showing its interest for its development in the treatment of LI. Therefore, it may have an 
effect on the differentiation and hyperproliferation of keratinocytes, and consequently improve 
hyperkeratotic skin of patients with LI. 
Within the overall acne development program at Galderma, CD5789 has been tested in different 
pharmaceutical forms for topical administration. As of 15-Jan-2018, 6 different formulations have 
been evaluated: a solution, a gel and 4 creams (CD5789 cream A, CD5789 cream B, 
CD5789 cream HE1 concept and its optimized version, cream HE1), with different concentrations 
(up to 400 µg/g). Therefore, several formulations at different CD5789 concentrations have been 
tested in nonclinical and clinical development programs. 
Galderma decided to develop a new cream formulation that might better address the issue of skin 
dryness in patients with LI. This formulation was named “Cream HE1 concept.” It has been 
preliminarily investigated in an exploratory trial in psoriasis at concentrations up to 400 µg/g 
(RD.03.SRE.40204E). In a proof-of-concept study (RD.03.SRE.40181E), positive results were 
also obtained in patients with LI with CD5789 cream (up to 100 µg/g) that was effective in 
decreasing scaling and roughness. Based on these results, a new CD5789 formulation (cream HE1) 
was developed for further clinical investigations in LI. The formulation cream HE1 was developed 
with the objective to obtain a formulation with appropriate stability of the active ingredient and in 
which CD5789 would be homogeneously dissolved in the oily phase at a higher concentration 
compared to the cream formulation used in the acne program. Cream HE1 contains 100, 200, or 
400 µg/g (0.01% [w/w], 0.02% [w/w], 0.04% [w/w], respectively) of CD5789. 
Galderma has granted Mayne Pharma LLC an exclusive license to develop and commercialize 
CD5789 (trifarotene) for LI and other orphan diseases; therefore, the LI indication is no longer 
pursued by Galderma. 
5.2. Clinical Experience 
The cream HE1 differs from the CD5789 cream used to treat acne vulgaris in that it contains fewer 
excipients with drying effects and therefore may be better suited for patients with LI. 
Throughout the 30 clinical studies that comprise the clinical development program for 
CD5789 topical products, 1976 subjects were exposed to CD5789. No systemic safety concerns 
related to CD5789 gel or creams, or cream HE1 at doses up to 400 µg/g were reported. The subjects 
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were exposed to a maximal total CD5789 dose of 36 g/day (Investigator’s Brochure [IB] for 
CD5789 Cutaneous Formulation). 
The CD5789 PK profile was also investigated using cream HE1 (Study GD.03.SRE.103813) in 
36 healthy volunteers of Japanese and non-Japanese origin. Subjects were treated daily on up to 
90% of body surface area (BSA) for 29 days with up to 36 g of cream formulation. Both CD5789 
100 µg/g and 200 µg/g cream HE1 were investigated. Plasma PK assessment demonstrated that 
repeated topical applications of CD5789 cream HE1 resulted in low and similar CD5789 systemic 
levels in all treatment groups. In addition, no systemic safety concerns were raised from this 
healthy volunteer study in which cream HE1 200 µg/g was applied daily under maximal-use 
conditions on almost the full body. In this study, however, the level of irritation resulted in the 
need to decrease the frequency of application to twice weekly (IB for CD5789 Cutaneous 
Formulation). 
5.3. Summary of Potential Risks and Benefits 
Although the primary objective of this study is safety in the patient population with LI, the 
potential benefits of study participation are that subjects with LI may experience a reduction in 
their LI symptoms as a result of treatment with trifarotene (CD5789) cream HE1. No other benefits 
of participation are anticipated. 
The potential risks of study participation include those associated with exposure to trifarotene 
(CD5789) cream HE1 and the risks of medical evaluation, including venipuncture.  
Animal studies with CD5789 have shown reproductive toxicity in the embryo-fetal studies. 
Despite low systemic levels with the CD5789 concentration of 50 µg/g used in patients with acne, 
CD5789 must not be administered during pregnancy. 
When CD5789 is used in the other formulations and/or for other indications and/or with higher 
concentrations or higher application surface areas, the potential risk of teratogenicity needs to be 
considered as the safety margin may be lower. Depending on the study population and conditions 
mentioned above, or other specific requirements, the appropriate contraception method is 
described in this protocol. 
It is unknown whether CD5789 or its metabolites are excreted in human milk. A risk to the 
newborns/infants cannot be excluded. Lactating women are not eligible for the clinical study. 
Certain cutaneous signs and symptoms of irritation and localized reactions at the application site 
such as erythema, scaling, dryness, stinging/burning, and pruritus may be experienced with use of 
CD5789. Depending upon the severity of these side effects, subjects may be instructed to reduce 
the frequency of application or to discontinue use.  
Trifarotene cream contains propylene glycol that is mildly irritant to the skin, eyes, and mucous 
membranes. Trifarotene (CD5789) cream HE1 also contains butylated hydroxytoluene that may 
cause local skin reactions (e.g., contact dermatitis), or irritation to the eyes and mucous membranes 
and sodium benzoate that is mildly irritant to the skin, eyes, and mucous membranes. 
CD 5789 is mildly irritant to the skin, eyes, and mucous membranes. Therefore, it should not come 
into contact with the eyes, mouth, or mucous membranes.  
There is a potential risk of skin sensitization. If a reaction suggesting sensitivity to trifarotene 
(CD5789) cream HE1 occurs, the use of the trifarotene cream HE1 must be discontinued. 
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There is a potential risk of photosensitivity disorder (sunburn). Excessive exposure to sunlight or 
ultraviolet (UV) radiation (i.e., occupational exposure to the sun, planned holidays in the sun 
during the study, phototherapy, tanning salon) must be avoided during the studies. 
As reported with other topical retinoids, there is a potential risk of pigmentation disorders. 
A summary of the pharmaceutical properties and known potential risks of trifarotene (CD5789) 
cream HE1 is provided in the current version of the IB. The investigator must become familiar 
with all sections of the trifarotene (CD5789) cream IB before the start of the study. 
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6. OBJECTIVES 
6.1. Primary Objective 
The primary objective is to compare the safety and efficacy of 2 concentrations of trifarotene cream 
HE1 versus vehicle in subjects with moderate to severe autosomal recessive ichthyosis with 
lamellar scale, also known as LI after 12 weeks of treatment. 
6.2. Secondary Objectives 
The secondary objectives are as follows: 
• To assess systemic exposure to trifarotene and its major metabolites after topical 
application of the investigational product (IP) on up to 90% BSA twice weekly. 
• To assess safety for up to 24 weeks of dosing with open-label trifarotene cream HE1 
200 µg/g. 
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7. STUDY DESIGN 
7.1. Overall Study Design and Plan 
The first part of this study is a phase 2, randomized, 2-cohort, double-blind, vehicle-controlled, 
multicenter study of the safety, tolerability, PK, and efficacy study of trifarotene cream HE1 
100 µg/g and 200 µg/g in subjects with LI. Subjects who complete the randomized, double-blind, 
vehicle-controlled period of the study will be eligible to continue into an open-label extension 
(OLE) period and be treated with trifarotene cream HE1 200 µg/g for an additional 12 weeks. 
The randomized, double-blind, vehicle-controlled period of the study in subjects with moderate to 
severe LI (i.e., 3–4 on a 5-point Visual Index for Ichthyosis Severity [VIIS] index for scaling where 
0 = clear and 4 = severe on at least 2 of 4 areas of the body: chest/abdomen, back, arms, and legs), 
is designed to compare the safety of 2 doses of trifarotene cream HE1 with that of vehicle in the 
treatment of LI.  
After Screening, eligible subjects for Cohorts A and B will enter a washout period of up to 35 days, 
during which they must stop using prohibited topical and systemic treatments with designated 
washout periods (Table 9-1). 
The first cohort of subjects (Cohort A) will randomize approximately 15 subjects in a 1:1:1 ratio 
to trifarotene (CD5789) cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle.  
Study drug will be packaged in 50-g tubes from which up to 36 g of IP may be dispensed per 
application, i.e., the maximum dose per application. Study staff will apply the first dose of study 
drug to each subject in the clinic on Day 1 after Baseline measurements, and will record the amount 
of study drug applied (i.e., study staff will measure the 50-g tube before and after the first 
application to determine the fixed dose amount for each subject). Thereafter, subjects will apply 
approximately the same amount (up to 36 g) of study drug as for the first dose on up to 90% of 
BSA twice weekly, sparing the scalp, inguinal, and axillary areas. Subjects will receive an 
adequate number of tubes to use 1 tube per application and will use a new tube for each treatment 
day. Subjects may use less than the full amount of IP in a tube. 
Subjects enrolled in Cohort A will continue treatment for up to 12 weeks.  
After the initial 15 subjects complete at least 28 days of treatment, an independent Data Safety 
Monitoring Board (DSMB) will review aggregate safety and tolerability data. If no safety issues 
are identified, additional subjects will be allowed to enroll in Cohort B (up to approximately 
105 subjects). Subjects in Cohort B will be randomized 1:1:1 to trifarotene cream HE1 100 µg/g, 
trifarotene cream HE1 200 µg/g, or vehicle and similarly treated twice weekly for up to 12 weeks 
in the same manner as subjects in Cohort A. 
Subjects will be provided with diaries in which to record study drug application (days/times and 
any areas of skin not treated [e.g., due to local reactions]), any application site reactions, adverse 
events (AEs), and concomitant medications used. Subjects will also be advised on permitted 
emollient(s) use on nontreatment days during the study; use of emollient(s) on study drug treatment 
days within 4 hours of study drug application is prohibited. 
Photographs will be taken at Baseline, Day 30, and Day 90 in the Double-blind Period at selected 
sites with photographic capability for subjects who signed a separate photographic informed 
consent form (ICF). 
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Samples for PK will be drawn from all subjects at Baseline and at each clinic visit, as indicated in 
the Schedule of Events (Table 2-1).  
In addition, a PK substudy will be conducted at specific sites with the capability to conduct it. 
Participation in the PK substudy will be optional and will include at least 30 subjects. Subjects 
who participate in the PK substudy will come from both study cohorts and will undergo serial 
blood sampling predose and at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1 and Day 30. Trough 
levels will be drawn for all subjects at specified time points. 
Efficacy will be assessed by the number of subjects in each treatment group who achieve “success” 
defined as clear/almost clear overall and at least a 50% reduction from Baseline at 
Week 12/end-of-treatment (EOT) in the Double-blind Period on the overall 16-point VIIS for 
scaling (i.e., 0-4 points on each of the 4 body areas: chest/abdomen, back, arms, and legs). In 
addition, efficacy criteria include assessment of the Investigator Global Assessment (IGA; scale: 
0-4 for each body area: chest/abdomen, back, legs, and arms), scales for palm/sole, roughness, 
fissuring, and the Dermatology Life Quality Index (DLQI), and the EQ-5D-5L Quality of Life 
(QoL) Questionnaire. Ectropion Severity Scores (ESS) between the active trifarotene cream HE1 
and vehicle groups will be an exploratory endpoint.
Plasma concentrations of CD5789 and its major metabolites will be measured. 
Safety will be assessed by evaluating reported AEs, changes in clinical laboratory test results, vital 
sign measurements, physical examinations, 12-lead electrocardiograms (ECGs), and local 
tolerability. 
All AEs observed by the study personnel or reported by the subject during the study (from the time 
of the signing of the informed consent through the posttreatment visit) will be documented. 
Topical trifarotene cream HE1 was generally well tolerated in recently completed phase 3 pivotal 
and long-term safety studies in subjects aged 9 years and older with acne vulgaris. The local 
tolerability of the trifarotene cream HE1 formulation in subjects with LI is unknown and will be 
monitored during the study. Subjects will receive information on study drug use and stopping rules 
and will be instructed to contact the site with any safety/tolerability issues. Study personnel will 
telephone subjects in between scheduled visits (i.e., on Day 7 and Day 45) to assess safety; an 
unscheduled clinic visit may be performed, if necessary. During all clinic visits, the investigator 
will assess local tolerability (Scale: 0–3 [none, mild, moderate, severe]) on each body area 
(chest/abdomen, back, legs, arms) and will follow the procedures detailed in Section 9.4. 
Subjects who complete the 12-week Double-blind Treatment Period will have an option to 
continue into an OLE Period for an additional 12 weeks with trifarotene cream HE1 200 µg/g. 
During the OLE Period, subjects will return to the site at Weeks 14, 16, 20, 24, and 26. Additional 
PK samples will be drawn at Week 16 and Week 24 from all subjects who continue into the 
OLE Period (Table 2-2). 
Stopping rules and treatment modification will be defined at the subject level based on local 
tolerability, selected laboratory parameters, and AEs; see Section 9.4. 
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Figure 7-1: 
Double-blind Study Design 
 
 
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Screening 
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Figure 7-2: 
Open-label Study Design 
 
 
Double-blind Treatment Period 
Study Day 90/Week 12 (- 7 days) 
= first visit of 
Open-label Extension Period with 
trifarotene 200 µg/g 
Continue through 12 weeks of treatment 
Follow-up Day 192 or 14 days after 
End of Treatment 
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7.2. Rationale and Discussion of Study Design 
The first part of this study is a randomized, double-blind, placebo-controlled study of the safety, 
tolerability, PK, and efficacy study of trifarotene cream HE1 100 µg/g and 200 µg/g in subjects 
with LI.  
In a previous proof-of-concept study (RD.03.SRE.40181E), subjects with LI applied trifarotene 
50 and 100 µg/g cream to limited areas, and results demonstrated a decrease in scaling with good 
safety and tolerance. In a phase 1 study in healthy Japanese and non-Japanese subjects 
(RD.03.SPR.103813), repeated topical applications of trifarotene (CD5789 cream HE1) 100 µg/g 
and 200 µg/g resulted in low and similar CD5789 systemic levels in all the cohorts. These studies 
are fully described in the current IB. 
To ensure safety, this phase 2 study will begin with an initial cohort (Cohort A) of 15 subjects 
randomized 1:1:1 to trifarotene cream HE1 100 µg/g, 200 µg/g, or vehicle to be applied twice 
weekly. An independent DSMB will review aggregate safety and tolerability data from the initial 
15 subjects’ first 28 days of treatment. If no safety issues are identified, and additional group of 
105 subjects will be allowed to enroll in Cohort B and will be randomized to trifarotene cream 
HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle and treated twice weekly in the same 
manner as subjects in Cohort A. All subjects in the randomized, double-blind portion of the study 
will be treated for up to 12 weeks, and data on safety, tolerability, PK, and efficacy collected.  
Subjects who successfully complete the initial 12 weeks of double-blind treatment will have the 
option to enter an OLE with trifarotene cream HE1 200 µg/g twice weekly for up to 12 weeks.  
The OLE will collect additional safety, tolerability, PK, and efficacy data. As designed, this study 
will provide important information on safety, tolerability, and PK with dosing of subjects with LI 
for up to 6 months.  
The protocol includes appropriate monitoring for safety and tolerability. If subjects develop 
significant local application site reactions or tolerability issues, the protocol includes language for 
reducing the frequency of application or halting study drug application until the symptoms abate. 
7.3. Selection of Doses in the Study 
Based on the results from Study RD.03.SRE.40181E and Study SRE.103813, the doses of 
100 µg/g and 200 µg/g were selected for further investigation in subjects with moderate to severe 
LI. The PoC study demonstrated efficacious treatment with 100 µg/g of trifarotene cream HE1. 
The PK and tolerability study showed that, when the frequency of application was reduced from 
daily to twice weekly, the 200 µg/g cream HE1 had good local tolerability. 
Therefore, the current study will use these doses compared with vehicle, applied twice weekly on 
up to approximately 90% BSA in subjects with LI.   
7.4. Study Sites 
The study will take place at approximately 40 sites in North America, Europe, Israel, and Australia.  
7.5. Point of Contact 
A point of contact will be identified to provide information to subjects about where to obtain 
information on the study, the rights of subjects, and whom to contact in case of a study-related 
injury. This information will be provided in the subject information and ICF. 
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7.6. End of Study Definition 
A clinical study is considered completed when the last participant’s last study visit has occurred. 
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8. SUBJECT POPULATION 
8.1. Selection of Study Population and Diagnosis 
Diagnosis of LI for the purposes of this study will be a clinical diagnosis. Although some younger 
subjects may have had genetic testing, older subjects may not.  
While LI is a rare disease and subject enrollment may be challenging, due to possible bias 
introduced by including household members in the same study, it is recommended that only 
1 household member be included in the study to maintain the blind and ensure all assessments are 
independent. 
8.2. Study Entry Criteria 
8.2.1. Inclusion Criteria 
A subject will be eligible for study participation if he or she meets all of the following criteria: 
1. Subject is ≥18 years old.  
2. Subject has known diagnosis of LI.  
3. Subject has moderate to severe (VIIS 3–4) LI on the at least 2 of the 4 body areas assessed 
(chest/abdomen, back, arms, and legs).  
4. Subject has signed an ICF at Screening before any investigational procedures.  
5. Subject who is participating in optional photography has signed a photography ICF. 
6. Subject who is participating in the optional PK substudy has signed a PK ICF. 
7. Subject is not of childbearing potential, i.e., a female who is postmenopausal (absence of 
menstrual bleeding for 1 year before Baseline, without any other medical reason, 
hysterectomy or bilateral oophorectomy),  
OR  
• Subject is a woman of childbearing potential (WOCBP) or a male subject with sexual 
partners capable of reproduction who agrees to use 2 effective forms of contraception during 
the study and for at least 1 month after the last study drug application. The 2 authorized 
forms of contraception are condom used with 1 of the following methods of contraception: 
• bilateral tubal ligation 
• combined oral contraceptives (estrogens and progesterone) or implanted or injectable 
contraceptives with a stable dose for at least 1 month before Baseline 
• hormonal intrauterine device (IUD) inserted at least 1 month before Baseline 
OR 
Agrees to abstain from sex during study participation and for 1 month after the last application 
of study drug and to use a highly effective contraceptive as backup if he or she becomes 
sexually active during the study. 
AND 
Male subjects may not donate sperm during the study and for at least 1 month after the last 
study drug application. 
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8. Women of child-bearing potential must be nonlactating and have negative pregnancy test 
results at Screening (serum) and on Day 1 before study drug administration (urine). 
9. Subject is reliable and capable of adhering to the protocol and visit schedule, in the 
investigator’s judgment, and has signed informed consent. 
10. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin). 
8.2.2. Exclusion Criteria 
A subject will be excluded from the study if he or she meets any of the following criteria: 
1. Subject has any variant of ichthyosis other than LI or another disorder of keratinization 
including syndromic ichthyoses.  
2. Subject has a history of or current moderate or severe stinging/burning at Screening. 
3. Subject has an ongoing cutaneous infection or any other significant concomitant skin disease 
(other than the LI) which, in the investigator’s opinion, may interfere with the study 
assessments. 
4. Subject with a known lipid disorder unless well controlled by stable doses of lipid-lowering 
agents for at least 6 months. 
5. Subject was previously treated with trifarotene/CD5789, including the acne formulation, or 
participated in previous studies for ichthyosis.  
6. Subject has known skeletal disease, hypertriglyceridemia, hypercholesterolemia, liver disease, 
or other poorly controlled medical conditions.  
7. Subject has a medical condition that potentially alters bone metabolism (e.g., osteoporosis, 
thyroid dysfunction, Cushing syndrome), Crohn’s disease, or any other significant concomitant 
disease other than LI that, in the investigator’s opinion, may put him or her at risk if he or she 
takes part in the study, and/or that may interfere with the study assessments. 
8. Subject is being treated for major depression disorder. 
9. Subject with positive serology for hepatitis B surface antigen, hepatitis C, or are known to be 
HIV-positive or to have AIDS at Screening. 
10. Subject with any of the following laboratory values at Screening: 
a. Aspartate aminotransferase or alanine aminotransferase >1.5 × upper limit of normal 
defined by the laboratory 
b. Triglycerides >200 mg/dL 
c. Total cholesterol >250 mg/dL 
d. Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women 
e. Platelets <150 × 109/L or >400 × 109/L. 
11. Subject has any clinically other significant abnormal laboratory value (hematology, chemistry, 
or urinalysis) at Screening that, in the investigator’s opinion, may put the subject at risk if he 
or she takes part in the study, and/or that may interfere with the study assessments. 
12. Subject has a history of long QT syndrome or clinically significant ECG abnormalities, 
including clinically significant conduction disorders or significant arrhythmias, QTcF interval 
>450 ms, PR interval is not between 120 and 220 ms (inclusive), HR >100 bpm or <50 bpm, 
QRS interval >110 ms, or QT intervals that cannot be consistently analyzed. 
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13. Subject has a known allergy or sensitivity to any of the components of the investigational 
products.  
14. Subject has been exposed to excessive UV radiations on the treated zones within 1 month 
before Baseline visit or who is planning intensive UV exposure during the study (e.g., 
occupational exposure to the sun, sunbathing, phototherapy, etc.). 
15. Subject is inherently sensitive to sunlight. 
16. Subject is presumed to be abusing drug or alcohol at Screening or Baseline Visits based on 
medical history or current clinical symptoms. 
17. Subject is participating in another interventional clinical trial. 
8.3. Premature Subject Withdrawal 
All subjects will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. The investigator should make every reasonable 
attempt to keep subjects in the study; however, subjects must be withdrawn from the study if they 
withdraw consent to participate. Investigators must attempt to contact subjects who fail to attend 
scheduled visits by telephone or other means to exclude the possibility of an AE being the cause 
of withdrawal. Should this be the cause, the AE must be documented, reported, and followed as 
described in Section 11.2. 
The sponsor reserves the right to request the withdrawal of a subject due to protocol deviations or 
other reasons. 
The investigator also has the right to withdraw subjects from the study at any time for lack of 
therapeutic effect that is intolerable or otherwise unacceptable to the subject, for intolerable or 
unacceptable AEs, intercurrent illness, noncompliance with study procedures, administrative 
reasons, or in the investigator’s opinion, to protect the subject’s best interest. 
If a subject is withdrawn before completing the study, the reason for withdrawal and the date of 
discontinuation will be recorded on the appropriate page of the electronic case report form (eCRF). 
Whenever possible and reasonable, the evaluations that were to be conducted at the completion of 
the study should be performed at the time of premature discontinuation. 
8.4. Discontinuation of Study Intervention 
Discontinuation from study treatment does not mean withdrawal from the study, and the remaining 
study procedures should be completed as indicated in the study protocol (see Section 10.2.4.5). If 
a clinically significant finding is identified (including, but not limited to changes from Baseline) 
after enrollment, the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an AE. 
An investigator may discontinue a participant’s study treatment for any of the following reasons: 
• Pregnancy 
• Significant study intervention noncompliance  
• If any clinical AE, laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the 
participant 
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• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for discontinuation of study treatment will be recorded on the eCRF. Subjects who sign 
the informed consent form and are randomized but do not receive the study intervention may be 
replaced. Subjects who sign the informed consent form, are randomized, and receive the study 
intervention, and subsequently discontinue study treatment, or are withdrawn from the study will 
not be replaced. 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site will attempt to contact the participant and reschedule the missed visit and counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
8.5. Subject Replacement Criteria 
Withdrawn subjects will not be replaced. If a substantial number of subjects are withdrawn from 
the study, the sponsor will evaluate the need for developing replacement criteria. 
Randomized subjects withdrawn from the study may not reenter. The subject number for a 
withdrawn subject will not be reassigned to another subject. 
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9. TREATMENTS 
9.1. Identification of Investigational Products 
Trifarotene cream HE1 is a cream containing 100 or 200 μg/g (0.01% [w/w] or 0.02% [w/w], 
respectively) of CD5789 and the following excipients: purified water, propylene glycol, allantoin, 
glycerin, medium-chain triglycerides, polypropylene glycol 15 stearyl ether, cyclomethicone, 
phenoxyethanol, copolymer of acrylamide and sodium acryloyldimethyltaurate, dispersion 40% in 
isohexadecane (simulgel 600 PHA), sodium benzoate, butylated hydroxytoluene, and 
gluconolactone. 
Vehicle contains the same ingredients, without the CD5789. 
Trifarotene cream HE1 and vehicle will be provided in cream form for topical application and will 
be supplied in 50-g tubes from which a maximum of 36 g of IP may be extracted. 
Trifarotene cream HE1 and vehicle will be supplied by G. Production, Inc. (Galderma) in 
Baie-D'Urfé, QC, Canada. 
9.2. Treatments Administered  
For the Double-blind Treatment Period, a fixed dose (determined at Visit 2) of trifarotene cream 
HE1 100 µg/g or 200 µg/g or vehicle cream will be applied topically twice weekly on up to 90% 
BSA of each subject. 
Study staff will apply the first administration of IP in the clinic on Day 1 after Baseline 
measurements, and the amount of IP used will be measured (i.e., 50-g tube will be measured before 
and after application to determine amount used). 
The maximum dose per application is 36 g (i.e., 1 tube). Subjects will receive an adequate number 
of tubes to use 1 tube per application and will use a new tube for each treatment day. Subjects may 
use less than full amount of product in a tube. 
After the Day 1 visit, subjects will apply approximately the same amount (up to 36 g) of study 
drug as for the first dose on up to 90% of BSA twice weekly, sparing the scalp, inguinal, and 
axillary areas. Subjects will continue treatment for up to 12 weeks. 
For the OLE Period, all subjects will receive trifarotene cream HE1 200 µg/g and apply the same 
fixed dose in the same manner as in the Double-blind Period for an additional 12 weeks. 
Subjects should not apply IP on visit days until after the visit. 
9.3. Selection of Timing of Dose for Each Subject 
Subjects will be randomized in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g or 200 µg/g or 
vehicle cream. After Day 1, on which the study staff will apply the first administration of IP in the 
clinic, each subject will apply approximately the same amount of IP on up to 90% of their BSA 
twice weekly. It is suggested that each subject choose 2 specific days per week at least 3 days apart 
on which to apply their IP (e.g., Tuesday and Friday), and maintain that regimen throughout the 
study. 
All subjects will be provided with diaries in which to record study drug application (days/times) 
and any areas of skin not treated (e.g., due to local reactions). 
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If a subject misses an IP application, they should apply the IP as soon as they remember and record 
the date/time in the subject diary, then wait at least 3 days and continue their regimen. 
Subjects should not shower, bathe, or swim for at least 4 hours after IP application. No occlusive 
dressings should be used on areas to which IP is applied. 
Subjects who continue into the Open-label Extension will receive trifarotene cream HE1 200 µg/g 
and apply the same fixed dose in the same manner as in the double-blind period for an additional 
12 weeks. 
9.4. Dose Adjustment Criteria 
Local tolerance will be followed very carefully during the study. Subjects will receive information 
on study drug use and stopping rules and will be instructed to contact the site with any 
safety/tolerability issues. Study personnel will telephone subjects in between scheduled visits (i.e., 
at Day 7 and Day 45) to assess safety; an unscheduled clinic visit may be performed, if necessary. 
During all clinic visits, the investigator will assess local tolerability on a 0–3 scale (0 = none, 1 = 
mild, 2 = moderate, 3 = severe) on each of the 4 body areas (chest/abdomen, back, legs, arms), and 
the following procedures will be followed: 
− If a score of 2 (moderate) is recorded on a local tolerability assessment scale 
(stinging/burning, pruritus, erythema) on any treated area, the study drug will be applied 
on this area only once weekly, until the score is back to <2; 
− If a score of 3 (severe) is recorded on a local tolerability assessment scale (stinging/burning, 
pruritus, erythema) on any treated area, the study drug will not be applied on that area until 
the score is back to <3. 
9.4.1. Stopping Rules 
A subject’s treatment in either the Double-blind Period or the Open-label Extension must be 
stopped if any of the following occur: 
• Subject becomes pregnant or suspects they are pregnant 
• Subject has severe (score of 3) local application site AEs that do not abate with ‘drug 
holiday’ and reintroduction of IP.  
• Subject has clinically significant changes in laboratory values (liver function tests, 
cholesterol/triglycerides – which may occur with systemic retinoid use) 
9.5. Treatment Compliance 
Subjects will be asked to record their twice-weekly applications of IP in the diary during both the 
Double-blind and OLE Periods. Deviations from the planned doses (missed dose or timing) will 
be recorded on the subject’s eCRF. Study personnel will review diaries at each visit and diaries 
will be collected as source documents. Information from subject diaries will be transcribed on the 
appropriate eCRF pages for documentation of subject compliance with the IP. 
Study personnel will assess treatment compliance with IP regimens by weighing IP tubes before 
dispensing and upon return and by questioning the subject, at every post-randomization visit. A 
participant is compliant with study product if he or she takes at least 80% of the scheduled doses 
as assessed by diary entries, supplemented by tube weight. A subject who is not compliant (i.e. 
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used ≤80% or ≥120% of IP tubes) will be counseled at each visit on the importance of using the 
IP as instructed.  
9.6. Method of Assigning Subjects to Treatment Groups 
In the double-blind, parallel-group, randomized period of the study, subjects who meet study entry 
criteria will be randomly assigned in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g or 200 µg/g 
or vehicle cream. The randomization schedule will be computer generated using a permuted block 
algorithm and will randomly allocate IP to randomization numbers. The randomization numbers 
will be assigned sequentially through a central interactive web response system (IWRS) as subjects 
are entered into the study. Study center will not be a blocking factor in the randomization schedule. 
Premier Research will prepare the randomization schedule before the start of the study. No one 
involved in the study performance will have access to the randomization schedule before the 
official unblinding of treatment assignments. No subject will be randomized into this study more 
than once. 
In the OLE Period, all subjects will receive trifarotene cream HE1 200 µg/g. 
9.7. Blinding and Unblinding Treatment Assignment 
All subjects, investigators, and study personnel involved in the conduct of the Double-blind Period 
of the study, including data management, will be blinded to treatment assignment with the 
exception of a specified unblinded statistician and programmer from Premier Research who will 
have access to the randomization code. The statistician will have access to unblinded data if there 
is an unblinded DSMB review.  
Study personnel will make every effort to safeguard the integrity of the study blind to minimize 
bias in the conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
subject’s treatment assignment. 
Unblinding should be discussed in advance with the medical monitor, if possible. For emergency 
unblinding, study personnel will use the IWRS code. If the investigator is not able to discuss 
treatment unblinding in advance, then he/she must notify the medical monitor as soon as possible 
about the unblinding incident without revealing the subject’s treatment assignment.  
The investigator or designee must record the date and reason for treatment unblinding on the 
appropriate eCRF for that subject. In all cases that are not emergencies, the investigator must 
discuss the event with the medical monitor prior to unblinding the subject’s treatment assignment. 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
that subject’s treatment assignment without unblinding the treatment assignments for the 
remaining subjects in the study. Thus, the overall study blind will not be compromised. If a 
subject’s treatment assignment is unblinded, he/she may or may not be asked to withdraw from 
the study. The investigator will make this decision after consultation with the medical monitor. 
The primary analysis period is the first 12 weeks of treatment (i.e., the Double-blind Period). 
Overall unblinding will take place at the end of the Double-blind Period of the study only after 
database lock has been achieved. A second analysis will take place for endpoints assessed from 
Week 12 through the OLE Period. 
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9.8. Permitted and Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate eCRF. 
All subjects must washout the following medications after enrollment and before randomization: 
Table 9-1: 
Washout Periods for Prohibited Medications 
Medication 
Washout Period 
Topical Treatments 
Corticosteroids (except inhaled and ophthalmic corticoids) 
2 weeks 
Retinoids (e.g. tretinoin, tazarotene) 
4 weeks 
Vitamin D analogues 
2 weeks 
Immunosuppressants (e.g. tacrolimus) 
2 weeks 
Antracen derivatives, tar and salicylic preparations 
2 weeks 
Keratolytics (such as urea, lactic acid, propylene glycol, salicylic acid) except keratolytic 
shampoo 
- 
Systemic treatments 
Retinoids 
8 weeks 
Oral Vitamin A supplementation more than 3500 IU per day 
2 weeks 
Medication interfering with bone activity, e.g., corticosteroids, thyroid hormones, cytotoxics, 
bisphosphonates, calcitonins, tetracyclines, quinolones, thiazides, salicylates in long-term 
course, heparin, theophylline, barbiturates, colchicines (except Vitamin D analogues taken at 
stable dose since at least 1 month) 
8 weeks 
QT prolonging drugs 
5 half lives 
Enzymatic inductors (such as rifampicine, phenytoin, carbamazepine, phenobarbital, St. 
John’s Wort) 
3 months 
CYP2C9 and 2C8 inhibitors (not all inclusive: gemfibrozil, fluconazole, fluvoxamine, 
sulfaphenazole, miconazole, amiodarone, sertraline, sulfamethoxazole, valproic acid, 
voriconazole, trimethoprim, rosiglitazone, pioglitazone) 
5 half lives 
9.8.1. Permitted Therapies 
Subjects will be advised on permitted emollient(s) for use on nontreatment days during the study; 
use of emollient(s) on study drug treatment days within 4 hours of study drug application is 
prohibited.  
Other concomitant medications are allowed (e.g., analgesics, antihistamines), but should be limited 
to those medications considered necessary. All concomitant medications, both prescribed and 
over-the-counter, should be recorded in the eCRF. 
9.8.2. Prohibited Therapies 
The therapies listed in Table 9-1 are prohibited during the study.  
Subjects may not use concomitant keratolytics such as urea, salicylic acid, alpha, or beta 
hydroxyacids. Subjects may not use topical or systemic retinoids. Subjects may not take more than 
3500 IU/day Vitamin A (e.g., as in a multivitamin). 
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Subjects receiving excluded therapies will be ineligible for study enrollment or for continued 
treatment in the study, at the investigator’s discretion with consultation with Mayne Pharma LLC 
and the medical monitor. 
9.8.3. Restrictions 
Subjects should not shower, bathe, or swim within 4 hours of study drug application. No occlusive 
dressings should be applied to areas where study drug was applied.  
Subjects should only use investigator-approved emollients, and should not use them on treatment 
days within 4 hours of study drug application. 
9.9. Treatment After End of Study 
After the end of the study, each subject will be treated according to standard clinical practice. 
9.10. Dispensing and Storage 
The test product supplied by Mayne Pharma LLC is to be used exclusively in the clinical study 
according to the instructions of this protocol. The investigator is responsible for dispensing the IP 
according to the dosage scheme and for ensuring proper storage of the IP. 
The investigator must confirm the receipt of the IP with his or her signature. A copy of this receipt 
must be kept by the investigator and another copy will be stored at Premier Research. Until the IP 
is dispensed to the subjects, it must be stored at 20–25°C (68–77°F), with excursions permitted to 
15–30°C (59–86°F); do not freeze and with the tube kept tightly closed in a securely locked area 
that is not generally accessible. 
The key to the storage area is to be kept by the investigator or designee responsible for the IP. The 
store will be accessible only to those persons authorized by the investigator to dispense the IP. 
9.11. Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the IPs, including the date, quantity, batch or code number, and identification of 
subjects (subject number) who received the IP. The investigator will not supply the IP to any 
person except those named as subinvestigators on the Form Food and Drug Administration 
(FDA) 1572, designated study personnel, and subjects in this study. The investigator will not 
dispense the IP from any study sites other than those listed on the Form FDA 1572. Investigational 
product(s) may not be relabeled or reassigned for use by other subjects. If any of the IP is not 
dispensed, is lost, stolen, spilled, unusable, or is received in a damaged container, this information 
must be documented and reported to the sponsor and appropriate regulatory agencies, as required. 
Each subject will be given enough tubes of study drug to apply up to 1 tube-full (approximately 
36 g of clinical trial material) per treatment day until the next study visit. Tubes will be packed 
2 to a carton, and each subject will receive enough cartons to have the maximum number of tubes 
needed until the next study visit. The number of study drug tubes the subject needs to provide 
enough IP until the next visit is shown in Table 9-2.  
 
 
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Table 9-2: 
Amount of Study Drug Needed Per Visit 
Treatment Period 
Number of Cartons 
Number of Tubes 
Double-blind Treatment Period 
Baseline 
3 
6 
Day 14 
4 
8 
Day 30 
6 
12 
Day 60 
6 
12 
OLE Period 
Day 90 
3 
6 
Day 104 
4 
8 
Day 120 
6 
12 
Day 150 
6 
12 
 
Each carton will be weighed before dispensing and subjects are to bring all cartons and tubes back 
at each study visit, whereupon study staff will weigh them again to estimate study drug use and 
compliance. 
Upon completion of the study, the IP (partly used, unused, and empty tubes) must be left in the 
original packaging and returned to the sponsor or designee for destruction. 
9.12. Labeling and Packaging 
Labeling and packaging of IP will be performed by Catalent Pharma Solutions, Philadelphia, PA, 
USA.  
Tubes will be packaged in cartons comprising 2 tubes each. Tubes will be labeled with inner and 
outer booklet labels, and carton number. Each carton will also be labeled with inner and outer 
booklet labels and numbered.  
9.12.1. Labeling 
The tubes will have a label affixed that meets the applicable regulatory requirements and may 
include, but is not limited to, the following: subject identifier, IP name, lot number, protocol 
number, carton number, caution statement, storage, and sponsor identification. 
Save all empty packaging or packaging containing unused tubes for final disposition by the 
sponsor or contract pharmacy. 
Final labeling will comply with the regulatory requirements of each country where the study will 
be conducted. 
9.12.2. Packaging 
Investigational products will be packaged in high-density polyethylene, 35 × 100 mm tubes 
weighing 50 g from which a maximum of 36 g of IP can be extracted. Trifarotene cream HE1 and 
vehicle will be packaged so as to be blinded to the investigator, the study clinic personnel, and the 
subjects. 
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10. STUDY PROCEDURES
Subjects must provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
Subjects who agree to participate in the photography and/or PK substudies must provide written 
informed consent before photographs or serial blood samples are collected. 
For the timing of assessments and procedures throughout the study, refer to the Schedule of Events 
(Section 2.2). Throughout the study, every reasonable effort should be made by study personnel to 
follow the timing of assessments and procedures in the Schedule of Events for each subject. If a 
subject misses a study visit for any reason, the visit should be rescheduled as soon as possible. 
10.1. Study Duration 
10.1.1. Overall Study Schedule 
The overall study duration is expected to be approximately 19 months. 
The planned sequence and maximum duration of the study periods will be as follows: 
1. Screening and Washout: up to 35 days to comprise washout of excluded medications (Table
9-1).
2. Double-blind Treatment: Twice weekly for 12 weeks.
3. Optional Open-label Extension Treatment: Twice weekly for 12 weeks.
4. Follow-up: 14 days after last study drug application.
The maximum treatment duration for each subject is approximately 12 weeks for subjects who 
choose not to continue into the open-label extension period, and 24 weeks for those who choose 
to continue.  
The maximum study duration for each subject is approximately 229 days (33 weeks). 
10.2. Study Periods and Visits 
10.2.1. Screening and Washout 
10.2.1.1. Screening Visit (Visit 1) 
The subject must be screened within 35 days before randomization in the study. The following 
procedures will be performed at Screening: 
1. Obtain written informed consent.
2. Assign a screening number when a subject begins screening.
3. Assess inclusion/exclusion criteria.
4. Collect demographic information.
5. Record medical history, including current therapies (e.g., prescription and nonprescription
medications).
6. Perform a physical examination.
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7. Measure vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and 
pulse). 
8. Perform a 12-lead ECG. 
9. Collect blood and urine for laboratory tests. 
10. Perform serum pregnancy test for WOCBP. 
11. Record VIIS.   
12. Record IGA. 
13. Record palm/sole assessment.  
14. Record assessment of roughness, and fissuring  
15. Record ectropion score. 
Procedures for rescreening subjects who initially fail to meet study entry criteria are described in 
Section 14.3. 
10.2.1.2. Washout Period 
Excluded medications must be washed over the time periods as shown in Table 9-1. The washout 
period is part of the 35-day Screening Period.  
10.2.2. Double-blind Treatment Period  
Eligible subjects who have washed out prohibited medications will be randomized to double-blind 
study drug. 
10.2.2.1. Baseline Visit (Visit 2, Day 1) 
The following procedures will be performed on Day 1 in the study clinic: 
1. Review inclusion/exclusion criteria. 
2. Perform urine pregnancy test for WOCBP. 
3. Collect blood and urine for routine laboratory tests (subject must be fasting; i.e., at least 
8 hours). 
4. Collect a predose PK blood sample (all subjects). 
5. Perform physical examination.  
6. Record concomitant medications and concomitant therapies. 
7. Record VIIS.  
8. Record IGA.  
9. Record palm/sole assessment. 
10. Record assessment of roughness and fissuring.  
11. Record ectropion score.  
12. Record responses to DLQI and EQ-5D Quality of Life Questionnaires 
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13. Record vital signs (blood pressure and pulse).  
14. Measure and record height, weight, and body mass index (BMI).  
15. Perform a 12-lead ECG. 
16. Assign randomization number.  
17. At sites where the photographic substudy is conducted, take photographs of subjects who 
have provided informed consent for the substudy. 
18. Among subjects who consent to participate in the PK substudy, samples will be taken at 1, 
2, 4, 8, 12, and 24 hours postdose on Day 1. 
19. Clinic staff instructs subject on study drug application, applies initial study drug dose and 
measures amount used (i.e., study staff will weigh the 50-g tube before and after the first 
application to determine the fixed dose amount for each subject). 
20. Assess and record local tolerance/AEs. 
21. Dispense study drug and diaries. 
22. Advise subjects regarding permitted emollient(s) for use on nontreatment days; use of 
emollient(s) on study drug treatment days within 4 hours of study drug application is 
prohibited. Remind subjects not to apply IP on visit days until after the visit. 
10.2.2.2. Telephone Visit (Day 7) 
Clinic staff will telephone subject to assess safety and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient(s) on study drug 
treatment days within 4 hours of study drug application is prohibited), and remind subjects not to 
apply IP on visit days until after the visit. An unscheduled clinic visit may be performed, if 
necessary. 
10.2.2.3. Visit 3 (Day 14 ±5 days) 
The following procedures will be performed on Day 14 in the study clinic: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Assess local tolerance. 
4. Record AEs and review diary. 
5. Record VIIS.   
6. Record IGA. 
7. Record palm/sole assessment.  
8. Record assessment of roughness and fissuring. 
9. Record ectropion score. 
10. Record responses to DLQI and EQ-5D Quality of Life Questionnaires. 
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11. Collect a PK blood sample (all subjects). 
12. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
13. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) on study drug treatment days 
within 4 hours of study drug application is prohibited. Remind subjects not to apply IP on 
visit days until after the visit.  
14. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
10.2.2.4. Visit 4 (Day 30 ±7 days) 
The following procedures will be performed on Day 30 in the study clinic: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Perform a 12-lead ECG. 
4. Collect blood and urine for routine laboratory tests (subject must be fasting at least 
8 hours). 
5. Collect a PK blood sample (all subjects). 
6. Perform a urine pregnancy test for WOCBP. 
7. Record AEs and review diary. 
8. Assess local tolerance. 
9. Record VIIS. 
10. Record IGA. 
11. Record palm/sole assessment.  
12. Assess roughness and fissuring and record findings. 
13. Record responses to DLQI and EQ-5D Quality of Life Questionnaires. 
14. Record ectropion score.  
15. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
16. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) on study drug treatment days 
within 4 hours of study drug application is prohibited. Remind subjects not to apply IP on 
visit days until after the visit.  
17. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
18. At sites where the optional photographic substudy is conducted, take photographs of 
subjects who have provided informed consent for the substudy. 
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19. Among subjects who consent to participate in the PK substudy, IP will be applied in the 
clinic at this visit, and samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours 
postdose.  
20. Provide information about OLE option. 
10.2.2.5. Telephone Visit (Day 45) 
Clinic staff will telephone subject to assess safety and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient[s] on study drug 
treatment days within 4 hours of study drug application is prohibited), and remind subjects not to 
apply IP on visit days until after the visit. An unscheduled clinic visit may be performed, if 
necessary. Staff will remind subject about OLE option. 
10.2.2.6. Visit 5 (Day 60 ±7 days) 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse).  
3. Record VIIS.   
4. Record IGA. 
5. Record palm/sole assessment.  
6. Assess roughness and fissuring and record findings. 
7. Record ectropion score.  
8. Record responses to DLQI and EQ-5D Quality of Life Questionnaires 
9. Perform a urine pregnancy test for WOCBP. 
10. Collect a PK blood sample (all subjects). 
11. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
12. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
13. Record AEs and review diary. 
14. Assess local tolerance.  
15. Provide information about OLE option. 
 
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10.2.2.7. Visit 6 (90 ±7 days) or Early Termination 
The following procedures will be performed on Day 90 in the study clinic: 
1. Record concomitant medications and concomitant therapies. 
2. Perform a physical examination. 
3. Record vital signs (blood pressure and pulse). 
4. Perform a 12-lead ECG. 
5. Collect blood and urine for routine laboratory tests (subject must be fasting at least 
8 hours). 
6. Collect a PK blood sample (all subjects). 
7. Perform a urine pregnancy test for WOCBP. 
8. Record AEs and review diary. 
9. Assess local tolerance. 
10. Record VIIS. 
11. Record IGA. 
12. Record palm/sole assessment.  
13. Assess roughness and fissuring and record findings. 
14. Record ectropion score.  
15. Record responses to DLQI and EQ-5D Quality of Life Questionnaires. 
16. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
17. At sites where the optional photographic substudy is conducted, take photographs of 
subjects who have provided informed consent for the substudy. 
For subjects who successfully complete the initial 12 weeks of double-blind treatment and choose 
to continue into the OLE, this visit will be the first visit of that portion of the study. All efficacy 
assessments, safety/tolerability assessments, including clinical laboratory testing, PK from 
Day 90/Week 12 will be carried over to the OLE Period and will not be repeated. Subjects will 
have up to 7 days to decide to enter the OLE; if the subject chooses to continue into OLE, the 
following additional procedures will be done: 
1. Have the subject sign OLE-specific informed consent.  
2. Measure subject’s weight. 
3. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) on study drug treatment days 
within 4 hours of study drug application is prohibited. Remind subjects not to apply IP on 
visit days until after the visit. 
4. Weigh new study drug tubes and dispense enough additional study drug until next visit 
(only for subjects who choose to continue into the Open-label Extension). 
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5. Dispense study diary. 
10.2.3. Follow-up Telephone Call (±14 days after Day 90) – Only Subjects Who Do Not 
Continue into Open-label Extension 
Clinic staff will telephone subjects who choose not to continue into the Open-label Extension 
within 14 days after Day 90 to assess any ongoing AEs.  
10.2.4. Open-label Extension  
Subjects who complete the 12-week Double-blind Treatment Period of the study may choose to 
continue into an optional 12-week Open-label Treatment Period with trifarotene cream HE1 
200 µg/g. During the OLE Period, subjects will return to the site at Weeks 14, 16, 20, 24, and 26. 
Additional PK samples will be drawn at Week 16 and 24 from all subjects who continue into the 
OLE Period.  
10.2.4.1. Telephone Visit (Day 97) 
Clinic staff will telephone subject to assess safety (AEs) and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient(s) on study drug 
treatment days within 4 hours of study drug application is prohibited), and remind subjects not to 
apply IP on visit days until after the visit. An unscheduled clinic visit may be performed, if 
necessary. 
10.2.4.2. Visit 7 (Week 14; Day 104 ±5 days) 
The following procedures will be performed at this study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Assess and record local tolerance/AEs and review diary. 
4. Record VIIS.   
5. Record IGA. 
6. Record palm/sole assessment.  
7. Record assessment of roughness and fissuring. 
8. Record ectropion score. 
9. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
10. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
11. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) on study drug treatment days 
within 4 hours of study drug application is prohibited. Remind subjects not to apply IP on 
visit days until after the visit. 
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10.2.4.3. Visit 8 (Week 16; Day 120 ±7 days) 
The following procedures will be performed at this study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Assess and record local tolerance/AEs and review diary. 
4. Record VIIS.   
5. Record IGA. 
6. Record palm/sole assessment.  
7. Record assessment of roughness and fissuring. 
8. Record ectropion score. 
9. Perform a 12-lead ECG. 
10. Collect blood and urine for routine laboratory tests. 
11. Perform a urine pregnancy test for WOCBP. 
12. Collect a PK blood sample (all subjects). 
13. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
14. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
15. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) on study drug treatment days 
within 4 hours of study drug application is prohibited. Remind subjects not to apply IP on 
visit days until after the visit. 
10.2.4.4. Telephone Visit (Day 134) 
Clinic staff will telephone subject to assess safety (AEs) and to record concomitant 
medications/therapies. Staff will to instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient[s] on study drug 
treatment days within 4 hours of study drug application is prohibited), and remind subjects not to 
apply IP on visit days until after the visit. An unscheduled clinic visit may be performed, if 
necessary. 
10.2.4.5. Visit 9 (Week 20; Day 150 ±7 days) 
The following procedures will be performed at each study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Perform a urine pregnancy test for WOCBP. 
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4. Assess and record local tolerance/AEs and review diary. 
5. Record VIIS.   
6. Record IGA. 
7. Record palm/sole assessment.  
8. Record assessment of roughness and fissuring. 
9. Record ectropion score. 
10. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
11. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
10.2.4.6. Visit 10 (Week 24; Day 180 ±7 days) or Early Termination 
The following procedures will be performed at Week 24 in the study clinic: 
1. Record concomitant medications and concomitant therapies. 
2. Perform a physical examination. 
3. Record vital signs (blood pressure and pulse). 
4. Perform a 12-lead ECG. 
5. Collect blood and urine for routine laboratory tests. 
6. Perform a urine pregnancy test for WOCBP. 
7. Collect a PK blood sample (all subjects). 
8. Assess and record local tolerance. 
9. Record AEs and review diary. 
10. Record VIIS. 
11. Record IGA. 
12. Record palm/sole assessment.  
13. Assess roughness and fissuring and record findings. 
14. Record ectropion score.  
15. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
10.2.4.7. Follow-up Evaluation – Open-Label Period (Week 26/Visit 11) 
At 14 days after the last administration of the IP, the following procedures will be performed: 
1. Perform a physical examination. 
2. Record vital signs (blood pressure and pulse). 
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3. Record VIIS.   
4. Record IGA. 
5. Record palm/sole assessment.  
6. Assess roughness and fissuring and record findings. 
7. Record ectropion score.  
8. Perform a urine pregnancy test for WOCBP. 
9. Assess and record AEs occurring since the last evaluation and review diary.  
10. Record any concomitant medications/therapies. 
10.3. Assessments 
The VIIS is a valid measure of disease severity and meets the need for a clinically meaningful 
measure of success for ichthyosis studies. The VIIS scale was developed to generate a reliable 
method to assess ichthyosis clinical severity using solely scale and erythema, which are the only 
findings present in ichthyosis of every genetic cause, and occur either upon skin of normal 
thickness (lamellar subtypes) or upon thickened skin (keratoderma subtypes).13 The VIIS uses a 
5-point index to assess the level of severity of scale and erythema in each of 4 body areas: 
chest/abdomen, back, legs, and arms, for a possible overall total of 16 points (Section 10.3.1.1). 
While retinoid treatment is expected to reduce scale, it may increase erythema; therefore, in this 
study, erythema will be evaluated as part of local tolerability. 
10.3.1. Efficacy Variables 
All efficacy measurements will use scales previously used for dermatological studies or as defined 
in the following sections. 
10.3.1.1. Visual Index for Ichthyosis Severity – Scaling 
The primary endpoint is the number of subjects in each treatment group who experience successful 
resolution of LI where “success” is defined as clear/almost clear overall and at least a 50% 
reduction from Baseline at Week 12/EOT on the overall 16-point VIIS for scaling. 
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The investigator will rate the subject’s condition using the 5-point VIIS for each body area 
(chest/abdomen, back, legs, and arms) and an overall score at each time point shown in the 
Schedule of Events (Section 2.2): 
0 
Clear 
Normal skin; no perceptible scale or smoothening 
1 
Almost clear 
Areas of normal skin intermixed with areas showing 
smoothening (diminished fine skin markings; shininess; 
waxiness) or small scales (visibly separated/fractured stratum 
corneum) 
2 
Mild 
Confluent smoothening (diminished fine skin markings; 
shininess; waxiness) or small scales (visibly 
separated/fractured stratum corneum) 
3 
Moderate 
Confluent scales (visibly separated/fractured stratum 
corneum) including some large (>1cm), thick scales 
4 
Severe 
Confluent, primarily large, thick scales 
10.3.1.2. Investigator’s Global Assessment 
The IGA will be measured on a 5-point scale. 
0 
Clear 
No scaling and no roughness, no fissure 
1 
Almost Clear 
Occasional fine scales, hardly palpable roughness (mostly 
smooth), no fissure 
2 
Mild 
Small and fine scales predominate, no more than a few large 
scales, mild roughness on palpation, few fissures may be 
present 
3 
Moderate 
Large rather thick scales predominate, coarse roughness on 
palpation, few fissures may be present 
4 
Severe 
Large coalescent scales dominate, sharp edges on palpation 
with plate-like hyperkeratosis, many fissures may be present 
 
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10.3.1.3. Palm/Sole Assessment 
Thickening of the skin on the palms and soles will be measured on a 5-point scale. 
0 
Clear 
No thickening, no roughness, no fissure 
1 
Almost Clear 
Only slight thickening, minimal to no roughness, no fissures 
2 
Mild 
Some thickening, mild roughness on palpation, few fissures 
may be present 
3 
Moderate 
Substantial and diffuse thickening, coarse roughness on 
palpation may be present, fissures may be present 
4 
Severe 
Very thickened and rough skin, numerous fissures 
10.3.1.4. Individual Score for Roughness 
The amount of roughness of the skin overall will be measured on a 5-point scale. 
0 
Clear 
Smooth skin 
1 
Almost Clear 
Hardly palpably roughness 
2 
Mild 
Mild roughness (fine sand paper-like) 
3 
Moderate 
Moderate, coarse roughness (coarse sand paper-like) 
4 
Severe 
Very coarse skin (broken cornflakes-like) 
10.3.1.5. Fissuring Assessment 
Fissuring will be assessed by recording the presence or absence of fissures, the number of fissures 
present, and the pain associated with each fissure. The subject will assess pain associated with 
fissures as ranging from 0–3 (none, mild, moderate, severe).  
10.3.1.6. Dermatology Life Quality Index 
The DLQI is a dermatology-specific Quality of Life instrument. It is a simple 10-question validated 
questionnaire with 6 domains (symptoms and feelings, daily activities, leisure, work and school, 
personal relationships, and treatment); higher scores indicate poorer quality of life. The DLQI is 
the most frequently used instrument in studies of randomized controlled trials in dermatology.  
10.3.1.7. EQ-5D Quality of Life Questionnaire 
The EQ-5D is a standardized instrument developed by the EuroQol Group as a measure of 
health-related quality of life used in a wide range of health conditions and treatments. The EQ-5D 
consists of a descriptive system and the EQ visual analog scale (VAS).  
The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. The EQ VAS records the subject’s self-rated health on a 
vertical VAS. This can be used as a quantitative measure of health outcome that reflects the 
subject’s own judgement. 
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10.3.1.8. Ectropion Severity Score  
The Ectropion Severity Score (ESS), has a maximum score of 8 points. A higher score indicates a 
worse ectropion. The score takes the severity of ectropion in terms of lateral and medial apposition, 
scleral show, conjunctival show, and roundness of the eye into account and gives an indication of 
the functional aspects involved in ectropion by scoring redness, excess tear film, and the position 
of the lacrimal punctum.14 
10.3.2. Clinical Pharmacology 
10.3.2.1. Pharmacokinetic Analysis Methods  
The pharmacokinetic characterization of drug concentrations for each dose to be profiled will use 
noncompartmental analysis (NCA).  
10.3.2.2. Pharmacokinetic Parameters 
Samples for PK will be drawn from all subjects at Baseline and at each clinic visit for trough 
values.  
Subjects who provide written informed consent to participate in the optional PK substudy will 
provide blood samples for PK analysis predose on Day 1 and at 1, 2, 4, 8, 12, and 24 hours postdose 
on Day 1 and Day 30. 
The PK parameter estimates will be completed using WinNonlin (Pharsight Corporation) software 
using the actual elapsed times from dose administration to sample collection (i.e., not nominal 
time). 
Standard PK parameters assessed will include measures of the extent of absorption using estimates 
of the area-under-the-curve (AUC) and rate-of-absorption using the maximum concentration 
(Cmax) and the time of Cmax (Tmax). Additional details of the parameters and their calculation and 
evaluation will be included in the SAP. 
Table 10-1 shows the PK parameters that will be computed for each subject for samples obtained 
over the planned sampling intervals. 
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Table 10-1: 
Pharmacokinetic Parameters 
Parameter 
Description of Parameter 
Cmax 
Maximum (or peak) serum concentration  
Tmax 
Time at which Cmax is observed 
AUC(0-t) 
Area under the plasma concentration-time curve from time 0 to the time of the last 
quantifiable plasma concentration 
AUC(0-inf) 
Area under the plasma concentration-time curve from time 0 to infinity (if data permit) 
t1/2 
Apparent first order terminal elimination half-life 
λz 
Apparent terminal phase rate constant (if data permit) 
10.3.3. Sample Collection 
Samples will be collected at the time points specified in the Schedule of Events (Section 2.2). 
Specimen preparation, handling, shipment, and storage for the complete blood count, chemistry, 
and urinalysis are described in the study laboratory manual. 
Blood 
Each blood sample will be 3 mL/kg in volume. The total amount of blood to be drawn for serial 
PK assessments will be a maximum of 5 mL/kg per subject over a 24-hour period.  
Urine 
Urinalysis will be performed at central laboratory. Dipstick and urine pregnancy tests will be 
conducted on site.  
10.3.4. Safety Variables 
Safety assessments will include the evaluation of AEs, including local tolerability 
(stinging/burning, pruritus, and erythema), clinical laboratory assessments, vital signs, 12-lead 
ECGs, and physical examinations. 
10.3.4.1. Clinical Laboratory Safety Assessments 
10.3.4.1.1. Clinical Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points specified in the 
Schedule of Events (Section 2.2). 
Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
platelet count (or estimate), white blood cell count including differential 
Serum Chemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, 
creatinine, glucose, sodium, potassium, chloride, bicarbonate, lactate 
dehydrogenase, uric acid, total cholesterol, high-density lipoprotein, low-
density lipoprotein, triglycerides 
Coagulation Panel: prothrombin time, partial thromboplastin time, fibrinogen 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones 
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Pregnancy Test: 
for women of childbearing potential only; serum at Screening, urine at 
each other visit. 
Serology 
Hepatitis B surface antigen, and hepatitis C 
 
All blood samples for the clinical laboratory tests must be taken in a fasting state, at least 8 hours 
after the previous drug application.  
Blood and urine samples for hematology and serum chemistry will be sent to a central laboratory 
for analysis. Urine pregnancy tests and dipstick will be conducted at the study sites. 
10.3.4.1.2. Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens in 
both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
In addition to appropriate handling of subject samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples. Procedures and regulations for the packaging and shipping 
of infectious samples are outlined in the study laboratory manual. The investigator is responsible 
for ensuring that all study samples that are to be transported to another location are packed and 
shipped appropriately according to the applicable regulations.  
Samples for assessment of clinical laboratory tests will be transported to Clinical Reference 
Laboratory (see the study laboratory manual for addresses). 
10.3.4.1.3. Evaluation of Clinical Laboratory Values 
The normal ranges of values for the clinical laboratory assessments in this study will be provided 
by the responsible laboratory and submitted to Mayne Pharma LLC prior to beginning the study. 
They will be regarded as the reference ranges on which decisions will be made. 
If a laboratory value is out of the reference range, it is not necessarily clinically significant. The 
investigator must evaluate the out-of-range values and record his or her assessment of the clinical 
significance in the appropriate eCRF. 
All clinical laboratory values that in the investigator’s opinion show clinically significant or 
pathological changes during or after termination of treatment must be reported as AEs and 
followed, as described in Section 11.2.5. 
All measurements described in this section are recognized standard methods. 
10.3.4.2. Clinical Examinations 
10.3.4.2.1. Vital Signs 
Vital signs, including height and weight (only assessed at Screening), blood pressure and pulse 
will be measured.  
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10.3.4.2.2. Twelve-lead Electrocardiogram 
A standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes. 
All ECG recordings will be identified with the subject number, date, and time of the recording. 
10.3.4.2.3. Physical Examination 
A complete physical examination excluding the genitourinary examination will be performed as 
indicated in the Schedule of Events (Section 2.2). 
10.3.4.2.4. Other Safety Variables 
Local tolerability will be assessed on a 0–3 scale (none, mild, moderate, severe). All application 
site reactions will be recorded as AEs. 
10.3.4.3. Adverse Events 
The definitions and management of AEs, and any special considerations for AEs, are provided in 
Section 11. 
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11. ADVERSE EVENTS 
11.1. Definitions 
11.1.1. Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not related to the medicinal product. 
Preexisting diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a 
preexisting condition is considered an AE.) 
Events that occur in subjects treated with control product are also considered AEs. 
11.1.2. Adverse Drug Reaction 
All noxious and unintended responses to an investigational product related to any dose should be 
considered adverse drug reactions (ADRs). 
The phrase “responses to an investigational product” means that a causal relationship between an 
IP and an AE is at least a reasonable possibility, i.e., the relationship cannot be ruled out. All AEs 
judged by either the reporting investigator or the sponsor as having a reasonable causal relationship 
to an IP qualify as ADRs. 
All AEs for which the judgment of relationship to IP is “possible” or higher will be considered 
ADRs. If a relationship to IP is not provided, then the AE must be treated as if it were “possible.”  
11.1.3. Unexpected Adverse Event/Adverse Drug Reaction 
An expected AE or ADR is one for which the nature or severity is consistent with the known 
AE profile of the product. For a preapproval test product, the known information is contained in 
the IB. For a marketed product, the known information is contained in the current package insert 
for the product. 
An unexpected adverse event (UAE) or unexpected adverse drug reaction (UADR) is one for 
which the nature or severity of which is not consistent with the applicable product information 
(e.g., IB for an unapproved IP or package insert/summary of product characteristics for an 
approved product). For example, hepatic necrosis would be unexpected (greater severity) if the IB 
only listed elevated hepatic enzymes or hepatitis. Likewise, cerebral thromboembolism and 
cerebral vasculitis would be unexpected (greater specificity) if the IB only listed cerebral vascular 
accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction constitute unexpected events.  
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11.1.4. Serious Adverse Events/Drug Reaction 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. 
An elective hospital admission to treat a condition present before exposure to the IP, or a 
hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or 
event as an SAE. Further, an overnight stay in the hospital that is only due to transportation, 
organization, or accommodation problems and without medical background does not need 
to be considered an SAE. 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the IP 
during pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject that has 
received an IP is not considered an SAE unless it is suspected that the IP(s) interacted with 
a contraceptive method and led to the pregnancy.  
• is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result 
in hospitalization, development of drug dependency, or drug abuse. The occurrence of 
malignant tumors is also to be considered serious.  
11.1.5. Significant Adverse Events 
Other significant AEs are defined as marked hematological and other laboratory abnormalities 
(other than those meeting the definition of serious) and any events that led to an intervention, 
including withdrawal of test drug, dose reduction, or significant additional concomitant therapy. 
11.1.6. Treatment-Emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening is after the first application 
of IP (trifarotene or vehicle) and not more than 14 days after the last application of IP. 
11.2. Event Assessment and Follow-up of Adverse Events 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care or upon review by a study 
monitor. 
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All reported AEs, including local and systemic AEs not meeting the criteria for SAEs will be 
captured on the appropriate eCRF. Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event. 
All reported AEs occurring while on study must be documented appropriately regardless of 
relationship. All reported AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
Changes in the severity of a reported AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
Study clinic personnel will record all reportable events with start dates occurring any time after 
informed consent is obtained until 14 (for nonserious AEs) or 30 days (for SAEs) after the last day 
of study participation. At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit. Events will be followed for outcome information until resolution or 
stabilization. 
11.2.1. Assessment 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. In addition, 
although local tolerability will be assessed on a 0-3 scale, all application site reactions should be 
recorded as AEs. 
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11.2.2. Evaluation 
11.2.2.1. Severity of Adverse Events 
The clinical severity of an AE will be classified as follows: 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.4. 
11.2.2.2. Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.4. 
11.2.2.3. Action(s) Taken 
All AEs will be treated/managed according to standard practice. The following actions may be 
taken with regard to the IP. Section 9.4 describes dose adjustment and stopping rules for individual 
subjects. 
Action(s) taken may consist of the following: 
Dose not changed 
An indication that a medication schedule was maintained. 
Dose reduced 
An indication that a medication schedule was modified by subtraction, 
either by changing the frequency, strength, or amount. 
Drug interrupted 
An indication that a medication schedule was modified by temporarily 
terminating a prescribed regimen of medication. 
Drug withdrawn 
An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
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11.2.2.4. Outcome at the Time of Last Observation 
The outcome of an AE at the time of last observation will be classified as follows: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
*Only select fatal as an outcome when the AE results in death. If more than one AE is judged to 
be possibly related to the subject’s death, the outcome of death should be indicated for each such 
AE. Although “fatal” is usually an event outcome, events such as sudden death or unexplained 
death should be reported as SAEs. 
11.2.2.5. Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AE’s relationship to the IP. The categories for 
classifying the investigator’s opinion of the relationship are as follows: 
Not related 
An AE with sufficient evidence to accept that there is no causal relationship 
to IP administration (e.g., no temporal relationship to drug administration, 
because the drug was administered after onset of event; investigation shows 
that the drug was not administered; another cause was proven.) 
Unlikely 
related 
An AE, including laboratory test abnormality, with a temporal relationship to 
IP administration that makes a causal relationship improbable, and in which 
other drugs, events, or underlying disease provide plausible explanations. 
Possibly related An AE with a reasonable time sequence to administration of the IP, but that 
could also be explained by concurrent disease or other drugs or events. 
Information on drug withdrawal may be lacking or unclear. 
Related 
An AE occurring in a causal plausible time relationship to IP administration 
that cannot be attributed to a concurrent disease or other drugs, chemicals, or 
events. The AE relationship to the IP must be assessed separately by the 
investigator and Mayne Pharma LLC. 
 
11.2.3. Documentation 
All AEs that occur within the period of observation for the study must be documented in the eCRF 
with the following information, where appropriate. (The period of observation for the study is 
described in Section 11.2.) 
• AE name or term 
• When the AE first occurred (start date and time) 
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• When the AE stopped (stop date and time or an indication of “ongoing”) 
• Severity of the AE 
• Seriousness (hospitalization, death, etc.) 
• Actions taken 
• Outcome 
• Investigator opinion regarding the AE relationship to the IPs 
11.2.4. Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. If such treatment constitutes a deviation from the protocol, the subject may be withdrawn 
for treatment but continue to be followed for efficacy and safety in the study. The decision about 
whether the subject may continue in the study will be made by the sponsor after consultation with 
the investigator and/or medical monitor. 
If AEs occur in a subject that are not tolerable, the investigator must decide whether to stop the 
subject’s involvement in the study and/or treat the subject. Special procedures may be 
recommended for the specific IP, such as the collection of a serum sample for determining blood 
concentrations of IP, specific tapering procedures, or treatment regimens, as appropriate. 
It is not necessary to unblind a subject’s treatment assignment in most circumstances, even if an 
SAE has occurred. If unblinding is necessary, see Section 9.6 for a description of the unblinding 
procedures. 
11.2.5. Follow-up 
Any AE will be followed (up to a maximum of 14 days after the last dose of IP) to a satisfactory 
resolution, until it becomes stable, or until it can be explained by another known cause(s) (i.e., 
concurrent condition or medication) and clinical judgment indicates that further evaluation is not 
warranted. All findings relevant to the final outcome of an AE must be reported in the subject’s 
medical record and recorded on the eCRF page.  
11.2.6. Reporting 
11.2.6.1. Serious Adverse Events 
The investigator or designee must report all SAEs promptly to Premier Research within 24 hours 
of first becoming aware of the event by e.g., completing, signing and dating the Serious Adverse 
Event Report Form, verifying the accuracy of the information recorded in the form with the source 
documents and eCRF, and sending the SAE form to the Premier Research by one of the following 
methods:  
Email: globalPV-US@premier-research.com 
Email: PVDS-ROW@premier-research.com 
Fax number: +1 215 972 8765 
Fax number: +421 2 6820 3713 
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This written report should be submitted on the SAE form provided for this purpose. At the time of 
first notification, the investigator or designee should provide the following information, if 
available: 
• Protocol number 
• Reporter (study site and investigator) 
• Suspect IP 
• Subject’s study number 
• Subject’s year of birth 
• Subject’s gender 
• Date of first dose of IPs 
• Date of last dose of IPs, if applicable 
• Adverse event term 
• Date of occurrence of the event 
• A brief description of the event, outcome to date, and any actions taken 
• The seriousness criteria(on) that were met 
• Concomitant medication at onset of the event 
• Relevant medical history information 
• Relevant laboratory test findings 
• Investigator’s opinion of the relationship to IPs (“Is there a reasonable possibility that the 
IP caused the SAE? Yes or No?”) 
• Whether and when the investigator was unblinded as to the subject’s treatment 
assignment  
Any missing or additional relevant follow-up information concerning the SAE should be sent to 
the sponsor/sponsor representative via the same contact details above as soon as possible on a 
follow-up SAE Report Form, together with the following minimal information (initial report, 
adverse event, date of occurrence, subject identification (ID), study ID, IP, and site number); this 
will allow the follow-up information to be linked to the initial SAE report.  
Specific information may be requested by the Premier Research Pharmacovigilance Department 
using a follow-up request form or via email communication. 
The investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his or her health authorities, institutional review board 
(IRB)/independent ethics committee (IEC), principal and coordinating investigators, study 
investigators, and institutions. Each investigator is obligated to learn about the reporting 
requirements for investigators in his/her country. The study monitor may be able to assist with 
this. 
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11.2.6.2. Adverse Drug Reactions 
All ADRs should be reported by the investigator in the eCRF.  
Suspected serious ADRs must be reported to the sponsor immediately, regardless of the time 
elapsed since the end of the observation period. 
11.2.6.3. Nonserious Adverse Events 
Nonserious AEs will be recorded in the eCRF and reported by Premier Research to Mayne Pharma 
LLC in aggregate monthly status reports. 
11.3. Special Considerations 
11.3.1. Adverse Events of Special Interest 
Since topical retinoids are associated with local application site AEs, particularly when beginning 
treatment, these events will be followed closely during the study and considered AEs of special 
interest (AESIs). 
11.3.2. Pregnancy 
All WOCBP who participate in the study should be counseled on the need to practice adequate 
birth control and on the importance of avoiding pregnancy during study participation. Women 
should be instructed to contact the investigator or study staff immediately if pregnancy occurs or 
is suspected. 
Pregnancy testing will be conducted prior to administration of the IP on every woman of 
childbearing potential. A woman who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered to be a screening failure. 
A woman who becomes pregnant during IP treatment will be immediately discontinued from study 
treatment. The investigator must report the pregnancy of any woman who becomes pregnant 
during or within 30 days after discontinuing treatment as if it were an SAE within 24 hours of 
learning of the pregnancy, to Premier Research Pharmacovigilance using the Pregnancy Data 
Collection Form via the same fax number and/or email address as for SAE reporting. The 
investigator should contact the designated individual(s) who receive SAE notification and record 
information related to the pregnancy on an SAE and AE form (entering the event temporarily as 
nonserious on both forms) provided by the sponsor or its designee. If a partner of a male study 
subject becomes pregnant, the investigator must report the pregnancy as soon as possible after 
learning of it to the Premier Research Pharmacovigilance using the Pregnancy Data Collection 
Form. A separate pregnant partner ICF will be required. 
Early Termination Visit assessments are required as soon as possible after learning of the 
pregnancy in a study subject. The investigator is also responsible for following the pregnancy until 
delivery or termination. These findings must be reported on the Exposure in Utero form and 
forwarded to the designated individual(s). The event meets the SAE criterion only if it results in a 
spontaneous abortion or a congenital anomaly. 
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12. DATA SAFETY MONITORING BOARD 
Safety oversight will be under the direction of a DSMB composed of individuals with the 
appropriate expertise, including LI. Members of the DSMB should be independent from the study 
conduct and free of conflict of interest, or measures should be in place to minimize perceived 
conflict of interest. The DSMB will operate under a charter that will be finalized prior to the start 
of the study. The DSMB will meet at least 3 times during the conduct of the study: when the study 
begins, when 15 subjects have enrolled in Cohort A and have completed at least 28 days of 
treatment, and after 60 subjects have enrolled in the study. 
The DSMB will meet after subjects in Cohort A have completed at least 28 days of double-blind 
treatment to review aggregate safety and tolerability data. The data will remain blinded unless an 
issue or trend arises that requires unblinding. At that time, the DSMB will decide whether Cohort B 
may begin enrolling. The DSMB will have the authority to recommend to the sponsor that the 
study be placed on hold or discontinued if serious safety issues are discovered. The DSMB will 
provide its input to Mayne Pharma LLC. 
In case of significant toxicity, the DSMB may choose to review the available safety data and 
recommend stopping recruitment in a particular dose group. If toxicity is observed, the treatment 
assignment for the subject(s) involved may be unblinded by the DSMB at its discretion. 
Stopping rules for individual subjects are in Section 9.4.1. 
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13. STATISTICS
13.1. Statistical Analysis 
This section presents a summary of the planned statistical analyses. An SAP that describes the 
details of the analyses to be conducted will be written prior to database lock.  
Unless otherwise indicated, all testing of statistical significance will be two-sided, and a difference 
resulting in a P value of ≤ 0.05 will be considered statistically significant.  
Summary statistics will be provided for the variables described below. For continuous variables, 
these statistics will include the number of subjects, mean, standard deviation (SD), median, 
minimum, and maximum. For categorical variables, these statistics will include the number and 
percentage of subjects in each category. 
The primary analysis period is the first 12 weeks of treatment (i.e., the Double-blind Period). 
Overall unblinding will take place at the end of the Double-blind Period of the study only after the 
database is locked. A second analysis will take place for endpoints assessed from Week 12 through 
the OLE Period. The baseline for the safety and efficacy parameters will be measured at Visit 1 or 
Visit 2, per the Schedule of Events for both the Double-blind (Table 2-1) and OLE (Table 2-2) 
Periods. 
13.1.1. Analysis Populations 
The following 5 analysis populations are planned for the Double-blind Period of this study: 
•
Safety: all subjects who are randomized to treatment and receive at least 1 application of
study drug in the Double-blind Period. This population will be the primary population for
analyses of safety.
•
Intent-to-treat (ITT): all randomized subjects.
•
Modified intent-to-treat (mITT): all subjects in the safety population with at least
1 postbaseline assessment of efficacy in the Double-blind Period.
•
Per-protocol (PP): subjects in the mITT Population who met all inclusion criteria and no
exclusion criteria, were compliant with study drug application, and who had no
significant protocol deviations.
•
Pharmacokinetic: all subjects in the Safety Population who have at least 1 plasma sample
with quantifiable concentration. This population will be used to summarize all
PK endpoints.
The following analysis populations are planned for the OLE Period of this study: 
•
OLE Safety: all subjects who complete the 12-week Double-blind Treatment Period and
receive at least 1 application of study drug in the OLE Period.
•
OLE ITT: all subjects who complete the 12-week Double-blind Treatment Period and
sign the OLE informed consent.
•
OLE mITT: all subjects in the OLE safety population with at least 1 assessment of
efficacy after Visit 6.
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• OLE PP: all subjects in the OLE mITT population who met all inclusion criteria and no 
exclusion criteria, were compliant with study drug application from baseline through 
EOT, and who had no significant protocol deviations throughout the study. 
Inclusion in the analysis populations will be determined prior to database lock. 
If a subject is randomized incorrectly or is administered the incorrect IP, analyses of the ITT and 
mITT populations will be based on the assigned treatment whereas all other analyses will be based 
on the actual treatment received. 
13.1.2. Study Subjects and Demographics 
13.1.2.1. Disposition and Withdrawals 
For the Double-blind Period, the numbers of subjects randomized, completing Week 12 of the 
study, and withdrawing early from the Double-blind Period, along with reasons for withdrawal, 
will be tabulated overall and by randomized treatment group. The number of subjects in each 
analysis population will be reported. The number of subjects completing study milestones will also 
be tabulated by randomized treatment group. This analysis will be conducted for the 
ITT population. 
For the OLE Period, the number of subjects entering the OLE Period, completing the study, and 
withdrawing early, along with reasons for withdrawal, will be tabulated overall. The number of 
subjects in each analysis population will be reported. The number of subjects completing study 
milestones will also be tabulated. This analysis will be conducted for the OLE ITT population. 
13.1.2.2. Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol or International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) requirements. The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions are 
to be developed by the site and implemented promptly.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations promptly. All deviations must be addressed in study source documents, and reported to 
Premier Research or Mayne Pharma LLC. Protocol deviations must be sent to the reviewing 
IRB/IEC per their policies. The site investigator is responsible for knowing and adhering to the 
reviewing IRB/IEC requirements. Further details about the handling of protocol deviations will be 
included in the protocol deviation guidance plan. 
13.1.2.3. Demographics and Other Baseline Characteristics 
These analyses will be conducted for the ITT and OLE ITT populations.  
Demographic variables will include age, sex, race, ethnicity, height, weight, and BMI. Baseline 
subject characteristics will include medical history, physical examination findings, and VIIS score. 
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Prior and concomitant medications will be summarized by randomized treatment group, by the 
number and percentage of subjects taking each medication, and classified using World Health 
Organization Drug Dictionary (WHO-DD) Anatomical Therapeutic Chemical (ATC) classes and 
preferred terms. 
13.1.3. Exposure and Compliance 
Investigational product administration will be summarized in terms of each subject’s dose, and in 
terms of duration of exposure for each period. Descriptive statistics for these quantities, including 
the mean, median, SD, minimum, maximum, and quartiles, will be provided by treatment group. 
Additionally, the number of subjects who are compliant with investigational product will be 
presented by treatment group for the Double-blind Period and overall for the OLE.  
13.1.4. Efficacy Analysis 
The mITT population will be used as the primary population for the primary analysis of efficacy 
at Week 12. All efficacy analyses will be repeated as secondary analyses in the ITT and 
PP populations for the Double-blind Period. Efficacy analyses will also be repeated in the 
OLE Period using the OLE mITT and OLE PP populations. No formal inferential analyses will be 
conducted for efficacy variables in the OLE Period. 
13.1.4.1. Efficacy Endpoints 
Primary efficacy endpoint: The number of subjects in each treatment group who experience 
successful resolution of LI where “success” is defined as clear/almost clear overall and at least a 
50% reduction from Baseline at Week 12/ EOT in the Double-blind Period on the overall 16-point 
VIIS for scaling (i.e., 0-4 points on each of the 4 body areas: chest/abdomen, back, arms, and legs). 
Secondary: The secondary endpoints are as follow: 
• The difference in mean scores between the active trifarotene cream HE1 and 
vehicle groups in the following assessment indices: 
▪ IGA (Scale: 0-4) for each body area 
▪ Palm/sole Assessment (Scale: 0–4)  
▪ Individual score for roughness (Scale: 0–4) overall 
• The difference in proportion of subjects with presence of fissures 
(presence/absence, number of fissures, and pain associated with fissures [on a 
0-3 scale]) between the active trifarotene cream HE1 and vehicle groups  
• Quality of life per Dermatology Life Quality Index (DLQI) 
Exploratory: The exploratory endpoints are as follow: 
• The difference in mean ectropion scores (ESS of 0–8) between the active trifarotene 
cream HE1 and vehicle groups  
• Quality of life per EQ-5D-5L 
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13.1.4.2. Primary Analysis 
For the Double-blind Period only, the number and proportion of subjects in each treatment group 
with successful resolution of LI by Week 12/EOT will be presented along with the difference in 
proportions between each trifarotene cream HE1 group and vehicle. 95% confidence intervals (CI) 
will be provided for proportions. Generalized estimating equations (GEE) for binary response will 
be used to model the odds of successful resolution of LI with treatment group as a predictor. Other 
covariates, such as baseline VIIS scores, baseline characteristics, and interactions may be included. 
Various correlation matrix structures will be explored to model the within subject correlation. 
Additionally, the difference in mean VIIS score at Week 12/EOT between the active trifarotene 
cream HE1 groups and vehicle group will be analyzed using a 2-sided, 2-sample Wilcoxon 
rank-sum test at the 5% significance level. The null hypothesis is that the mean of each trifarotene 
cream HE1 group is equal to the mean of the vehicle group.  
Descriptive summaries (such as mean, standard error, median, minimum, and maximum) and the 
changes from Baseline will be provided for VIIS scores for both periods.  
13.1.4.3. Secondary Analyses 
Secondary and exploratory efficacy endpoints will be analyzed separately for each period 
(Double-blind and OLE) using descriptive statistics.  
Additionally, for the Double-blind Period only, change from Baseline through Week 12 will be 
presented and analyzed using a mixed model for repeated measures (MMRM). The model will 
include the change from baseline score as the dependent variable, treatment group as a fixed effect, 
subject as a random effect, and baseline score value as a covariate. Frequencies of results and 
95% CIs will also be reported, and scores will be analyzed as categorical variables using the 
Cochran-Mantel-Haenszel test. 
For subjects who report having fissures, descriptive summaries of the number of fissures and pain 
related to fissures will also be presented by treatment group and body area for each period. 
The DLQI scores will also be analyzed using descriptive statistics through Week 12. 
13.1.4.4. Exploratory Analyses 
Descriptive summaries and the changes from Baseline will be provided for ectropion scores and 
EQ-5D-5L scores by visit for each period. No formal inferential analyses will be conducted for 
exploratory endpoints. 
13.1.4.5. Corroborative, Sensitivity, and Other Analyses 
To assess the effect of missing data on the primary efficacy analysis, a sensitivity analysis will be 
performed using LOCF for the Double-blind Period only. Imputation will not be performed in the 
OLE period.  
For analyses involving study site, if the number of subjects per site is small, sites may be pooled 
for safety and efficacy analysis or omitted from statistical models as the anticipated number of 
subjects per site is small, treatment is self-administered, and the sites are using standardized 
procedures for all assessments. If the distribution of enrollments at sites is such that one or few are 
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enrolling a majority of subjects, a subgroup analysis by site may be performed. The final 
determination will be made prior to database lock.  
Details of these analyses will be further detailed in the SAP. 
13.1.5. Clinical Pharmacology Analyses 
13.1.5.1. Pharmacokinetics 
For noncompartmental analysis, plasma concentrations will be listed and summarized at each time 
point using descriptive statistics. Descriptive statistics reported will include the arithmetic mean, 
SD, CV%, geometric mean, minimum, maximum, and median. Only the range and the median will 
be reported for Tmax, as this is a categorical parameter. The PK parameters will also be summarized 
by treatment using descriptive statistics.  
Individual plasma concentration plots and mean data graphs will be produced using both linear 
and semi-logarithmic scales. Mean data graphs will show plasma concentration profiles by 
treatment group. 
Pharmacokinetic plasma parameter estimates and summaries will be completed for the subjects in 
the PK population. Testing of PK parameters will be outlined in the SAP. 
13.1.6. Safety and Tolerability Analyses 
Safety analyses through Week 12 of the Double-blind Period will be conducted using data from 
the Safety Population and safety analyses in the OLE Period will be conducted using the OLE 
Safety Population (as defined in Section 13.1.1). Safety variables include treatment-emergent AEs, 
clinical laboratory values, vital signs, ECG readings, and physical examination results. No formal 
inferential analyses will be conducted for safety variables in either period. 
13.1.6.1. Local Tolerability 
During all clinic visits, the investigator will assess local tolerability (Scale: 0–3 [none, mild, 
moderate, severe]) on each of the 4 body areas (chest/abdomen, back, legs, arms). Descriptive 
summaries will be presented by period, treatment group, and visit. 
13.1.6.2. Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 20.1 or higher.  
Treatment-emergent AEs are defined as: 
• AEs with onset at the time of or following the start of treatment with IP through the 
Follow-up Visit or Early Termination Visit, whichever occurs first, or 
• AEs starting prior to the start of treatment but increasing in severity or relationship at the 
time of, or following, the start of treatment with IP through the Follow-up Visit or Early 
Termination Visit, whichever occurs first. 
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The number and percentage of subjects with AEs will be displayed by each treatment group in the 
Double-blind Period and overall in the OLE by system organ class and preferred term. Summaries 
of AEs by severity and relationship to IP will also be provided. Serious adverse events and AEs 
resulting in discontinuation of IP will be summarized separately in a similar manner. Subject 
listings of AEs, SAEs, and AEs causing discontinuation of IP will be produced. 
13.1.6.3. Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from baseline values will be presented for clinical laboratory values for each treatment 
group at each time point in each period. 
The number of subjects with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from Baseline (shift tables) for each clinical 
laboratory parameter by treatment group and by study visit in each period.  
Laboratory values that are outside the normal range will also be flagged in the data listings and 
presented with the corresponding normal ranges. Any out-of-range values that are identified by 
the investigator as being clinically significant will also be shown in a data listing. 
13.1.6.4. Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for systolic blood pressure (SBP), diastolic blood pressure 
(DBP), and pulse for each period. 
The number of subjects with vital signs values categorized as below, within, or above normal 
ranges will be tabulated showing change from baseline (shift tables) for each parameter by period, 
by treatment group and by study visit. Pre- and post-treatment values may also be presented with 
an analysis of mean changes from Baseline. 
13.1.6.5. Twelve-lead Electrocardiograms 
The number and percentage of subjects with normal and abnormal ECG findings will be 
summarized for each treatment group at each time point in each period. Abnormal results will be 
grouped as clinically significant and not clinically significant. 
A comparison of QT results will be presented. Summary statistics will be displayed by period, by 
treatment group, and by visit for QT and the QT interval corrected for heart rate (QTc) calculated 
using Fridericia’s QT correction methods.  
Descriptive summaries (mean, SD, median, minimum, and maximum) will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTcF interval (Fredericia’s correction 
methods), and HR for each treatment group at each time point in each period. 
13.1.6.6. Physical Examination Findings 
The number and percentage of subjects with normal and abnormal findings in the complete 
physical examination will be displayed for each treatment group in each period. 
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13.1.7. Interim Analysis 
No interim analyses are planned.  
13.2. Sample Size Determination 
Accounting for a 20% drop-out/nonevaluable rate, a total sample size of 120 subjects randomized 
in a 1:1:1 ratio to 2 active trifarotene cream HE1 arms and a vehicle cream arm will provide >80% 
power to detect a difference between each separate trifarotene cream HE1 arm (32 evaluable 
subjects) and the vehicle cream arm (32 evaluable subjects) using a 2-sample t-test assuming a 
mean difference of at least 1.0 and a standard deviation of 1.4 or lower. This study is not powered 
to detect a difference between the 2 active arms. 
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14. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
14.1. Sponsor and Investigator Responsibilities 
14.1.1. Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 16). The sponsor reserves the right to withdraw a subject from the study (Section 8.3), to 
terminate participation of a study site at any time (Section 14.7), and/or to discontinue the study 
(Section 14.6 for US studies/Section 14.6.1 for studies conducted outside of the US). 
Mayne Pharma LLC agrees to provide the investigator with sufficient material and support to 
permit the investigator to conduct the study according to the study protocol. 
14.1.2. Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 18.1), the investigator indicates that he or she 
has read the protocol carefully, fully understands the requirements, and agrees to conduct the study 
in accordance with the procedures and requirements described in this protocol.  
The trial will be conducted in accordance with ICH GCP, and the applicable United States (US) 
Code of Federal Regulations (CFR). The principal investigator will assure that no deviation from, 
or changes to, the protocol will take place without prior agreement from the Investigational New 
Drug (IND) sponsor, funding agency and documented approval from the IRB/IEC, except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection and ICH GCP training. 
Investigators should ensure that all persons who are delegated study-related responsibilities are 
adequately qualified and informed about the protocol, the IPs, and their specific duties within the 
context of the study. Investigators are responsible for providing Mayne Pharma LLC with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
14.1.3. Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
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The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying study product may inspect all 
documents and records required to be maintained by the investigator, including, but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. 
The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB/IEC, institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at Premier Research. This will not include the participant’s contact 
or identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by clinical sites and by Premier Research staff will be secured and password protected. At the end 
of the study, all study databases will be de-identified and archived at the Premier Research 
14.2. Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from the sponsor or its designee that the study can be initiated at the study site. The study site will 
not be authorized for study initiation until: 
1. The study site has received the appropriate IRB/IEC approval for the protocol and the 
appropriate ICF. 
2. All regulatory/GCP documents have been submitted to and approved by the sponsor or its 
designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
14.3. Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study. Subjects may 
only be rescreened once 30 days or more after the original Screening Visit. If a subject is eligible 
to enter the study after having previously failed screening, the subject will be assigned a new 
subject identification number. 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
14.4. Study Documents 
All documentation and material provided by Mayne Pharma LLC for this study are to be retained 
in a secure location and treated as confidential material. 
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14.4.1. Informed Consent 
Consent forms describing in detail the study intervention, study procedures, and risks are given to 
the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. The informed consent forms are submitted with this 
protocol. 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be 
IRB/IEC-approved, and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may 
arise. A verbal explanation will be provided in terms suited to the participant’s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research participants. 
Participants will have the opportunity to carefully review the written consent forms and ask 
questions before signing. The participants should have the opportunity to discuss the study with 
their family or surrogates or think about it before agreeing to participate. The participant will sign 
the informed consent document prior to any procedures being done specifically for the study. 
Participants must be informed that participation is voluntary and that they may withdraw from the 
study at any time, without prejudice. A copy of the informed consent document will be given to 
the participants for their records. The informed consent process will be conducted and documented 
in the source document (including the date) and the form signed before the participant undergoes 
any study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
14.4.2. Investigator’s Regulatory/Good Clinical Practice Documents 
The regulatory/GCP documents are listed below. 
• Signed original protocol (i.e., Investigator’s Agreement) 
• Curricula vitae of all investigators and subinvestigators 
• Name and address of the laboratories 
• List of laboratory reference ranges, and if available, a quality certificate 
• Form Signature Log/Delegation of Study-related Duties 
• Approved ICF and subject materials 
• FDA1572 and financial disclosure forms, as applicable (US sites) 
• Any other relevant GCP documents 
The regulatory/GCP documents must be received from the investigator and reviewed and approved 
by Mayne Pharma LLC or its designee before the study site can initiate the study and before Mayne 
Pharma LLC will authorize shipment of IP to the study site. Copies of the investigator’s 
regulatory/GCP documents must be retained at the study site in a secure location. Additional 
documents, including a copy of the protocol and applicable amendment(s), the trifarotene 
(CD5789) Cream IB, eCRF completion guidelines, copies of regulatory references, copies of 
IRB/IEC correspondence, and IP accountability records should also be retained as part of the 
investigator’s regulatory/GCP documents. It is the investigator’s responsibility to ensure that 
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copies of all required regulatory/GCP documents are organized, current, and available for 
inspection. 
14.4.3. Case Report Forms 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign an 
ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the study to ensure that the study information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered in the electronic data capture 
(EDC) system according to the completion guidelines provided by the sponsor or its designee. 
The eCRFs must be signed by the investigator or a subinvestigator. These signatures serve to attest 
that the information contained in the eCRF is accurate and true. 
14.4.4. Source Documents 
Information recorded in the EDC system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
Clinical laboratory data required by the protocol will be electronically transferred from the 
central/local laboratory to the sponsor or its designee. A paper copy of the laboratory results will 
be provided to the study site and should be retained with each subject’s source data. 
14.5. Data Quality Control 
Mayne Pharma LLC and its designees will perform quality control checks on this clinical study. 
14.5.1. Monitoring Procedures 
Mayne Pharma LLC and/or its designee will conduct site visits to monitor the study and ensure 
compliance with the protocol, GCP, and applicable regulations and guidelines. The assigned 
clinical research associate(s) (CRA[s]) will visit the investigator and study site at periodic intervals 
and maintain periodic communication. The investigator agrees to allow the CRA(s) and other 
authorized Mayne Pharma LLC personnel access. The CRA(s) will maintain current personal 
knowledge of the study through observation, review of study records and source documentation, 
and discussion of the conduct of the study with the investigator and staff. While on site, the CRA(s) 
will review 
• regulatory documents, directly comparing entries in the EDC system with the source 
documents 
• consenting procedures 
• AE procedures 
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• storage and accountability of IP and study materials 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRF will be provided to the sites. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow Mayne Pharma LLC or designee auditors or inspectors from regulatory agencies 
to review records and to assist the inspectors in their duties, if requested.  
For additional information, please refer to the clinical monitoring plan (CMP). 
14.5.2. Data Management 
Mayne Pharma LLC or designee will be responsible for activities associated with the data 
management of this study. The standard procedures for handling and processing records will be 
followed per GCP and Premier Research’s standard operating procedures. A comprehensive data 
management plan (DMP) will be developed, including a data management overview, description 
of database contents, annotated CRF, pre-entry review list, self-evident correction conventions, 
query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries will be provided to the sites. 
14.5.3. Quality Assurance/Audit 
This study will be subject to audit by Mayne Pharma LLC or its designee. Audits may be performed 
to check compliance with GCP guidelines and can include: 
• site audits 
• Trial Master File audits 
• database audits 
• document audits (e.g., protocol and/or clinical study report [CSR]) 
Mayne Pharma LLC or its designee may conduct additional audits on a selection of study sites, 
requiring access to subject notes, study documentation, and facilities or laboratories used for the 
study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB/IEC or regulatory authorities according to 
GCP guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify Mayne Pharma LLC immediately. 
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14.6. Study Termination 
The study may be terminated at Mayne Pharma LLC’s discretion at any time and for any reason. 
The DSMB may recommend discontinuation of the study if they find evidence of unacceptable 
risk to subjects. 
14.6.1. Regular Study Termination 
The end of this study is defined as the date of the last visit of the last subject (last subject out or 
last subject last visit) participating in the study. Within 90 days of the end of the clinical study, 
Mayne Pharma LLC or designee will notify the IECs and regulatory authorities about the regular 
termination of the study as required according to national laws and regulations. 
14.6.2. Premature Study Termination 
The study may be temporarily suspended or terminated prematurely if there is sufficient reasonable 
cause at any time by Mayne Pharma LLC, IECs, regulatory authorities, respective steering 
committees, or the coordinating investigator. A decision to prematurely terminate the study is 
binding to all investigators of all study sites. 
Within 15 days of premature termination of a clinical study, Mayne Pharma LLC or its designee 
will notify the IECs and regulatory authorities about the premature termination as required 
according to national laws and regulations. Mayne Pharma LLC or its designee must clearly 
explain the reasons for premature termination. 
Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigator, funding agency, the IND 
or IDE sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the 
PI will promptly inform study participants, the IRB, and sponsor and will provide the reason(s) for 
the termination or suspension. Study participants will be contacted, as applicable, and be informed 
of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
If the study is terminated prematurely, all investigators have to inform their subjects and take care 
of appropriate follow-up and further treatment of the subjects to ensure protection of the subjects’ 
interests. Study sites may be asked to have all subjects currently participating in the study complete 
all of the assessments for the Follow-up Visit. 
The study might resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB/IEC and/or FDA. 
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14.7. Study Site Closure 
At the end of the study, all study sites will be closed. Mayne Pharma LLC may terminate 
participation of a study site at any time. Examples of conditions that may require premature 
termination of a study site include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate subject enrollment 
14.7.1. Record Retention 
For sites in the US, the investigator shall retain and preserve 1 copy of all data generated in the 
course of the study, specifically including, but not limited to, those defined by GCP as essential 
until 1 of the following occurs: 
• At least 2 years after the last marketing authorization for the IP has been approved or the 
sponsor has discontinued its research with the IP, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development of 
the IP. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor has 30 days to respond to the investigator’s notice, and the 
sponsor has further opportunity to retain such materials at the sponsor’s expense. 
Outside of the US, after completing the study, Mayne Pharma LLC will receive the original eCRFs 
or at least a legible copy and retain the documents for at least 5 years after the completion of the 
study. 
One copy will remain with the investigator. The investigator shall arrange for the retention of the 
subject identification codes, subject files and other source data until at least 5 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or until at least 2 years have elapsed since 
the formal discontinuation of the clinical development of the product. These documents need to be 
retained for a longer period of time if required by applicable regulatory authorities or by agreement 
with the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor shall have 30 days to respond to the investigator’s notice, 
and the sponsor shall have a further opportunity to retain such materials at the sponsor’s expense. 
Copies of these study records (and all study-related documents, including source data) shall be 
kept by the investigator for the maximum period of time permitted by the hospital, institution, or 
private practice. 
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14.7.2. Sample Retention 
Blood samples will be used for purposes related to this research. The samples will be stored until 
the sponsor has determined that specimens are no longer needed, and the decision has been made 
that none of the samples needs to be reanalyzed. In addition, identifiable samples can be destroyed 
at any time at the request of the subject. 
Data collected for this study will be analyzed and stored at Premier Research.  
14.8. Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Mayne Pharma LLC. The protocol amendment must be signed by 
the investigator and approved by the IRB or IEC before it may be implemented. Protocol 
amendments will be filed with the appropriate regulatory agency(s) having jurisdiction over the 
conduct of the study. 
14.9. Use of Information and Publication 
All information concerning trifarotene (CD5789) cream HE1, Mayne Pharma LLC’s operations, 
patent applications, formula, manufacturing processes, basic scientific data, and formulation 
information supplied by Mayne Pharma LLC or its designee to the investigator, and not previously 
published, is considered confidential and remains the sole property of Mayne Pharma LLC. Case 
report forms also remain the property of Mayne Pharma LLC. The investigator agrees to use this 
information for purposes of study execution through finalization and will not use it for other 
purposes without the written consent of the sponsor. 
The information developed in this study will be used by Mayne Pharma LLC in connection with 
the continued development of trifarotene (CD5789) cream HE1 and thus, may be disclosed as 
required to other clinical investigators or government regulatory agencies. 
The information generated by this study is the property of Mayne Pharma LLC. Publication or 
other public presentation of trifarotene (CD5789) cream HE1 data resulting from this study 
requires prior review and written approval of Mayne Pharma LLC. Abstracts, manuscripts, and 
presentation materials should be provided to Mayne Pharma LLC for review and approval at least 
30 days prior to the relevant submission deadline. Data from individual study sites must not be 
published separately. 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition, or publication by the investigator until Mayne Pharma LLC has reviewed and 
commented on such a presentation or manuscript for publication. If applicable, this study will be 
registered at ClinicalTrials.gov and clinicaltrialsregister.eu, and results information from this study 
will be submitted. 
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15. FINAL CLINICAL STUDY REPORT 
Mayne Pharma LLC will retain ownership of the data. 
The final CSR will be written within 1 year of completion of the clinical part of the study. This 
report will include a summary of the study results based on a statistical evaluation and clinical 
assessment of the protocol-defined endpoints. 
The final CSR may be submitted to the regulatory authorities.  
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16. ETHICAL AND LEGAL CONSIDERATIONS 
16.1. Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry GCP 
E6 (including archiving of essential study documents), the Integrated Addendum to ICH E6 (R2) 
of November 2016, the Declaration of Helsinki, the applicable regulations of the country(ies) in 
which the study is conducted, and with the Commission Directives 2001/20/EC and 2005/28/EC. 
16.2. Subject Information and Informed Consent 
A properly constituted, valid IRB or IEC must review and approve the protocol, the investigator’s 
ICF, and related subject information and recruitment materials before the start of the study. 
It is the responsibility of the investigator to ensure that written informed consent is obtained from 
the subject before any activity or procedure is undertaken that is not part of routine care. 
According to the Declaration of Helsinki and ICH GCP, subjects must provide their written 
informed consent prior to enrollment in a clinical study and before any protocol-specified 
procedures are performed. Subjects must declare their consent by personally signing and dating 
the ICF. The written ICF will embody the elements of informed consent as described in the 
Declaration of Helsinki and will also comply with local regulations.  
Each subject should be made aware by the investigator of the nature of the study (objectives, 
methods, and potential hazards and benefits) and the procedures involved, using the information 
on the ICF. Information should be given in both oral and written form whenever possible and 
deemed appropriate by the IRB/IEC. Subjects, their relatives, or, if necessary, legal representatives 
must be given ample opportunity to inquire about details of the study.  
Subject information and the ICF must be in a language fully comprehensible to the prospective 
subject. The written information must be provided to the subject to give him or her sufficient time 
to understand the information and to prepare questions before being asked for his or her consent. 
The investigator must confirm that the text was understood by the subject. The subject will then 
sign and date the IRB/IEC-approved consent form indicating that he or she has given his or her 
consent to participate in the study. The signature confirms that the consent is based on information 
that has been understood. The form will also be signed by the investigator obtaining the consent 
and annotated with the study subject number. Each subject’s signed ICF must be kept on file by 
the investigator for possible inspection by regulatory authorities, Mayne Pharma LLC, and/or the 
sponsor’s designee. Collection of informed consent has to be documented in the eCRF. 
Furthermore, the subject will be informed that if he or she wishes to dropout or withdraw (see 
Section 8.3) at any time during the study, this will not have any negative consequences. Subjects 
may be withdrawn by the investigator if any change related to safety or ethics precludes further 
participation in the study. Subjects will be asked to agree to a final assessment in the event of an 
early termination of the study. 
Subjects will be informed that data from their case may be stored in a computer without inclusion 
of their name and that such data will not be revealed to any unauthorized third party. Data will be 
reviewed by the monitor, an independent auditor, and possibly by representatives of regulatory 
authorities and/or IRBs/IECs. The terms of the local data protection legislation will be applied as 
appropriate. 
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16.3. Approval by Institutional Review Board and Independent Ethics Committee 
A valid IRB/IEC must review and approve this protocol before study initiation. Written 
notification of approval is to be provided by the investigator to the sponsor’s or the sponsor’s 
representative before shipment of investigational drug supplies, and will include the date of the 
committee’s approval and the chairperson’s signature. This written approval must follow local 
country requirements. 
Until written approval by the IRB/IEC has been received by the investigator, no subject may 
undergo any procedure not part of routine care for the subject’s condition. 
Protocol amendments must also be reviewed and approved by the IRB/IEC. Written approval from 
the IRB/IEC, or a designee, must be received by Mayne Pharma LLC before implementation.  
16.4. Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator 
and the sponsor. 
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17. REFERENCES 
1. Vahlquist A, Blockhuys S, Steijlen P, 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 Derm. 2014;170(1):173-181. 
2. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited 
ichthyoses: results of the first ichthyosis consensus conference in sorèze 2009. J Am Acad 
Dermatol. 2010;63(4):607–-641. 
3. Vahlquist A, Gånemo A, Virtanen M. Congenital ichthyosis: an overview of current and 
emerging therapies. Acta Derm Venereol. 2008;88(1):4–14. 
4. Blanchet-Bardon C, Nazzaro V, Rognin C, Geiger JM, Puissant A. Acitretin in the 
treatment of severe disorders of keratinization. J Am Acad Dermatol. 1991;24(6):982–986. 
5. Kullavanijaya P and Kulthanan K. Clinical efficacy and side effects of acitretin on the 
disorders of keratinization: a one-year study. J Dermatol. 1993;20:501–506. 
6. Lacour M, Nikhar-Mehta B, Atherton DJ, Harper JI. An appraisal of acitretin therapy in 
children with inherited disorders of keratinization. Br J Dermatol. 1996;134:1023–1029. 
7. Steijlen PM, Van Dooren-Greebe RJ, Van De Kerkhof PCM. Acitretin in the treatment of 
lamellar ichthyosis. Br J Dermatol. 1994;130(2):211–214. 
8. Katugampola RP, Finlay AY. Oral retinoid therapy for disorders of keratinization: single-
centre retrospective 25 years’ experience on 23 patients. Br J Dermatol. 
2006;154(2):267-276. 
9. Gånemo A, Virtanen M, Vahlquist A. Improved topical treatment of lamellar ichthyosis: a 
double‐blind study of four different cream formulations. Br J Derm. 1999;141(6):1027–
1032. 
10. Kiistala R, Lauharanta J, Kanerva L. Transepidermal water loss and sweat gland response 
in lamellar ichthyosis before and during treatment with etretinate: report of three cases. 
Acta Derm Venereol. 1982;62(3):268–270. 
11. Ramirez ME, Youseef WF, Romero RG. Acute percutaneous lactic acid poisoning in a 
child. Pediatr Dermatol. 2006;23(3):282–285. 
12. Chiaretti A, Wismayer DS, Tortorolo L, Piastra M, Polidori G. Salicylate intoxication using 
a skin ointment. Acta Paediatr. 1997;86(3):330–331. 
13. Marukian NV, Deng Y, Gan G, et al. Establishing and validating an ichthyosis severity 
index. J Invest Dermatol. 2017;137(9):1834-1841. 
14. Korteweg SFS, Stenekes MW, van Zyl FE, Werker PMN. Paralytic Ectropion treatment 
with lateral periosteal flap canthoplasty and introduction of the ectropion severity score. 
Plast Reconstr Surg Glob Open. 2014;2(5):e151. 
 
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18. ATTACHMENTS 
18.1. Investigator’s Agreement 
PROTOCOL 
NUMBER: 
18-ICH-001 
PROTOCOL TITLE: 
A Phase 2 Randomized, Multi-center, Double-blind, 
Vehicle-controlled, 12-Week, Safety, Efficacy, and Systemic 
Exposure Study followed by a 12-Week Open-label Extension of 
Trifarotene (CD5789) Cream HE1 in Subjects with Autosomal 
Recessive Ichthyosis with Lamellar Scale 
FINAL PROTOCOL 
DATE: 
v2.0 for Ukraine, 21-Oct-2019 
I have read this protocol and agree to conduct this clinical study as outlined herein. I will ensure 
that all subinvestigators and other study staff members have read and understand all aspects of this 
protocol. I agree to cooperate fully with Mayne Pharma LLC and Premier Research during the 
study. I will adhere to all FDA, ICH, and other applicable regulations and guidelines regarding 
clinical studies on an IP during and after study completion. 
Principal Investigator: 
 
Printed Name: 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
 
 
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PROTOCOL NUMBER: 
18-ICH-001 
PROTOCOL TITLE: 
A 
Phase 
2 
Randomized, 
Multi-center, 
Double-blind, 
Vehicle-controlled, 12-Week, Safety, Efficacy, and Systemic 
Exposure Study followed by a 12-Week Open-label Extension of 
Trifarotene (CD5789) Cream HE1 in Subjects with Autosomal 
Recessive Ichthyosis with Lamellar Scale 
FINAL PROTOCOL 
DATE: 
v2.0 for Ukraine, 21-Oct-2019 
The undersigned acknowledges possession of and has read the product information (e.g., the IB) 
on the IP and has discussed these data with the study monitor. Having considered fully all the 
available information, the undersigned considers that it is ethically justifiable to give the IP to 
selected subjects in his/her care, according to the study protocol. 
He or she agrees to use the study material, including IP, only as specified in the protocol. He or 
she understands that changes cannot be made to the protocol without prior written approval of 
Mayne Pharma LLC. 
He or she understands that any deviation from the protocol may lead to early termination of the 
study. 
He or she agrees to report to Mayne Pharma LLC within time any clinical AE or abnormal 
laboratory value that is serious, whether or not considered related to the administration of IP. 
He or she agrees to comply with Mayne Pharma LLC and regulatory requirements for the 
monitoring and auditing of this study. 
In addition, he or she agrees that the study will be carried out in accordance ICH, the Declaration 
of Helsinki, and the local laws and regulations relevant to the use of new therapeutic agents. 
I, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the study. 
Principal Investigator: 
 
Printed Name: 
 
 
 
Signature: 
 
 
 
 
Date: 
 
 
 
 
Investigator’s name and address (stamp) 
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APPENDICES 
A. Regulations and Good Clinical Practice Guidelines 
 
 
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A. Regulations and Good Clinical Practice Guidelines 
1. Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
Refer to the following European Directives (and applicable regulations/guidances): 
• European Directive 2001/20/EC and related guidance documents 
• European Directive 2005/28/EC and related guidance documents> 
2. Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URLs: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf 
 
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Page 1 of 134 
PROTOCOL/CLINICAL INVESTIGATION PLAN AMENDMENT 
PRODUCT NAME/NUMBER: 
Trifarotene (CD5789) Cream HE1 
PROTOCOL NUMBER: 
IND NUMBER: 
NCT NUMBER:  
EUDRACT NUMBER: 
DEVELOPMENT PHASE: 
PROTOCOL TITLE: 
PROTOCOL DATE: 
AMENDMENT 1 DATE: 
COORDINATING/PRINCIPAL 
INVESTIGATOR: 
SPONSORED BY: 
CONTRACT RESEARCH 
ORGANIZATION: 
18-ICH-001
140538 
NCT03738800 
2018-003272-12 
2 
A Phase 2 Randomized, Multicenter, Double-blind, 
Vehicle-controlled, 12-Week, Safety, Efficacy, and 
Systemic Exposure Study followed by a 12-Week 
Open-label Extension of Trifarotene (CD5789) Cream HE1 
in Adults and Adolescents with Autosomal Recessive 
Ichthyosis with Lamellar Scale  
Original: 28-Nov-2018; Version 2.0: 10-Jul-2019 
Final, 10-Jul-2019 
Keith A. Choate, MD 
Department of Dermatology, Yale University School of 
Medicine,  
PO Box 208059 
333 Cedar Street 
New Haven, CT 06520, USA 
+1 203 789 1249
Mayne Pharma LLC 
1240 Sugg Parkway   
Greenville, NC 27834, USA 
+1 984 242 1400
Premier Research  
One Park Drive, Suite 150 
Durham, NC 27709, USA 
+1 919 627 9100
This study will be performed in compliance with ICH Good Clinical Practices and applicable 
regulatory requirements, including the archiving of essential documents. Information contained in 
this protocol is confidential in nature and may not be used, divulged, published, or otherwise 
disclosed to others except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. Persons to whom this information 
is disclosed should be informed that it is confidential and may not be further disclosed without the 
express permission of Mayne Pharma LLC. 
· pharma 
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1.
APPROVAL SIGNATURES
PROTOCOL NUMBER:
18-ICH-001
PROTOCOL TITLE:
A Phase 2 Randomized, Multi-center, Double-blind, 
Vehicle-controlled, 12-Week, Safety, Efficacy, and Systemic 
Exposure Study followed by a 12-Week Open-label Extension of 
Trifarotene (CD5789) Cream HE1 in Adults and Adolescents with 
Autosomal Recessive Ichthyosis with Lamellar Scale
I, the undersigned, have read this protocol and confirm that to the best of my knowledge, it 
accurately describes the planned conduct of the study.
SIGNATURE
DATE:
Ilana Stancovski, PhD 
Chief Scientific Officer 
Mayne Pharma LLC
Phoevos Hughes, JD
Associate Director, Clinical Operations
Mayne Pharma LLC
Marlis Sarkany, MD
Senior Medical Director
Premier Research
Adrienne Kuxhausen, MS
Senior Biostatistician
Premier Research
r DocuSigned by: 
I l~~ttW...UM-11:.i 
IJ 
l 
Signer Name: Ilana Stancovski 
Signing Reason: I approve this document 
Signing Time: 16-Jul-2019 [ 10:49 EDT 
EDOeBBBBaAEe401189B9e1E2GeOe0B77 
(.DocuSigned by: 
I R.o'-"-"',*~ 
IJ 
Signer Name: Phoevos Hughes 
Signing Reason: I approve this document 
_Signing Time: 16-Jul-2019111:48 EDT 
r DocuSigned by: 
I 
-,.,...,t;., 
IJ 
Signer Name: Marlis Sarkany 
Signing Reason: I have reviewed this document 
r
DocuSigned by: 
I 
J/;,-.. ;'--'V\,<. t..~ 
IJ 
Signer Name: Adrienne Kuxhausen 
t Signing Reason: I approve this document 
Sig11i11g Ti111e. 17-Jul-2019108.44 EElT 
AD-MW-07.06 08-Dec-2017 
16-Jul-2019 I 10:49:28 EDT 
16-Jul-2019 I 08:49:00 PDT 
17-Jul-2019 I 07:53:06 EDT 
17-Jul-2019 I 08:44:28 EDT 
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2. PROTOCOL SUMMARY 
2.1. Synopsis 
PRODUCT 
NAME/NUMBER 
Trifarotene (CD5789) Cream HE1 
PROTOCOL 
NUMBER 
18-ICH-001 
EUDRACT 
NUMBER 
2018-003272-12 
DEVELOPMENT 
PHASE 
2 
PROTOCOL TITLE 
A Phase 2 Randomized, Multi-center, Double-blind, Vehicle-controlled, 12-Week, 
Safety, and Efficacy, and Systemic Exposure Study followed by a 12-Week Open-label 
Extension of Trifarotene (CD5789) Cream HE1 in Adults and Adolescents with 
Autosomal Recessive Ichthyosis with Lamellar Scale  
INDICATION 
Lamellar ichthyosis 
OBJECTIVES 
Primary: To compare the safety and efficacy of 2 concentrations of trifarotene cream HE1 
versus vehicle in adults and adolescents with moderate to severe autosomal recessive 
ichthyosis with lamellar scale, also known as lamellar ichthyosis (LI) after 12 weeks of 
treatment. 
Secondary:  
• 
To assess systemic exposure to trifarotene and its major metabolites after topical 
application of the investigational product (IP) on up to 90% body surface area (BSA) 
twice weekly. 
• 
To assess safety for up to 24 weeks of dosing with open-label trifarotene cream HE1 
200 µg/g. 
STUDY DESIGN 
 
This is a 2-cohort, multicenter study in subjects with moderate to severe LI (i.e., 3–4 on 
a 5-point Investigator’s Global Assessment [IGA] where 0 = clear; 1 = almost clear; 2 = 
mild; 3 = moderate; 4 = severe). Adults (Cohort A) and adults and adolescents (Cohort 
B) will be randomized in a double-blind fashion to 1 of 2 doses of trifarotene cream HE1 
or vehicle and treated twice weekly for 12 weeks. Subjects who complete the randomized, 
Double-blind Period of the study will be eligible to enter a 12-week, Open-label Extension 
(OLE) in which additional PK, safety, and efficacy data will be collected. 
Approximately 15 adults (≥18 years old) will be randomized into the first cohort of 
subjects (Cohort A) in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g, trifarotene cream 
HE1 200 µg/g, or vehicle and treated twice weekly for up to 12 weeks. After the initial 
15 subjects complete at least 28 days of treatment, an independent data safety monitoring 
board (DSMB) will review aggregate safety and tolerability data (including PK and 
electrocardiogram [ECG] data). If no safety issues are identified, both adults and 
adolescents (ages 12 to 17 years, inclusive) will be allowed to enroll in Cohort B. Subjects 
in Cohort B will be randomized 1:1:1 to trifarotene cream HE1 100 µg/g, trifarotene 
cream HE1 200 µg/g, or vehicle and treated twice weekly for up to 12 weeks in the same 
manner as subjects in Cohort A. All subjects (Cohort A and Cohort B) who complete the 
12-week Double-blind Treatment Period will be eligible to enroll in the 12-week OLE. 
Subjects in the OLE will receive open-label trifarotene cream HE1 200 µg/g twice weekly 
for up to 12 weeks.  
Written informed consent will be obtained from a parent/legal guardian for any minor and 
minors will provide assent before any study-related procedures are performed. 
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Upon signing informed consent and entering the Screening Period, subjects may begin 
washout, during which they will stop using physical and medical treatments for LI, 
including balneotherapy and the following prohibited medications, as applicable. 
Washout may be up to 3 months, as necessary.  
a. 
Topical treatments 
Medication 
Washout  
Corticosteroids (except inhaled and ophthalmic corticoids) 
2 weeks 
Retinoids (e.g., tretinoin, tazarotene) 
4 weeks 
Vitamin D analogues 
2 weeks 
Immunosuppressants (e.g., tacrolimus) 
2 weeks 
Antracen derivatives, tar and salicylic preparations 
2 weeks 
Keratolytics (such as urea, lactic acid, propylene glycol, 
salicylic acid) except keratolytic shampoo 
2 weeks 
b. Systemic treatments 
Medication 
Washout  
Retinoids 
8 weeks 
Oral Vitamin A supplementation more than 3500 IU per day 
2 weeks 
Medication interfering with bone activity, e.g., corticosteroids, 
thyroid hormones, cytotoxics, bisphosphonates, calcitonins, 
tetracyclines, quinolones, thiazides, salicylates in long-term 
course, heparin, theophylline, barbiturates, colchicines (except 
Vitamin D analogues taken at stable dose since at least 1 month) 
8 weeks 
QT prolonging drugs 
5 half lives 
Enzymatic inductors (such as rifampicine, phenytoin, 
carbamazepine, phenobarbital, St. John’s Wort) 
3 months 
CYP2C9 and 2C8 inhibitors (not all inclusive: gemfibrozil, 
fluconazole, fluvoxamine, sulfaphenazole, miconazole, 
amiodarone, sertraline, sulfamethoxazole, valproic acid, 
voriconazole, trimethoprim, rosiglitazone, pioglitazone) 
5 half lives 
Monoclonal antibody treatment (e.g., anti-IL17) 
5 half lives 
During washout, subjects may continue taking usual care of visible skin (face and scalp) 
for cosmetic reasons and of extremities (hands and feet) to avoid functional consequences 
on walking or moving their fingers. Subjects may shower but not bathe or swim during 
the Screening Period.  
After completing any necessary washout of prohibited medications, subjects will return 
to the site to complete the study eligibility requirements. 
Study drug will be packaged in 50-g tubes from which up to 36 g of investigational 
product (IP) may be dispensed per application, i.e., the maximum dose per application. 
Study staff will apply the first dose of study drug to each subject in the clinic on Day 1 
after Baseline measurements, and will record the amount of study drug applied. If the 
product will be applied at home by someone other than the study subject, it is 
recommended that person assist with application at the first visit to learn how the IP is 
applied. 
Thereafter, each subject will apply approximately the same amount (up to 36 g) of study 
drug as for the first dose on up to 90% of BSA twice weekly, sparing the scalp, inguinal, 
and axillary areas. Subjects will receive an adequate number of tubes to use 1 tube per 
application and will use a new tube for each treatment day. Subjects may use less than the 
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full amount of product in a tube. Subjects will record the date and time of study treatment 
administration in the subject diary. 
Local tolerability may differ in subjects with LI compared to healthy subjects, as their 
skin is drier and may be more sensitive. Local tolerability will be followed very carefully 
during the study. Subjects will receive information on study drug use and stopping rules 
and will be instructed to contact the site with any safety/tolerability issues. Study 
personnel will telephone subjects in between scheduled visits (i.e., at Day 7 and Day 45 
in the Double-blind Period; at Day 97 and 134 in the OLE) to assess safety; an 
unscheduled clinic visit may be performed, if necessary. If the treatment causes 
application site reactions, the frequency of application will be reduced or interrupted only 
on the area of concern, as indicated herein. During all clinic visits, the investigator will 
assess local tolerability (Scale: 0-3 [none, mild, moderate, severe]) for stinging/burning, 
pruritus, erythema) for each body area (chest/abdomen, back, arms, legs, and face/neck), 
and the following procedures will be followed: 
- 
If a score of 2 (moderate) is recorded on a local tolerability assessment scale 
(stinging/burning, pruritus, erythema) on any treated area, the study drug will be 
applied on that area only once weekly, until the score is back to <2. Continue to 
treat all other areas twice weekly provided the score is <2 on those areas. 
- 
If a score of 3 (severe) is recorded on a local tolerability assessment scale 
(stinging/burning, pruritus, erythema) on any treated area, the study drug will not 
be applied on that area until the score is back to <3 (i.e., “drug holiday”). Continue 
to treat all other areas twice weekly provided the score is <2 on those areas. 
Stopping rules and treatment modification will be defined at the subject level based on 
local tolerability, selected laboratory parameters, and adverse events (AEs). Any changes 
in dosing must be documented in the subject diary and the electronic case report form. 
All subjects will be provided with diaries in which to record study drug application 
(days/times and any areas of skin not treated [e.g., due to local reactions]) and any AEs, 
including application site reactions and concomitant medications used. Subjects will also 
be advised on permitted emollient(s) use on nontreatment days during the study; use of 
emollient(s) and/or sunscreen(s) on study drug treatment days within 4 hours before or 
after study drug application is prohibited. 
At all sites with photographic capability, photographs will be taken as source data to 
support scoring at Baseline, Day 30, and Day 90. A central reader who will not be an 
investigator in the study will review the photographs to assess consistency of investigator 
scoring of LI severity as a quality check. Photographs may also be used for scientific 
publication purposes. Subjects will sign a separate, optional photographic informed 
consent form (ICF). 
Samples for pharmacokinetic (PK) analysis will be drawn from all subjects at Baseline 
and at each clinic visit. Visits for PK must occur at least 24 hours after the last application 
of the IP to avoid contamination of the blood samples with any IP that may have remained 
on the skin after the last application. Subjects should not apply IP on visit days until after 
the visit. 
In addition, a PK substudy will be conducted on Days 1 and 30 at sites with the capability 
to conduct it. Participation in the PK substudy will be optional and will include at least 
30 subjects, 15 adults and 15 adolescents. Subjects who participate in the PK substudy 
will come from both study cohorts and will undergo serial blood sampling predose and at 
1, 2, 4, 8, 12, and 24 hours postdose on Day 1 and Day 30. Trough levels will be drawn 
for these subjects at each of the other clinic visits. For the subjects in the PK substudy, 
postdose ECGs will be performed at each serial blood draw on Day 1 and Day 30. 
Subjects who complete the Double-blind Treatment Period will have the option to 
continue into the OLE to assess safety for an additional 12-weeks with trifarotene cream 
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HE1 200 µg/g twice weekly, on up to 90% of BSA, sparing the scalp, inguinal, and 
axillary areas. Subjects with heavy facial hair should not apply IP to hair-bearing areas. 
During the OLE, subjects will return to the site at Weeks 14, 16, 20, 24, and 26 for safety, 
tolerability, and efficacy assessments. Blood samples will be drawn for clinical laboratory 
safety tests and PK at Weeks 16 and 24. Study personnel will telephone subjects in 
between scheduled visits (i.e., at Day 97 and Day 134) to assess safety; an unscheduled 
clinic visit may be performed, if necessary.  
PLANNED 
NUMBER OF 
SUBJECTS 
Approximately 120 total subjects; 15 adult subjects in Cohort A and 105 adult and 
adolescent subjects in Cohort B. 
STUDY ENTRY 
CRITERIA 
Inclusion criteria:  
1. For Cohort A: subject is ≥18 years old; for Cohort B: subject is ≥12 years old.  
2. Subject has known diagnosis of LI.  
3. Subject has moderate to severe (IGA 3-4) LI on the IGA of LI severity.  
4. Subject has signed an ICF at Screening before any investigational procedures. 
Subjects <18 years of age (or Age of Majority) must sign an assent form in 
conjunction with an ICF signed by the parent/legal representative. 
5. Subject who is participating in photography has signed a photography ICF. 
6. Subject who is participating in the optional PK substudy has signed a PK ICF. 
7. Subject is not of childbearing potential, i.e., a female who has not yet begun 
menstruating or who is postmenopausal (absence of menstrual bleeding for 1 year 
before Baseline, without any other medical reason, hysterectomy or bilateral 
oophorectomy),  
OR  
Subject is a woman of childbearing potential (WOCBP) or a male subject with sexual 
partners capable of reproduction who agrees to use 2 effective forms of contraception 
during the study and for at least 1 month after the last study drug application. The 
2 authorized forms of contraception are condom used with 1 of the following 
methods of contraception: 
• bilateral tubal ligation 
• combined oral contraceptives (estrogens and progesterone) or implanted or 
injectable contraceptives with a stable dose for at least 1 month before Baseline; 
hormonal contraceptives must inhibit ovulation 
• hormonal intrauterine device (IUD) inserted at least 1 month before Baseline 
OR 
Agrees to abstain from heterosexual intercourse during study participation and for 
1 month after the last application of study drug and to use a highly effective 
contraceptive as backup if he or she becomes sexually active during the study. 
Abstinence is only acceptable if this is the subject’s usual lifestyle. Periodic 
abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception. 
AND 
Male subjects may not donate sperm during the study and for at least 1 month after 
the last study drug application. 
Note: Subjects who are premenstrual at Screening but begin menses during the study 
should follow the pregnancy testing schedule for WOCBP and must abstain from 
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sexual intercourse while in the study and for at least 1 month after the last study drug 
application. 
8. Women of child-bearing potential must be nonlactating and have negative pregnancy 
test results at Screening (serum) and on Day 1 before study drug administration 
(urine). 
9. Subject is reliable and capable of adhering to the protocol and visit schedule, in the 
investigator’s judgment, and has signed informed consent/assent, as applicable. 
10. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin). 
 
Exclusion criteria: 
1. Subject has any variant of ichthyosis other than LI or another disorder of 
keratinization, including syndromic ichthyoses.  
2. Subject has current moderate or severe stinging/burning at Screening. 
3. Subject has an ongoing cutaneous infection or any other significant concomitant skin 
disease (other than the LI) which, in the investigator’s opinion, may interfere with 
the study assessments. 
4. Subject with a known lipid disorder (hypertriglyceridemia >200 mg/dL, 
hypercholesterolemia >250 mg/dL) unless well controlled by stable doses of 
lipid-lowering agents for at least 6 months. 
5. Subject was previously treated with trifarotene/CD5789 in an acne or ichthyosis 
study.  
6. Subject has any other significant concomitant disease, or poorly controlled medical 
condition other than LI that in the investigator’s opinion may put him or her at risk if 
he or she takes part in the study, and/or that may interfere with the study assessments.. 
7. Subject has a medical condition that potentially alters bone metabolism 
(e.g., osteoporosis, thyroid dysfunction, Cushing syndrome, Crohn’s disease, or 
ulcerative colitis). 
8. Subject is being treated for major depression disorder and/or has a history of major 
depression or suicide attempt requiring hospitalization, medications, and close 
psychiatric surveillance to prevent suicide attempts.  
9. Subject with positive serology for hepatitis B surface antigen, hepatitis C, or are 
known to be HIV positive or to have AIDS at Screening. 
10. Subject with any of the following laboratory values at Screening: 
a. 
Aspartate aminotransferase or alanine aminotransferase >1.5 × upper limit 
of normal defined by the laboratory 
b. Total bilirubin >1.1 mg/dL or, in case of Gilbert’s syndrome, total bilirubin 
>3 mg/dL 
c. 
Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women 
d. Platelets <150 × 109/L or >400 × 109/L 
11. Subject has any clinically other significant abnormal laboratory value (hematology, 
chemistry, or urinalysis) at Screening that, in the investigator’s opinion, may put the 
subject at risk if he or she takes part in the study, and/or that may interfere with the 
study assessments. 
12. Subject has had recent systemic malignancy (e.g., within 5 years) with exception of 
nonmelanoma skin cancer or cervical intraepithelial neoplasia of Grade 1 who are 
>6 months post-treatment. 
13. Subject has a history of long QT syndrome or clinically significant electrocardiogram 
(ECG) abnormalities, including clinically significant conduction disorders or 
significant arrhythmias, QTcF interval >450 ms, PR interval is not between 120 and 
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220 ms (inclusive), HR >100 bpm or <50 bpm, QRS interval >110 ms, or 
QT intervals that cannot be consistently analyzed. 
14. Subject has a known allergy or sensitivity to any of the components of the 
investigational products.  
15. Subject has been exposed to excessive ultraviolet (UV) radiations on the treated 
zones within 1 month before Baseline visit or is planning intensive UV exposure 
during the study (e.g., occupational exposure to the sun, sunbathing, phototherapy, 
etc.). 
16. Subject is inherently sensitive to sunlight. 
17. Subject is unable or unwilling to stop use of topical or systemic retinoids. 
18. Subject is presumed to be abusing drugs or alcohol at Screening or Baseline Visits 
based on medical history or current clinical symptoms. 
19. Subject is participating in another interventional clinical trial. 
20. Subject is institutionalized. 
21. Subject is in any way related to the sponsor, investigator, or site personnel. 
INVESTIGATIONAL 
PRODUCT 
Name: Trifarotene (CD5789) cream HE1  
Double-blind Period dose, route, frequency: A fixed dose (up to 36 g per dose, determined 
at Visit 2) of 100 µg/g or 200 µg/g applied topically twice weekly on up to 90% BSA  
Open-label Extension dose, route, frequency: A fixed dose (up to 36 g per dose, 
determined at Visit 2) of 200 µg/g applied topically twice weekly on up to 90% BSA 
REFERENCE 
PRODUCT(S) 
Name: Vehicle cream 
Double-blind Period dose, route, frequency: A fixed dose (up to 36 g per dose, determined 
at Visit 2) applied topically twice weekly on up to 90% BSA  
TREATMENT 
REGIMENS 
Topical application twice weekly to all affected skin except the scalp, axillae, and inguinal 
area.   
COORDINATING/ 
PRINCIPAL 
INVESTIGATOR 
Keith A. Choate, MD 
Department of Dermatology, Yale University School of Medicine 
New Haven, CT 06520, USA 
PLANNED STUDY 
SITES 
Approximately 40 sites across North America, Europe, Israel, and Australia 
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CRITERIA FOR 
EVALUATION 
Primary efficacy endpoint: The proportion of subjects in each treatment group who 
experience successful resolution of LI where “success” is defined as clear/almost clear on 
treated areas and at least a 2-grade change from Baseline at Week 12/end-of-treatment 
(EOT) in the Double-blind Period on the 5-point IGA full body scale.  
Secondary endpoints:  
− 
The difference in mean scores between the active trifarotene cream HE1 and 
vehicle groups in the following assessment indices from Baseline through Week 12: 
− 
5-point Visual Index for Ichthyosis Severity (VIIS) for scaling from 
Baseline through Week 12 (overall 16 points for scaling, i.e. 0-4 points for 
4 body areas: chest/abdomen, back, arms and legs) 
− 
Individual score for roughness (Scale: 0–4) overall 
− 
Palm/sole Assessment (Scale: 0–4)  
− 
Quality of life per Dermatology Life Quality Index (DLQI) and children’s 
DLQI (cDLQI) 
− 
The difference in proportion of subjects with presence of fissures on palms/soles 
(presence/absence, number of fissures, and pain associated with fissures on a 0-3 
scale) at Week 12 between the active trifarotene cream HE1 and vehicle groups 
Exploratory endpoints:  
− 
The difference in mean ectropion (Ectropion Severity Score [ESS] of 0–8) scores 
between the active trifarotene cream HE1 and vehicle groups from Baseline through 
Week 12 
− 
The difference in quality of life per EQ-5D-5L and EQ-5D-Y score between the 
active trifarotene cream HE1 and vehicle groups from Baseline through  Week 12 
Safety endpoints:  
− 
Reported serious adverse events (SAEs), treatment-emergent AEs (TEAEs), and 
changes in clinical laboratory tests, vital signs, physical examinations, and 12-lead 
ECGs  
− 
Local tolerability (Scale: 0-3 [none, mild, moderate, severe], determined by the 
investigator) for each body area (chest/abdomen, back, legs, arms, and face/neck). 
Pharmacokinetic endpoints: Plasma concentrations of CD5789 and its major metabolites 
will be measured. 
STATISTICAL 
METHODS 
Analysis Populations:  
The following are planned for the Double-blind Period of the study: 
The Safety population will be the primary population for analyses of safety and 
tolerability and will comprise all subjects who are randomized to treatment and receive at 
least 1 application of study drug.  
The intent-to-treat (ITT) population will comprise all randomized subjects. This 
population will be used as the primary population for the analysis of efficacy for the 
Double-blind Period of the study. 
The modified intent-to-treat (mITT) population comprises all subjects in the safety 
population with at least 1 postbaseline assessment of efficacy in the Double-blind Period. 
This population will be used as the primary population for the analysis of efficacy for the 
Double-blind Period of the study. 
The per protocol (PP) population will be defined prior to database lock and will comprise 
subjects in the mITT population who met all inclusion criteria and no exclusion criteria, 
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were compliant with study drug application, and who had no significant protocol 
deviations.  
The PK population includes all subjects in the Safety Population who have at least 
1 plasma sample with quantifiable concentration. The PK population will be used to 
summarize all PK endpoints. 
The following populations are planned for the OLE of this study: 
The OLE Safety population: all subjects who complete the 12-week Double-blind 
Treatment Period and receive at least 1 application of study drug in the OLE. 
OLE ITT population: all subjects who complete the 12-week Double-blind Period and 
who sign the OLE informed consent. 
The OLE mITT population: all subjects in the OLE safety population with at least 
1 assessment of efficacy after Visit 6. 
The OLE PP population: all subjects in the OLE mITT population who met all inclusion 
criteria and no exclusion criteria, were compliant with study drug application from 
baseline through EOT, and who had no significant protocol deviations throughout the 
study. 
Subject Characteristics and Disposition: Descriptive statistics will be used to summarize 
demographic characteristics (age, sex, ethnicity, and race) and baseline characteristics for 
all enrolled subjects. Medical history, physical examination findings, and vital sign 
measurements for all randomized subjects will be presented in listings. 
Efficacy Analyses: The number and proportion of subjects in each treatment group with 
successful resolution of LI by Week 12/EOT in the Double-blind Period will be presented. 
The primary efficacy endpoint will be analyzed using a logistic regression model with 
treatment and age group as factors. Other baseline characteristics and interactions may be 
included. The odds ratios and 95% CIs for the odds ratios will be presented. The difference 
in proportions between the active trifarotene cream HEI and vehicle cream groups, 
95% CIs for the differences, and P-values for the differences in treatment will also be 
presented. 
The IGA scores as well as secondary and exploratory efficacy endpoints will be analyzed 
by visit using descriptive statistics through Week 24. Change from Baseline through 
Week 12 will be presented and analyzed using a mixed model for repeated measures 
(MMRM). The model will include the change from Baseline score as the dependent 
variable, treatment group as a fixed effect, subject as a random effect, and Baseline score 
value as a covariate. Frequencies of results and 95% confidence intervals will also be 
reported, and scores will be analyzed as categorical variables using the Cochran-Mantel-
Haenszel test. For subjects who report having fissures, the number of fissures and pain 
related to fissures will also be presented on a scale of 0-3 (none, mild, moderate, severe). 
Clinical Pharmacology Analyses: Noncompartmental PK analysis will be performed for 
the PK subset of subjects, as data permit. Plasma concentrations of CD5789 and its major 
metabolites will be measured and will be listed by subject. 
Safety Analyses: Safety and tolerability will be assessed based on the incidence of 
reported TEAEs, and SAEs, including relationship to study drug and severity, as well as 
physical examination findings, vital sign measurements (supine systolic blood pressure 
[SBP] and diastolic blood pressure [DBP] and pulse), clinical laboratory results 
(hematology, including serum aminotransferases and serum lipids, coagulation, clinical 
chemistry, and urinalysis) and 12-lead ECGs. Descriptive statistics for observed values 
and change from Baseline will be calculated at each visit within each study period and by 
treatment group within cohort. 
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SAMPLE SIZE 
DETERMINATION 
The first cohort of 15 adult subjects is a reasonable sample size to assess safety and 
tolerability before enrolling adolescents. Accounting for a 20% drop-out/nonevaluable 
rate, a total sample size of 120 subjects randomized in a 1:1:1 ratio to 2 active trifarotene 
cream HE1 arms and a vehicle cream arm will provide >80% power to detect a difference 
between each separate trifarotene cream HE1 arm (32 evaluable subjects) and the vehicle 
cream arm (32 evaluable subjects) 2-sided Fisher’s Exact Test assuming a 70% success 
rate and a 40% success rate, respectively.. This study is not powered to detect a difference 
between the 2 active arms. 
STUDY AND 
TREATMENT 
DURATION 
The sequence and maximum duration of the study will be as follows:  
1. Screening: Up to 35 days (after signing informed consent, if necessary, washout may 
be up to 3 months, and subjects should return to the site after washout to complete 
the study eligibility requirements). 
2. Double-blind study drug application: Twice weekly for up to 12 weeks.  
3. Optional Open-label Extension: Twice weekly for up to 12 weeks. 
4. Follow-up: 14 days after last study drug application. 
The maximum study duration for each subject is approximately 229 days 
(33 weeks).  
The maximum treatment duration for each subject is 24 weeks. 
 
 
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2.2. Schedule of Events  
Table 2-1: 
Schedule of Events for Double-blind Period 
 
 
Double-blind Treatment Period 
Screening 
(-35 days to -1 day) 
Washout up to 3 monthsa 
 
Baseline  
(Day 1) 
Telephone 
Visit 
(Day 7) 
Day 14  
± 5 days 
Day 30  
± 7 days 
Telephone 
Visit 
(Day 45) 
Day 60  
± 7 days 
Day 90b,c 
± 7 days 
(ET) 
Visit 
1 
2 
 
3 
4 
 
5 
6 
Week 
 
1 
 
2 
4 
 
8 
12 
Written informed consent/assent  
X 
 
 
 
 
 
 
Xa 
Assign screening number 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
Physical examination  
X 
X d 
 
 
 
 
 
X c 
Vital signs (blood pressure and pulse)  
X 
X 
 
X 
X 
 
X 
X 
Height, weight, and BMI  
X 
 
 
 
 
 
 
X 
IGA assessmente 
X 
X 
 
X 
X 
 
X 
X 
VIISf assessment 
X 
X 
 
X 
X 
 
X 
X 
Roughness assessmentg 
X 
X 
 
X 
X 
 
X 
X 
Palm/sole assessment  
X 
X 
 
X 
X 
 
X 
X 
Palm/sole fissuring assessmenth 
X 
X 
 
X 
X 
 
X 
X 
Ectropion score  
X 
X 
 
X 
X 
 
X 
X 
Photographsi 
 
X 
 
 
X 
 
 
X 
Quality of life per Dermatology Life 
Quality Index (DLQI) 
 
X 
 
X 
X 
 
X 
X 
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Double-blind Treatment Period 
Screening 
(-35 days to -1 day) 
Washout up to 3 monthsa 
 
Baseline  
(Day 1) 
Telephone 
Visit 
(Day 7) 
Day 14  
± 5 days 
Day 30  
± 7 days 
Telephone 
Visit 
(Day 45) 
Day 60  
± 7 days 
Day 90b,c 
± 7 days 
(ET) 
Visit 
1 
2 
 
3 
4 
 
5 
6 
Week 
 
1 
 
2 
4 
 
8 
12 
EQ-5D Quality of Life Questionnaire 
 
X 
 
X 
X 
 
X 
X 
12-lead ECGj 
X 
X 
 
 
X 
 
 
X 
Clinical laboratory tests (hematology, 
chemistry, urinalysis)k 
X 
X 
 
 
X 
 
 
X 
Serology (hepatitis B surface antigen, 
hepatitis C) 
X 
 
 
 
 
 
 
 
Pregnancy test for female subjects 
(serum at Screening; urine 
subsequently)l 
X 
X 
 
 
X 
 
X 
X 
Randomization  via IWRS 
 
X 
 
 
 
 
 
 
PK blood sample collectionm 
 
X 
 
X 
X 
 
X 
X 
Initial study drug application by clinic 
staff and measurementn 
 
X 
 
 
 
 
 
 
Application instructions, advice on 
emollient and sunscreen use 
 
X 
X 
X 
X 
X 
 
 
Dispense study drug and diarieso 
 
Xp 
 
X 
X 
 
X 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
Tolerability assessment  
 
X 
 
X 
X 
 
X 
X 
Adverse events (and review diaries) 
 
X 
X 
X 
X 
X 
X 
X 
Collect all used/unused study drugq 
 
 
 
X 
X 
 
X 
X 
Provide information about OLE option 
 
 
 
 
X 
X 
X 
 
Abbreviations: BMI = body mass index; DLQI = Dermatology Life Quality Index; ECG = electrocardiogram; ET = early termination; HEENT = head, eyes, ears, 
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nose, throat; ICF = informed consent form; IGA = Investigator’s Global Assessment; IWRS = interactive web response system; OLE = open-label extension; 
PK = pharmacokinetic; WOCBP = women of childbearing potential; VIIS = Visual Index for Ichthyosis Severity 
a. 
Upon signing informed consent and entering the Screening Period, subjects will stop using physical and medical treatments for LI, including balneotherapy, 
and may begin to washout prohibited topical and systemic treatments with designated washout periods, as applicable. Washout may be up to 3 months, as 
necessary. During washout, subjects may continue taking usual care of visible skin (face and scalp) for cosmetic reasons and of extremities (hands and feet) 
to avoid functional consequences on walking or moving their fingers. Subjects may shower but not bathe or swim during the Screening Period. After 
completing any necessary washout of prohibited medications, subjects will return to the site to complete the study eligibility requirements. 
b. Day 90 procedures should be conducted for subjects who terminate the study early. If a subject discontinues IP, but continues to attend clinic visits, Day 90 
will occur as scheduled. Day 90/Week 12 will be the first visit of the OLE for subjects who choose to continue (subjects will have up to 7 days to decide to 
sign the ICF and begin the OLE). Subjects who decide to continue into the OLE will have the following additional procedures: 1) sign informed consent; 2) 
will be weighed; 3) will be instructed on study drug application; 4) will be given new diaries, and 5) will be provided with study drug. 
c. 
A Follow-up telephone call will be made within 14 days after Day 90 to subjects who choose not to continue into the OLE. 
d. Limited physical examination to include HEENT, cardiorespiratory, abdomen, range of motion.  
e. 
IGA: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe. 
f. 
VIIS scale for each body area: chest/abdomen, back, legs, and arms, for a possible overall score = 16. 
g. Roughness (0-4 scale);  
h. Palm/sole fissuring assessment: present/absent/number/pain (0-3 scale). 
i. 
Photography will be performed at sites with the capability for subjects who sign a photographic ICF. A central reader who will not be an investigator in the 
study will review the photographs to assess consistency of investigator scoring of LI severity as a quality check. 
j. 
ECG to be conducted at Screening, Baseline, Day 30, and Day 90 for all subjects. Subjects in the PK substudy will also have postdose ECGs at each serial 
blood draw on Day 1 and Day 30. 
k. Subjects must be fasting (i.e., at least 8 hours) 
l. 
Note: Subjects who are premenstrual at Screening but begin menses during the course of the study should follow the pregnancy testing schedule for WOCBP 
correlating to the visit menses began. 
m. Samples for PK will be drawn from all subjects at Baseline and at each clinic visit. At selected sites among subjects who consent to participate in the PK 
substudy, samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1. On Day 30, IP will be applied in the clinic for PK substudy 
subjects, and PK samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose. Trough levels will be drawn when the subjects are in the clinic 
for other study visits (i.e., Day 14, Day 60, and Day 90). Visits for PK must occur at least 24 hours after the last application of the IP to avoid contamination 
of the blood samples with any IP that may have remained in the skin after the last application. 
n. Study staff will apply initial dose of study drug in the clinic after Baseline measurements, and the amount of study drug used will be measured (i.e., 
36-g tube will be measured before and after application to determine amount used) to determine fixed dose. 
o. Study drug provided in 50-g tubes (maximum single application is 36 g). Measure study drug tubes before dispensing; subjects must record days/times of 
study drug application in the diaries and any areas of skin not treated, e.g., due to local reactions). Dispense enough additional study drug until next visit 
(except at Day 90, unless subject consents to continue into OLE). 
p. Confirm study drug compliance by measuring tube weight and reviewing diary.  
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Table 2-2: 
Schedule of Events for Open-label Extension  
 
Open-label Treatment Period 
Follow-up 
 
 
Telephone 
Visit 
(Day 97)a 
Day 104  
± 5 days 
Day 120  
± 7 days 
Telephone 
Visit 
(Day 134) 
Day 150 
± 7 days 
Day 180  
± 7 
days/ET 
Day 194 or 14 days after End of 
Open-label Treatment 
Visit 
 
7 
8 
 
9 
10 
11 
Week 
 
14 
16 
 
20 
24 
26 
Informed consenta 
 
 
 
 
 
 
 
Physical examinationb 
 
 
 
 
 
X 
X 
Vital signs (blood pressure and 
pulse)  
 
 
X 
X 
 
X 
X 
Weight 
X 
 
 
 
 
 
 
Record IGAc  
 
X 
X 
 
X 
X 
X 
VIISd assessment 
 
X 
X 
 
X 
X 
X 
Roughness assessmente 
 
X 
X 
 
X 
X 
X 
Palm/sole assessment 
 
X 
X 
 
X 
X 
X 
Palm/sole fissuring assessment 
 
X 
X 
 
X 
X 
X 
Ectropion score  
 
 
X 
X 
 
X 
X 
Clinical laboratory tests 
(hematology, chemistry, 
urinalysis)f 
 
 
X 
 
 
X 
 
Pregnancy test for female 
subjects (urine)g 
 
 
X 
 
X 
X 
X 
ECG 
 
 
X 
 
 
X 
 
PK blood sample collectionh 
 
 
X 
 
 
X 
 
Application instructions, advice 
on emollient and sunscreen usei 
X 
X 
X 
X 
 
 
 
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Open-label Treatment Period 
Follow-up 
 
 
Telephone 
Visit 
(Day 97)a 
Day 104  
± 5 days 
Day 120  
± 7 days 
Telephone 
Visit 
(Day 134) 
Day 150 
± 7 days 
Day 180  
± 7 
days/ET 
Day 194 or 14 days after End of 
Open-label Treatment 
Visit 
 
7 
8 
 
9 
10 
11 
Week 
 
14 
16 
 
20 
24 
26 
Dispense study drug and 
diariesj 
 
X 
X 
 
X 
 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
Tolerability assessment  
 
X 
X 
 
X 
X 
 
Adverse events (and review 
diaries) 
X 
X 
X 
X 
X 
X 
X 
Collect all used/unused study 
drugk  
 
X 
X 
 
X 
X 
 
Abbreviations: ECG = electrocardiogram; ET = early termination; HEENT = head, eyes, ears, nose, throat; ICF = informed consent form; IGA = Investigator’s 
Global Assessment; PK = pharmacokinetic; OLE = open-label extension; VIIS = Visual Index for Ichthyosis Severity; WOCBP = women of childbearing 
potential 
a. Subjects will sign the OLE ICF at the Double-blind Day 90/Week 12 Visit or within 7 days thereafter. All efficacy assessments, safety/tolerability 
assessments, including clinical laboratory testing and PK from Day 90/Week 12 will be carried over for the OLE and will not be repeated.  
b. Limited physical examination to include HEENT, cardiorespiratory, abdomen, range of motion.  
c. IGA: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe  
d. VIIS scale for each body area: chest/abdomen, back, legs, and arms, for a possible overall score = 16. 
e. Roughness (0-4 scale); fissuring assessment on palms/soles: present/absent/number/pain (0-3 scale). 
f. Subjects must be fasting (at least 8 hours) 
g. Subjects who are premenstrual at Screening but begin menses during the course of the study should follow the pregnancy testing schedule for WOCBP 
correlating to the visit menses began. 
h. Samples for PK will be drawn from all subjects at Day 120 and Day 180. Visits for PK must occur at least 24 hours after the last application of the IP to avoid 
contamination of the blood samples with any IP that may have remained in the skin after the last application. 
i. Subjects must record days/times of study drug application in the diaries and any areas of skin not treated (e.g., due to local reactions).  
j. All subjects in the OLE will receive trifarotene 200 µg/g. Study drug provided in 50-g tubes (maximum single application is 36 g). Measure study drug tubes 
before dispensing. Dispense enough additional study drug until the next visit (except at Day 180). 
k. Confirm study drug compliance by measuring tube weight and reviewing diary. 
 
 
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3. TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES ...................................................................................................2 
2. 
PROTOCOL SUMMARY ........................................................................................................3 
2.1. Synopsis ..........................................................................................................................3 
2.2. Schedule of Events ........................................................................................................12 
3. 
TABLE OF CONTENTS .......................................................................................................17 
3.1. List of In-Text Tables....................................................................................................21 
3.2. List of In-Text Figures ..................................................................................................22 
REASONS FOR AMENDMENT .................................................................................................23 
SUMMARY OF AMENDED SECTIONS ....................................................................................25 
AMENDED PROTOCOL .............................................................................................................57 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...........................................58 
5. 
INTRODUCTION ..................................................................................................................60 
5.1. Background and Rationale ............................................................................................60 
5.1.1 CD5789 (Trifarotene) ........................................................................................61 
5.2. Clinical Experience .......................................................................................................61 
5.3. Summary of Potential Risks and Benefits .....................................................................62 
6. 
OBJECTIVES .........................................................................................................................64 
6.1. Primary Objective .........................................................................................................64 
6.2. Secondary Objectives ....................................................................................................64 
7. 
STUDY DESIGN ...................................................................................................................65 
7.1. Overall Study Design and Plan .....................................................................................65 
7.2. Rationale and Discussion of Study Design ...................................................................70 
7.3. Selection of Doses in the Study ....................................................................................70 
7.4. Study Sites .....................................................................................................................70 
7.5. Point of Contact ............................................................................................................71 
7.6. End of Study Definition ................................................................................................71 
8. 
SUBJECT POPULATION .....................................................................................................72 
8.1. Selection of Study Population and Diagnosis ...............................................................72 
8.2. Study Entry Criteria ......................................................................................................72 
8.2.1 Inclusion Criteria ...............................................................................................72 
8.2.2 Exclusion Criteria ..............................................................................................73 
8.3. Premature Subject Withdrawal .....................................................................................74 
8.4. Discontinuation of Study Intervention ..........................................................................75 
8.5. Subject Replacement Criteria ........................................................................................75 
9. 
TREATMENTS ......................................................................................................................76 
9.1. Identification of Investigational Product(s) ..................................................................76 
9.2. Treatments Administered ..............................................................................................76 
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9.3. Selection of Timing of Dose for Each Subject..............................................................77 
9.4. Dose Adjustment Criteria ..............................................................................................77 
9.4.1 Stopping Rules ..................................................................................................78 
9.5. Treatment Compliance ..................................................................................................78 
9.6. Method of Assigning Subjects to Treatment Groups ....................................................78 
9.7. Blinding and Unblinding Treatment Assignment .........................................................79 
9.8. Permitted and Prohibited Therapies ..............................................................................79 
9.8.1 Permitted Therapies ...........................................................................................80 
9.8.2 Prohibited Therapies ..........................................................................................81 
9.8.3 Restrictions ........................................................................................................81 
9.9. Treatment after End of Study ........................................................................................81 
9.10. Dispensing and Storage .................................................................................................81 
9.11. Drug Accountability ......................................................................................................82 
9.12. Labeling and Packaging ................................................................................................82 
9.12.1 Labeling .............................................................................................................83 
9.12.2 Packaging ..........................................................................................................83 
10. STUDY PROCEDURES ........................................................................................................84 
10.1. Study Duration ..............................................................................................................84 
10.1.1 Overall Study Schedule .....................................................................................84 
10.2. Study Periods and Visits ...............................................................................................84 
10.2.1 Screening and Washout .....................................................................................84 
10.2.1.1 Screening Visit (Visit 1)........................................................................84 
10.2.1.2 Washout ................................................................................................85 
10.2.2 Double-blind Treatment Period .........................................................................85 
10.2.2.1 Baseline Visit (Visit 2, Day 1) ..............................................................85 
10.2.2.2 Telephone Visit (Day 7) ........................................................................87 
10.2.2.3 Visit 3 (Day 14 ±5 days) .......................................................................87 
10.2.2.4 Visit 4 (Day 30 ±7 days) .......................................................................88 
10.2.2.5 Telephone Visit (Day 45) ......................................................................89 
10.2.2.6 Visit 5 (Day 60 ±7 days) .......................................................................89 
10.2.2.7 Visit 6 (90 ±7 days) or Early Termination ............................................90 
10.2.3 Follow-up Telephone Call (±14 days after Day 90) – Only Subjects Who Do Not 
Continue into Open-label Extension .................................................................91 
10.2.4 Open-label Extension ........................................................................................91 
10.2.4.1 Telephone Visit (Day 97) ......................................................................91 
10.2.4.2 Visit 7 (Week 14; Day 104 ±5 days) .....................................................91 
10.2.4.3 Visit 8 (Week 16; Day 120 ±7 days) .....................................................92 
10.2.4.4 Telephone Visit (Day 134) ....................................................................92 
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10.2.4.5 Visit 9 (Week 20; Day 150 ±7 days) .....................................................93 
10.2.4.6 Visit 10 (Week 24; Day 180 ±7 days) or Early Termination ................93 
10.2.4.7 Follow-up Evaluation – Open-Label Extension (Week 26/Visit 11) ....94 
10.3. Assessments ..................................................................................................................94 
10.3.1 Efficacy Variables .............................................................................................94 
10.3.1.1 Investigator’s Global Assessment .........................................................94 
10.3.1.2 Visual Index for Ichthyosis Severity – Scaling .....................................95 
10.3.1.3 Individual Score for Roughness ............................................................95 
10.3.1.4 Palm/Sole Assessment ..........................................................................96 
10.3.1.5 Palm/Sole Fissuring Assessment ..........................................................96 
10.3.1.6 Dermatology Life Quality Index ...........................................................96 
10.3.1.7 EQ-5D Quality of Life Questionnaires .................................................96 
10.3.1.8 Ectropion Severity Score.......................................................................97 
10.3.1.9 Photography Substudy ..........................................................................97 
10.3.2 Clinical Pharmacology ......................................................................................98 
10.3.2.1 Pharmacokinetic Analysis Methods ......................................................98 
10.3.2.2 Pharmacokinetic Parameters .................................................................98 
10.3.3 Sample Collection .............................................................................................99 
10.3.4 Safety Variables ................................................................................................99 
10.3.4.1 Clinical Laboratory Safety Assessments .............................................100 
10.3.4.2 Clinical Examinations .........................................................................101 
10.3.4.3 Adverse Events....................................................................................102 
11. ADVERSE EVENTS............................................................................................................103 
11.1. Definitions ...................................................................................................................103 
11.1.1 Adverse Events ................................................................................................103 
11.1.2 Adverse Drug Reaction ...................................................................................103 
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction ......................................103 
11.1.4 Serious Adverse Events/Drug Reaction ..........................................................104 
11.1.5 Significant Adverse Events .............................................................................104 
11.1.6 Treatment-Emergent Adverse Events .............................................................104 
11.2. Event Assessment and Follow-up of Adverse Events ................................................104 
11.2.1 Assessment ......................................................................................................105 
11.2.2 Evaluation ........................................................................................................106 
11.2.2.1 Severity of Adverse Events .................................................................106 
11.2.2.2 Seriousness ..........................................................................................106 
11.2.2.3 Action(s) Taken ...................................................................................106 
11.2.2.4 Outcome at the Time of Last Observation ..........................................107 
11.2.2.5 Adverse Event Relationship to Investigational Product......................107 
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11.2.3 Documentation ................................................................................................108 
11.2.4 Treatment of Adverse Events ..........................................................................108 
11.2.5 Follow-up ........................................................................................................108 
11.2.6 Reporting .........................................................................................................109 
11.2.6.1 Serious Adverse Events.......................................................................109 
11.2.6.2 Adverse Drug Reactions .....................................................................110 
11.2.6.3 Nonserious Adverse Events ................................................................110 
11.3. Special Considerations ................................................................................................110 
11.3.1 Adverse Events of Special Interest ..................................................................110 
11.3.2 Pregnancy ........................................................................................................110 
12. DATA SAFETY MONITORING BOARD .........................................................................112 
13. STATISTICS ........................................................................................................................113 
13.1. Statistical Analysis ......................................................................................................113 
13.1.1 Analysis Populations .......................................................................................113 
13.1.2 Study Subjects and Demographics ..................................................................114 
13.1.2.1 Disposition and Withdrawals ..............................................................114 
13.1.2.2 Protocol Deviations .............................................................................114 
13.1.2.3 Demographics and Other Baseline Characteristics .............................114 
13.1.3 Exposure and Compliance ...............................................................................115 
13.1.4 Efficacy Analysis ............................................................................................115 
13.1.4.1 Efficacy Endpoints ..............................................................................115 
13.1.4.2 Primary Analysis .................................................................................116 
13.1.4.3 Secondary Analyses ............................................................................116 
13.1.4.4 Exploratory Analyses ..........................................................................116 
13.1.4.5 Corroborative, Sensitivity, and Other Analyses ..................................116 
13.1.5 Clinical Pharmacology Analyses .....................................................................117 
13.1.5.1 Pharmacokinetics ................................................................................117 
13.1.6 Safety and Tolerability Analyses ....................................................................117 
13.1.6.1 Local Tolerability ................................................................................117 
13.1.6.2 Adverse Events....................................................................................118 
13.1.6.3 Clinical Laboratory Evaluations .........................................................118 
13.1.6.4 Vital Signs ...........................................................................................118 
13.1.6.5 Twelve-lead Electrocardiograms ........................................................118 
13.1.6.6 Physical Examination Findings ...........................................................119 
13.1.7 Interim Analysis ..............................................................................................119 
13.2. Sample Size Determination .........................................................................................119 
14. STUDY CONDUCT .............................................................................................................120 
14.1. Sponsor and Investigator Responsibilities ..................................................................120 
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14.1.1 Sponsor Responsibilities .................................................................................120 
14.1.2 Investigator Responsibilities ...........................................................................120 
14.1.3 Confidentiality and Privacy .............................................................................120 
14.2. Site Initiation ...............................................................................................................121 
14.3. Screen Failures ............................................................................................................121 
14.4. Study Documents ........................................................................................................121 
14.4.1 Informed Consent ............................................................................................122 
14.4.2 Investigator’s Regulatory/Good Clinical Practice Documents .......................122 
14.4.3 Case Report Forms ..........................................................................................123 
14.4.4 Source Documents ...........................................................................................123 
14.5. Data Quality Control ...................................................................................................123 
14.5.1 Monitoring Procedures ....................................................................................123 
14.5.2 Data Management ............................................................................................124 
14.5.3 Quality Assurance/Audit .................................................................................124 
14.6. Study Termination .......................................................................................................125 
14.6.1 Regular Study Termination .............................................................................125 
14.6.2 Premature Study Termination .........................................................................125 
14.7. Study Site Closure .......................................................................................................126 
14.7.1 Record Retention .............................................................................................126 
14.7.2 Sample Retention ............................................................................................126 
14.8. Changes to the Protocol ..............................................................................................127 
14.9. Use of Information and Publication ............................................................................127 
15. FINAL CLINICAL STUDY REPORT ................................................................................128 
16. ETHICAL AND LEGAL CONSIDERATIONS ..................................................................129 
16.1. Declaration of Helsinki and Good Clinical Practice ...................................................129 
16.2. Subject Information and Informed Consent and/or Assent .........................................129 
16.3. Approval by Institutional Review Board and Independent Ethics Committee ...........130 
16.4. Finance and Insurance .................................................................................................130 
17. REFERENCES .....................................................................................................................131 
18. ATTACHMENTS .................................................................................................................132 
18.1. Investigator’s Agreement ............................................................................................132 
APPENDICES .............................................................................................................................133 
A. 
Regulations and Good Clinical Practice Guidelines ...................................................134 
 
 
3.1. List of In-Text Tables 
Table 2-1: 
Schedule of Events for Double-blind Period .....................................................12 
Table 2-2: 
Schedule of Events for Open-label Extension ...................................................15 
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Table 9-1: 
Washout Periods for Prohibited Medications ....................................................80 
Table 9-2: 
Amount of Study Drug Needed Per Visit ..........................................................82 
Table 10-1: 
Pharmacokinetic Parameters .............................................................................99 
 
3.2. List of In-Text Figures 
Figure 7-1: 
Double-blind Study Design ...............................................................................68 
Figure 7-2: 
Open-label Study Design ...................................................................................69 
Figure 10-1: 
Ectropion Severity Score ...................................................................................97 
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REASONS FOR AMENDMENT 
Protocol Amendment 1 is a major amendment that addresses feedback from the Regulatory 
Agencies, Competent Authorities, Central Ethics Committees, and investigators. The following 
changes were made: 
1. Changed the primary endpoint to the Investigator’s Global Assessment (IGA) and made the 
Visual Index for Ichthyosis Severity (VIIS) a secondary endpoint. 
2. Aligned power calculation and parameter assumptions with the new primary endpoint. 
3. Added optional photography evaluation of scoring by a central reader who is not a study 
investigator as a quality check. 
4. Clarified body areas that should be excluded from treatment and/or assessment, and clarified 
dose adjustment for local tolerability and documentation thereof. 
5. Clarified inclusion and exclusion criteria, and added that subjects with recent systemic 
malignancy (e.g., within 5 years) are excluded, with exceptions for those with nonmelanoma 
skin cancer or cervical intraepithelial neoplasia Grade 1 who are >6 months post-treatment. 
6. Added exclusion criteria for subjects unable or unwilling to stop use of topical or systemic 
retinoids; institutionalized subjects, and subjects in any way related to the sponsor, 
investigator, or site personnel. 
7. Specified that a legal guardian must sign an ICF for every minor. 
8. Specified when the data safety monitoring board (DSMB) will meet and what data will be 
reviewed. 
9. Added characterization of the investigational product. 
10. Added background information about Study RD.03.SRE.40181E with CD5789 in subjects 
with ichthyosis. 
11. Added rationale for 200 µg/g dose in OLE. 
12. Added risk of absorption. 
13. Added protective measures for risk of photosensitivity. 
14. Specified that a tool will be supplied to apply investigational product to the back, and that if 
the investigational product (IP) is applied to the subject by someone other than the study 
subject, they should attend the first visit to learn how to apply it, and that hands must be 
washed immediately afterward or vinyl gloves should be used. 
15. Specified windows and procedures for preventing blood draw contamination by the IP. 
16. Specified that fissuring assessment is limited to palms/soles. 
17. Added washout durations for keratolytics and monoclonal antibody medications, specified 
that washout includes physical treatments such as balneotherapy, and clarified that washout 
must be completed before study treatment begins. 
18. Clarified that subjects may continue taking usual care of visible skin (face and scalp) for 
cosmetic reasons and of extremities (hands and feet) to avoid functional consequences on 
walking or moving their fingers. 
19. Clarified that hormonal contraceptives must inhibit ovulation, and that abstinence relates to 
heterosexual intercourse and must be evaluated in relation to the duration of the clinical trial 
and the preferred and usual lifestyle of the subject. 
20. Revised the statistical analyses to reflect the change in endpoints. 
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21. Clarified permitted and prohibited therapies and medications, and use of standard of care 
treatment and timing thereof. 
22. Specified that lamellar ichthyosis (LI) assessments must be done in order of presentation. 
23. Revised descriptions of LI assessment tools scores (IGA and VIIS). 
24. Defined fissures. 
25. Clarified that investigators should use their judgment as to which quality-of-life tools should 
be used based on the subject’s maturity. 
26. Added a new section describing the photographic substudy. 
27. Added electrocardiogram (ECG) for subjects in the PK substudy during serial blood draws 
on Days 1 and 30. 
28. Clarified eligibility for OLE. 
29. Reordered sections to put assessments in order of performance and renumbered all sections 
and lists accordingly. 
30. Corrected duplicate endnote reference and typographical errors. 
 
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SUMMARY OF AMENDED SECTIONS 
Section 
Previous Text 
Revision 
Rationale 
Synopsis and 
Section 7.1 
This is a 2-cohort, multicenter 
study in subjects with 
moderate to severe LI (i.e., 3-4 
on a 5-point Visual Index for 
Ichthyosis Severity (VIIS) for 
scaling where 0 = clear and 4 = 
severe on at least 2 areas of the 
4 body areas assessed 
(chest/abdomen, back, arms, 
and legs). 
This is a 2-cohort, multicenter 
study in subjects with 
moderate to severe LI (i.e., 3–4 
on a 5-point Investigator 
Global Assessment [IGA)] 
scale where 0 = clear; 
1 = almost clear; 2 = mild; 
3 = moderate; and 
4 = severe). 
To follow FDA 
recommendation to use 
IGA as primary endpoint 
Synopsis and 
Section 7.1 
After the initial 15 subjects 
complete at least 28 days of 
treatment, an independent Data 
Safety Monitoring Board 
(DSMB) will review aggregate 
safety and tolerability data. 
After the initial 15 subjects 
complete at least 28 days of 
treatment, an independent Data 
Safety Monitoring Board 
(DSMB) will review aggregate 
safety and tolerability data 
(including PK and 
electrocardiogram [ECG] 
data). 
To clarify what data the 
DSMB will review 
Synopsis and 
Section 7.1 
All subjects who complete the 
12-week Double-blind 
Treatment Period will be 
eligible to enroll in the 
12-week OLE Period.  
All subjects (Cohort A and 
Cohort B) who complete the 
12-week Double-blind 
Treatment Period will be 
eligible to enroll in the 
12-week OLE.  
To specify that subjects 
from both double-blind 
cohorts will be eligible to 
continue into the Open-
label Extension (OLE).  
Synopsis, 
Section 7.1, and 
Section 10 
 
Added: Written informed 
consent will be obtained 
from a parent/legal guardian 
for any minor and minors 
will provide assent before 
any study-related procedures 
are performed. 
To ensure that 
parents/legal guardians 
sign ICF 
Synopsis, 
Table 2-1, 
Sections 7.1, 
Section 9.8, and 
10.2.1.2 
After Screening, eligible 
subjects for Cohort A and B 
will enter a Washout Period of 
up to 35 days, during which 
they must stop using the 
following prohibited 
medications 
Upon signing informed 
consent and entering the 
Screening Period, subjects 
will stop using physical and 
medical treatments for LI, 
including balneotherapy, and 
may begin to washout 
prohibited topical and 
systemic treatments with 
designated washout periods, 
as applicable. Washout may 
be up to 3 months, as 
necessary 
To allow for full washout 
of any prohibited 
medications before 
randomization. 
Therapeutic baths can 
substantially improve 
scaling and affect the 
IGA evaluation. 
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Section 
Previous Text 
Revision 
Rationale 
 
 
Added: During washout, 
subjects may continue taking 
usual care of visible skin 
(face and scalp) for cosmetic 
reasons and of extremities 
(hands and feet) to avoid 
functional consequences on 
walking or moving their 
fingers. Subjects may shower 
but not bathe or swim. The 
IGA will be evaluated on the 
rest of the body at Baseline. 
After completing any 
necessary washout of 
prohibited medications, 
subjects will return to the 
site to complete the study 
eligibility requirements. 
For psycho-social and 
functional reasons, and 
to not deter them from 
entering the study, allow 
subjects to use usual care 
on visible skin and on 
hands and feet.  
To exclude bathing to 
better assess moderate to 
severe LI and evaluate 
IGA on rest of body. 
To ensure subjects 
complete screening and 
eligibility within 35 days 
of randomization after 
any necessary washout. 
Synopsis and 
Table 9-1 
 
Added a washout period of 
2 weeks for topical 
keratolytics (e.g., urea, lactic 
acid, propylene glycol, 
salicylic acid) except 
keratolytic shampoo. 
Added a washout period for 
monoclonal antibody 
treatment (e.g., anti-IL17) of 
5 half lives. 
To clarify length of the 
washout periods for 
these treatments. 
Synopsis, 
Section 7.1, and 
Section 9.2 
Thereafter, each subject will 
apply approximately the same 
amount (up to 36 g) of study 
drug as for the first dose on up 
to 90% of BSA twice weekly, 
sparing the scalp, inguinal, and 
axillary areas. Subjects will 
receive an adequate number of 
tubes to use 1 tube per 
application and will use a new 
tube for each treatment day. 
Subjects may use less than the 
full amount of product in a 
tube. Subjects will record the 
date and time of study 
treatment administration in the 
subject diary. 
Added: If the product will be 
applied at home by someone 
other than the study subject, 
it is recommended that 
person assist with application 
at the first visit to learn how 
the IP is applied. 
Subjects with heavy facial 
hair should not apply IP to 
hair-bearing areas. 
To specify areas not to 
be treated. 
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Section 
Previous Text 
Revision 
Rationale 
Synopsis 
 
Added: If the treatment 
causes application site 
reactions, the frequency of 
application will be reduced 
or interrupted only on the 
area concerned, as indicated 
herein.  
To clarify dose 
adjustment and 
evaluation. 
Synopsis, 
Table 2-1 
footnote, and 
Section 9.4 
During all clinic visits, the 
investigator will assess local 
tolerability (Scale: 0-3 [none, 
mild, moderate, severe]) for 
stinging/burning, pruritus, 
erythema) and the following 
procedures will be followed: 
During all clinic visits, the 
investigator will assess local 
tolerability (Scale: 0-3 [none, 
mild, moderate, severe]) for 
stinging/burning, pruritus, 
erythema) for each body area 
(chest/abdomen, back, arms, 
legs, and face/neck) and the 
following procedures will be 
followed: 
To clarify areas to be 
assessed for local 
tolerability. 
Synopsis and 
Section 9.4 
− If a score of 2 (moderate) 
is recorded on a local 
tolerability assessment 
scale (stinging/burning, 
pruritus, erythema) on any 
treated area, the study drug 
will be applied on this area 
only once weekly, until the 
score is back to <2. 
− If a score of 3 (severe) is 
recorded on a local 
tolerability assessment 
scale (stinging/burning, 
pruritus, erythema) on any 
treated area, the study drug 
will not be applied on that 
area until the score is back 
to <3. 
− If a score of 2 (moderate) 
is recorded on a local 
tolerability assessment 
scale (stinging/burning, 
pruritus, erythema) on any 
treated area (e.g., the 
face), the study drug will 
be applied on this area 
only once weekly, until 
the score returns to <2. 
Continue to treat all 
other areas twice weekly 
provided the score is <2 
on those areas. 
− If a score of 3 (severe) is 
recorded on a local 
tolerability assessment 
scale (stinging/burning, 
pruritus, erythema) on any 
treated area, the study 
drug will not be applied 
on that area until the score 
is back to <3 (i.e., “drug 
holiday”). Continue to 
treat all other areas 
twice weekly provided 
the score is <2 on those 
areas. 
Any changes in dosing must 
be documented in the 
subject diary and the eCRF. 
To clarify dose 
adjustment for local 
tolerability, and how it 
should be documented. 
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Section 
Previous Text 
Revision 
Rationale 
Synopsis and 
Section 10.1 
 
Added: Written informed 
consent will be obtained 
from a parent/legal guardian 
for any minor and minors 
will provide assent before 
any study-related procedures 
are performed. 
To clarify that a legal 
guardian must sign an 
ICF for every minor. 
Synopsis and 
Section 7.1, and 
Section 10.3.1.9 
Photographs will be taken at 
Baseline, Day 30 and Day 90 
at selected sites with 
photographic capability for 
subjects who sign a separate 
photographic informed consent 
form (ICF). 
At all sites with photographic 
capability photographs will be 
taken as source data to 
support scoring at Baseline, 
Day 30, and Day 90. A central 
reader who will not be an 
investigator in the study will 
review the photographs to 
assess consistency of 
investigator scoring of LI 
severity as a quality check. 
Photographs may also be 
used for scientific publication 
purposes. Subjects will sign a 
separate, optional 
photographic informed consent 
form (ICF). 
To obtain photographic 
evidence, where 
possible, for 
confirmation of scoring 
consistency, as assessed 
by a central reader. 
Synopsis and 
Section 7.1 
 
Added: Visits for PK must 
occur at least 24 hours after 
the last application of the 
study drug, to avoid 
contamination of the blood 
samples with any IP that 
may have remained in the 
skin after the last 
application.  
To ensure 
pharmacokinetic (PK) 
blood draws are not 
contaminated with IP. 
Synopsis and 
Section 7.1 
In addition, a PK substudy will 
be conducted at specific sites 
with the capability to conduct 
it. 
In addition, a PK substudy will 
be conducted on Days 1 and 
30 at sites with the capability 
to conduct it. 
Added: For the subjects in 
the PK substudy, postdose 
ECGs will be performed at 
each serial blood draw on 
Day 1 and Day 30. 
To clarify on which days 
the PK substudy will be 
performed, and that 
postdose ECGs will be 
performed during serial 
sampling on those days 
(per MHRA request). 
Synopsis and 
Section 8.2.1 
Inclusion criterion #3: 
Subject has moderate to severe 
(VIIS 3-4) LI on at least 2 of 
the 4 body areas assessed 
(chest/abdomen, back, arms, 
and legs). 
Inclusion criterion #3: 
Subject has moderate to severe 
(IGA 3-4) LI on the IGA of LI 
severity. 
To follow FDA 
recommendation to 
change primary endpoint 
to IGA.  
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Section 
Previous Text 
Revision 
Rationale 
Synopsis and 
Section 8.2.1 
Inclusion criterion #7: 
• combined oral 
contraceptives (estrogens 
and progesterone) or 
implanted or injectable 
contraceptives with a stable 
dose for at least 1 month 
before Baseline 
• hormonal intrauterine device 
(IUD) inserted at least 
1 month before Baseline 
OR 
Agrees to abstain from sex 
during study participation 
and for 1 month after the 
last application of study 
drug and to use a highly 
effective contraceptive as 
backup if he or she becomes 
sexually active during the 
study. 
Inclusion criterion #7: 
• combined oral 
contraceptives (estrogens 
and progesterone) or 
implanted or injectable 
contraceptives with a stable 
dose for at least 1 month 
before Baseline; hormonal 
contraceptives must 
inhibit ovulation 
• hormonal intrauterine device 
(IUD) inserted at least 
1 month before Baseline 
OR 
Agrees to abstain from 
heterosexual intercourse 
during study participation 
and for 1 month after the 
last application of study 
drug and to use a highly 
effective contraceptive as 
backup if he or she becomes 
sexually active during the 
study. Abstinence is only 
acceptable if this is the 
subject’s usual lifestyle. 
Periodic abstinence 
(calendar, symptothermal, 
postovulation methods), 
withdrawal (coitus 
interruptus), spermicides 
only, and lactational 
amenorrhoea method are 
not acceptable methods of 
contraception. 
To align with Clinical 
Trial Facilitation Group 
(CTFG) 
recommendations related 
to contraception and 
pregnancy testing in 
clinical trials, per 
MHRA. 
Synopsis and 
Section 8.2.2 
Exclusion criterion #2: 
Subject has a history of or 
current moderate or severe 
stinging/burning at Screening. 
Exclusion criterion #2: 
Subject has a history of or 
current moderate or severe 
stinging/burning at Screening. 
To clarify that history of 
stinging/burning does not 
prevent enrollment. 
Synopsis and 
Section 8.2.2 
Exclusion criterion #4: 
Subject with a known lipid 
disorder unless well controlled 
by stable doses of 
lipid-lowering agents for at 
least 6 months. 
 
Exclusion criterion #4: 
Subject with a known lipid 
disorder 
(hypertriglyceridemia 
>200 mg/dL, 
hypercholesterolemia 
>250 mg/dL) unless well 
controlled by stable doses of 
lipid-lowering agents for at 
least 6 months. 
To group all lipidema 
criteria together. 
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Section 
Previous Text 
Revision 
Rationale 
Synopsis and 
Section 8.2.2 
Exclusion criterion #5: 
Subject was previously treated 
with trifarotene/CD5789, 
including the acne formulation, 
or participated in previous 
studies for ichthyosis. 
Exclusion criterion #5: 
Subject was previously treated 
with trifarotene/CD5789 in an 
acne or ichthyosis study. 
To avoid restricting 
enrollment. 
Synopsis and 
Section 8.2.2 
Exclusion criterion #6: 
Subject has known skeletal 
disease, hypertriglyceridemia, 
hypercholesterolemia, liver 
disease, or other poorly 
controlled medical conditions. 
Exclusion criterion #6: 
Subject has any other 
significant concomitant 
disease, or poorly controlled 
medical condition other than 
LI that, in the investigator’s 
opinion, may put him or her 
at risk if he or she takes part 
in the study, and/or that may 
interfere with the study 
assessments. 
To add 
hypertriglyceridemia and 
hypercholesterolemia as 
exclusion criteria and 
combine Exclusion 
Criterion #4 and 
Exclusion Criterion #7 to 
avoid restricting 
enrollment 
Synopsis and 
Section 8.2.2 
Exclusion criterion #7: 
Subject has a medical 
condition that potentially alters 
bone metabolism (e.g., 
osteoporosis, thyroid 
dysfunction, Cushing 
syndrome), Crohn’s disease, or  
any other significant 
concomitant disease other than 
LI that, in the investigator’s 
opinion, may put him or her at 
risk if he or she takes part in 
the study, and/or that may 
interfere with the study 
assessments 
Exclusion criterion #7: 
Subject has a medical 
condition that potentially alters 
bone metabolism (e.g., 
osteoporosis, thyroid 
dysfunction, Cushing 
syndrome, Crohn’s disease, 
or ulcerative colitis).any other 
significant concomitant disease 
other than LI that, in the 
investigator’s opinion, may put 
him or her at risk if he or she 
takes part in the study, and/or 
that may interfere with the 
study assessments 
To exclude subjects with 
conditions that may 
affect skeletal integrity. 
Synopsis and 
Section 8.2.2 
Exclusion criterion #8: 
Subject is being treated for 
major depression disorder  
Exclusion criterion #8: 
Subject is being treated for 
major depression disorder 
and/or has a history of major 
depression or suicide attempt 
requiring hospitalization, 
medications, and close 
psychiatric surveillance to 
prevent suicide attempts.  
To define major 
depressive disorder and 
to allow subjects with 
treated mild depression 
to be enrolled. 
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Section 
Previous Text 
Revision 
Rationale 
Synopsis and 
Section 8.2.2 
Exclusion criterion #10: 
Subject with any of the 
following laboratory values at 
Screening: 
a. Aspartate aminotransferase 
or alanine aminotransferase 
>1.5 × upper limit of normal 
defined by the laboratory 
b. Triglycerides >200 mg/dL 
c. Total cholesterol 
>250 mg/dL 
d. Hemoglobin <12.5 g/dL for 
men and <11.5 g/dL for 
women 
e. Platelets <150 × 109/L or 
>400 × 109/L 
Exclusion criterion #10: 
Subject with any of the 
following laboratory values at 
Screening: 
a. Aspartate aminotransferase 
or alanine aminotransferase 
>1.5 × upper limit of 
normal defined by the 
laboratory 
b. Total bilirubin 
>1.1 mg/dL or, in case of 
Gilbert’s syndrome, total 
bilirubin >3 mg/dL 
c. Hemoglobin <12.5 g/dL for 
men and <11.5 g/dL for 
women 
d. Platelets <150 × 109/L or 
>400 × 109/L 
Moved triglycerides and 
total cholesterol to 
Exclusion Criterion #4 
and add total bilirubin 
and Gilbert’s syndrome 
(per MHRA request). 
Synopsis and 
Section 8.2.2 
 
Added: 
Exclusion criterion #12: 
Subject has had recent 
systemic malignancy (e.g., 
within 5 years) with 
exception of nonmelanoma 
skin cancer or cervical 
intraepithelial neoplasia of 
Grade 1 who are >6 months 
post-treatment. 
To exclude subjects with 
recent systemic 
malignancies. 
Synopsis and 
Section 8.2.2 
 
Added: 
Exclusion criterion #17: 
Subject is unable or 
unwilling to stop use of 
topical or systemic retinoids. 
To exclude subjects 
using topical or systemic 
retinoids, per MHRA 
request. 
Synopsis and 
Section 8.2.2 
 
Added: Exclusion criterion 
#20: 
Subject is institutionalized 
Added: Exclusion criterion 
#21: 
Subject is in any way related 
to the sponsor, investigator, 
or site personnel. 
To exclude vulnerable or 
biased subjects 
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Synopsis, 
Section 7.1, and 
Section 10.3 
Primary efficacy endpoint: The 
number of subjects in each 
treatment group who 
experience successful 
resolution of LI where 
“success” is defined as 
clear/almost clear overall and 
at least a 50% reduction from 
Baseline at Week 12/end-of-
treatment (EOT) in the 
Double-blind Period on the 
overall 16-point VIIS for 
scaling (i.e., 0-4 points on each 
of the 4 body areas: 
chest/abdomen, back, arms, 
and legs). 
Primary efficacy endpoint:  
The number of subjects in each 
treatment group who 
experience successful 
resolution of LI where 
“success” is defined as 
clear/almost clear on treated 
areas and at least a 2-grade 
change from Baseline at 
Week 12/end-of-treatment 
(EOT) in the Double-blind 
Period on the 5-point IGA 
full body scale. 
To follow FDA 
recommendation to 
change primary endpoint 
from VIIS to IGA. 
Synopsis and 
Section 13.1.4.1 
 
The number of subjects in each 
treatment group who 
experience successful 
resolution of LI where 
“success” is defined as 
clear/almost clear on treated 
areas and at least a 2-grade 
change from Baseline at Week 
12/end-of-treatment (EOT) in 
the Double-blind Period on the 
5-point IGA full body scale. 
The number of subjects in each 
treatment group who 
experience successful 
resolution of LI where 
“success” is defined as 
clear/almost clear overall and 
at least a 50% reduction from 
Baseline at Week 12/end-of-
treatment (EOT) in the 
Double-blind Period on the 
overall 16-point VIIS for 
scaling (i.e., 0 4 points on each 
of the 4 body areas: 
chest/abdomen, back, arms, 
and legs). 
 
Secondary endpoints: 
• 
The difference in mean 
scores between the active 
trifarotene cream HE1 and 
vehicle groups in the 
following assessment 
indices: 
The proportion of subjects in 
each treatment group who 
experience successful 
resolution of LI where 
“success” is defined as 
clear/almost clear on treated 
areas and at least a 2-grade 
change from Baseline at 
Week 12/end-of-treatment 
(EOT) in the Double-blind 
Period on the 5-point IGA full 
body scale.  
 
Secondary endpoints: 
• The difference in mean 
scores between the active 
trifarotene cream HE1 and 
vehicle groups in the 
following assessment 
indices from baseline 
through Week 12: 
− 
5-point Visual Index for 
Ichthyosis Severity 
(VIIS) scale for scaling 
from Baseline through 
Week 12 (overall 16 
points for scaling, i.e. 0-4 
points for 4 body areas: 
chest/abdomen, back, 
arms and legs) 
− Individual score for 
roughness (Scale: 0–4) 
overall 
− Palm/sole Assessment 
(Scale: 0–4)  
To reflect change in 
endpoints; IGA is now 
primary endpoint (and 
thus, no individual 
scaling score is needed), 
and VIIS is a secondary 
endpoint.  
To limit fissure 
evaluation to the 
palms/soles. 
To clarify endpoints for 
statistical analysis. 
To add the children’s 
versions of the DLQI 
(cDLQI) and EQ-5D 
(EQ-5D-Y) 
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− Palm/sole Assessment 
(Scale: 0–4)  
− Individual score of 
scaling (Scale: 0–4)  
− Individual score for 
roughness (Scale: 0–4) 
overall 
• 
The difference in 
proportion of subjects 
with presence of fissures 
(presence/absence, 
number of fissures, and 
pain associated with 
fissures on a 0-3 scale) 
between the active 
trifarotene cream HE1 and 
vehicle groups. 
• 
Quality of life per 
EQ-5D-5L  
• 
The difference in mean 
ectropion (Ectropion 
Severity Score [ESS] of 
0–8) scores between the 
active trifarotene cream 
HE1 and vehicle groups 
• 
Quality of life per DLQI  
 
− Quality of life per 
DLQI and cDLQI 
 
• 
The difference in 
proportion of subjects 
with presence of fissures 
on palms/soles 
(presence/absence, 
number of fissures, and 
pain associated with 
fissures on a 0-3 scale) at 
Week 12 between the 
active trifarotene cream 
HE1 and vehicle groups. 
• 
The difference in mean 
ectropion (Ectropion 
Severity Score [ESS] of 
0–8) scores between the 
active trifarotene cream 
HE1 and vehicle groups 
from Baseline through 
Week 12 
• 
The difference in quality 
of life per EQ-5D-5L and 
EQ-5D-Y scores between 
the active trifarotene 
cream HE1 and vehicle 
groups from Baseline 
through Week 12 
Synopsis  
Safety endpoints:  
• Reported serious adverse 
events (SAEs), treatment-
emergent AEs (TEAEs), 
and changes in clinical 
laboratory tests, vital signs, 
physical examinations, and 
12-lead ECGs  
• Local tolerability (Scale: 
0-3 [none, mild, moderate, 
severe], determined by the 
investigator)  
 
Safety endpoints:  
• Reported serious adverse 
events (SAEs), treatment-
emergent AEs (TEAEs), 
and changes in clinical 
laboratory tests, vital signs, 
physical examinations, and 
12-lead ECGs  
• Local tolerability (Scale: 
0-3 [none, mild, moderate, 
severe], determined by the 
investigator) for each body 
area (chest/abdomen, 
back, legs, arms, and 
face/neck). 
To clarify that 
tolerability will be 
assessed on all body 
areas where the 
treatment is applied. 
Synopsis and 
Section 13.1.4.2 
The intent-to-treat (ITT) 
population will comprise all 
randomized subjects.  
The modified intent-to-treat 
(mITT) population comprises 
all subjects in the safety 
The intent-to-treat (ITT) 
population will comprise all 
randomized subjects. This 
population will be used as the 
primary population for the 
analysis of efficacy for the 
To clarify that the intent-
to-treat population will 
be used for the primary 
analyses of efficacy for 
the double-blind period. 
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population with at least 1 
postbaseline assessment of 
efficacy in the Double-blind 
Period. This population will be 
used as the primary population 
for the analysis of efficacy for 
the Double-blind Period of the 
study. 
 
The number and proportion of 
subjects in each treatment 
group with successful 
resolution of LI by Week 
12/EOT in the Double-blind 
Period will be presented. 
Generalized estimating 
equations (GEE) for binary 
response will be used to model 
the odds of successful 
resolution of LI with treatment 
group as a predictor. Other 
covariates, such as baseline 
IGAVIIS scores, baseline 
characteristics, and interactions 
may be included. Various 
correlation matrix structures 
will be explored to model the 
within subject correlation. 
Additionally, the difference in 
mean VIIS score at Week 
12/EOT between the active 
trifarotene cream HE1 groups 
and vehicle group will be 
analyzed using a 2-sided, 2-
sample Wilcoxon rank-sum 
test at the 5% significance 
level; 95% confidence 
intervals will be presented.  
The VIIS scores as well as 
secondary and exploratory 
efficacy endpoints will be 
analyzed by visit using 
descriptive statistics through 
Week 24.   
Double-blind Period of the 
study. 
The modified intent-to-treat 
(mITT) population comprises 
all subjects in the safety 
population with at least 1 
postbaseline assessment of 
efficacy in the Double-blind 
Period. 
The number and proportion of 
subjects in each treatment 
group with successful 
resolution of LI by Week 
12/EOT in the Double-blind 
Period will be presented. The 
primary efficacy endpoint 
will be analyzed using a 
logistic regression model 
with treatment and age 
group as factors. Other 
baseline characteristics and 
interactions may be included. 
The odds ratios and 95% CIs 
for the odds ratios will be 
presented. The difference in 
proportions between the 
active trifarotene cream HEI 
and vehicle cream group, 
95% CIs for the differences, 
and P-values for the 
differences in treatment will 
also be presented. 
 
The IGA scores as well as 
continuous secondary and 
exploratory efficacy endpoints 
will be analyzed by visit using 
descriptive statistics through 
Week 24. 
Deleted: Frequencies of results 
and 95% confidence intervals 
will also be reported, and 
scores will be analyzed as 
categorical variables using the 
Cochran-Mantel-Haenszel test. 
To follow change in 
primary endpoint and 
addition of secondary 
endpoints. 
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Synopsis and 
Section 10.1.1 
Screening and washout: Up to 
35 days 
Screening: Up to 35 days 
(after signing informed 
consent, if necessary, 
washout may be up to 3 
months, and subjects should 
return to the site after 
washout to complete the 
study eligibility 
requirements) 
To allow for full washout 
of any prohibited 
medications before 
randomization. 
Synopsis and 
Section 13.2 
Accounting for a 20% drop-
out/nonevaluable rate, a total 
sample size of 120 subjects 
randomized in a 1:1:1 ratio to 
2 active trifarotene cream HE1 
arms and a vehicle cream arm 
will provide >80% power to 
detect a difference between 
each separate trifarotene cream 
HE1 arm (32 evaluable 
subjects) and the vehicle cream 
arm (32 evaluable subjects) 
using a 2-sample t-test 
assuming a mean difference of 
at least 1.0 and a standard 
deviation of 1.4 or lower. 
Accounting for a 20% drop-
out/nonevaluable rate, a total 
sample size of 120 subjects 
randomized in a 1:1:1 ratio to 
2 active trifarotene cream HE1 
arms and a vehicle cream arm 
will provide >80% power to 
detect a difference between 
each separate trifarotene cream 
HE1 arm (32 evaluable 
subjects) and the vehicle cream 
arm (32 evaluable subjects) 
using a 2-sided Fisher’s 
Exact Test assuming a 70% 
success rate and a 40% 
success rate, respectively. 
To align power 
calculation and 
parameter assumptions 
with the new primary 
endpoint. 
Table 2-1 
Screening (-35 days to -1 day) 
Screening (-35 days to -1 day) 
Washout up to 3 months 
Added footnote a: Upon 
signing informed consent and 
entering the Screening 
Period, subjects will stop 
using physical and medical 
treatments for LI, including 
balneotherapy, and may 
begin to washout prohibited 
topical and systemic 
treatments with designated 
washout periods, as 
applicable. Washout may be 
up to 3 months, as necessary. 
During washout, subjects 
may continue taking usual 
care of visible skin (face and 
scalp) for cosmetic reasons 
and of extremities (hands 
and feet) to avoid functional 
consequences on walking or 
moving their fingers. 
Subjects may shower but not 
bathe or swim during the 
Screening Period. After 
completing any necessary 
To allow for full washout 
of any prohibited 
medications before 
randomization. 
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washout of prohibited 
medications, subjects will 
return to the site to complete 
the study eligibility 
requirements. 
Table 2-1  
Schedule of Events for 
Double-blind Period 
Reordered assessments of 
IGA, VIIS, and roughness to 
be in order of conduct. 
Added “palm/sole” to 
fissuring assessment. 
Changed “assign 
randomization number” to 
“Randomization via IWRS.” 
Added “and sunscreen” to 
advice on emollient use. 
Changed complete physical 
examination to be done at 
Screening and limited physical 
examinations at other time 
points as indicated. 
Changed height, weight, and 
BMI to be done at Screening 
instead of Baseline. 
Added abbreviation IWRS and 
definition. 
Added to footnote: 
Photography will be performed 
at sites with the capability for 
subjects who sign a 
photographic ICF. A central 
reader who will not be an 
investigator in the study will 
review the photographs to 
assess consistency of 
investigator scoring of LI 
severity as a quality check. 
Added to footnote subjects in 
PK substudy will have 
postdose ECG at each serial 
blood draw on Day 1 and 
Day 30. 
Added to footnote: Visits for 
PK must occur at least 
24 hours after the last 
application of the IP to avoid 
contamination of the blood 
samples with any IP that 
may have remained in the 
To clarify that IGA 
should be performed first 
and all efficacy 
assessments should be 
performed in the order in 
which they are listed 
within the protocol. 
To limit fissure 
evaluation to the 
palms/soles. 
To specify that 
randomization will be 
conducted via IWRS to 
avoid confusing site 
personnel. 
To include sunscreen to 
instructions regarding 
emollient use. 
To clarify when physical 
examinations and height, 
weight, and BMI are 
performed. 
To specify that a central 
reader will assess the 
photographs as a quality 
check of scoring 
consistency from Days 
30 and 90. 
To ensure postdose 
ECGs are collected (per 
MHRA advice) for 
subjects in PK substudy 
during serial sampling. 
To ensure PK samples 
are not contaminated by 
recent application of 
study drug. 
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skin after the last 
application. 
Table 2-2 
Schedule of Events for Open-
label Extension 
Revised footnote to IGA 
criteria. 
Reordered and revised 
assessments 
To specify order of 
assessment performance 
and that assessment of 
scaling is no longer 
done, and to clarify that 
fissuring only applies to 
palms/soles. 
Section 5.2 
 
Added: One study was 
conducted with CD5789 
50 μg/g, 100 μg/g, and 
placebo in subjects with 
icthyosis (Study 
RD.03.SRE.40181E). Among 
31 subjects treated in this 
study, 17 were treated with 
CD5789 100 μg/g, and 14 
were treated with 50 μg/g (all 
subjects received placebo 
[vehicle] on the contralateral 
zone). Mean (SD) baseline 
IGA score was 5.7 ± 1.6 
among the 31 subjects. 
Improvement in the 
investigator’s global 
assessment (IGA) of scaling 
and roughness was observed 
by Day 8 with both doses. 
The primary efficacy 
criterion was the change in 
IGA from the Baseline Visit 
(Day 1) to the Final Visit 
(Day 43). At Endpoint 
(intent-to-treat population, 
last observation carried 
forward [LOCF]), the 
CD5789 100 μg/g group had 
a statistically significant 
decrease from Baseline in 
IGA compared with Vehicle 
(-1.4±2.2; p=0.018) 
(Investigator’s Brochure for 
CD5789 Cutaneous 
Formulation). 
Added: However, it is 
possible that absorption in 
subjects with LI may be 
greater than in healthy 
To add experience with 
CD5789 in subjects with 
ichthyosis and to clarify 
that systemic absorption 
may differ in subjects 
with ichthyosis. 
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volunteers, due to the skin 
being compromised. 
Based on these data, both the 
100 µg/g and 200 µg/g doses 
showed an acceptable safety 
profile and will be used in 
this phase 2 LI study, to 
determine which of the 2 
doses is most effective. The 
open-label extension (OLE) 
will evaluate the long-term 
safety of the higher dose in 
this patient population. 
Section 5.3 
The potential risks of study 
participation include those 
associated with exposure to 
tifarotene (CD5789) cream 
HE1 and the risks of medical 
evaluation, including 
venipuncture. 
The potential risks of study 
participation for all subjects 
include those associated with 
exposure to trifarotene 
(CD5789) cream HE1 and the 
risks of medical evaluation, 
including venipuncture. The 
study population will 
comprise adults and 
adolescents aged 12 to 17 
years. 
Added: In addition, subjects 
should take protective 
measures such as applying 
sunscreen (except within 
4 hours before and/or 
4 hours after study drug 
application), and/or wearing 
protective clothing (e.g., long 
sleeves, hats, and covering 
legs and feet), and/or seeking 
shade or shelter from the 
sun. 
Added: No clinically 
significant systemic risks 
associated with CD5789 have 
been identified. Given the 
mechanism of action for 
CD5789 Cream HE1, it is 
assumed that efficacy will 
increase as the dose is 
increased. As such, the 
200 µg/g dose was selected 
for the OLE based on its 
previously established safety 
profile, expected superiority 
to placebo and 100 µg/g. 
However the Data Safety 
Monitoring Board (DSMB), 
To specify protective 
measures for avoiding 
sunlight/UV light (per 
MHRA request). 
To include systemic 
risks, and to add that the 
DSMB applies to both 
parts of the study and 
that if the 200 µg/g dose 
causes safety issues, the 
protocol will be amended 
if necessary. 
 
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who will routinely review 
aggregate safety and 
tolerability data, as well as 
any safety concerns brought 
to the their attention by the 
study investigators or 
medical monitor, may 
determine that the study 
should be modified, placed 
on hold, or stopped if serious 
safety issues are discovered. 
This is applicable for both 
the double-blind portion and 
OLE. If the 200 µg/g dose in 
raises any safety concerns, 
the protocol will be amended 
and the dose will be reduced. 
Section 7.1 
During all clinic visits, the 
investigator will assess local 
tolerability (Scale: 0-3 [none, 
mild, moderate, severe]) 
averaged over the BSA and 
will follow the procedures 
detailed in Section 9.4 
During all clinic visits, the 
investigator will assess local 
tolerability (Scale: 0-3 [none, 
mild, moderate, severe]) for 
each treated body area 
(chest/abdomen, back, legs, 
arms, and face/neck) and will 
follow the procedures detailed 
in Section 9.4 
To clarify that local 
tolerability assessments 
will be performed on all 
treated areas. 
Figure 7-1 
Redrawn 
Removed extraneous 
arrows; improved layout 
Section 8.4 
An investigator may 
discontinue a participant’s 
study treatment for any of the 
following reasons 
•
If any clinical AE,
laboratory abnormality, or
other medical condition or
situation occurs such that
continued participation in
the study would not be in
the best interest of the
participant
An investigator must 
discontinue a participant’s 
study treatment for any of the 
following reasons 
•
If any clinical AE,
laboratory abnormality, or
other medical condition or
situation occurs such that
continued participation in
the study would result in a
significant burden to the
participant
To clarify that this is 
mandatory. 
To clarify that these 
would be burdensome to 
the participant. 
Section 9.1 
Added: It is a potent RARγ 
agonist characterized by its 
high specificity to this 
receptor. 
To further characterize 
the investigational 
product. 
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Section 9.2 
 
Added: The IP should be 
applied thinly and gently 
rubbed in. 
Added: If the product will be 
applied at home by someone 
other than the study subject, 
it is recommended that 
person assist with application 
at the first visit to learn how 
the IP is applied. 
To clarify how IP should 
be administered. 
To clarify that anyone 
other than the study 
subject, who may apply 
the IP to the subject, is 
trained on application of 
IP. 
 
Subjects should not apply IP 
on visit days until after the 
visit. 
Added: Persons other than 
the study subject applying 
the study drug must wash 
their hands after application 
or use disposable vinyl 
gloves. In addition, a long-
handled applicator will be 
provided for application on 
the back. The applicator 
must be washed with warm 
water and soap after every 
application.  
Trifarotene cream should not 
come into contact with the 
eyes, mouth, angles of the 
nose, or mucous membranes. 
For the ectropion treatment, 
Q-tips are recommended for 
precise application on 
eyelids, without contact to 
the eye or conjunctiva. If the 
IP gets into the eye, it must 
be flushed immediately with 
warm water. In case of eye 
irritation, the subject must 
be seen by an 
ophthalmologist.  
To specify areas not to 
be treated. 
To ensure the safety of 
others who may apply 
the IP to the study 
subject and to improve 
application. 
To ensure PK blood 
draws are not 
contaminated with IP. 
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At least 24 hours must have 
elapsed since last IP 
administration before PK 
blood draws are performed. 
Subjects should not apply IP 
to the area where blood will 
be drawn for at least 24 
hours before the next PK 
sample draw. Subjects should 
not apply IP on visit days until 
after the visit, unless they are 
participating in the PK 
substudy, in which case the 
IP will be applied in the 
clinic on Day 30 after the 
blood draw. Among subjects 
participating in the PK 
substudy, ensure the PK line 
is inserted before study drug 
application to prevent 
contamination with the IP 
and protect the skin around 
the needle insertion point 
from study drug application. 
 
Section 9.3 
 
Added: Visits for PK must 
occur at least 24 hours after 
the last application of the IP 
to avoid contamination of the 
blood samples with any IP 
that may have remained in 
the skin after the last 
application. Subjects should 
not apply the IP on visit days 
until after the visit, unless 
they participate in the PK 
substudy, in which case the 
IP will be applied in the 
clinic on Day 30 after the PK 
blood draw. 
To ensure PK blood 
draws are not 
contaminated with IP. 
Section 9.4.1 
 
Added: Any changes in 
dosing must be documented 
in the subject diary and the 
eCRF. 
To ensure documentation 
of any dosing changes. 
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Section 9.5 
 
Added: Subjects who taper to 
once weekly application or 
who take a “drug holiday” 
for tolerability will not be 
reported as having deviated 
from the protocol (see 
Section 9.4 for dose 
adjustment and stopping 
rules); any changes in dosing 
must be documented in the 
subject diary and the eCRF. 
To clarify that subjects 
who require dose 
adjustment because of 
local tolerability will not 
be counted as having 
deviated from the 
protocol. 
Section 9.7 
Unblinding should be 
discussed in advance with the 
medical monitor, if possible.  
The investigator may discuss 
with the medical monitor in 
advance of unblinding a 
subject, if possible, if it is not 
deemed as an emergency. 
However, the investigator 
has the ultimate decision for 
unblinding a subject for 
medical treatment and no 
procedures will prevent or 
delay necessary unblinding 
in an emergency for the 
subject’s safety. 
To clarify that the 
investigator has the 
authority to make 
decisions about 
unblinding a subject (per 
MHRA 
recommendation). 
Section 9.8.1 
Subjects will be advised on 
permitted emollient(s) for use 
on nontreatment days during 
the study; use of emollient(s) 
on study drug treatment days 
within 4 hours of study drug 
application is prohibited. 
Subjects will be advised on 
permitted emollient(s) for use 
as often as needed on 
nontreatment days during the 
study; on treatment days, the 
use of emollient(s) is 
permitted except within 
4 hours before or after study 
drug application. Similarly, 
protective sunscreen should 
be applied as often as 
needed, except within 
4 hours before or after study 
drug application. Subjects 
may use their standard of 
care treatment on their faces 
and/or palms/soles after the 
Week 4 assessment if they 
experience a worsening of 
IGA in those areas. In the 
US/EU, this may include 
compounded emollients with 
keratolytics (alpha or beta 
hydroxyl acids) and/or urea. 
These standard of care 
treatments should be 
approved by the investigator 
and documented in the 
eCRF.  
To clarify when use of 
emollients and protective 
sunscreen is permitted.  
To add sunscreen as 
protection from 
sunlight/UV light. 
To allow subjects who 
experience worsening of 
IGA to return to standard 
of care treatment, as 
approved by the 
investigator, after 
Day 30. 
To avoid combination 
treatment during the 
OLE (no washout is 
necessary). Standard of 
care is permitted after the 
OLE Week 16 visit, as 
long as it does not 
contain prohibited 
medications, 
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Subjects who enter the OLE 
must stop standard of care 
treatment. If they experience 
a worsening of IGA they may 
use standard of care 
treatment on their faces 
and/or palms/soles after the 
Week 16 visit if the standard 
of care does not contain 
prohibited medications. If 
those standard of care 
treatments include 
prohibited medications, the 
subject should be 
discontinued from the study. 
Section 9.8.2 
 
The therapies listed in Table 
9-1 are prohibited during the 
study. 
The medications listed in 
Table 9 1 are prohibited during 
the study. 
Added: Balneotherapy is also 
prohibited during the 
Screening Period and during 
the study. 
Added: Use of benzoyl 
peroxide is permitted on 
non-treatment days for 
subjects with concomitant 
acne only; it must not be 
applied on treatment days 
due to risk of inactivation of 
trifarotene by benzoyl 
peroxide. 
Added: For enrolled subjects 
who require prescription of a 
systemic azole, the principal 
investigator should discuss 
with the medical monitor 
whether the subject may 
continue in the study. 
To allow subjects with 
acne to use benzoyl 
peroxide on 
nontreatment days. 
To specify that physical 
treatments such as 
balneotherapy are also 
prohibited. 
To specify that if 
subjects are prescribed 
an azole after study 
enrollment, their 
continued participation 
must be discussed with 
the medical monitor.  
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Section 9.8.3 
Subjects should not shower, 
bathe, or swim within 4 hours 
of after study drug application. 
No occlusive dressings should 
be applied to areas where study 
drug was applied.  
Subjects should only use 
investigator-approved 
emollients, and should not use 
them on treatment days within 
4 hours of study drug 
application. 
Subjects should not shower, 
bathe, or swim for at least 
4 hours after study drug 
application. No occlusive 
dressings should be applied to 
areas where study drug was 
applied.  
Subjects should only use 
investigator-approved 
emollients, and should not use 
them on treatment days for at 
least 4 hours before and after 
study drug application. 
Added: In addition, subjects 
should take protective 
measures to avoid exposure 
of treated areas to sunlight, 
such as applying sunscreen 
(except within 4 hours before 
and/or 4 hours after study 
drug application), and/or 
wearing protective clothing 
(e.g., long sleeves, hats, and 
covering legs and feet), 
and/or seeking shade or 
shelter from the sun.  
To clarify the window 
for showering or bathing 
and use of emollients on 
treatment days. 
To improve safety with 
regard to exposure to 
sunlight/UV light. 
Section 10.2 
 
Added: It is suggested that 
quality of life assessments be 
conducted first to avoid any 
bias, and that the IGA be 
recorded as the first LI 
assessment at every visit. 
To clarify order of 
assessment and to ensure 
IGA is recorded first as 
primary efficacy 
endpoint. 
Section 10.2.1.1 
Subjects must be screened 
within 35 days before 
randomization in the study. 
The following procedures will 
be performed at Screening 
The subject must complete 
eligibility screening within 35 
days before randomization in 
the study. The following 
procedures will be performed 
during Screening 
Reordered assessments to be in 
order of performance.  
Revised assessments to 
exclude individual scaling, to 
limit fissuring to palms/soles, 
and to add photographs as 
source documents. 
To reflect that subjects 
who require washout 
may return to the site to 
complete eligibility 
assessments within 
35 days of 
randomization. 
To reflect the changes in 
primary and secondary 
endpoints, the limit of 
fissuring to palms/soles, 
and the addition of 
photographs as source 
documents, and to ensure 
the order of assessments 
is correct. 
Section 10.2.2.1 
 
Reordered assessments to be in 
order of performance.  
To specify order of 
assessments; to specify 
that randomization is via 
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Revised assessments to 
exclude individual scaling, to 
limit fissuring to palms/soles, 
and to add cross-reference to 
Sections 10.3.1.5 and 10.3.1.6. 
Specified randomization to be 
done via IWRS. 
Added caution to ensure that 
PK lines are placed before IP 
application.  
Added instructions if the 
product will be applied at 
home by someone other than 
the study subject. 
Added sunscreen(s) use on 
nontreatment days and time 
frame for use on treatment 
days. 
Added: Among subjects in 
the PK study, perform an 
additional ECGs at times of 
serial sampling. 
the IWRS,; to specify 
that fissuring is only to 
be assessed on 
palms/soles, to provide 
location of specific 
quality of life scales, to 
specify procedures and 
times for PK serial blood 
draws to prevent 
contamination with IP, to 
ensure persons other than 
the study subject who 
may apply IP to the 
study subject are trained 
in IP application 
procedure; and to specify 
when emollients and 
protective sunscreen may 
be used on treatment 
days. 
Section 10.2.2.2 
and 
Section 10.2.2.5 
Staff will instruct subject on 
study drug application, advise 
subjects regarding permitted 
emollient(s) for use on 
nontreatment days (use of 
emollient(s) on study drug 
treatment days within 4 hours 
of study drug application is 
prohibited), and remind 
subjects not to apply IP on 
visit days until after the visit.  
Staff will instruct subject on 
study drug application, advise 
subjects regarding permitted 
emollient(s) for use on 
nontreatment days (use of 
emollient(s) and/or 
sunscreen(s) on study drug 
treatment days within 4 hours 
before or after study drug 
application is prohibited), and 
remind subjects that 24 hours 
must have elapsed since IP 
application before the 
subject’s next visit. Subjects 
should not apply IP on visit 
days until after the visit.  
To specify when 
emollients and protective 
sunscreen may be used 
on treatment days, and to 
add a window for IP 
application before next 
visit to prevent 
IP-contamination of PK 
blood samples. 
Sections 
10.2.2.3, 10.2.2.4, 
10.2.2.6, and 
10.2.2.7 
 
 
Reordered assessments to be in 
order of performance. Revised 
assessments to exclude 
individual scaling, to limit 
fissuring to palms/soles, and 
to add cross-reference to 
Sections 10.3.1.5 and 10.3.1.6. 
Added sunscreen(s) use on 
nontreatment days and time 
frame for use on treatment 
days. 
To specify order of 
assessments; to specify 
that fissuring is only to 
be assessed on 
palms/soles; to provide 
location of specific 
quality of life scales; to 
specify when emollients 
and protective sunscreen 
may be used on 
treatment days, and to 
add a window for IP 
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Added reminder that 24 hours 
must have elapsed since IP 
application before the 
subject’s next visit. Subjects 
should not apply IP on visit 
days until after the visit. 
application before next 
visit to prevent 
IP-contamination of PK 
blood samples. 
10.2.2.4  
 
Added caution to ensure that 
PK lines are placed before IP 
application.  
Added: Among subjects in 
the PK study, perform an 
additional ECGs at times of 
serial sampling. 
 
To specify order of 
assessments; to specify 
that fissuring is only to 
be assessed on 
palms/soles; to provide 
location of specific 
quality of life scales; to 
specify procedures and 
times for PK serial blood 
draws to prevent 
contamination with IP; to 
add postdose ECGs for 
subjects in PK substudy; 
and to specify when 
emollients and protective 
sunscreen may be used 
on treatment days. 
Section 10.2.2.7 
For subjects who successfully 
complete the initial 12 weeks 
of double-blind treatment and 
choose to continue into the 
OLE, this visit will be the first 
visit of that portion of the 
study.  
 
For subjects who successfully 
complete (i.e., have reliable 
visit attendance and 
compliance with IP 
application, in the 
investigator’s opinion) the 
initial 12 weeks of double-
blind treatment and choose to 
continue into the OLE, this 
visit will be the first visit of 
that portion of the study.  
To define “successful 
completion” of the 
Double-blind Period and 
to clarify eligibility for 
OLE. 
Section 10.2.4 
Subjects who complete the 
12-week Double-blind 
Treatment Period of the study 
may choose to continue into an 
optional 12-week Open-label 
Extension with trifarotene 
cream HE1 200 µg/g. 
Subjects who successfully 
complete (i.e., have reliable 
visit attendance and 
compliance with IP 
application, in the 
investigator’s opinion) the 
initial 12 weeks of double-
blind treatment may choose 
to continue into an optional 
12-week OLE with trifarotene 
cream HE1 200 µg/g. 
To clarify eligibility for 
OLE. 
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Section 10.2.4.2 
– 10.4.2.7 
 
Reordered assessments to be in 
order of performance, and 
revised assessments to limit 
fissuring to palms/soles. 
Added sunscreen(s) use on 
nontreatment days and time 
frame for use on treatment 
days. 
Added reminder that at least 
24 hours must have elapsed 
since IP application before 
the subject’s next PK blood 
draw. 
To specify order of 
assessments; to specify 
that fissuring is only to 
be assessed on 
palms/soles. 
To specify when 
emollients and protective 
sunscreen may be used 
on treatment days. 
To add a window for IP 
application before next 
visit to prevent 
IP-contamination of PK 
blood samples. 
Section 10.3 
The 5-point VIIS is a valid 
measure of disease severity 
and meets the need for a 
clinically meaningful measure 
of success for ichthyosis 
studies. The VIIS scale was 
developed to generate a 
reliable method to assess 
ichthyosis clinical severity 
using solely scale and 
erythema, which are the only 
findings present in ichthyosis 
of every genetic cause, and 
occur either upon skin of 
normal thickness (lamellar 
subtypes) or upon thickened 
skin (keratoderma subtypes).13 
The VIIS uses a 5 point index 
to assess the level of severity 
of scale and erythema in each 
of 4 body areas: 
chest/abdomen, back, legs, and 
arms, for a possible overall 
total of 16 points 
(Section 10.3.1.1).  
The 5-point IGA is a valid 
measure of disease severity 
and meets the need for a 
clinically meaningful measure 
of success for ichthyosis 
studies. The IGA scale was 
developed with the support 
of experts from academic 
reference centers for the 
treatment of ichthyosis. Each 
level of severity will consider 
both the severity of scaling 
and the severity of roughness 
(Section 10.3.1.1).  
To reflect the change in 
primary endpoint to IGA. 
Section 10.3.1.1 
10.3.1.1 Visual Index for 
Ichthyosis Severity – Scaling 
The primary endpoint is the 
number of subjects in each 
treatment group who 
experience successful 
resolution of LI where 
“success” is defined as 
clear/almost clear overall and 
at least a 50% reduction from 
Baseline at Week 12/EOT on 
10.3.1.1 Investigator’s 
Global Assessment 
The primary endpoint is the 
number of subjects in each 
treatment group who 
experience successful 
resolution of LI where 
“success” is defined as 
clear/almost clear and at least 
a 2-grade change from 
Baseline at Week 12/EOT in 
the Double-blind Period on 
To reflect the change in 
primary endpoint to IGA 
and that fissuring will 
only be assessed on 
palms/soles. 
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the overall 16-point VIIS for 
scaling. 
The investigator will rate the 
subject’s condition using the 
5-point VIIS for each body 
area (chest/abdomen, back, 
legs, and arms) and an overall 
score at each time point shown 
in the Schedule of Events 
(Section 2.2): 
0 Clear  
Normal skin; no perceptible 
scale or smoothening 
1 Almost clear 
Areas of normal skin 
intermixed with areas 
showing smoothening 
(diminished fine skin 
markings; shininess; 
waxiness) or small scales 
(visibly separated/fractured 
stratum corneum) 
2 Mild 
Confluent smoothening 
(diminished fine skin 
markings; shininess; 
waxiness) or small scales 
(visibly separated/fractured 
stratum corneum) 
3 Moderate 
Confluent scales (visibly 
separated/fractured stratum 
corneum) including some 
large (>1cm), thick scales 
4 Severe 
Confluent, primarily large, 
thick scales 
the 5-point IGA full body 
scale. 
The investigator will rate the 
subject’s condition using the 
5-point IGA at each time point 
shown in the Schedule of 
Events (Section 2.2).  
The IGA will be measured on 
a 5-point scale, excluding the 
following areas: knees, 
elbows, neck, palms, soles, 
axillae, groin, and scalp: 
0 Clear 
No scaling and no 
roughness 
1 Almost Clear 
Occasional fine scales; 
hardly palpable 
roughness (mostly 
smooth) 
2 Mild  
Small and fine scales 
predominate; no more 
than a few large scales; 
mild roughness on 
palpation 
3 Moderate 
Some large scales that 
may be thick; coarse 
roughness on palpation 
4 Severe 
Confluent, primarily 
large (>1 cm), thick scales 
with plate-like 
hyperkeratosis  
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Section 10.3.1.2 
10.3.1.2 Investigator’s Global 
Assessment 
 
Changed to : 
10.3.1.2 Visual Index for 
Ichthyosis Severity – Scaling 
The primary secondary 
endpoint is the number of 
subjects in each treatment 
group who experience a 
severity score of 0 or 1 and at 
least a 50% reduction from 
Baseline at Week 12/EOT on 
the overall 16 point VIIS for 
scaling. 
The investigator will rate the 
subject’s condition using the 
5-point VIIS for each body 
area (chest/abdomen, back, 
legs, and arms) and an overall 
score at each time point shown 
in the Schedule of Events 
(Section 2.2). 
Deleted clear/almost 
clear/mild/moderate/severe 
from scoring scale. 
To reflect the change in 
primary endpoint to IGA. 
Section 10.3.1.3 
Individual Score of Scaling 
(Scale: 0-4) 
 
Changed to: 
Individual Score for 
Roughness 
 
No individual score for 
scaling is needed now 
that IGA is primary 
endpoint. 
Section 10.3.1.5 
 
Added: A fissure is a 
longitudinal and deep crack 
that separates the stratum 
corneum and may penetrate 
down to the dermis, causing 
pain and sometimes bleeding.  
To clarify the definition 
of a fissure. 
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Section 10.3.1.6 
The DLQI is a dermatology-
specific Quality of Life 
instrument.  
10.3.1.6 Dermatology Life 
Quality Index 
The DLQI is a dermatology-
specific Quality of Life 
instrument for subjects aged 
17 years and older (1992). 
The child DLQI (cDLQI; 
May 1993) is for subjects 
aged 12 to 16 years. 
Added: The investigator 
should use his or her 
judgment of the maturity of 
the subject to decide which 
version of the questionnaire 
to use; the same version must 
be used for the subject 
throughout the study. 
To specify which DLQI 
instrument should be 
used based on the 
investigator’s judgment 
of the study subject’s 
maturity. 
Section 10.3.1.7 
The EQ-5D consists of a 
descriptive system and the EQ 
visual analog scale (VAS). 
The EQ VAS records the 
subject’s self-rated health on a 
vertical VAS. 
The EQ-5D consists of a 
descriptive system and the EQ 
visual analog scale (VAS). 
The EQ-5D-5L (2009) is 
intended for use in adult 
subjects, while the EQ-5D-Y 
(2012) is to be used for 
children and adolescents. 
Added: The investigator 
should use his or her 
judgment of the maturity of 
the subject to decide which 
version of the questionnaire 
to use; the same version must 
be used for the subject 
throughout the study. 
To specify which EQ-5D 
instrument should be 
used based on study 
subject age, and to 
clarify the VAS is 0-100. 
Section 10.3.1.8 
 
Added: Figure 10-1 
Ectropion Severity Score 
(from reference #14)  
To show how the 
ectropion score should 
be calculated. 
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Section 10.3.3 
Sample Collection: 
Blood: 
Each blood sample will be 
3 mL/kg in volume. The total 
amount of blood to be drawn 
for serial PK assessments will 
be a maximum of 5 mL/kg per 
subject over a 24-hour period. 
 
Added: Finding veins in 
subjects with this disease can 
be challenging. Blood draws 
will be done at the 
corresponding study visits 
before application of the IP 
and should be 24 hours after 
IP application. Subjects must 
not apply the IP to the area 
where blood will be drawn 
within 24 hours before their 
next study visit to avoid 
contamination of the blood 
by IP that remained in the 
skin. For subjects in the PK 
substudy, a cannula should 
be placed before IP 
application and the cannula 
site may be occluded to 
prevent contamination with 
IP. 
Actual PK sample times for 
subjects in the PK substudy 
will be recorded in the eCRF. 
Blood: 
For subjects not in PK 
substudy: 
The expected amount of 
blood to be drawn at each 
visit varies from 
approximately 6 mL to a 
maximum of 21 mL 
(Screening Visit only). The 
total amount of blood drawn 
for the study will be about 
123 mL per subject, unless 
the subject takes part in the 
PK substudy. 
For subjects in PK substudy: 
For subjects who opt to 
participate in the PK 
substudy, extra blood 
samples will be drawn at 
Visit 2 and at Visit 4 for PK 
analysis. The amount of 
blood to be drawn per 
subject at each of these visits 
will be approximately 54 mL. 
For subjects taking part in 
the substudy, the total 
amount of blood drawn for 
To clarify how blood 
draws should be 
performed to prevent 
contamination with IP. 
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the entire study will be 
approximately 195 mL. 
Section 
10.3.4.2.2 
 
Added: Gel ECG electrodes 
may be used for ECGs 
because they are more 
conductive and cause less 
trauma on compromised 
skin. Efficacy assessments 
should be conducted before 
ECGs to avoid possible 
artefact/changes from the 
ECG.  
For subjects in the PK 
substudy, additional ECGs 
will be performed postdose 
during serial blood sampling 
on Day 1 and Day 30. 
If there is a marked 
prolongation of the QT/QTc 
interval during treatment, a 
subject should be 
discontinued from the IP, but 
remain in the study until full 
resolution of the event. The 
DSMB will be informed 
immediately of such an 
occurrence. 
To ensure the most 
comfortable method is 
used; to address order of 
assessments; to add 
ECGs postdose at Day 1 
and Day 30 (per MHRA 
request) among subjects 
in the PK substudy; and 
to address procedures 
should QT/QTc 
prolongation occur. 
10.3.4.2.3 
A complete physical 
examination excluding the 
genitourinary examination will 
be performed as indicated in 
the Schedule of Events 
(Section 2.2). 
A complete physical 
examination excluding the 
genitourinary examination will 
be performed at Screening, 
while limited physical 
examinations (to include 
HEENT, cardiorespiratory, 
abdomen, and range of 
motion) will be performed as 
indicated in the Schedule of 
Events (Section 2.2). 
To clarify when 
complete and limited 
physical examinations 
are to be performed. 
Section 
10.3.4.2.4 
All application site reactions 
will be recorded as AEs. 
All application site reactions 
will be recorded as TEAEs in 
the diary. These should 
include the date and severity 
of the TEAE. 
To specify that all 
application site reactions 
should be recorded in the 
subjects’ diaries in detail.  
Section 11.2.3 
 
Added: Any AE that occurs 
during the Screening Period 
will be captured as such on 
the AE page of the eCRF 
(not medical history).  
To clarify that any AE 
that occurs after signing 
of the ICF is to be 
captured as such and not 
as medical history. 
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Section 11.3.2 
All WOCBP who participate in 
the study should be counseled 
on the need to practice 
adequate birth control and on 
the importance of avoiding 
pregnancy during study 
participation.  
All WOCBP who participate in 
the study should be counseled 
on the need to practice highly 
effective birth control and on 
the importance of avoiding 
pregnancy during study 
participation.  
Added: Among the clinical 
studies, 12 pregnancies were 
reported: 4 resulted in 
normal births; 5 resulted in 
spontaneous abortions (none 
of which was considered 
related to CD5789); 1 was 
electively aborted, and 2 
were lost to follow-up 
(Investigator’s Brochure for 
CD5789 Cutaneous 
Formulation). 
To clarify that birth 
control must be “highly 
effective” (per MHRA).  
To add data on 
pregnancy from clinical 
studies with CD5789. 
Section 12 
The DSMB will meet after 
subjects in Cohort A have 
completed at least 28 days of 
double-blind treatment to 
review aggregate safety and 
tolerability data. The data will 
remain blinded unless an issue 
or trend arises that requires 
unblinding. At that time, the 
DSMB will decide whether 
Cohort B (adults and subjects 
aged 12–17) may begin 
enrolling. The DSMB will 
have the authority to 
recommend to the sponsor that 
the study be placed on hold, or 
discontinued if serious safety 
issues are discovered.  
The DSMB will meet after 
15 subjects in Cohort A have 
completed at least 28 days of 
double-blind treatment to 
review aggregate safety and 
tolerability data (including PK 
and ECG results). The safety 
data will be unblinded. At that 
time, the DSMB will decide 
whether Cohort B (adults and 
subjects aged 12–17) may 
begin enrolling, or if additional 
adult safety data are required 
before allowing subjects aged 
12 – 17 to participate in the 
study. The DSMB will have 
the authority to recommend to 
the sponsor that the study be 
modified, placed on hold, or 
stopped if serious safety issues 
are discovered.  
Added: Any protocol changes 
the DSMB may suggest will 
be submitted to all applicable 
regulatory bodies for review 
and approval. 
To clarify when the 
DSMB will meet, and 
what data they will 
review. 
 
Section 13.1.2.2 
and 
Section 13.1.3 
 
Added: Subjects who taper to 
once-weekly application or 
who take a “drug holiday” 
will not be reported as 
having deviated from the 
protocol. 
Clarified that subjects 
requiring dose 
adjustment or temporary 
interruption are not 
protocol deviators. 
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Section 13.1.2.3 
Baseline subject characteristics 
will include medical history, 
physical examination findings, 
and VIIS score. 
Baseline subject characteristics 
will include medical history, 
physical examination findings, 
and IGA score. 
To reflect change in 
primary endpoint to IGA. 
Section 13.1.4 
The mITT population will be 
used as the primary population 
for the primary analysis of 
efficacy at Week 12. All 
efficacy analyses will be 
repeated as secondary analyses 
in the ITT and PP populations 
for the Double-blind Period. 
Efficacy analyses will also be 
repeated in the OLE using the 
OLE mITT and OLE PP 
populations. No formal 
inferential analyses will be 
conducted for efficacy 
variables in the OLE. 
The ITT population will be 
used as the primary population 
for the primary analysis of 
efficacy at Week 12. Select 
efficacy analyses will be 
repeated as secondary analyses 
in the ITT and PP populations 
for the Double-blind Period. 
Efficacy analyses will also be 
repeated in the OLE using the 
OLE ITT, OLE mITT, and 
OLE PP populations. No 
formal inferential analyses will 
be conducted for efficacy 
variables in the OLE 
 
Section 13.1.4.2 
Descriptive summaries (such 
as mean, standard error, 
median, minimum, and 
maximum) and the changes 
from baseline will be provided 
for VIIS scores for both 
periods. 
Descriptive summaries (such 
as mean, standard error, 
median, minimum, and 
maximum) and the changes 
from baseline will be provided 
for IGA scores for both 
periods. 
To reflect the change in 
primary endpoint to IGA. 
Section 13.1.4.3 
Additionally, for the Double-
blind Period only, change from 
Baseline endpoints through 
Week 12 will be presented and 
analyzed using a mixed model 
for repeated measures 
(MMRM). The model will 
include the change from 
baseline score as the dependent 
variable, treatment group as a 
fixed effect, subject as a 
random effect, and baseline 
score value as a covariate. 
Frequencies of results and 95% 
CIs will also be reported and 
scores will be analyzed as 
categorical variables using the 
Cochran-Mantel-Haenszel test. 
Additionally, for the Double-
blind Period only, change from 
Baseline in continuous 
secondary endpoints through 
Week 12 will be presented and 
analyzed using a mixed model 
for repeated measures 
(MMRM). The model will 
include the change from 
baseline score as the dependent 
variable, treatment group as a 
fixed effect, subject as a 
random effect, and baseline 
score value as a covariate.  
Added: The proportion of 
subjects with at least a 50% 
reduction in IGA score from 
Baseline will be analyzed 
using the same logistic 
regression analysis described 
in Section 13.1.4.2. 
To reflect and clarify 
changes in secondary 
endpoints. 
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Section 13.1.4.5 
To assess the effect of missing 
data on the primary efficacy 
analysis, a sensitivity analysis 
will be performed using LOCF 
for the Double-blind Period 
only. Imputation will not be 
performed in the OLD period.  
 
To assess the effect of missing 
data on the primary efficacy 
analysis, a sensitivity analysis 
will be performed using 
multiple imputation (MI) for 
the Double-blind Period only. 
Multiple-imputations will be 
used to replace missing IGA 
outcomes using multiple 
draws from the posterior 
predictive distribution 
estimated from the treatment 
groups. IGA scores will be 
imputed and then 
categorized as treatment 
success according to Section 
13.1.4.1. Imputation will not 
be performed in the OLE 
period. Full details will be 
specified in the Statistical 
Analysis Plan (SAP).  
Added: The proportion of 
subjects who experience a 
2-grade change from baseline 
to Week 12 in individual 
score for roughness and 
palm/sole assessment will 
also be explored using a 
logistic regression model 
with treatment and age 
group as factors. Other 
baseline characteristics and 
interactions may be included. 
The odds ratios and 95% CIs 
for the odds ratios will be 
presented. The difference in 
proportions between the 
active trifarotene cream HEI 
and vehicle cream group and 
the 95% CIs for the 
differences will be presented. 
To align with current 
FDA thinking. Single 
imputation does not 
consider all missingness 
patterns. 
To explore a defined 
threshold for a clinically 
meaningful endpoint for 
phase 3. 
Section 13.1.6.1 
During all clinic visits, the 
investigator will assess local 
tolerability (Scale: 0-3 [none, 
mild, moderate, severe]) 
averaged over the BSA.  
During all clinic visits, the 
investigator will assess local 
tolerability (Scale: 0-3 [none, 
mild, moderate, severe]) for 
each treated body area 
(chest/abdomen, back, arms, 
legs, and face/neck). 
To clarify that all treated 
areas are included in the 
local tolerability 
assessment. 
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Section 
Previous Text 
Revision 
Rationale 
Section 14.7.2 
Blood samples will be used for 
purposes related to this 
research. The samples will be 
stored until the sponsor has 
determined that specimens are 
no longer needed, and the 
decision has been made that 
none of the samples needs to 
be reanalyzed 
Blood samples will be used for 
purposes related to this study 
only, and will not be stored 
for future research. The 
samples will be stored until 
they are no longer needed, 
and the decision has been 
made that none of the samples 
needs to be reanalyzed.  
To clarify that no 
samples will be stored 
for future research 
 
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AMENDED PROTOCOL 
The following are the amended protocol and appendices, including all revisions specified above. 
 
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4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABBREVIATION 
EXPLANATION 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse events of special interest 
ATC 
anatomical therapeutic chemical 
AUC 
area-under-the-curve 
BMI 
body mass index 
BSA 
body surface area 
CFR 
code of federal regulations 
CI 
confidence interval 
Cmax 
maximum concentration 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
DBP 
diastolic blood pressure 
DLQI 
dermatology life quality index 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
ESS 
ectropion severity score 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GEE 
generalized estimating equations 
HR 
heart rate 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification 
IEC 
independent ethics committee 
IGA  
Investigator’s Global Assessment 
IND 
investigational new drug 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent-to-treat 
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ABBREVIATION 
EXPLANATION 
IUD 
intrauterine device 
IWRS 
interactive web response system 
LI 
lamellar ichthyosis 
MedDRA 
medical dictionary for regulatory activities 
mITT 
modified intent-to-treat 
MMRM 
mixed model of repeated measures 
NCA 
noncompartmental analysis 
OC 
observed case 
OLE 
open-label extension 
PG 
propylene glycol 
PK 
Pharmacokinetic(s) 
PoC 
proof-of-concept 
PP 
per-protocol 
QTc 
QT interval corrected for heart rate 
RARγ 
retinoid acid receptor γ  
RBC 
red blood count 
RR 
respiratory rate 
RXR 
retinoid X receptor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
Tmax 
time of Cmax 
UAE 
unexpected adverse event 
UADR 
unexpected adverse drug reaction 
US 
United States 
UV 
ultraviolet 
VIIS 
Visual Index for Ichthyosis Severity 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
women of child-bearing potential 
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5. INTRODUCTION 
5.1. Background and Rationale 
The ichthyoses comprise a large group of skin scaling disorders with diverse etiology. The 
stereotypic pathophysiology is epidermal hyperplasia and the formation of excess stratum corneum 
accompanied by abnormal (delayed and/or disordered) desquamation, with visible accumulation 
of squames (scales) on the skin’s surface – the clinical hallmark of all the ichthyoses. 
Lamellar ichthyosis (LI) is recognized as a severe form of ichthyosis that persists throughout life. 
During the first postnatal weeks, the hyperkeratotic membrane patients are typically born with is 
gradually shed, and is replaced by scaling and lichenification that involves the entire body 
including the intertriginous areas, palms, soles, and scalp. While usually not life threatening, LI 
can result in disability, partial deafness, poor adaptation to environmental conditions (due to 
hypohydrosis), severe discomfort (pruritus, fissuring of the skin) and significant psychosocial 
impact. 
Lamellar ichthyosis, a member of the nonsyndromic autosomal recessive congenital ichthyosis 
group of ichthyoses, has an incidence of 1 per 100,000-300,000 live births.1 Lamellar ichthyosis 
is undoubtedly a rare disease. 
Therapeutic approaches for LI are mainly based on the use of topical emollients, keratolytic agents 
(urea, lactic acid, salicylic acid), topical retinoids and, in severe cases, oral retinoids.2,3 
Oral retinoid usage in LI is mainly based on case reports and case series.4,5,6,7,8 The mechanism of 
retinoid action involves modulation of keratinocyte differentiation, keratinocyte hyperproliferation 
and tissue infiltration by inflammatory cells. Systemic retinoids (such as acitretin, etretinate, or 
isotretinoin) have been found to be efficacious in the treatment of severe ichthyoses, especially in 
LI.6 
Vahlquist, et al (2008)3 report that by combining 2 or more keratolytic agents and moisturizers in 
the same lipophilic cream base, it is often possible to achieve additive or even synergistic effects 
in LI without the need to use irritating concentrations of either agent alone. In a double-blind trial 
of 4 different cream mixtures in 20 patients with LI, a mixture of 5% lactic acid and 20% propylene 
glycol (PG) in a semi-occlusive cream for 4 weeks twice daily was significantly more effective 
than 20% PG or 5% urea alone in the same vehicle.9 Although the treatments were well tolerated, 
an efficient removal of hyperkeratosis without correcting the underlying biochemical defect in LI 
is likely to deteriorate the patient’s intrinsic barrier problem, because an excessive production of 
corneocytes probably represents a homeostatic response to an ineffective barrier. Indeed, 
transepidermal water loss increased after successful treatment of LI with either topical 
keratolytics9 or oral retinoid.10 Although this may not be noticeable by the patient, even minor 
deteriorations in the barrier function can enhance transcutaneous penetration of active cream 
ingredients or other topically applied chemicals, which is a matter of special concern in children. 
Accordingly, α-hydroxy acids and salicylic acid should not be used at all in babies and only with 
great caution when treating large, eroded skin areas in adult patients.11,12 
Many patients with LI use pumice, foot files, or gentle rubbing of the skin after a hot bath or a 
shower to remove scales and hyperkeratosis. Overnight occlusion of problematic skin areas with 
plastic sheets after applying a thick layer of emollient or keratolytic agents is another way of 
potentiating therapy, especially on the scalp, which is notoriously difficult to treat. Although 
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usually effective, all these remedies may further damage the skin barrier and lead to exaggerated 
epidermal proliferation, erythema, painful erosions and increased transcutaneous penetration.3 
Based on this information, LI has significant unmet medical need for safer and more effective 
therapies. 
5.1.1 CD5789 (Trifarotene) 
CD5789 is a new chemical entity discovered by Galderma R&D SNC and formulated for topical 
application. It is a novel retinoid acid receptor γ (RARγ) agonist, characterized by its high 
specificity to this receptor. CD5789 is selective for RARγ over RARα and RARβ (approximately 
50- and 8-fold, respectively), with no retinoid X receptor (RXR) activity. CD5789 is currently 
under clinical development for the topical treatment of various dermatoses, including acne vulgaris 
and LI. 
The pharmacological retinoid-like properties of CD5789 were confirmed in in vitro and in vivo 
models, showing its interest for its development in the treatment of LI. Therefore, it may have an 
effect on the differentiation and hyperproliferation of keratinocytes, and consequently improve 
hyperkeratotic skin of patients with lamellar ichthyosis. 
Within the overall acne development program at Galderma, CD5789 has been tested in different 
pharmaceutical forms for topical administration. As of 15-Jan-2018, 6 different formulations have 
been evaluated: a solution, a gel and 4 creams (CD5789 cream A, CD5789 cream B, CD5789 
cream HE1 concept and its optimized version, cream HE1), with different concentrations (up to 
400 µg/g). Therefore, several formulations at different CD5789 concentrations have been tested in 
nonclinical and clinical development programs. 
Galderma decided to develop a new cream formulation that might better address the issue of skin 
dryness in patients with LI. This formulation was named “Cream HE1 concept.” It has been 
preliminarily investigated in an exploratory trial in psoriasis at concentrations up to 400 μg/g 
(RD.03.SRE.40204E). In a proof-of-concept study (RD.03.SRE.40181E), positive results were 
also obtained in patients with LI with CD5789 cream (up to 100 µg/g) that was effective in 
decreasing scaling and roughness. Based on these results, a new CD5789 formulation (cream HE1) 
was developed for further clinical investigations in LI. The formulation cream HE1 was developed 
with the objective to obtain a formulation with appropriate stability of the active ingredient and in 
which CD5789 would be homogeneously dissolved in the oily phase at a higher concentration 
compared to the cream formulation used in the acne program. Cream HE1 contains 100, 200, or 
400 μg/g (0.01% [w/w], 0.02% [w/w], 0.04% [w/w], respectively) of CD5789. 
Galderma has granted Mayne Pharma LLC an exclusive license to develop and commercialize 
CD5789 (trifarotene) for LI and other orphan diseases; therefore, the LI indication is no longer 
pursued by Galderma. 
5.2. Clinical Experience 
The cream HE1 differs from the CD5789 cream used to treat acne vulgaris in that it contains fewer 
excipients with drying effects and therefore may be better suited for patients with LI. 
Throughout the 30 clinical studies that comprise the clinical development program for CD5789 
topical products, 1976 subjects were exposed to CD5789. No systemic safety concerns related to 
CD5789 gel or creams, or cream HE1 at doses up to 400 μg/g were reported. The subjects were 
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exposed to a maximal total CD5789 dose of 36 g/day (Investigator’s Brochure for CD5789 
Cutaneous Formulation). 
One study was conducted with CD5789 50 μg/g, 100 μg/g, and placebo in subjects with ichthyosis 
(Study RD.03.SRE.40181E). Among 31 subjects treated in this study, 17 were treated with 
CD5789 100 μg/g, and 14 were treated with 50 μg/g (all subjects received placebo [vehicle] on the 
contralateral zone). Mean (SD) baseline IGA score was 5.7 ± 1.6 among the 31 subjects. 
Improvement in the investigator’s global assessment (IGA) of scaling and roughness was observed 
by Day 8 with both doses. The primary efficacy criterion was the change in IGA from the Baseline 
Visit (Day 1) to the Final Visit (Day 43). At Endpoint (intent-to-treat population, last observation 
carried forward [LOCF]), the CD5789 100 μg/g group had a statistically significant decrease from 
Baseline in IGA compared with Vehicle (-1.4±2.2; p=0.018) (Investigator’s Brochure for CD5789 
Cutaneous Formulation). 
The CD5789 PK profile was also investigated using cream HE1 (Study GD.03.SRE.103813) in 
36 healthy volunteers of Japanese and non-Japanese origin. Subjects were treated daily on up to 
90% of body surface area (BSA) for 29 days with up to 36 g of cream formulation. Both CD5789 
100 μg/g and 200 μg/g cream HE1 were investigated. Plasma PK assessment demonstrated that 
repeated topical applications of CD5789 cream HE1 resulted in low and similar CD5789 systemic 
levels in all treatment groups. In addition, no systemic safety concerns were raised from this 
healthy volunteer study in which cream HE1 200 μg/g was applied daily under maximal-use 
conditions on almost the full body. In this study, however, the level of irritation resulted in the 
need to decrease the frequency of application to twice weekly (Investigator’s Brochure for CD5789 
Cutaneous Formulation). However, it is possible that absorption in subjects with LI may be greater 
than in healthy volunteers, due to the skin being compromised. 
Based on these data, both the 100 µg/g and 200 µg/g doses showed an acceptable safety profile 
and will be used in this phase 2 LI study, to determine which of the 2 doses is most effective. The 
open-label extension (OLE) will evaluate the long-term safety of the higher dose in this patient 
population.  
5.3. Summary of Potential Risks and Benefits 
Although the primary objective of this study is safety in the patient population with LI, the 
potential benefits of study participation are that subjects with LI may experience a reduction in 
their LI symptoms as a result of treatment with trifarotene (CD5789) cream HE1. No other benefits 
of participation are anticipated. 
The potential risks of study participation for all subjects include those associated with exposure to 
trifarotene (CD5789) cream HE1 and the risks of medical evaluation, including venipuncture. The 
study population will comprise adults and adolescents aged 12 to 17 years. 
Animal studies with CD5789 have shown reproductive toxicity in the embryo-fetal studies. 
Despite low systemic levels with the CD5789 concentration of 50 μg/g used in patients with acne, 
CD5789 must not be administered during pregnancy. 
When CD5789 is used in the other formulations and/or for other indications and/or with higher 
concentrations or higher application surface areas, the potential risk of teratogenicity needs to be 
considered as the safety margin may be lower. Depending on the study population and conditions 
mentioned above, or other specific requirements, the appropriate contraception method is 
described in this protocol. 
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It is unknown whether CD5789 or its metabolites are excreted in human milk. A risk to the 
newborns/infants cannot be excluded. Lactating women are not eligible for the clinical study. 
Certain cutaneous signs and symptoms of irritation and localized reactions at the application site 
such as erythema, scaling, dryness, stinging/burning, and pruritus may be experienced with use of 
CD5789. Depending upon the severity of these side effects, subjects may be instructed to reduce 
the frequency of application or to discontinue use.  
Trifarotene cream contains propylene glycol that is mildly irritant to the skin, eyes, and mucous 
membranes. Trifarotene (CD5789) cream HE1 also contains butylated hydroxytoluene that may 
cause local skin reactions (e.g., contact dermatitis), or irritation to the eyes and mucous membranes 
and sodium benzoate that is mildly irritant to the skin, eyes, and mucous membranes. 
CD 5789 is mildly irritant to the skin, eyes, and mucous membranes. Therefore, it should not come 
into contact with the eyes, mouth, or mucous membranes.  
There is a potential risk of skin sensitization. If a reaction suggesting sensitivity to trifarotene 
(CD5789) cream HE1 occurs, the use of the trifarotene cream HE1 must be discontinued. 
There is a potential risk of photosensitivity disorder (sunburn). Excessive exposure to sunlight or 
ultraviolet (UV) radiation (i.e., occupational exposure to the sun, planned holidays in the sun 
during the study, phototherapy, tanning salon) must be avoided during the studies. In addition, 
subjects should take protective measures such as applying sunscreen (except within 4 hours before 
and/or 4 hours after study drug application), and/or wearing protective clothing (e.g., long sleeves, 
hats, and covering legs and feet) and/or seeking shade or shelter from the sun. 
As reported with other topical retinoids, there is a potential risk of pigmentation disorders. 
No clinically significant systemic risks associated with CD5789 have been identified. Given the 
mechanism of action for CD5789 Cream HE1, it is assumed that efficacy will increase as the dose 
is increased. As such, the 200 µg/g dose was selected for the OLE based on its previously 
established safety profile, expected superiority to placebo and 100 µg/g. However the Data Safety 
Monitoring Board (DSMB), who will routinely review aggregate safety and tolerability data, as 
well as any safety concerns brought to the their attention by the study investigators or medical 
monitor, may determine that the study should be modified, placed on hold, or stopped if serious 
safety issues are discovered. This is applicable for both the double-blind portion and OLE. If the 
200 µg/g dose in raises any safety concerns, the protocol will be amended and the dose will be 
reduced. 
A summary of the pharmaceutical properties and known potential risks of trifarotene (CD5789) 
cream HE1 is provided in the current version of the investigator brochure (IB). The investigator 
must become familiar with all sections of the trifarotene (CD5789) cream IB before the start of the 
study. 
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6. OBJECTIVES 
6.1. Primary Objective 
The primary objective is to compare the safety and efficacy of 2 concentrations of trifarotene cream 
HE1 versus vehicle in adults and adolescents with moderate to severe autosomal recessive 
ichthyosis with lamellar scale, also known as lamellar ichthyosis (LI) after 12 weeks of treatment. 
6.2. Secondary Objectives 
The secondary objectives are as follows: 
• To assess systemic exposure to trifarotene and its major metabolites after topical 
application of the investigational product (IP) on up to 90% BSA twice weekly. 
• To assess safety for up to 24 weeks of dosing with open-label trifarotene cream HE1 
200 µg/g. 
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7. STUDY DESIGN 
7.1. Overall Study Design and Plan 
The first part of this study is a phase 2, randomized, 2-cohort, double-blind, vehicle-controlled, 
multicenter study of the safety, tolerability, PK, and efficacy study of trifarotene cream HE1 
100 µg/g and 200 µg/g in adults and adolescents with LI. Adult and adolescent subjects who 
complete the randomized, double-blind, vehicle-controlled period of the study will be eligible to 
continue into an open-label extension (OLE) and be treated with trifarotene cream HE1 200 µg/g 
for an additional 12 weeks. 
The randomized, double-blind, vehicle-controlled period of the study in subjects with moderate to 
severe LI (i.e., 3–4 on a 5-point Investigator Global Assessment [IGA] scale where 0 = clear; 1 = 
almost clear; 2 = mild; 3 = moderate; and 4 = severe, is designed to compare the safety of 2 doses 
of trifarotene cream HE1 with that of vehicle in the treatment of LI.  
Written informed consent will be obtained from a parent/legal guardian for any minor and minors 
will provide assent before any study-related procedures are performed. 
Upon signing informed consent and entering the Screening Period, subjects will stop using 
physical and medical treatments for LI, including balneotherapy, and may begin to washout 
prohibited topical and systemic treatments with designated washout periods (Table 9-1), as 
applicable. Washout may be up to 3 months, as necessary. 
During washout, subjects may continue taking usual care of visible skin (face and scalp) for 
cosmetic reasons and of extremities (hands and feet) to avoid functional consequences on walking 
or moving their fingers. Subjects may shower, but not bathe or swim. The IGA will be evaluated 
on the rest of the body at Baseline. After completing any necessary washout of prohibited 
medications, subjects will return to the site to complete the study eligibility requirements. 
The first cohort of subjects (Cohort A) will randomize approximately 15 adults (≥18 years old) in 
a 1:1:1 ratio to trifarotene (CD5789) cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or 
vehicle.  
Study drug will be packaged in 50-g tubes from which up to 36 g of IP may be dispensed per 
application, i.e., the maximum dose per application. Study staff will apply the first dose of study 
drug to each subject in the clinic on Day 1 after Baseline measurements, and will record the amount 
of study drug applied (i.e., study staff will measure the 50-g tube before and after the first 
application to determine the fixed dose amount for each subject). If the product will be applied at 
home by someone other than the study subject, it is recommended that person assist with 
application at the first visit to learn how the IP is applied. 
Thereafter, subjects will apply approximately the same amount (up to 36 g) of study drug as for 
the first dose on up to 90% of BSA twice weekly, sparing the scalp, inguinal, and axillary areas. 
Subjects with heavy facial hair should not apply IP to hair-bearing areas. Subjects will receive an 
adequate number of tubes to use 1 tube per application and will use a new tube for each treatment 
day. Subjects may use less than the full amount of IP in a tube. 
Subjects enrolled in Cohort A will continue treatment for up to 12 weeks.  
After the initial 15 subjects complete at least 28 days of treatment, an independent DSMB will 
review aggregate safety and tolerability data (including PK and electrocardiogram [ECG] data). If 
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no safety issues are identified, both adults and adolescents (ages 12–17 years, inclusive) will be 
allowed to enroll in Cohort B (up to approximately 105 subjects). Subjects in Cohort B will be 
randomized 1:1:1 to trifarotene cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle 
and similarly treated twice weekly for up to 12 weeks in the same manner as subjects in Cohort A.  
All subjects will be provided with diaries in which to record study drug application (days/times 
and any areas of skin not treated [e.g., due to local reactions]), any application site reactions, 
adverse events (AEs), and concomitant medications used. Subjects will also be advised on 
permitted emollient(s) and/or sunscreen(s) use on nontreatment days during the study; use of 
emollient(s) and/or sunscreen on study drug treatment days within 4 hours before or after study 
drug application is prohibited. 
At all sites with photographic capability photographs will be taken as source data to support 
scoring at Baseline, Day 30, and Day 90. A central reader who will not be an investigator in the 
study will review the photographs to assess consistency of investigator scoring of LI severity as a 
quality check. Photographs may also be used for scientific publication purposes. Subjects will sign 
a separate, optional, photographic informed consent form (ICF).  
Samples for PK will be drawn from all subjects at Baseline and at each clinic visit, as indicated in 
the Schedule of Events (Table 2-1). Visits for PK must occur at least 24 hours after the last 
application of the IP to avoid contamination of the blood samples with any IP that may have 
remained in the skin after the last application. Subjects should not apply IP on visit days until after 
the visit. 
In addition, a PK substudy will be conducted on Days 1 and 30 at sites with the capability to 
conduct it. Participation in the PK substudy will be optional and will include at least 15 adults and 
15 adolescents. Subjects who participate in the PK substudy will come from both study cohorts 
and will undergo serial blood sampling predose and at 1, 2, 4, 8, 12, and 24 hours postdose on 
Day 1 and Day 30. Trough levels will be drawn for all subjects at specified time points. For the 
subjects in the PK substudy, postdose ECGs will be performed at each serial blood draw on Day 1 
and Day 30. 
Efficacy will be assessed by the number of subjects in each treatment group who achieve “success” 
defined as clear/almost clear overall and at least a 50% reduction from Baseline at 
Week 12/end-of-treatment (EOT) in the Double-blind Period on the 5-point IGA scale (i.e., 0 = 
clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe). In addition, efficacy criteria include 
assessment scales for palm/sole, scaling, roughness, fissuring, and the Dermatology Life Quality 
Index (DLQI), and the EQ-5D Quality of Life (QoL) Questionnaire. Ectropion Severity Scores 
(ESS) between the active trifarotene cream HE1 and vehicle groups will be an exploratory 
endpoint. 
Plasma concentrations of CD5789 and its major metabolites will be measured. 
Safety will be assessed by evaluating reported adverse events (AEs), changes in clinical laboratory 
test results, vital sign measurements, physical examinations, 12-lead ECGs, and local tolerability. 
All AEs observed by the study personnel or reported by the subject during the study (from the time 
of the signing of the informed consent and/or assent through the posttreatment visit) will be 
documented. 
Topical trifarotene cream HE1 was generally well tolerated in recently completed phase 3 pivotal 
and long-term safety studies in subjects aged 9 years and older with acne vulgaris. The local 
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tolerability of the trifarotene cream HE1 formulation in subjects with LI is unknown and will be 
monitored during the study. Subjects will receive information on study drug use and stopping rules 
and will be instructed to contact the site with any safety/tolerability issues. Study personnel will 
telephone subjects in between scheduled visits (i.e., at Day 7 and Day 45) to assess safety; an 
unscheduled clinic visit may be performed, if necessary. During all clinic visits, the investigator 
will assess local tolerability (Scale: 0-3 [none, mild, moderate, severe]) on each treated body area 
(chest/abdomen, back, legs, arms, and face/neck) and will follow the procedures detailed in Section 
9.4. 
All subjects (Cohort A and Cohort B) who complete the 12-week Double-blind Treatment Period 
will be eligible to enroll in the 12-week OLE. Subjects in the OLE will receive open-label 
trifarotene cream HE1 200 µg/g twice weekly for up to 12 weeks. During the OLE, subjects will 
return to the site at Weeks 14, 16, 20, 24, and 26. Additional PK samples will be drawn at Week 16 
and Week 24 from all subjects who continue into the OLE (Table 2-2).  
Stopping rules and treatment modification will be defined at the subject level based on local 
tolerability, selected laboratory parameters, and AEs; see Section 9.4. 
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Figure 7-1: 
Double-blind Study Design 
 
 
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Photographs at 
Raseline, 
Day 30, and 
Day 9() 
Se-:reening 
lS dlay s -0f tre.:atrne,nt 
No, safetyissnes 
C-0hort B enrolls 
(up to 105 subjects 
aged~l1 ye.ars) 
Continue tlll-0ugb 1 
e.eks of beatrnmt 
Optimal PK substudy 
(-30 subjects) 
Serial blood sampling 
predoseand at 1, 2. -!, &, 
l2, and n hours postdose 
on Day l and Day 30 
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Figure 7-2: 
Open-label Study Design 
 
 
Double-blind Treatment Period 
Study Day 90/Week 12 (- 7 days) 
= first visit of 
Open-label Extension Period with 
trifarotene 200 µg/g 
Continue through 12 weeks of treatment 
Follow-up Day 192 or 14 days after 
End of Treatment 
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7.2. Rationale and Discussion of Study Design 
The first part of this study is a randomized, double-blind, placebo-controlled study of the safety, 
tolerability, PK, and efficacy study of trifarotene cream HE1 100 µg/g and 200 µg/g in adults and 
adolescents with LI.  
In a previous proof-of-concept study (RD.03.SRE.40181E), subjects with LI applied trifarotene 
50 and 100 µg/g cream to limited areas and results demonstrated a decrease in scaling with good 
safety and tolerance. In a phase 1 study in healthy Japanese and non-Japanese subjects 
(RD.03.SPR.103813), repeated topical applications of trifarotene (CD5789 cream HE1) 100 µg/g 
and 200 µg/g resulted in low and similar CD5789 systemic levels in all the cohorts. These studies 
are fully described in the current Investigational Brochure. 
To ensure safety, this phase 2 study will begin with an initial cohort (Cohort A) of 15 adults 
randomized 1:1:1 to trifarotene cream HE1 100 µg/g, 200 µg/g, or vehicle to be applied twice 
weekly. An independent DSMB will review aggregate safety and tolerability data from the initial 
15 subjects’ first 28 days of treatment. If no safety issues are identified, 105 adults and adolescents 
(ages 12–17 years, inclusive) will be allowed to enroll in Cohort B and randomized to trifarotene 
cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle and treated twice weekly in the 
same manner as subjects in Cohort A. All subjects in the randomized, double-blind portion of the 
study will be treated for up to 12 weeks and data on safety, tolerability, PK, and efficacy collected.  
Adult and adolescent subjects who successfully complete the initial 12 weeks of double-blind 
treatment will have the option to enter an OLE with trifarotene cream HE1 200 ug/g twice weekly 
for up to 12 weeks.  
The OLE will collect additional safety, tolerability, PK, and efficacy data. As designed, this study 
will provide important information on safety, tolerability, and PK with dosing of adolescents and 
adults with LI for up to 6 months.  
The protocol includes appropriate monitoring for safety and tolerability. If subjects develop 
significant local application site reactions or tolerability issues, the protocol includes language for 
reducing the frequency of application or halting study drug application until the symptoms abate. 
7.3. Selection of Doses in the Study 
Based on the results from Study RD.03.SRE.40181E and Study SRE.103813, the doses of 
100 µg/g and 200 µg/g were selected for further investigation in adult and adolescent subjects with 
moderate to severe LI to determine which of the 2 doses is most effective.. The PoC study 
demonstrated efficacious treatment with 100 µg/g in adults. The PK and tolerability study showed 
that, when the frequency of application was reduced from daily to twice weekly, the 200 µg/g 
cream HE1 had good local tolerability. 
Therefore, the current study will use these doses compared with vehicle, applied twice weekly on 
up to approximately 90% BSA in subjects with LI. The OLE will evaluate the long-term safety of 
the higher dose in this patient population. 
7.4. Study Sites 
The study will take place at approximately 40 sites in North America, Europe, Israel, and Australia.  
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7.5. Point of Contact 
A point of contact will be identified to provide information to subjects about where to obtain 
information on the study, the rights of subjects, and whom to contact in case of a study-related 
injury. This information will be provided in the subject information and informed consent form 
(ICF). 
7.6. End of Study Definition 
A clinical trial is considered completed when the last participant’s last study visit has occurred. 
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8. SUBJECT POPULATION 
8.1. Selection of Study Population and Diagnosis 
Diagnosis of LI for the purposes of this study will be a clinical diagnosis. Although some younger 
subjects may have had genetic testing, older subjects may not.  
While LI is a rare disease and subject enrollment may be challenging, due to possible bias 
introduced by including household members in the same study, it is recommended that only 
1 household member be included in the study to maintain the blind and ensure all assessments are 
independent. 
8.2. Study Entry Criteria 
8.2.1 Inclusion Criteria 
A subject will be eligible for study participation if he or she meets all of the following criteria: 
1. For Cohort A: subject is ≥18 years old; for Cohort B: subject is ≥12 years old.  
2. Subject has known diagnosis of LI.  
3. Subject has moderate to severe (IGA 3–4) LI on the IGA of LI severity.  
4. Subject has signed an ICF at Screening before any investigational procedures. Subjects 
<18 years of age (or Age of Majority) must sign an assent form in conjunction with an ICF 
signed by the parent/legal representative. 
5. Subject who is participating in optional photography has signed a photography ICF. 
6. Subject who is participating in the optional PK substudy has signed a PK ICF. 
7. Subject is not of childbearing potential, i.e., a female who has not yet begun menstruating or 
who is postmenopausal (absence of menstrual bleeding for 1 year before Baseline, without 
any other medical reason, hysterectomy or bilateral oophorectomy),  
OR  
• Subject is a woman of childbearing potential (WOCBP) or a male subject with sexual partners 
capable of reproduction who agrees to use 2 effective forms of contraception during the study 
and for at least 1 month after the last study drug application. The 2 authorized forms of 
contraception are condom used with 1 of the following methods of contraception: 
• bilateral tubal ligation 
• combined oral contraceptives (estrogens and progesterone) or implanted or injectable 
contraceptives with a stable dose for at least 1 month before Baseline; hormonal 
contraceptives must inhibit ovulation 
• hormonal intrauterine device (IUD) inserted at least 1 month before Baseline 
OR 
Agrees to abstain from heterosexual intercourse during study participation and for 1 month 
after the last application of study drug and to use a highly effective contraceptive as backup if 
he or she becomes sexually active during the study. Abstinence is only acceptable if this is the 
subject’s usual lifestyle. Periodic abstinence (calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method are not acceptable methods of contraception. 
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AND 
Male subjects may not donate sperm during the study and for at least 1 month after the last 
study drug application. 
Note: Subjects who are premenstrual at Screening but begin menses during the study should 
follow the pregnancy testing schedule for WOCBP and must abstain from sexual intercourse 
while in the study and for at least 1 month after the last study drug application. 
8. Women of child-bearing potential must be nonlactating and have negative pregnancy test 
results at Screening (serum) and on Day 1 before study drug administration (urine). 
9. Subject is reliable and capable of adhering to the protocol and visit schedule, in the 
investigator’s judgment, and has signed informed consent/assent, as applicable. 
10. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin). 
8.2.2 Exclusion Criteria 
A subject will be excluded from the study if he or she meets any of the following criteria: 
1. Subject has any variant of ichthyosis other than LI or another disorder of keratinization, 
including syndromic ichthyoses.  
2. Subject has current moderate or severe stinging/burning at Screening. 
3. Subject has an ongoing cutaneous infection or any other significant concomitant skin disease 
(other than the LI) which, in the investigator’s opinion, may interfere with the study 
assessments. 
4. Subject with a known lipid disorder (hypertriglyceridemia >200 mg/dL, hypercholesterolemia 
>250 mg/dL) unless well controlled by stable doses of lipid-lowering agents for at least 
6 months. 
5. Subject was previously treated with trifarotene/CD5789 in an acne or ichthyosis study.  
6. Subject has any other significant concomitant disease, or poorly controlled medical condition 
other than LI that in the investigator’s opinion may put him or her at risk if he or she takes part 
in the study, and/or that may interfere with the study assessments. 
7. Subject has a medical condition that potentially alters bone metabolism (e.g., osteoporosis, 
thyroid dysfunction, Cushing syndrome, Crohn’s disease, or ulcerative colitis). 
8. Subject is being treated for major depression disorder and/or has a history of major depression 
or suicide attempt requiring hospitalization, medications, and close psychiatric surveillance to 
prevent suicide attempts.   
9. Subject with positive serology for hepatitis B surface antigen, hepatitis C, or are known to be 
HIV positive or to have AIDS at Screening. 
10. Subject with any of the following laboratory values at Screening: 
a. Aspartate aminotransferase or alanine aminotransferase >1.5 × upper limit of normal 
defined by the laboratory 
b. Total bilirubin >1.1 mg/dL or , in case of Gilbert’s syndrome, total bilirubin >3 mg/dL 
c. Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women 
d. Platelets <150 × 109/L or >400 × 109/L. 
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11. Subject has any clinically other significant abnormal laboratory value (hematology, chemistry, 
or urinalysis) at Screening that, in the investigator’s opinion, may put the subject at risk if he 
or she takes part in the study, and/or that may interfere with the study assessments. 
12. Subject has had recent systemic malignancy (e.g., within 5 years) with exception of 
nonmelanoma skin cancer or cervical intraepithelial neoplasia of Grade 1 who are >6 months 
post-treatment. 
13. Subject has a history of long QT syndrome or clinically significant ECG abnormalities, 
including clinically significant conduction disorders or significant arrhythmias, QTcF interval 
>450 ms, PR interval is not between 120 and 220 ms (inclusive), HR >100 bpm or <50 bpm, 
QRS interval >110 ms, or QT intervals that cannot be consistently analyzed. 
14. Subject has a known allergy or sensitivity to any of the components of the investigational 
products.  
15. Subject has been exposed to excessive UV radiations on the treated zones within 1 month 
before Baseline visit or is planning intensive UV exposure during the study (e.g., occupational 
exposure to the sun, sunbathing, phototherapy, etc.). 
16. Subject is inherently sensitive to sunlight. 
17. Subject is unable or unwilling to stop use of topical or systemic retinoids. 
18. Subject is presumed to be abusing drug or alcohol at Screening or Baseline Visits based on 
medical history or current clinical symptoms. 
19. Subject is participating in another interventional clinical trial. 
20. Subject is institutionalized. 
21. Subject is in any way related to the sponsor, investigator, or site personnel. 
8.3. Premature Subject Withdrawal 
All subjects will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. The investigator should make every reasonable 
attempt to keep subjects in the study; however, subjects must be withdrawn from the study if they 
withdraw consent to participate. Investigators must attempt to contact subjects who fail to attend 
scheduled visits by telephone or other means to exclude the possibility of an AE being the cause 
of withdrawal. Should this be the cause, the AE must be documented, reported, and followed as 
described in Section 11.2. 
The sponsor reserves the right to request the withdrawal of a subject due to protocol deviations or 
other reasons. 
The investigator also has the right to withdraw subjects from the study at any time for lack of 
therapeutic effect that is intolerable or otherwise unacceptable to the subject, for intolerable or 
unacceptable AEs, intercurrent illness, noncompliance with study procedures, administrative 
reasons, or in the investigator’s opinion, to protect the subject’s best interest. 
If a subject is withdrawn before completing the study, the reason for withdrawal and the date of 
discontinuation will be recorded on the appropriate page of the electronic case report form (eCRF). 
Whenever possible and reasonable, the evaluations that were to be conducted at the completion of 
the study should be performed at the time of premature discontinuation. 
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8.4. Discontinuation of Study Intervention 
Discontinuation from study treatment does not mean withdrawal from the study, and the remaining 
study procedures should be completed as indicated in the study protocol (see Section 10.2.4.5). If 
a clinically significant finding is identified (including, but not limited to changes from Baseline) 
after enrollment, the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an AE. 
An investigator must discontinue a participant’s study treatment for any of the following reasons: 
• Pregnancy 
• Significant study intervention noncompliance  
• If any clinical AE, laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would result in a significant burden to the 
participant 
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for discontinuation of study treatment will be recorded on the eCRF. Subjects who sign 
the informed consent form and are randomized but do not receive the study intervention may be 
replaced. Subjects who sign the informed consent form, are randomized, and receive the study 
intervention, and subsequently discontinue study treatment, or are withdrawn from the study will 
not be replaced. 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site will attempt to contact the participant and reschedule the missed visit and counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
8.5. Subject Replacement Criteria 
Withdrawn subjects will not be replaced. If a substantial number of subjects are withdrawn from 
the study, the sponsor will evaluate the need for developing replacement criteria. 
Randomized subjects withdrawn from the study may not reenter. The subject number for a 
withdrawn subject will not be reassigned to another subject. 
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9. TREATMENTS 
9.1. Identification of Investigational Product(s) 
Trifarotene cream HE1 is a cream containing 100 or 200 μg/g (0.01% [w/w] or 0.02% [w/w], 
respectively) of CD5789 and the following excipients: purified water, propylene glycol, allantoin, 
glycerin, medium-chain triglycerides, polypropylene glycol 15 stearyl ether, cyclomethicone, 
phenoxyethanol, copolymer of acrylamide and sodium acryloyldimethyltaurate, dispersion 40% in 
isohexadecane (simulgel 600 PHA), sodium benzoate, butylated hydroxytoluene, and 
gluconolactone. It is a potent RARγ agonist characterized by its high specificity to this receptor. 
Vehicle contains the same ingredients, without the CD5789. 
Trifarotene cream HE1 and vehicle will be provided in cream form for topical application and will 
be supplied in 50-g tubes from which a maximum of 36 g of IP may be extracted, 
Trifarotene cream HE1 and vehicle will be supplied by G. Production, Inc. (Galderma) in 
Baie-D'Urfé, QC, Canada. 
9.2. Treatments Administered  
For the Double-blind Treatment Period, a fixed dose (determined at Visit 2) of trifarotene cream 
HE1 100 µg/g or 200 µg/g or vehicle cream will be applied topically twice weekly on up to 90% 
BSA of each subject. The IP should be applied thinly and gently rubbed in. 
Study staff will apply the first administration of IP in the clinic on Day 1 after Baseline 
measurements, and the amount of IP used will be measured (i.e., 50-g tube will be measured before 
and after application to determine amount used). If the product will be applied at home by someone 
other than the study subject, it is recommended that person assist with application at the first visit 
to learn how the IP is applied. 
The maximum dose per application is 36 g (i.e., 1 tube). Subjects will receive an adequate number 
of tubes to use 1 tube per application and will use a new tube for each treatment day. Subjects may 
use less than full amount of product in a tube. Subjects will continue treatment for up to 12 weeks. 
After the Day 1 visit, subjects will apply approximately the same amount (up to 36 g) of study 
drug as for the first dose on up to 90% of BSA twice weekly, sparing the scalp, inguinal, and 
axillary areas. Subjects with heavy facial hair should not apply IP to hair-bearing areas. Persons 
other than the study subject applying the study drug must wash their hands after application or use 
disposable vinyl gloves. In addition, a long-handled applicator will be provided for application on 
the back. The applicator must be washed with warm water and soap after every application.  
Trifarotene cream should not come into contact with the eyes, mouth, angles of the nose, or mucous 
membranes. For the ectropion treatment, Q-tips are recommended for precise application on 
eyelids, without contact to the eye or conjunctiva. If the IP gets into the eye, it must be flushed 
immediately with warm water. In case of eye irritation, the subject must be seen by an 
ophthalmologist.  
For the OLE, all subjects will receive trifarotene cream HE1 200 µg/g and apply the same fixed 
dose in the same manner as in the Double-blind Period for an additional 12 weeks. 
Visits for PK must occur at least 24 hours after the last application of the IP to avoid contamination 
of the blood samples with any IP that may have remained in the skin after the last application. 
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Subjects should not apply IP on visit days until after the visit, unless they are participating in the 
PK substudy, in which case the IP will be applied in the clinic on Day 30 after the blood draw. 
Among subjects participating in the PK substudy, ensure the PK line is inserted before study drug 
application to prevent contamination with the IP and to protect the skin around the needle insertion 
point from study drug application. 
9.3. Selection of Timing of Dose for Each Subject 
Subjects will be randomized in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g or 200 µg/g or 
vehicle cream. After Day 1, on which the study staff will apply the first administration of IP in the 
clinic, each subject will apply approximately the same amount of IP on up to 90% of their BSA 
twice weekly. It is suggested that each subject choose 2 specific days per week at least 3 days apart 
on which to apply their IP (e.g., Tuesday and Friday), and maintain that regimen throughout the 
study. Visits for PK must occur at least 24 hours after the last application of the IP to avoid 
contamination of the blood samples with any IP that may have remained on the skin after the last 
application. Subjects should not apply the IP on visit days until after the visit, unless they 
participate in the PK substudy, in which case the IP will be applied in the clinic on Day 30 after 
the PK blood draw.  
All subjects will be provided with diaries in which to record study drug application (days/times) 
and any areas of skin not treated (e.g., due to local reactions). 
If a subject misses an IP application, they should apply the IP as soon as they remember and record 
the date/time in the subject diary, then wait at least 3 days and continue their regimen. 
Subjects should not shower, bathe, or swim for at least 4 hours after IP application. No occlusive 
dressings should be used on areas to which IP is applied. 
Subjects who continue into the Open-label Extension will receive trifarotene cream HE1 200 µg/g 
and apply the same fixed dose in the same manner as in the Double-blind Period for an additional 
12 weeks. 
9.4. Dose Adjustment Criteria 
Local tolerance will be followed very carefully during the study. Subjects will receive information 
on study drug use and stopping rules and will be instructed to contact the site with any 
safety/tolerability issues. Study personnel will telephone subjects in between scheduled visits (i.e., 
at Day 7 and Day 45) to assess safety; an unscheduled clinic visit may be performed, if necessary. 
During all clinic visits, the investigator will assess local tolerability on a 0-3 scale (0 = none, 1 = 
mild, 2 = moderate, 3 = severe) for each treated body area (chest/abdomen, back, arms, legs, and 
face/neck), and the following procedures will be followed: 
− If a score of 2 (moderate) is recorded on a local tolerability assessment scale 
(stinging/burning, pruritus, erythema) on any treated area (e.g., the face), the study drug 
will be applied on this area only once weekly, until the score returns to <2. Continue to 
treat all other areas twice weekly provided the score is <2 on those areas. 
− If a score of 3 (severe) is recorded on a local tolerability assessment scale (stinging/burning, 
pruritus, erythema) on any treated area, the study drug will not be applied on that area until 
the score is back to <3 (i.e., “drug holiday”). Continue to treat all other areas twice weekly 
provided the score is <2 on those areas. 
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Any changes in dosing must be documented in the subject diary and the eCRF. 
9.4.1 Stopping Rules 
A subject’s treatment in either the Double-blind Period or the Open-label Extension must be 
stopped if any of the following occur: 
• Subject becomes pregnant or suspects they are pregnant 
• Subject has severe (score of 3) local application site AEs that do not abate with “drug 
holiday” and reintroduction of IP.  
• Subject has clinically significant changes in laboratory values (liver function tests, 
cholesterol/triglycerides – which may occur with systemic retinoid use) 
Any changes in dosing must be documented in the subject diary and the eCRF. 
9.5. Treatment Compliance 
Subjects will be asked to record their twice-weekly applications of IP in the diary during both the 
Double-blind Period and the OLE. Deviations from the planned doses (missed dose or timing) will 
be recorded on the subject’s eCRF. Study personnel will review diaries at each visit and diaries 
will be collected as source documents. Information from subject diaries will be transcribed on the 
appropriate eCRF pages for documentation of subject compliance with the IP. 
Study personnel will assess treatment compliance with IP regimens by weighing IP tubes before 
dispensing and upon return and by questioning the subject, at every postrandomization visit. A 
participant is compliant with study product if he or she takes at least 80% of the scheduled doses 
as assessed by diary entries, supplemented by tube weight. A subject who is not compliant (used 
80–120% of IP tubes) will be counseled at each visit on the importance of using the IP as 
instructed.  
Subjects who taper to once-weekly application or who take a “drug holiday” for tolerability will 
not be reported as having deviated from the protocol (see Section 9.4 for dose adjustment and 
stopping rules); any changes in dosing must be documented in the subject diary and the eCRF. 
9.6. Method of Assigning Subjects to Treatment Groups 
In the double-blind, parallel-group, randomized period of the study, subjects who meet study entry 
criteria will be randomly assigned in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g or 200 µg/g 
or vehicle cream. The randomization schedule will be computer generated using a permuted block 
algorithm and will randomly allocate IP to randomization numbers. The randomization numbers 
will be assigned sequentially through a central interactive web response system (IWRS) as subjects 
are entered into the study. Study center will not be a blocking factor in the randomization schedule. 
Premier Research will prepare the randomization schedule before the start of the study. No one 
involved in the study performance will have access to the randomization schedule before the 
official unblinding of treatment assignments. No subject will be randomized into this study more 
than once. 
In the OLE, all subjects will receive trifarotene cream HE1 200 µg/g. 
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9.7. Blinding and Unblinding Treatment Assignment 
All subjects, investigators, and study personnel involved in the conduct of the Double-blind Period 
of the study, including data management, will be blinded to treatment assignment with the 
exception of a specified unblinded statistician and programmer from Premier Research who will 
have access to the randomization code. The statistician will have access to unblinded data if there 
is an unblinded DSMB review.  
Study personnel will make every effort to safeguard the integrity of the study blind to minimize 
bias in the conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
subject’s treatment assignment. 
The investigator may discuss with the medical monitor in advance of unblinding a subject, if 
possible, if it is not deemed an emergency. However, the investigator has the ultimate decision for 
unblinding a subject for medical treatment and no procedures will prevent or delay necessary 
unblinding in an emergency for the subject’s safety. For emergency unblinding, study personnel 
will use the IWRS code. If the investigator is not able to discuss treatment unblinding in advance, 
then he/she must notify the medical monitor as soon as possible about the unblinding incident 
without revealing the subject’s treatment assignment.  
The investigator or designee must record the date and reason for treatment unblinding on the 
appropriate eCRF for that subject. In all cases that are not emergencies, the investigator must 
discuss the event with the medical monitor prior to unblinding the subject’s treatment assignment. 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
that subject’s treatment assignment without unblinding the treatment assignments for the 
remaining subjects in the study. Thus, the overall study blind will not be compromised. If a 
subject’s treatment assignment is unblinded, he/she may or may not be asked to withdraw from 
the study. The investigator will make this decision after consultation with the medical monitor. 
The primary analysis period is the first 12 weeks of treatment (i.e., the Double-blind Period). 
Overall unblinding will take place at the end of the Double-blind Period of the study only after 
database lock has been achieved. A second analysis will take place for endpoints assessed from 
Week 12 through the OLE. 
9.8. Permitted and Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate eCRF. 
Upon signing informed consent and entering the Screening Period, subjects will stop using 
physical and medical treatments for LI, including balneotherapy, and may begin to washout 
prohibited topical and systemic treatments with designated washout periods (Table 9-1), as 
applicable. Washout may be up to 3 months, as necessary. 
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Table 9-1: 
Washout Periods for Prohibited Medications 
Medication 
Washout Period 
Topical Treatments 
Corticosteroids (except inhaled and ophthalmic corticoids) 
2 weeks 
Retinoids (e.g., tretinoin, tazarotene) 
4 weeks 
Vitamin D analogues 
2 weeks 
Immunosuppressants (e.g., tacrolimus) 
2 weeks 
Antracen derivatives, tar and salicylic preparations 
2 weeks 
Keratolytics (such as urea, lactic acid, propylene glycol, salicylic acid) except keratolytic 
shampoo 
2 weeks 
Systemic treatments 
Retinoids 
8 weeks 
Oral Vitamin A supplementation more than 3500 IU per day 
2 weeks 
Medication interfering with bone activity, e.g., corticosteroids, thyroid hormones, cytotoxics, 
bisphosphonates, calcitonins, tetracyclines, quinolones, thiazides, salicylates in long-term 
course, heparin, theophylline, barbiturates, colchicines (except Vitamin D analogues taken at 
stable dose since at least 1 month) 
8 weeks 
QT prolonging drugs 
5 half lives 
Enzymatic inductors (such as rifampicine, phenytoin, carbamazepine, phenobarbital, 
St. John’s Wort) 
3 months 
CYP2C9 and 2C8 inhibitors (not all inclusive: gemfibrozil, fluconazole, fluvoxamine, 
sulfaphenazole, miconazole, amiodarone, sertraline, sulfamethoxazole, valproic acid, 
voriconazole, trimethoprim, rosiglitazone, pioglitazone) 
5 half lives 
Monoclonal antibodies (e.g., anti-IL17) 
5 half lives 
 
During washout, subjects may continue taking usual care of visible skin (face and scalp) for 
cosmetic reasons and of extremities (hands and feet) to avoid functional consequences on walking 
or moving their fingers. Subjects may shower, but not bathe or swim. The IGA will be evaluated 
on the rest of the body at Baseline.  
After completing any necessary washout of prohibited medications, subjects will return to the site 
to complete the study eligibility requirements. 
9.8.1 Permitted Therapies 
Subjects will be advised on permitted emollient(s) for use as often as needed on nontreatment days 
during the study; on treatment days, the use of emollient(s) is permitted except within 4 hours 
before or after study drug application. Similarly, protective sunscreen should be applied as often 
as needed, except within 4 hours before or after study drug application. Subjects may use their 
standard of care treatment on their faces and/or palms/soles after the Week 4 assessment if they 
experience a worsening of IGA in those areas. In the US/EU, this may include compounded 
emollients with keratolytics (alpha or beta hydroxyl acids) and/or urea. These standard of care 
treatments should be approved by the investigator and documented in the eCRF.  
Subjects who enter the OLE must stop standard of care treatment. If they experience a worsening 
of IGA they may use standard of care treatment on their faces and/or palms/soles after the Week 16 
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visit if the standard of care does not contain prohibited medications. If those standard of care 
treatments include prohibited medications, the subject should be discontinued from the study. 
Other concomitant medications are allowed (e.g., analgesics, antihistamines), but should be limited 
to those medications considered necessary. All concomitant medications, both prescribed and 
over-the-counter, should be recorded in the eCRF. 
9.8.2 Prohibited Therapies 
The medications listed in Table 9-1 are prohibited during the study. Balneotherapy is also 
prohibited during the Screening Period and during the study. 
Subjects may not use concomitant keratolytics such as urea, salicylic acid, alpha, or beta 
hydroxyacids. Subjects may not use topical or systemic retinoids. Subjects may not take more than 
3500 IU/day Vitamin A (e.g., as in a multivitamin). Use of benzoyl peroxide is permitted on 
nontreatment days for subjects with concomitant acne only); it must not be applied on treatment 
days due to risk of inactivation of trifarotene by benzoyl peroxide. 
Subjects receiving excluded therapies will be ineligible for study enrollment or for continued 
treatment in the study, at the investigator’s discretion with consultation with Mayne Pharma LLC 
and the medical monitor. For enrolled subjects who require prescription of a systemic azole, the 
principal investigator should discuss with the medical monitor whether the subject may continue 
in the study.  
9.8.3 Restrictions 
Subjects should not shower, bathe, or swim for at least 4 hours after study drug application. No 
occlusive dressings should be applied to areas where study drug was applied.  
Subjects should only use investigator-approved emollients, and should not use them on treatment 
days within at least 4 hours before and after study drug application.  
In addition, subjects should take protective measures to avoid exposure of treated areas to sunlight, 
such as applying sunscreen (except within 4 hours before and/or 4 hours after study drug 
application), and/or wearing protective clothing (e.g., long sleeves, hats, and covering legs and 
feet), and/or seeking shade or shelter from the sun. 
9.9. Treatment after End of Study 
After the end of the study, each subject will be treated according to standard clinical practice. 
9.10. Dispensing and Storage 
The test product supplied by Mayne Pharma LLC is to be used exclusively in the clinical study 
according to the instructions of this protocol. The investigator is responsible for dispensing the IP 
according to the dosage scheme and for ensuring proper storage of the IP. 
The investigator must confirm the receipt of the IP with his or her signature. A copy of this receipt 
must be kept by the investigator and another copy will be stored at Premier Research. Until the IP 
is dispensed to the subjects, it must be stored at 20–25°C (68–77°F), with excursions permitted to 
15–30°C (59–86°F); do not freeze and with the tube kept tightly closed in a securely locked area 
that is not generally accessible. 
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The key to the storage area is to be kept by the investigator or designee responsible for the IP. The 
store will be accessible only to those persons authorized by the investigator to dispense the IP. 
9.11. Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the IPs, including the date, quantity, batch or code number, and identification of 
subjects (subject number) who received the IP. The investigator will not supply the IP to any 
person except those named as subinvestigators on the Form Food and Drug Administration 
(FDA) 1572, designated study personnel, and subjects in this study. The investigator will not 
dispense the IP from any study sites other than those listed on the Form FDA 1572. Investigational 
product(s) may not be relabeled or reassigned for use by other subjects. If any of the IP is not 
dispensed, is lost, stolen, spilled, unusable, or is received in a damaged container, this information 
must be documented and reported to the sponsor and appropriate regulatory agencies, as required. 
Each subject will be given enough tubes of study drug to apply up to 1 tube-full (approximately 
36 g of clinical trial material) per treatment day until the next study visit. Tubes will be packed 
2 to a carton, and each subject will receive enough cartons to have the maximum number of tubes 
needed until the next study visit. The number of study drug tubes the subject needs to provide 
enough IP until the next visit is shown in Table 9-2.  
Table 9-2: 
Amount of Study Drug Needed Per Visit 
Treatment Period 
Number of Cartons 
Number of Tubes 
Double-blind Treatment Period 
Baseline 
3 
6 
Day 14 
4 
8 
Day 30 
6 
12 
Day 60 
6 
12 
OLE  
Day 90 
3 
6 
Day 104 
4 
8 
Day 120 
6 
12 
Day 150 
6 
12 
 
Each carton will be weighed before dispensing and subjects are to bring all cartons and tubes back 
at each study visit, whereupon study staff will weigh them again to estimate study drug use and 
compliance. 
Upon completion of the study, the IP (partly used, unused, and empty tubes) must be left in the 
original packaging and returned to the sponsor or designee for destruction. 
9.12. Labeling and Packaging 
Labeling and packaging of IP will be performed by Catalent Pharma Solutions, Philadelphia, PA, 
USA.  
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Tubes will be packaged in cartons comprising 2 tubes each. Tubes will be labeled with inner and 
outer booklet labels, and carton number. Each carton will also be labeled with inner and outer 
booklet labels and numbered.  
9.12.1 Labeling 
The tubes will have a label affixed that meets the applicable regulatory requirements and may 
include, but is not limited to, the following: subject identifier, IP name, lot number, protocol 
number, carton number, caution statement, storage, and sponsor identification. 
Save all empty packaging or packaging containing unused tubes for final disposition by the 
sponsor or contract pharmacy. 
Final labeling will comply with the regulatory requirements of each country where the study will 
be conducted. 
9.12.2 Packaging 
Investigational products will be packaged in high-density polyethylene, 35×100 mm tubes 
weighing 50 g from which a maximum of 36 g of IP can be extracted. Trifarotene cream HE1 and 
vehicle will be packaged so as to be blinded to the investigator, the study clinic personnel, and the 
subjects. 
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10. STUDY PROCEDURES 
Subjects must provide written informed consent and/or assent before any study-related procedures 
are initiated, including the cessation of prohibited concomitant therapy. Written informed consent 
will be obtained from a parent/legal guardian for any minor and minors will provide assent before 
any study-related procedures are performed.  
Subjects who agree to participate in the photography and/or PK substudies must provide written 
informed consent before photographs or serial blood samples are collected. 
For the timing of assessments and procedures throughout the study, refer to the Schedule of 
Events (Section 2.2). Throughout the study, every reasonable effort should be made by study 
personnel to follow the timing of assessments and procedures in the Schedule of Events for each 
subject. If a subject misses a study visit for any reason, the visit should be rescheduled as soon as 
possible. 
10.1. Study Duration 
10.1.1 Overall Study Schedule 
The overall study duration is expected to be approximately 19 months. 
The planned sequence and maximum duration of the study periods will be as follows: 
1. Screening: up to 35 days (after signing informed consent, if necessary, washout may be up 
to 3 months, and subjects should return to the site after washout to complete the study 
eligibility requirements).  
2. Double-blind treatment: Twice weekly for 12 weeks. 
3. Optional Open-label Extension treatment: Twice weekly for 12 weeks. 
4. Follow-up: 14 days after last study drug application. 
The maximum treatment duration for each subject is approximately 12 weeks for subjects who 
choose not to continue into the OLE, and 24 weeks for those who choose to continue.  
The maximum study duration for each subject is approximately 229 days (33 weeks). 
10.2. Study Periods and Visits 
It is suggested that quality of life assessments be conducted first to avoid any bias, and that the 
IGA be recorded as the first LI assessment at every visit. 
10.2.1 Screening and Washout 
10.2.1.1 Screening Visit (Visit 1) 
The subject must complete eligibility screening within 35 days before randomization in the study. 
The following procedures will be performed during Screening: 
1. Obtain written informed consent and/or assent. 
2. Assign a screening number when a subject begins screening. 
3. Assess inclusion/exclusion criteria. 
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4. Collect demographic information. 
5. Record medical history, including current therapies (e.g., prescription and nonprescription 
medications). 
6. Perform a physical examination. 
7. Measure vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and 
pulse). 
8. Measure height, weight, and calculate body mass index (BMI). 
9. Record IGA.   
10. Record VIIS. 
11. Record roughness assessment. 
12. Record palm/sole assessment.  
13. Record palm/sole assessment of fissuring. 
14. Record ectropion score. 
15. Perform a 12-lead ECG. 
16. Collect blood and urine for laboratory tests. 
17. Perform serum pregnancy test for WOCBP. 
Procedures for rescreening subjects who initially fail to meet study entry criteria are described in 
Section 14.3. 
10.2.1.2 Washout  
Upon signing informed consent and entering the Screening Period, subjects will stop using 
physical and medical treatments for LI, including balneotherapy, and may begin to washout the 
prohibited topical and systemic treatments with designated washout periods, as applicable 
(Table 9-1). Washout may be up to 3 months, as necessary.  
During washout, subjects may continue taking usual care of visible skin (face and scalp) for 
cosmetic reasons and of extremities (hands and feet) to avoid functional consequences on walking 
or moving their fingers. Subjects may shower but not bathe or swim. The IGA will be evaluated 
on the rest of the body at Baseline. 
After completing any necessary washout of prohibited medications, subjects will return to the site 
to complete the study eligibility requirements (Section 10.2.1.1). 
10.2.2 Double-blind Treatment Period  
Eligible subjects who have washed out prohibited medications will be randomized to double-blind 
study drug. 
10.2.2.1 Baseline Visit (Visit 2, Day 1) 
The following procedures will be performed on Day 1 in the study clinic: 
1. Review inclusion/exclusion criteria. 
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2. Record responses to DLQI and EQ-5D Quality of Life Questionnaires (see Sections 
10.3.1.5 and 10.3.1.6 for which version of questionnaire to use). 
3. Perform physical examination.  
4. Record vital signs (blood pressure and pulse).  
5. Record concomitant medications and concomitant therapies. 
6. Record IGA.  
7. Record VIIS.  
8. Record roughness assessment.  
9. Record palm/sole assessment. 
10. Record palm/sole assessment of fissuring. 
11. Record ectropion score.  
12. At sites where the photographic substudy is conducted, take photographs of subjects who 
have provided informed consent for the photography. 
13. Perform a 12-lead ECG. 
14. Perform urine pregnancy test for WOCBP. 
15. Collect blood and urine for routine laboratory tests (subject must be fasting; i.e., at least 
8 hours). 
16. Randomize via IWRS. 
17. Collect a predose PK blood sample (all subjects).  
18. Among subjects who consent to participate in the PK substudy, ensure that PK lines are 
placed before IP application. The IP will be applied in the clinic at this visit, and samples 
for PK will be taken at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1.  
19. Among subjects in the PK study, perform additional ECGs at times of serial sampling. 
20. Clinic staff instructs subject on study drug application, applies initial study drug dose and 
measures amount used (i.e., study staff will weigh the 50-g tube before and after the first 
application to determine the fixed dose amount for each subject). If the product will be 
applied at home by someone other than the study subject, it is recommended that person 
assists with application at this visit to learn how the IP is applied. 
21. Assess and record local tolerance/AEs. 
22. Dispense study drug and diaries. 
23. Advise subjects regarding permitted emollient(s) for use on nontreatment days; use of 
emollient(s) and/or sunscreen on study drug treatment days within 4 hours before or after 
study drug application is prohibited. Remind subjects that at least 24 hours must have 
elapsed since IP application before their next visit. Subjects should not to apply IP on visit 
days until after the visit. 
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10.2.2.2 Telephone Visit (Day 7) 
Clinic staff will telephone subject to assess safety and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient(s) and/or 
sunscreen on study drug treatment days within 4 hours before or after  study drug application is 
prohibited), and remind subjects that at least 24 hours must have elapsed since IP application 
before their next visit. Subjects should not apply IP on visit days until after the visit. An 
unscheduled clinic visit may be performed, if necessary. 
10.2.2.3 Visit 3 (Day 14 ±5 days) 
The following procedures will be performed on Day 14 in the study clinic: 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires (see 
Sections 10.3.1.6 and 10.3.1.7 for which version of questionnaire to use). 
2. Record concomitant medications and concomitant therapies. 
3. Record vital signs (blood pressure and pulse). 
4. Record IGA.   
5. Record VIISIGA. 
6. Record roughness assessment.  
7. Record palm/sole assessment. 
8. Record palm/sole assessment of fissuring 
9. Record ectropion score. 
10. Assess local tolerance. 
11. Record AEs and review diary. 
12. Collect a PK blood sample (all subjects). 
13. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
14. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
Remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit. Subjects should not apply IP on visit days until after the visit.  
15. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
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10.2.2.4 Visit 4 (Day 30 ±7 days) 
The following procedures will be performed on Day 30 in the study clinic: 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires (see 
Sections 10.3.1.6 and 10.3.1.7 for which version of questionnaire to use). 
2. Record concomitant medications and concomitant therapies. 
3. Record vital signs (blood pressure and pulse). 
4. Record IGA. 
5. Record VIIS. 
6. Record roughness assessment.  
7. Record palm/sole assessment. 
8. Record palm/sole assessment of fissuring 
9. Record ectropion score.  
10. At sites where the optional photographic substudy is conducted, take photographs of 
subjects who have provided informed consent for the substudy. 
11. Assess local tolerance. 
12. Record AEs and review diary. 
16. Perform a 12-lead ECG 
17. Perform a urine pregnancy test for WOCBP. 
18. Collect blood and urine for routine laboratory tests (subject must be fasting at least 
8 hours). 
19. Collect a PK blood sample (all subjects). 
20. Among subjects who consent to participate in the PK substudy, ensure that PK lines are 
placed before IP application. The IP will be applied in the clinic at this visit, and samples 
will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose. 
21. Among subjects in the PK study, perform an additional ECGs at times of serial sampling. 
22. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
23. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) on study 
drug treatment days within 4 hours before and after study drug application is prohibited. 
Remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit. Subjects should not apply IP on visit days until after the visit.  
24. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
25. Provide information about OLE option to study subject. 
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10.2.2.5 Telephone Visit (Day 45) 
Clinic staff will telephone subject to assess safety and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) and/or sunscreen for use on nontreatment days (use of 
emollient(s) on study drug treatment days within 4 hours before or after study drug application is 
prohibited), and remind subjects that 24 hours must have elapsed since IP application before the 
subject’s next visit. Subjects should not to apply IP on visit days until after the visit. An 
unscheduled clinic visit may be performed, if necessary. Staff will remind subject about OLE 
option. 
10.2.2.6 Visit 5 (Day 60 ±7 days) 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires (see 
Sections 10.3.1.6 and 10.3.1.7 for which version of questionnaire to use). 
2. Record concomitant medications and concomitant therapies. 
3. Record vital signs (blood pressure and pulse).  
4. Perform a urine pregnancy test for WOCBP. 
5. Record IGA.  
6. Record VIIS.   
7. Record roughness assessment.  
8. Record palm/sole assessment. 
9. Record palm/sole assessment of fissuring 
10. Record ectropion score.  
11. Assess local tolerance.  
12. Record AEs and review diary. 
13. Collect a PK blood sample (all subjects). 
14. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
15. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
16. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) and/or 
sunscreen on study drug treatment days within 4 hours before and after study drug 
application is prohibited. Remind subjects that Added reminder that 24 hours must have 
elapsed since IP application before the subject’s next visit. Subjects should not apply IP on 
visit days until after the visit.. 
17. 
Provide information about OLE option. 
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10.2.2.7 Visit 6 (90 ±7 days) or Early Termination 
The following procedures will be performed on Day 90 in the study clinic: 
1. Record responses to DLQI and EQ-5D Quality of Life Questionnaires (see 
Sections 10.3.1.6 and 10.3.1.7 for which version of questionnaire to use). 
2. Perform a physical examination. 
3. Record vital signs (blood pressure and pulse). 
4. Record concomitant medications and concomitant therapies. 
5. Record IGA. 
6. Record VIIS. 
7. Record roughness assessment.  
8. Record palm/sole assessment. 
9. Record palm/sole assessment of fissuring. 
10. Record ectropion score.  
11. At sites where the optional photographic substudy is conducted, take photographs of 
subjects who have provided informed consent for the substudy. 
12. Assess local tolerance. 
13. Record AEs and review diary. 
14. Perform a 12-lead ECG. 
15.  Perform a urine pregnancy test for WOCBP. 
16. Collect blood and urine for routine laboratory tests (subject must be fasting at least 
8 hours). 
17. Collect a PK blood sample (all subjects). 
18. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
For subjects who successfully complete (i.e., have reliable visit attendance and compliance with 
IP application, in the investigator’s opinion) the initial 12 weeks of double-blind treatment and 
choose to continue into the OLE, this visit will be the first visit of that portion of the study. All 
efficacy assessments, safety/tolerability assessments, including clinical laboratory testing, PK 
from Day 90/Week 12 will be carried over to the OLE and will not be repeated. Subjects will have 
up to 7 days to decide to enter the OLE; if the subject chooses to continue into OLE, the following 
additional procedures will be done: 
1. Have the subject sign OLE-specific informed consent.  
2. Measure subject’s weight. 
3. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) and/or sunscreen for use on nontreatment days; use of emollient(s) on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
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Remind subjects that at least 24 hours must have elapsed since IP application before the 
PK draws at the Week 16 and Week 24 Visits, and not to apply IP on visit days until after 
the visits. 
4. Weigh new study drug tubes and dispense enough additional study drug until next visit 
(only for subjects who choose to continue into the OLE). 
5. Dispense study diary. 
10.2.3 Follow-up Telephone Call (±14 days after Day 90) – Only Subjects Who Do Not 
Continue into Open-label Extension 
Clinic staff will telephone subjects who choose not to continue into the Open-label Extension 
within 14 days after Day 90 to assess any ongoing AEs.  
10.2.4 Open-label Extension  
Subjects who successfully complete (i.e., have reliable visit attendance and compliance with IP 
application, in the investigator’s opinion) the initial 12 weeks of double-blind treatment may 
choose to continue into an optional 12-week OLE with trifarotene cream HE1 200 µg/g. During 
the OLE, subjects will return to the site at Weeks 14, 16, 20, 24, and 26. Additional PK samples 
will be drawn at Week 16 and 24 from all subjects who continue into the OLE.  
10.2.4.1 Telephone Visit (Day 97) 
Clinic staff will telephone subject to assess safety (AEs) and to record concomitant 
medications/therapies. Staff will to instruct subject on study drug application, to advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient(s) on study drug 
treatment days within 4 hours of study drug application is prohibited), and to remind subjects not 
to apply IP on visit days until after the visit. An unscheduled clinic visit may be performed, if 
necessary. 
10.2.4.2 Visit 7 (Week 14; Day 104 ±5 days) 
The following procedures will be performed at this study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Record IGA.   
4. Record VIIS. 
5. Record assessment of roughness. 
6. Record palm/sole assessment. 
7.  Record palm/sole assessment of fissuring. 
8. Record ectropion score. 
9. Assess and record local tolerance/AEs and review diary. 
10. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
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11. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
12. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) and/or sunscreen on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
Remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit. Subjects should not apply IP on visit days until after the visit.at the Week 16 and 
Week 24 Visits, and not to apply IP on visit days until after the visit. 
10.2.4.3 Visit 8 (Week 16; Day 120 ±7 days) 
The following procedures will be performed at this study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Record IGA. 
4. Record VIIS.   
5. Record assessment of roughness. 
6. Record palm/sole assessment.  
7. Record palm/sole assessment of fissuring. 
8. Record ectropion score. 
9. Assess and record local tolerance/AEs and review diary. 
10. Perform a 12-lead ECG. 
11. Perform a urine pregnancy test for WOCBP. 
12. Collect blood and urine for routine laboratory tests (subject must be fasting at least 
8 hours). 
13. Collect a PK blood sample (all subjects) 
14. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
15. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
16. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) and/or sunscreen on study 
drug treatment days within 4 hours before or after study drug application is prohibited. 
Remind subjects not to apply IP on visit days until after the visit. 
10.2.4.4 Telephone Visit (Day 134) 
Clinic staff will telephone subject to assess safety (AEs) and to record concomitant 
medications/therapies. Staff will to instruct subject on study drug application, to advise subjects 
regarding permitted emollient(s) and/or sunscreen for use on nontreatment days (use of 
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emollient(s) on study drug treatment days within 4 hours of study drug application is prohibited), 
and to remind subjects that 24 hours must have elapsed since IP application before the subject’s 
next visit. Subjects should not apply IP on visit days until after the visit. An unscheduled clinic 
visit may be performed, if necessary. 
10.2.4.5 Visit 9 (Week 20; Day 150 ±7 days) 
The following procedures will be performed at each study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Record IGA. 
4. Record VIIS.   
5. Record assessment of roughness. 
6. Record palm/sole assessment.  
7. Record palm/sole assessment of fissuring. 
8. Record ectropion score. 
9. Assess and record local tolerance/AEs and review diary. 
10. Perform a urine pregnancy test for WOCBP. 
11. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
12. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
10.2.4.6 Visit 10 (Week 24; Day 180 ±7 days) or Early Termination 
The following procedures will be performed at Week 24 in the study clinic: 
1. Perform a physical examination. 
2. Record vital signs (blood pressure and pulse). 
3. Record concomitant medications and concomitant therapies. 
4. Record IGA. 
5. Record VIIS. 
6. Assess roughness. 
7. Record palm/sole assessment.  
8. Record palm/sole assessment of fissuring. 
9. Record ectropion score.  
10. Assess local tolerance 
11. Record AEs and review diary. 
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12. Perform a 12-lead ECG. 
13. Perform a urine pregnancy test for WOCBP. 
14. Collect blood and urine for routine laboratory tests (subject must be fasting at least 
8 hours). 
15. Collect a PK blood sample (all subjects) 
16. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
10.2.4.7 Follow-up Evaluation – Open-Label Extension (Week 26/Visit 11) 
At 14 days after the last administration of the IP, the following procedures will be performed: 
1. Perform a physical examination. 
2. Record vital signs (blood pressure and pulse). 
3. Record any concomitant medications/therapies. 
4. Record IGA. 
5. Record VIIS.   
6. Assess roughness. 
7. Record palm/sole assessment.  
8. Record palm/sole assessment of fissuring. 
9. Record ectropion score.  
10. Assess and record AEs occurring since the last evaluation and review diary.  
11. Perform a urine pregnancy test for WOCBP. 
10.3. Assessments 
The 5-point IGA is a valid measure of disease severity and meets the need for a clinically 
meaningful measure of success for ichthyosis studies. The IGA scale was developed with the 
support of experts from academic reference centers for the treatment of ichthyosis. Each level of 
severity will consider both the severity of scaling and the severity of roughness (Section 10.3.1.2). 
While retinoid treatment is expected to reduce scale, it may increase erythema; therefore, in this 
study, erythema will be evaluated as part of local tolerability. 
10.3.1 Efficacy Variables 
All efficacy measurements will use scales previously used for dermatological studies or as defined 
in the following sections. 
10.3.1.1 Investigator’s Global Assessment 
The primary endpoint is the number of subjects in each treatment group who experience successful 
resolution of LI where “success” is defined as clear/almost clear and at least a 2-grade change from 
Baseline at Week 12/EOT in the Double-blind Period on a 5-point IGA full body scale. 
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The investigator will rate the subject’s condition using the 5-point IGA at each time point shown 
in the Schedule of Events (Section 2.2).  
The IGA will be measured on a 5-point scale, excluding the following areas: knees, elbows, neck, 
palms, soles, axillae, groin, and scalp: 
0 
Clear 
No scaling and no roughness 
1 
Almost Clear 
Occasional fine scales; hardly palpable roughness 
(mostly smooth) 
2 
Mild 
Small and fine scales predominate; no more than a few 
large scales; mild roughness on palpation 
3 
Moderate 
Some large scales that may be thick,; coarse roughness 
on palpation 
4 
Severe 
Confluent, primarily large (>1 cm), thick scales with 
plate-like hyperkeratosis  
10.3.1.2 Visual Index for Ichthyosis Severity – Scaling 
The secondary endpoint is the number of subjects in each treatment group who experience a 
severity score of 0 or 1 at Week 12/EOT on the overall 16-point VIIS for scaling. 
The investigator will rate the subject’s condition using the 5-point VIIS for each body area 
(chest/abdomen, back, legs, and arms) and an overall score at each time point shown in the 
Schedule of Events (Section 2.2): 
0 
Normal skin; no perceptible scale or smoothening 
1 
Areas of normal skin intermixed with areas showing smoothening (diminished fine skin 
markings; shininess; waxiness) or small scales (visibly separated/fractured stratum 
corneum) 
2 
Confluent smoothening (diminished fine skin markings; shininess; waxiness) or small 
scales (visibly separated/fractured stratum corneum) 
3 
Confluent scales (visibly separated/fractured stratum corneum) including some large 
(>1 cm), thick scales 
4 
Confluent, primarily large, thick scales 
 
10.3.1.3 Individual Score for Roughness 
The amount of roughness of the skin overall will be measured on a 5-point scale. 
0 Clear 
Smooth skin 
1 Almost Clear 
Hardly palpable roughness 
2 Mild 
Mild roughness (fine sand paper-like) 
3 Moderate 
Moderate, coarse roughness (coarse sand paper-like) 
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4 Severe 
Very coarse skin (broken cornflakes-like) 
10.3.1.4 Palm/Sole Assessment 
Thickening of the skin on the palms and soles will be measured on a 5-point scale. 
0 Clear 
No thickening, no roughness, no fissure 
1 Almost Clear 
Only slight thickening, minimal to no roughness, no 
fissures 
2 Mild 
Some thickening, mild roughness on palpation, few 
fissures may be present 
3 Moderate 
Substantial and diffuse thickening, coarse roughness on 
palpation may be present, fissures may be present 
4 Severe 
Very thickened and rough skin, numerous fissures 
10.3.1.5 Palm/Sole Fissuring Assessment 
Fissuring will be assessed by recording the presence or absence of fissures, the number of fissures 
present, and the pain associated with each fissure. A fissure is a longitudinal and deep crack that 
separates the stratum corneum and may penetrate down to the dermis, causing pain and sometimes 
bleeding. The subject will assess pain associated with fissures as ranging from 0-3 (none, mild, 
moderate, severe).  
10.3.1.6 Dermatology Life Quality Index 
The DLQI is a dermatology-specific Quality of Life instrument for subjects aged 17 years and 
older (1992). The child DLQI (cDLQI; May 1993) is for subjects aged 12 to 16 years. It is a simple 
10-question validated questionnaire with 6 domains (symptoms and feelings, daily activities, 
leisure, work and school, personal relationships, and treatment); higher scores indicate poorer 
quality of life. The DLQI is the most frequently used instrument in studies of randomized 
controlled trials in dermatology. The investigator should use his or her judgment of the maturity 
of the subject to decide which version of the questionnaire to use; the same version must be used 
for the subject throughout the study. 
10.3.1.7 EQ-5D Quality of Life Questionnaires 
The EQ-5D is a standardized instrument developed by the EuroQol Group as a measure of health-
related quality of life used in a wide range of health conditions and treatments. The EQ-5D consists 
of a descriptive system and the EQ visual analog scale (VAS). The EQ-5D-5L (2009) is intended 
for use in adult subjects, while the EQ-5D-Y (2012) is to be used for children and adolescents. The 
investigator should use his or her judgment of the maturity of the subject to decide which version 
of the EQ-5D to use; the same version must be used for the subject throughout the study.  
The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. The EQ VAS records the subject’s self-rated health on a 
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vertical 0-100 VAS. This can be used as a quantitative measure of health outcome that reflects the 
subject’s own judgement. 
10.3.1.8 Ectropion Severity Score  
The Ectropion Severity Score (ESS), has a maximum score of 8 points. A higher score indicates a 
worse ectropion. The score takes the severity of ectropion in terms of lateral and medial apposition, 
scleral show, conjunctival show, and roundness of the eye into account and gives an indication of 
the functional aspects involved in ectropion by scoring redness, excess tear film, and the position 
of the lacrimal punctum.14 
 
Figure 10-1: Ectropion Severity Score 
Source: Korteweg SFS, Stenekes MW, van Zyl FE, Werker PMN. Paralytic Ectropion treatment with lateral periosteal 
flap canthoplasty and introduction of the ectropion severity score. Plast Reconstr Surg Glob Open. 2014;2(5):e151. 
10.3.1.9 Photography Substudy 
All sites that have photographic capability will take photographs as source data to support scoring 
at Baseline, Day 30, and Day 90. A central reader who will not be an investigator in the study will 
review the photographs to assess consistency of investigator scoring of LI severity as a quality 
check. Photographs may also be used for scientific publication purposes. Subjects will sign a 
separate, optional photographic informed consent form (ICF). 
Lateral appo ition 
Medial appo ition 
ceral ho\v 
Conjun tival how 
Exce 
t ar film 
Redne of the e e 
Round canthus 
Punctum lacrin1ale 
Maxin11u11 core 
Points per Item 
0 
onaffected 
onaffe t d 
0 
0 
0 
0 
0 
Invi ible 
0.5 
1 
Af£ cted 
Af£ cted 
::;;1 n1m 
> I mm 
Ye 
Ye 
Ye 
Ye 
E1nerging 
v· ibl 
8 point 
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10.3.2 Clinical Pharmacology 
10.3.2.1 Pharmacokinetic Analysis Methods  
The pharmacokinetic characterization of drug concentrations for each dose to be profiled will use 
noncompartmental analysis (NCA).  
10.3.2.2 Pharmacokinetic Parameters 
Samples for PK will be drawn from all subjects at Baseline and at each clinic visit for trough 
values.  
Subjects who provide written informed consent to participate in the optional PK substudy will 
provide blood samples for PK analysis predose on Day 1 and at 1, 2, 4, 8, 12, and 24 hours postdose 
on Day 1 and Day 30. 
The PK parameter estimates will be completed using WinNonlin (Pharsight Corporation) software 
using the actual elapsed times from dose administration to sample collection (i.e., not nominal 
time). 
Standard PK parameters assessed will include measures of the extent of absorption using estimates 
of the area-under-the-curve (AUC) and rate-of-absorption using the maximum concentration 
(Cmax) and the time of Cmax (Tmax). Additional details of the parameters and their calculation and 
evaluation will be included in the statistical analysis plan (SAP). 
Table 10-1 shows the PK parameters that will be computed for each subject for samples obtained 
over the planned sampling intervals. 
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Table 10-1: 
Pharmacokinetic Parameters 
Parameter 
Description of Parameter 
Cmax 
Maximum (or peak) serum concentration  
Tmax 
Time at which Cmax is observed 
AUC(0-t) 
Area under the plasma concentration-time curve from time 0 to the time of the last 
quantifiable plasma concentration 
AUC(0-inf) 
Area under the plasma concentration-time curve from time 0 to infinity (if data permits) 
t1/2 
Apparent first order terminal elimination half-life 
λz 
Apparent terminal phase rate constant (if data permits) 
10.3.3 Sample Collection 
Samples will be collected at the time points specified in the Schedule of Events (Section 2.2). 
Specimen preparation, handling, shipment, and storage for the complete blood count, chemistry, 
and urinalysis are described in the study laboratory manual. Finding veins in subjects with this 
disease can be challenging. Blood draws will be done at the corresponding study visits before 
application of the IP and should be 24 hours after IP application. Subjects must not apply the IP to 
the area where blood will be drawn within 24 hours before their next study visit to avoid 
contamination of the blood by IP that remained in the skin. For subjects in the PK substudy, a 
cannula should be placed before IP application and the cannula site may be occluded to prevent 
contamination with IP.  
Actual PK sample times for subjects in the PK substudy will be recorded in the eCRF. 
Blood 
For subjects not in PK substudy: 
The expected amount of blood to be drawn at each visit varies from approximately 6 mL to a 
maximum of 21 mL (Screening Visit only). The total amount of blood drawn for the study will be 
about 123 mL per subject, unless the subject takes part in the PK substudy. 
 
For subjects in PK substudy: 
For subjects who opt to participate in the PK substudy, extra blood samples will be drawn at Visit 2 
and at Visit 4 for PK analysis. The amount of blood to be drawn per subject at each of these visits 
will be approximately 54 mL. For subjects taking part in the substudy, the total amount of blood 
drawn for the entire study will be approximately 195 mL. 
Urine 
Urinalysis will be performed at central laboratory. Dipstick and urine pregnancy tests will be 
conducted on site.  
10.3.4 Safety Variables 
Safety assessments will include the evaluation of AEs, including local tolerability 
(stinging/burning, pruritus, and erythema), clinical laboratory assessments, vital signs, 12-lead 
ECGs, and physical examinations. 
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10.3.4.1 Clinical Laboratory Safety Assessments 
10.3.4.1.1 Clinical Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points specified in the 
Schedule of Events (Section 2.2). 
Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
platelet count (or estimate), white blood cell count including differential 
Serum Chemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, 
creatinine, glucose, sodium, potassium, chloride, bicarbonate, lactate 
dehydrogenase, uric acid, total cholesterol, high-density lipoprotein, low-
density lipoprotein, triglycerides 
Coagulation Panel: prothrombin time, partial thromboplastin time, fibrinogen 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones 
Pregnancy Test: 
for women of childbearing potential only; serum at Screening, urine at 
each other visit. 
Serology 
Hepatitis B surface antigen, and hepatitis C 
 
All blood samples for the clinical laboratory tests must be taken in a fasting state, at least 8 hours 
after the previous drug application.  
Blood and urine samples for hematology, and serum chemistry will be sent to a central laboratory 
for analysis. Urine pregnancy tests and dipstick will be conducted at the study sites. 
10.3.4.1.2 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens in 
both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
In addition to appropriate handling of subject samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples. Procedures and regulations for the packaging and shipping 
of infectious samples are outlined in the study laboratory manual. The investigator is responsible 
for ensuring that all study samples that are to be transported to another location are packed and 
shipped appropriately according to the applicable regulations.  
Samples for assessment of clinical laboratory tests will be transported to the Clinical Reference 
Laboratory (see the study laboratory manual for addresses). 
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10.3.4.1.3 Evaluation of Clinical Laboratory Values 
The normal ranges of values for the clinical laboratory assessments in this study will be provided 
by the responsible laboratory and submitted to Mayne Pharma LLC prior to beginning the study. 
They will be regarded as the reference ranges on which decisions will be made. 
If a laboratory value is out of the reference range, it is not necessarily clinically significant. The 
investigator must evaluate the out-of-range values and record his or her assessment of the clinical 
significance in the appropriate eCRF. 
All clinical laboratory values that in the investigator’s opinion show clinically significant or 
pathological changes during or after termination of treatment must be reported as AEs and 
followed, as described in Section 11.2.5. 
All measurements described in this section are recognized standard methods. 
10.3.4.2 Clinical Examinations 
10.3.4.2.1 Vital Signs 
Vital signs, including height and weight (only assessed at Screening), blood pressure, and pulse 
will be measured.  
10.3.4.2.2 Twelve-lead Electrocardiogram 
A standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes. 
All ECG recordings will be identified with the subject number, date, and time of the recording. 
Gel ECG electrodes may be used for ECGs because they are more conductive and cause less 
trauma on compromised skin. Efficacy assessments should be conducted before ECGs to avoid 
possible artefact/changes from the ECG.  
For subjects in the PK substudy, additional ECGs will be performed postdose during serial blood 
sampling on Day 1 and Day 30. 
If there is a marked prolongation of the QT/QTc interval during treatment, a subject should be 
discontinued from the IP but remain in the study until full resolution of the event. The DSMB will 
be informed immediately of such an occurrence. 
10.3.4.2.3 Physical Examination 
A complete physical examination excluding the genitourinary examination will be performed at 
Screening, while limited physical examinations (to include HEENT, cardiorespiratory, abdomen, 
and range of motion) will be performed as indicated in the Schedule of Events (Section 2.2). 
10.3.4.2.4 Other Safety Variables 
Local tolerability will be assessed on a 0-3 scale (none, mild, moderate, severe). All application 
site reactions will be recorded as TEAEs in the diary. These should include the date and severity 
of the TEAE. 
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10.3.4.3 Adverse Events 
The definitions and management of AEs, and any special considerations for AEs, are provided in 
Section 11. 
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11. ADVERSE EVENTS 
11.1. Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not related to the medicinal product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a 
pre-existing condition is considered an AE.) 
Events that occur in subjects treated with control product are also considered AEs. 
11.1.2 Adverse Drug Reaction 
All noxious and unintended responses to an investigational product related to any dose should be 
considered adverse drug reactions (ADRs). 
The phrase “responses to an investigational product” means that a causal relationship between an 
investigational product and an AE is at least a reasonable possibility, i.e., the relationship cannot 
be ruled out. All AEs judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship to an IP qualify as ADRs. 
All AEs for which the judgment of relationship to IP is “possible” or higher will be considered 
ADRs. If a relationship to IP is not provided, then the AE must be treated as if it were “possible.”  
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction 
An expected AE or ADR is one for which the nature or severity is consistent with the known AE 
profile of the product. For a preapproval test product, the known information is contained in the 
IB. For a marketed product, the known information is contained in the current package insert for 
the product. 
An unexpected adverse event (UAE) or unexpected adverse drug reaction (UADR) is one for 
which the nature or severity of which is not consistent with the applicable product information 
(e.g., Investigator’s Brochure [IB] for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product). For example, hepatic necrosis 
would be unexpected (greater severity) if the IB only listed elevated hepatic enzymes or hepatitis. 
Likewise, cerebral thromboembolism and cerebral vasculitis would be unexpected (greater 
specificity) if the IB only listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction constitute unexpected events.  
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11.1.4 Serious Adverse Events/Drug Reaction 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. 
An elective hospital admission to treat a condition present before exposure to the IP, or a 
hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or 
event as an SAE. Further, an overnight stay in the hospital that is only due to transportation, 
organization, or accommodation problems and without medical background does not need 
to be considered an SAE. 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the IP 
during pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject that has 
received an IP is not considered an SAE unless it is suspected that the IP(s) interacted with 
a contraceptive method and led to the pregnancy.  
• is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result 
in hospitalization, development of drug dependency, or drug abuse. The occurrence of 
malignant tumors is also to be considered serious.  
11.1.5 Significant Adverse Events 
Other significant AEs are defined as marked hematological and other laboratory abnormalities 
(other than those meeting the definition of serious) and any events that led to an intervention, 
including withdrawal of test drug, dose reduction, or significant additional concomitant therapy. 
11.1.6 Treatment-Emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening is after the first application 
of IP (trifarotene or vehicle) and not more than 14 days after the last application of IP. 
11.2. Event Assessment and Follow-up of Adverse Events 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care or upon review by a study 
monitor. 
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All reported AEs, including local and systemic AEs not meeting the criteria for SAEs, will be 
captured on the appropriate eCRF. Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event. 
All reported AEs occurring while on study must be documented appropriately regardless of 
relationship. All reported AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
Changes in the severity of a reported AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
Study clinic personnel will record all reportable events with start dates occurring any time after 
informed consent is obtained until 14 (for nonserious AEs) or 30 days (for SAEs) after the last day 
of study participation. At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit. Events will be followed for outcome information until resolution or 
stabilization. 
11.2.1 Assessment 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. In addition, 
although local tolerability will be assessed on a 0-3 scale, all application site reactions should be 
recorded as AEs. 
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11.2.2 Evaluation 
11.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as follows: 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.4. 
11.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.4. 
11.2.2.3 Action(s) Taken 
All AEs will be treated/managed according to standard practice. The following actions may be 
taken with regard to the IP. Section 9.4 describes dose adjustment and stopping rules for individual 
subjects. 
Action(s) taken may consist of the following: 
Dose not changed 
An indication that a medication schedule was maintained. 
Dose reduced 
An indication that a medication schedule was modified by subtraction, 
either by changing the frequency, strength, or amount. 
Drug interrupted 
An indication that a medication schedule was modified by temporarily 
terminating a prescribed regimen of medication. 
Drug withdrawn 
An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
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11.2.2.4 Outcome at the Time of Last Observation 
The outcome of an AE at the time of last observation will be classified as follows: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
*Only select fatal as an outcome when the AE results in death. If more than one AE is judged to 
be possibly related to the subject’s death, the outcome of death should be indicated for each such 
AE. Although “fatal” is usually an event outcome, events such as sudden death or unexplained 
death should be reported as SAEs. 
11.2.2.5 Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AE’s relationship to the IP. The categories for 
classifying the investigator’s opinion of the relationship are as follows: 
Not related 
An AE with sufficient evidence to accept that there is no causal relationship 
to IP administration (e.g., no temporal relationship to drug administration, 
because the drug was administered after onset of event; investigation shows 
that the drug was not administered; another cause was proven.) 
Unlikely 
related 
An AE, including laboratory test abnormality, with a temporal relationship to 
IP administration that makes a causal relationship improbable, and in which 
other drugs, events, or underlying disease provide plausible explanations. 
Possibly related An AE with a reasonable time sequence to administration of the IP, but that 
could also be explained by concurrent disease or other drugs or events. 
Information on drug withdrawal may be lacking or unclear. 
Related 
An AE occurring in a causal plausible time relationship to IP administration 
that cannot be attributed to a concurrent disease or other drugs, chemicals, or 
events. The AE relationship to the IP must be assessed separately by the 
investigator and Mayne Pharma LLC. 
 
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11.2.3 Documentation 
Any AE that occurs during the Screening Period will be captured as on the AE page of the eCRF 
(not medical history). All AEs that occur within the period of observation for the study must be 
documented in the eCRF with the following information, where appropriate. (The period of 
observation for the study is described in Section 11.2.) 
• AE name or term 
• When the AE first occurred (start date and time) 
• When the AE stopped (stop date and time or an indication of “ongoing”) 
• Severity of the AE 
• Seriousness (hospitalization, death, etc.) 
• Actions taken 
• Outcome 
• Investigator opinion regarding the AE relationship to the IP(s) 
11.2.4 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. If such treatment constitutes a deviation from the protocol, the subject may be withdrawn 
for treatment but continue to be followed for efficacy and safety in the study. The decision about 
whether the subject may continue in the study will be made by the sponsor after consultation with 
the investigator and/or medical monitor. 
If AEs occur in a subject that are not tolerable, the investigator must decide whether to stop the 
subject’s involvement in the study and/or treat the subject. Special procedures may be 
recommended for the specific IP, such as the collection of a serum sample for determining blood 
concentrations of IP, specific tapering procedures, or treatment regimens, as appropriate. 
It is not necessary to unblind a subject’s treatment assignment in most circumstances, even if an 
SAE has occurred. If unblinding is necessary, see Section 9.6 for a description of the unblinding 
procedures. 
11.2.5 Follow-up 
Any AE will be followed (up to a maximum of 14 days after the last dose of IP) to a satisfactory 
resolution, until it becomes stable, or until it can be explained by another known cause(s) (i.e., 
concurrent condition or medication) and clinical judgment indicates that further evaluation is not 
warranted. All findings relevant to the final outcome of an AE must be reported in the subject’s 
medical record and recorded on the eCRF page.  
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11.2.6 Reporting 
11.2.6.1 Serious Adverse Events 
The investigator or designee must report all SAEs promptly to Premier Research within 24 hours 
of first becoming aware of the event by e.g., completing, signing and dating the Serious Adverse 
Event Report Form, verifying the accuracy of the information recorded in the form with the source 
documents and eCRF, and sending the SAE form to the Premier Research by one of the following 
methods:  
Email: globalPV-US@premier-research.com 
Email: PVDS-ROW@premier-research.com 
Fax number: +1 215 972 8765 
Fax number: +421 2 6820 3713 
This written report should be submitted on the SAE form provided for this purpose. At the time of 
first notification, the investigator or designee should provide the following information, if 
available: 
• Protocol number 
• Reporter (study site and investigator) 
• Suspect IP 
• Subject’s study number 
• Subject’s year of birth 
• Subject’s gender 
• Date of first dose of IP(s) 
• Date of last dose of IP(s), if applicable 
• Adverse event term 
• Date of occurrence of the event 
• A brief description of the event, outcome to date, and any actions taken 
• The seriousness criteria(on) that were met 
• Concomitant medication at onset of the event 
• Relevant medical history information 
• Relevant laboratory test findings 
• Investigator’s opinion of the relationship to IP(s) (“Is there a reasonable possibility that 
the IP caused the SAE? Yes or No?”) 
• Whether and when the investigator was unblinded as to the subject’s treatment 
assignment  
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Any missing or additional relevant follow-up information concerning the SAE should be sent to 
the sponsor/sponsor representative via the same contact details above as soon as possible on a 
follow-up SAE Report Form, together with the following minimal information (initial report, 
adverse event, date of occurrence, subject identification (ID), study ID, IP, and site number); this 
will allow the follow-up information to be linked to the initial SAE report.  
Specific information may be requested by the Premier Research Pharmacovigilance Department 
using a follow-up request form or via email communication. 
The investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his or her health authorities, institutional review board 
(IRB)/independent ethics committee (IEC), principal and coordinating investigators, study 
investigators, and institutions. Each investigator is obligated to learn about the reporting 
requirements for investigators in his/her country. The study monitor may be able to assist with 
this. 
11.2.6.2 Adverse Drug Reactions 
All ADRs should be reported by the investigator in the eCRF.  
Suspected serious ADRs must be reported to the sponsor immediately, regardless of the time 
elapsed since the end of the observation period. 
11.2.6.3 Nonserious Adverse Events 
Nonserious AEs will be recorded in the eCRF and reported by Premier Research to Mayne Pharma 
LLC in aggregate monthly status reports. 
11.3. Special Considerations 
11.3.1 Adverse Events of Special Interest 
Since topical retinoids are associated with local application site AEs, particularly when beginning 
treatment, these events will be followed closely during the study and considered AEs of special 
interest (AESIs). 
11.3.2 Pregnancy 
All WOCBP who participate in the study should be counseled on the need to practice highly 
effective birth control and on the importance of avoiding pregnancy during study participation. 
Women should be instructed to contact the investigator or study staff immediately if pregnancy 
occurs or is suspected. 
Pregnancy testing will be conducted prior to administration of the IP on every woman of 
childbearing potential. A woman who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered to be a screening failure. 
A woman who becomes pregnant during IP treatment will be immediately discontinued from study 
treatment. The investigator must report the pregnancy of any woman who becomes pregnant 
during or within 30 days after discontinuing treatment as if it were an SAE within 24 hours of 
learning of the pregnancy, to Premier Research Pharmacovigilance using the Pregnancy Data 
Collection Form via the same fax number and/or email address as for SAE reporting. The 
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investigator should contact the designated individual(s) who receive SAE notification and record 
information related to the pregnancy on an SAE and AE form (entering the event temporarily as 
nonserious on both forms) provided by the sponsor or its designee. If a partner of a male study 
subject becomes pregnant, the investigator must report the pregnancy as soon as possible after 
learning of it to the Premier Research Pharmacovigilance using the Pregnancy Data Collection 
Form. A separate pregnant partner ICF will be required. 
Early Termination Visit assessments are required as soon as possible after learning of the 
pregnancy in a study subject. The investigator is also responsible for following the pregnancy until 
delivery or termination. These findings must be reported on the Exposure in Utero form and 
forwarded to the designated individual(s). The event meets the SAE criterion only if it results in a 
spontaneous abortion or a congenital anomaly. 
Among the clinical studies, 12 pregnancies were reported: 4 resulted in normal births; 5 resulted 
in spontaneous abortions (none of which was considered related to CD5789); 1 was electively 
aborted, and 2 were lost to follow-up (Investigator’s Brochure for CD5789 Cutaneous 
Formulation). 
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12. DATA SAFETY MONITORING BOARD 
Safety oversight will be under the direction of a DSMB composed of individuals with the 
appropriate expertise, including LI. Members of the DSMB should be independent from the study 
conduct and free of conflict of interest, or measures should be in place to minimize perceived 
conflict of interest. The DSMB will operate under a charter that will be finalized prior to the start 
of the study. The DSMB will meet at least 3 times during the conduct of the study: when the study 
begins, when 15 adult subjects have enrolled in Cohort A and have completed at least 28 days of 
treatment, and after 60 subjects have enrolled in the study. 
The DSMB will meet after 15 subjects in Cohort A have completed at least 28 days of double-
blind treatment to review aggregate safety and tolerability data (including PK and ECG results). 
The safety data will be unblinded. At that time, the DSMB will decide whether Cohort B (adults 
and subjects aged 12–17) may begin enrolling, or if additional adult safety data are required before 
allowing subjects aged 12 – 17 to participate in the study. The DSMB will have the authority to 
recommend to the sponsor that the study be modified, placed on hold, or stopped if serious safety 
issues are discovered. The DSMB will provide its input to Mayne Pharma LLC. Any protocol 
changes the DSMB may suggest will be submitted to all applicable regulatory bodies for review 
and approval. 
In case of significant toxicity, the DSMB may choose to review the available safety data and 
recommend stopping recruitment in a particular dose group. 
Stopping rules for individual subjects are in Section 9.4.1. 
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13. STATISTICS 
13.1. Statistical Analysis 
This section presents a summary of the planned statistical analyses. A SAP that describes the 
details of the analyses to be conducted will be written prior to database lock.  
Unless otherwise indicated, all testing of statistical significance will be two-sided, and a difference 
resulting in a P value of ≤ 0.05 will be considered statistically significant.  
Summary statistics will be provided for the variables described below. For continuous variables, 
these statistics will include the number of subjects, mean, standard deviation (SD), median, 
minimum, and maximum. For categorical variables, these statistics will include the number and 
percentage of subjects in each category. 
The primary analysis period is the first 12 weeks of treatment (i.e., the Double-blind Period). 
Overall unblinding will take place at the end of the Double-blind Period of the study only after the 
database is locked. A second analysis will take place for endpoints assessed from Week 12 through 
the OLE Period. The baseline for the safety and efficacy parameters will be measured at Visit 1 or 
Visit 2, per the Schedule of Events for both the Double-blind Period (Table 2-1) and OLE 
(Table 2-2). 
13.1.1 Analysis Populations 
The following 5 analysis populations are planned for the Double-blind Period of this study:  
• Safety: all subjects who are randomized to treatment and receive at least 1 application of 
study drug in the Double-blind Period. This population will be the primary population for 
analyses of safety. 
• Intent-to-treat (ITT): all randomized subjects. This population will be used as the primary 
population for the analysis of efficacy for the Double-blind Period of the study. 
• Modified intent-to-treat (mITT): all subjects in the safety population with at least 
1 postbaseline assessment of efficacy in the Double-blind Period.  
• Per-protocol (PP): subjects in the mITT Population who met all inclusion criteria and no 
exclusion criteria, were compliant with study drug application, and who had no 
significant protocol deviations. 
• Pharmacokinetic: all subjects in the Safety Population who have at least 1 plasma sample 
with quantifiable concentration. This population will be used to summarize all PK 
endpoints. 
The following analysis populations are planned for the OLE of this study: 
• OLE Safety: all subjects who complete the 12-week Double-blind Treatment Period and 
receive at least 1 application of study drug in the OLE. 
• OLE ITT: all subjects who complete the 12-week Double-blind Treatment Period and 
sign the OLE informed consent. 
• OLE mITT: all subjects in the OLE safety population with at least 1 assessment of 
efficacy after Visit 6. 
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• OLE PP: all subjects in the OLE mITT population who met all inclusion criteria and no 
exclusion criteria, were compliant with study drug application from baseline through 
EOT, and who had no significant protocol deviations throughout the study. 
Inclusion in the analysis populations will be determined prior to database lock. 
If a subject is randomized incorrectly or is administered the incorrect IP, analyses of the ITT and 
mITT populations will be based on the assigned treatment whereas all other analyses will be based 
on the actual treatment received. 
13.1.2 Study Subjects and Demographics 
13.1.2.1 Disposition and Withdrawals 
For the Double-blind Period, the numbers of subjects randomized, completing Week 12 of the 
study, and withdrawing early from the Double-blind Period, along with reasons for withdrawal, 
will be tabulated overall and by randomized treatment group. The number of subjects in each 
analysis population will be reported. The number of subjects completing study milestones will also 
be tabulated by randomized treatment group. This analysis will be conducted for the ITT 
population. 
For the OLE, the number of subjects entering the OLE, completing the study, and withdrawing 
early, along with reasons for withdrawal, will be tabulated overall. The number of subjects in each 
analysis population will be reported. The number of subjects completing study milestones will also 
be tabulated. This analysis will be conducted for the OLE ITT population. 
13.1.2.2 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol or International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) requirements. The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions are 
to be developed by the site and implemented promptly.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations promptly. All deviations must be addressed in study source documents, and reported to 
Premier Research or Mayne Pharma LLC. Protocol deviations must be sent to the reviewing IRB 
per their policies. The site investigator is responsible for knowing and adhering to the reviewing 
IRB requirements. Further details about the handling of protocol deviations will be included in the 
protocol deviation guidance plan. 
Subjects who taper to once-weekly application or who take a “drug holiday” will not be reported 
as having deviated from the protocol. 
13.1.2.3 Demographics and Other Baseline Characteristics 
These analyses will be conducted for the ITT and OLE ITT populations.  
Demographic variables will include age, sex, race, ethnicity, height, weight, and BMI. Baseline 
subject characteristics will include medical history, physical examination findings, and IGA score. 
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Prior and concomitant medications will be summarized by randomized treatment group, by the 
number and percentage of subjects taking each medication, and classified using World Health 
Organization Drug Dictionary (WHO-DD) Anatomical Therapeutic Chemical (ATC) classes and 
preferred terms. 
13.1.3 Exposure and Compliance 
Investigational product administration will be summarized in terms of each subject’s dose, and in 
terms of duration of exposure for each period. Descriptive statistics for these quantities, including 
the mean, median, SD, minimum, maximum, and quartiles, will be provided by treatment group. 
Additionally, the number of subjects who are compliant with investigational product will be 
presented by treatment group for the Double-blind Period and overall for the OLE.  
Subjects who taper to once-weekly application or who take a “drug holiday” will not be reported 
as having deviated from the protocol. 
13.1.4 Efficacy Analysis 
The ITT population will be used as the primary population for the primary analysis of efficacy at 
Week 12. Select efficacy analyses will be repeated as secondary analyses in the ITT and PP 
populations for the Double-blind Period. Efficacy analyses will also be repeated in the OLE using 
the OLE ITT, OLE mITT, and OLE PP populations. No formal inferential analyses will be 
conducted for efficacy variables in the OLE. 
13.1.4.1 Efficacy Endpoints 
Primary efficacy endpoint: The proportion of subjects in each treatment group who experience 
successful resolution of LI where “success” is defined as clear/almost clear overall and at least a 
2-grade change from Baseline at Week 12/EOT in the Double-blind Period on the 5-point IGA 
scale.  
Secondary: The secondary endpoints are as follow: 
• The difference in mean scores between the active trifarotene cream HE1 and 
vehicle groups in the following assessment indices from Baseline through Week 
12: 
 5-point VIIS scale for scaling from Baseline through Week 12 
 Individual score for roughness (Scale: 0–4) overall 
 Palm/sole Assessment (Scale: 0–4)  
 Quality of life per DLQI and cDLQI 
• The difference in proportion of subjects with presence of fissures on palm/soles 
(presence/absence, number of fissures, and pain associated with fissures [on a 
0-3 scale]) at Week 12 between the active trifarotene cream HE1 and vehicle 
groups  
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Exploratory: The exploratory endpoints are as follow: 
• The difference in mean ectropion scores (ESS of 0–8) between the active trifarotene 
cream HE1 and vehicle groups from Baseline through Week 12 
• The difference in quality of life per EQ-5D-5L and EQ-5D-Y scores between the 
active trifarotene cream HE1 and vehicle groups from Baseline through Week 12 
13.1.4.2 Primary Analysis 
For the Double-blind Period only, the number and proportion of subjects in each treatment group 
with successful resolution of LI by Week 12/EOT will be presented. The primary efficacy endpoint 
will be analyzed using a logistic regression model with treatment and age group as factors. Other 
baseline characteristics and interactions may be included. The odds ratios and 95% CIs for the 
odds ratios will be presented. The difference in proportions between the active trifarotene cream 
HEI and vehicle cream group, 95% CIs for the differences, and P-values for the differences in 
treatment will also be presented. 
Descriptive summaries (such as mean, standard error, median, minimum, and maximum) and the 
changes from baseline will be provided for IGA scores for both periods.  
13.1.4.3 Secondary Analyses 
Secondary and exploratory efficacy endpoints will be analyzed separately for each period 
(Double-blind and OLE) using descriptive statistics.  
Additionally, for the Double-blind Period only, change from Baseline in continuous secondary 
endpoints through Week 12 will be presented and analyzed using a mixed model for repeated 
measures (MMRM). The model will include the change from baseline score as the dependent 
variable, treatment group as a fixed effect, subject as a random effect, and baseline score value as 
a covariate.  
For subjects who report having fissures, descriptive summaries of the number of fissures and pain 
related to fissures will also be presented by treatment group and body area for each period. 
The DLQI scores will also be analyzed using descriptive statistics through Week 12. 
The proportion of subjects with at least a 50% reduction in IGA score from Baseline will be 
analyzed using the same logistic regression analysis described in Section 13.1.4.2. 
13.1.4.4 Exploratory Analyses 
Descriptive summaries and the changes from baseline will be provided for ectropion scores and 
EQ-5D-5L scores by visit for each period. No formal inferential analyses will be conducted for 
exploratory endpoints. 
13.1.4.5 Corroborative, Sensitivity, and Other Analyses 
To assess the effect of missing data on the primary efficacy analysis, a sensitivity analysis will be 
performed using multiple imputation (MI) for the Double-blind Period only. Multiple-imputations 
will be used to replace missing IGA outcomes using multiple draws from the posterior predictive 
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distribution estimated from the treatment groups. IGA scores will be imputed and then categorized 
as treatment success according to Section 13.1.4.1. Imputation will not be performed for the OLE. 
Full details will be specified in the SAP. 
The proportion of subjects who experience a 2-grade change from baseline to Week 12 in 
individual score for roughness and palm/sole assessment will also be explored using a logistic 
regression model with treatment and age group as factors. Other baseline characteristics and 
interactions may be included. The odds ratios and 95% CIs for the odds ratios will be presented. 
The difference in proportions between the active trifarotene cream HEI and vehicle cream group 
and the 95% CIs for the differences will be presented. 
For analyses involving study site, if the number of subjects per site is small, sites may be pooled 
for safety and efficacy analysis or omitted from statistical models as the anticipated number of 
subjects per site is small, treatment is self-administered, and the sites are using standardized 
procedures for all assessments. If the distribution of enrollments at sites is such that one or few are 
enrolling a majority of subjects, a subgroup analysis by site may be performed. The final 
determination will be made prior to database lock.  
Details of these analyses will be further detailed in the SAP. 
13.1.5 Clinical Pharmacology Analyses 
13.1.5.1 Pharmacokinetics 
For noncompartmental analysis, plasma concentrations will be listed and summarized at each time 
point using descriptive statistics. Descriptive statistics reported will include the arithmetic mean, 
SD, CV%, geometric mean, minimum, maximum, and median. Only the range and the median will 
be reported for Tmax, as this is a categorical parameter. The PK parameters will also be summarized 
by treatment using descriptive statistics.  
Individual plasma concentration plots and mean data graphs will be produced using both linear 
and semi-logarithmic scales. Mean data graphs will show plasma concentration profiles by 
treatment group. 
Pharmacokinetic plasma parameter estimates and summaries will be completed for the subjects in 
the PK population. Testing of PK parameters will be outlined in the SAP. 
13.1.6 Safety and Tolerability Analyses 
Safety analyses through Week 12 of the Double-blind Period will be conducted using data from 
the Safety Population and safety analyses in the OLE will be conducted using the OLE Safety 
Population (as defined in Section 13.1.1). Safety variables include treatment-emergent AEs, 
clinical laboratory values, vital signs, ECG readings, and physical examination results. No formal 
inferential analyses will be conducted for safety variables in either period. 
13.1.6.1 Local Tolerability 
During all clinic visits, the investigator will assess local tolerability (Scale: 0-3 [none, mild, 
moderate, severe]) for each treated body area (chest/abdomen, back, arms, legs, and face/neck). 
Descriptive summaries will be presented by period, treatment group, and visit. 
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13.1.6.2 Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 20.1 or higher.  
Treatment-emergent AEs are defined as: 
• AEs with onset at the time of or following the start of treatment with IP through the 
Follow-up Visit or Early Termination Visit, whichever occurs first, or 
• AEs starting prior to the start of treatment but increasing in severity or relationship at the 
time of, or following, the start of treatment with IP through the Follow-up Visit or Early 
Termination Visit, whichever occurs first. 
The number and percentage of subjects with AEs will be displayed by each treatment group in the 
Double-blind Period and overall in the OLE by system organ class and preferred term. Summaries 
of AEs by severity and relationship to IP will also be provided. Serious adverse events and AEs 
resulting in discontinuation of IP will be summarized separately in a similar manner. Subject 
listings of AEs, SAEs, and AEs causing discontinuation of IP will be produced. 
13.1.6.3 Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from baseline values will be presented for clinical laboratory values for each treatment 
group at each time point in each period. 
The number of subjects with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from baseline (shift tables) for each clinical 
laboratory parameter by treatment group and by study visit in each period.  
Laboratory values that are outside the normal range will also be flagged in the data listings and 
presented with the corresponding normal ranges. Any out-of-range values that are identified by 
the investigator as being clinically significant will also be shown in a data listing. 
13.1.6.4 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for systolic blood pressure (SBP), diastolic blood pressure 
(DBP), and pulse for each period. 
The number of subjects with vital signs values categorized as below, within, or above normal 
ranges will be tabulated showing change from baseline (shift tables) for each parameter by period, 
by treatment group and by study visit. Pre and post-treatment values may also be presented with 
an analysis of mean changes from baseline. 
13.1.6.5 Twelve-lead Electrocardiograms 
The number and percentage of subjects with normal and abnormal ECG findings will be 
summarized for each treatment group at each time point in each period. Abnormal results will be 
grouped as clinically significant and not clinically significant. 
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A comparison of QT results will be presented. Summary statistics will be displayed by period, by 
treatment group, and by visit for QT and the QT interval corrected for heart rate (QTc) calculated 
using Fridericia’s QT correction methods.  
Descriptive summaries (mean, SD, median, minimum, and maximum) will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTcF interval (Fredericia’s correction 
methods), and HR for each treatment group at each time point in each period. 
13.1.6.6 Physical Examination Findings 
The number and percentage of subjects with normal and abnormal findings in the complete 
physical examination will be displayed for each treatment group in each period. 
13.1.7 Interim Analysis 
No interim analyses are planned.  
13.2. Sample Size Determination 
Accounting for a 20% drop-out/nonevaluable rate, a total sample size of 120 subjects randomized 
in a 1:1:1 ratio to 2 active trifarotene cream HE1 arms and a vehicle cream arm will provide 
>80% power to detect a difference between each separate trifarotene cream HE1 arm (32 evaluable 
subjects) and the vehicle cream arm (32 evaluable subjects) 2-sided Fisher’s Exact Test assuming 
a 70% success rate and a 40% success rate, respectively. This study is not powered to detect a 
difference between the 2 active arms. 
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14. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
14.1. Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 16). The sponsor reserves the right to withdraw a subject from the study (Section 8.3), to 
terminate participation of a study site at any time (Section 14.7), and/or to discontinue the study 
(Section 14.6). 
Mayne Pharma LLC agrees to provide the investigator with sufficient material and support to 
permit the investigator to conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 18.1), the investigator indicates that he or she 
has read the protocol carefully, fully understands the requirements, and agrees to conduct the study 
in accordance with the procedures and requirements described in this protocol.  
The trial will be conducted in accordance with ICH GCP, and the applicable United States (US) 
Code of Federal Regulations (CFR). The principal investigator will assure that no deviation from, 
or changes to, the protocol will take place without prior agreement from the Investigational New 
Drug (IND) sponsor, funding agency and documented approval from the IRB, except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection and ICH GCP training. 
Investigators should ensure that all persons who are delegated study-related responsibilities are 
adequately qualified and informed about the protocol, the IP(s), and their specific duties within the 
context of the study. Investigators are responsible for providing Mayne Pharma LLC with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
14.1.3 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying study product may inspect all 
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documents and records required to be maintained by the investigator, including, but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. 
The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at Premier Research. This will not include the participant’s contact 
or identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by clinical sites and by Premier Research staff will be secured and password protected. At the end 
of the study, all study databases will be de-identified and archived at the Premier Research 
14.2. Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from the sponsor or its designee that the study can be initiated at the study site. The study site will 
not be authorized for study initiation until: 
1. The study site has received the appropriate IRB/IEC approval for the protocol and the 
appropriate ICF. 
2. All regulatory/GCP documents have been submitted to and approved by the sponsor or its 
designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
14.3. Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study. Subjects may 
only be rescreened once 30 days or more after the original Screening Visit. If a subject is eligible 
to enter the study after having previously failed screening, the subject will be assigned a new 
subject identification number. 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
14.4. Study Documents 
All documentation and material provided by Mayne Pharma LLC for this study are to be retained 
in a secure location and treated as confidential material. 
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14.4.1 Informed Consent 
Consent and assent forms describing in detail the study intervention, study procedures, and risks 
are given to the participant and written documentation of informed consent is required prior to 
starting intervention/administering study intervention. The informed consent and assent forms are 
submitted with this protocol. 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent and assent forms will 
be IRB-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may 
arise. A verbal explanation will be provided in terms suited to the participant’s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research participants. 
Participants will have the opportunity to carefully review the written consent and assent forms and 
ask questions before signing. The participants should have the opportunity to discuss the study 
with their family or surrogates or think about it before agreeing to participate. The participant will 
sign the informed consent or assent document prior to any procedures being done specifically for 
the study. Participants must be informed that participation is voluntary and that they may withdraw 
from the study at any time, without prejudice. A copy of the informed consent and assent document 
will be given to the participants for their records. The informed consent process will be conducted 
and documented in the source document (including the date) and the form signed before the 
participant undergoes any study-specific procedures. The rights and welfare of the participants will 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
14.4.2 Investigator’s Regulatory/Good Clinical Practice Documents 
The regulatory/GCP documents are listed below. 
• Signed original protocol (i.e., Investigator’s Agreement) 
• Curricula vitae of all investigators and subinvestigators 
• Name and address of the laboratories 
• List of laboratory reference ranges, and if available, a quality certificate 
• Form Signature Log/Delegation of Study-related Duties 
• Approved ICF and subject materials 
• FDA1572 and financial disclosure forms, as applicable (US sites) 
• Any other relevant GCP documents 
The regulatory/GCP documents must be received from the investigator and reviewed and approved 
by Mayne Pharma LLC or its designee before the study site can initiate the study and before Mayne 
Pharma LLC will authorize shipment of IP to the study site. Copies of the investigator’s 
regulatory/GCP documents must be retained at the study site in a secure location. Additional 
documents, including a copy of the protocol and applicable amendment(s), the trifarotene 
(CD5789) Cream IB, eCRF completion guidelines, copies of regulatory references, copies of 
IRB/IEC correspondence, and IP accountability records should also be retained as part of the 
investigator’s regulatory/GCP documents. It is the investigator’s responsibility to ensure that 
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copies of all required regulatory/GCP documents are organized, current, and available for 
inspection. 
14.4.3 Case Report Forms 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign an 
ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the study to ensure that the study information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered in the electronic data capture 
(EDC) system according to the completion guidelines provided by the sponsor or its designee. 
The eCRFs must be signed by the investigator or a subinvestigator. These signatures serve to attest 
that the information contained in the eCRF is accurate and true. 
14.4.4 Source Documents 
Information recorded in the EDC system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
Clinical laboratory data required by the protocol will be electronically transferred from the 
central/local laboratory to the sponsor or its designee. A paper copy of the laboratory results will 
be provided to the study site and should be retained with each subject’s source data. 
14.5. Data Quality Control 
Mayne Pharma LLC and its designees will perform quality control checks on this clinical study. 
14.5.1 Monitoring Procedures 
Mayne Pharma LLC and/or its designee will conduct site visits to monitor the study and ensure 
compliance with the protocol, GCP, and applicable regulations and guidelines. The assigned 
clinical research associate(s) (CRA[s]) will visit the investigator and study site at periodic intervals 
and maintain periodic communication. The investigator agrees to allow the CRA(s) and other 
authorized Mayne Pharma LLC personnel access. The CRA(s) will maintain current personal 
knowledge of the study through observation, review of study records and source documentation, 
and discussion of the conduct of the study with the investigator and staff. While on site, the CRA(s) 
will review 
• regulatory documents, directly comparing entries in the EDC system with the source 
documents 
• consenting procedures 
• AE procedures 
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• storage and accountability of IP and study materials 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRF will be provided to the sites. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow Mayne Pharma LLC or designee auditors or inspectors from regulatory agencies 
to review records and to assist the inspectors in their duties, if requested.  
For additional information, please refer to the clinical monitoring plan (CMP). 
14.5.2 Data Management 
Mayne Pharma LLC or designee will be responsible for activities associated with the data 
management of this study. The standard procedures for handling and processing records will be 
followed per GCP and Premier Research’s standard operating procedures. A comprehensive data 
management plan (DMP) will be developed, including a data management overview, description 
of database contents, annotated CRF, pre-entry review list, self-evident correction conventions, 
query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries will be provided to the sites. 
14.5.3 Quality Assurance/Audit 
This study will be subject to audit by Mayne Pharma LLC or its designee. Audits may be performed 
to check compliance with GCP guidelines and can include: 
• site audits 
• Trial Master File audits 
• database audits 
• document audits (e.g., protocol and/or clinical study report [CSR]) 
Mayne Pharma LLC or its designee may conduct additional audits on a selection of study sites, 
requiring access to subject notes, study documentation, and facilities or laboratories used for the 
study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB/IEC or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify Mayne Pharma LLC immediately. 
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14.6. Study Termination 
The study may be terminated at Mayne Pharma LLC’s discretion at any time and for any reason. 
The DSMB may recommend discontinuation of the study if they find evidence of unacceptable 
risk to subjects. 
14.6.1 Regular Study Termination 
The end of this study is defined as the date of the last visit of the last subject (last subject out or 
last subject last visit) participating in the study. Within 90 days of the end of the clinical study, 
Mayne Pharma LLC or designee will notify the IECs and regulatory authorities about the regular 
termination of the study as required according to national laws and regulations. 
14.6.2 Premature Study Termination 
The study may be temporarily suspended or terminated prematurely if there is sufficient reasonable 
cause at any time by Mayne Pharma LLC, IECs, regulatory authorities, respective steering 
committees, or the coordinating investigator. A decision to prematurely terminate the study is 
binding to all investigators of all study sites. 
Within 15 days of premature termination of a clinical study, Mayne Pharma LLC or its designee 
will notify the IECs and regulatory authorities about the premature termination as required 
according to national laws and regulations. Mayne Pharma LLC or its designee must clearly 
explain the reasons for premature termination. 
Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigator, funding agency, the IND 
or IDE sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the 
PI will promptly inform study participants, the IRB, and sponsor and will provide the reason(s) for 
the termination or suspension. Study participants will be contacted, as applicable, and be informed 
of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
If the study is terminated prematurely, all investigators have to inform their subjects and take care 
of appropriate follow-up and further treatment of the subjects to ensure protection of the subjects’ 
interests. Study sites may be asked to have all subjects currently participating in the study complete 
all of the assessments for the Follow-up Visit. 
The study might resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB/IEC and/or FDA. 
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14.7. Study Site Closure 
At the end of the study, all study sites will be closed. Mayne Pharma LLC may terminate 
participation of a study site at any time. Examples of conditions that may require premature 
termination of a study site include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate subject enrollment 
14.7.1 Record Retention 
For sites in the US, the investigator shall retain and preserve 1 copy of all data generated in the 
course of the study, specifically including, but not limited to, those defined by GCP as essential 
until 1 of the following occurs: 
• At least 2 years after the last marketing authorization for the IP has been approved or the 
sponsor has discontinued its research with the IP, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development of 
the IP. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor has 30 days to respond to the investigator’s notice, and the 
sponsor has further opportunity to retain such materials at the sponsor’s expense. 
Outside of the US, after completing the study, Mayne Pharma LLC will receive the original eCRFs 
or at least a legible copy and retain the documents for at least 5 years after the completion of the 
study. 
One copy will remain with the investigator. The investigator shall arrange for the retention of the 
subject identification codes, subject files and other source data until at least 5 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or until at least 2 years have elapsed since 
the formal discontinuation of the clinical development of the product. These documents need to be 
retained for a longer period of time if required by applicable regulatory authorities or by agreement 
with the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor shall have 30 days to respond to the investigator’s notice, 
and the sponsor shall have a further opportunity to retain such materials at the sponsor’s expense. 
Copies of these study records (and all study-related documents, including source data) shall be 
kept by the investigator for the maximum period of time permitted by the hospital, institution, or 
private practice. 
14.7.2 Sample Retention 
Blood samples will be used for purposes related to this study only, and will not be stored for future 
research. The samples will be stored until they are no longer needed, and the decision has been 
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made that none of the samples needs to be reanalyzed. In addition, identifiable samples can be 
destroyed at any time at the request of the subject. 
Data collected for this study will be analyzed and stored at Premier Research.  
14.8. Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Mayne Pharma LLC. The protocol amendment must be signed by 
the investigator and approved by the IRB or IEC before it may be implemented. Protocol 
amendments will be filed with the appropriate regulatory agency(s) having jurisdiction over the 
conduct of the study. 
14.9. Use of Information and Publication 
All information concerning trifarotene (CD5789) cream HE1, Mayne Pharma LLC’s operations, 
patent applications, formula, manufacturing processes, basic scientific data, and formulation 
information supplied by Mayne Pharma LLC or its designee to the investigator, and not previously 
published, is considered confidential and remains the sole property of Mayne Pharma LLC. Case 
report forms also remain the property of Mayne Pharma LLC. The investigator agrees to use this 
information for purposes of study execution through finalization and will not use it for other 
purposes without the written consent of the sponsor. 
The information developed in this study will be used by Mayne Pharma LLC in connection with 
the continued development of trifarotene (CD5789) cream HE1 and thus, may be disclosed as 
required to other clinical investigators or government regulatory agencies. 
The information generated by this study is the property of Mayne Pharma LLC. Publication or 
other public presentation of trifarotene (CD5789) cream HE1 data resulting from this study 
requires prior review and written approval of Mayne Pharma LLC. Abstracts, manuscripts, and 
presentation materials should be provided to Mayne Pharma LLC for review and approval at least 
30 days prior to the relevant submission deadline. Data from individual study sites must not be 
published separately. 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition, or publication by the investigator until Mayne Pharma LLC has reviewed and 
commented on such a presentation or manuscript for publication. If applicable, this study will be 
registered at ClinicalTrials.gov, and results information from this study will be submitted to 
ClinicalTrials.gov. 
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15. FINAL CLINICAL STUDY REPORT 
Mayne Pharma LLC will retain ownership of the data. 
The final CSR will be written within 1 year of completion of the clinical part of the study. For 
pediatric studies, the final CSR will be written within 6 months. This report will include a summary 
of the study results based on a statistical evaluation and clinical assessment of the protocol-defined 
endpoints. 
The final CSR may be submitted to the regulatory authorities.  
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16. ETHICAL AND LEGAL CONSIDERATIONS
16.1. Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry GCP 
E6 (including archiving of essential study documents), the Integrated Addendum to ICH E6 (R2) 
of November 2016, the Declaration of Helsinki, the applicable regulations of the country(ies) in 
which the study is conducted, and with the Commission Directives 2001/20/EC and 2005/28/EC. 
16.2. Subject Information and Informed Consent and/or Assent 
A properly constituted, valid IRB or IEC must review and approve the protocol, the investigator’s 
ICF, and related subject information and recruitment materials before the start of the study. 
It is the responsibility of the investigator to ensure that written informed consent and/or assent is 
obtained from the subject before any activity or procedure is undertaken that is not part of routine 
care. 
According to the Declaration of Helsinki and ICH GCP, subjects must provide their written 
informed assent or consent prior to enrollment in a clinical study and before any protocol-specified 
procedures are performed. Subjects must declare their consent by personally signing and dating 
the ICF. The written ICF will embody the elements of informed consent and/or assent as described 
in the Declaration of Helsinki and will also comply with local regulations.  
Each subject should be made aware by the investigator of the nature of the study (objectives, 
methods, and potential hazards and benefits) and the procedures involved, using the information 
on the ICF. Information should be given in both oral and written form whenever possible and 
deemed appropriate by the IRB/IEC. Subjects, their relatives, or, if necessary, legal representatives 
must be given ample opportunity to inquire about details of the study.  
Subject information and the ICF must be in a language fully comprehensible to the prospective 
subject. The written information must be provided to the subject to give him or her sufficient time 
to understand the information and to prepare questions before being asked for his or her consent. 
The investigator must confirm that the text was understood by the subject. The subject will then 
sign and date the IRB/IEC-approved consent form indicating that he or she has given his or her 
consent to participate in the study. The signature confirms that the consent is based on information 
that has been understood. The form will also be signed by the investigator obtaining the consent 
and annotated with the study subject number. Each subject’s signed ICF must be kept on file by 
the investigator for possible inspection by regulatory authorities, Mayne Pharma LLC, and/or the 
sponsor’s designee. Collection of informed consent and/or assent has to be documented in the 
eCRF. 
Furthermore, the subject will be informed that if he or she wishes to dropout or withdraw (see 
Section 8.3) at any time during the study, this will not have any negative consequences. Subjects 
may be withdrawn by the investigator if any change related to safety or ethics precludes further 
participation in the study. Subjects will be asked to agree to a final assessment in the event of an 
early termination of the study. 
Subjects will be informed that data from their case may be stored in a computer without inclusion 
of their name and that such data will not be revealed to any unauthorized third party. Data will be 
reviewed by the monitor, an independent auditor, and possibly by representatives of regulatory 
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authorities and/or IRBs/IECs. The terms of the local data protection legislation will be applied as 
appropriate. 
16.3. Approval by Institutional Review Board and Independent Ethics Committee 
A valid IRB/IEC must review and approve this protocol before study initiation. Written 
notification of approval is to be provided by the investigator to the sponsor’s or the sponsor’s 
representative before shipment of investigational drug supplies, and will include the date of the 
committee’s approval and the chairperson’s signature. This written approval must follow local 
country requirements. 
Until written approval by the IRB/IEC has been received by the investigator, no subject may 
undergo any procedure not part of routine care for the subject’s condition. 
Protocol amendments must also be reviewed and approved by the IRB/IEC. Written approval from 
the IRB/IEC, or a designee, must be received by Mayne Pharma LLC before implementation.  
16.4. Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator 
and the sponsor. 
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17. REFERENCES 
1. Vahlquist A, Blockhuys S, Steijlen P, 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 Derm. 2014;170(1):173-181. 
2. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited 
ichthyoses: results of the first ichthyosis consensus conference in sorèze 2009. J Am Acad 
Dermatol. 2010;63(4):607–-641. 
3. Vahlquist A, Gånemo A, Virtanen M. Congenital ichthyosis: an overview of current and 
emerging therapies. Acta Derm Venereol. 2008;88(1):4–14. 
4. Blanchet-Bardon C, Nazzaro V, Rognin C, Geiger JM, Puissant A. Acitretin in the 
treatment of severe disorders of keratinization. J Am Acad Dermatol. 1991;24(6):982–986. 
5. Kullavanijaya P and Kulthanan K. Clinical efficacy and side effects of acitretin on the 
disorders of keratinization: a one-year study. J Dermatol. 1993;20:501–506. 
6. Lacour M, Nikhar-Mehta B, Atherton DJ, Harper JI. An appraisal of acitretin therapy in 
children with inherited disorders of keratinization. Br J Dermatol. 1996;134:1023–1029. 
7. Steijlen PM, Van Dooren-Greebe RJ, Van De Kerkhof PCM. Acitretin in the treatment of 
lamellar ichthyosis. Br J Dermatol. 1994;130(2):211–214. 
8. Katugampola RP, Finlay AY. Oral retinoid therapy for disorders of keratinization: single-
centre retrospective 25 years’ experience on 23 patients. Br J Dermatol. 
2006;154(2):267-276. 
9. Gånemo A, Virtanen M, Vahlquist A. Improved topical treatment of lamellar ichthyosis: a 
double‐blind study of four different cream formulations. Br J Derm. 1999;141(6):1027–
1032. 
10. Kiistala R, Lauharanta J, Kanerva L. Transepidermal water loss and sweat gland response 
in lamellar ichthyosis before and during treatment with etretinate: report of three cases. 
Acta Derm Venereol. 1982;62(3):268–270. 
11. Ramirez ME, Youseef WF, Romero RG. Acute percutaneous lactic acid poisoning in a 
child. Pediatr Dermatol. 2006;23(3):282–285. 
12. Chiaretti A, Wismayer DS, Tortorolo L, Piastra M, Polidori G. Salicylate intoxication using 
a skin ointment. Acta Paediatr. 1997;86(3):330-331. 
13. Marukian NV, Deng Y, Gan G, et al. Establishing and validating an ichthyosis severity 
index. J Invest Dermatol. 2017;137(9):1834-1841. 
14. Korteweg SFS, Stenekes MW, van Zyl FE, Werker PMN. Paralytic ectropion treatment 
with lateral periosteal flap canthoplasty and introduction of the ectropion severity score. 
Plast Reconstr Surg Glob Open. 2014;2(5):e151. 
 
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18. ATTACHMENTS 
18.1. Investigator’s Agreement 
 
PROTOCOL NUMBER: 
18-ICH-001 
PROTOCOL TITLE: 
A Phase 2 Randomized, Multi-center, Double-blind, 
Vehicle-controlled, 12-Week, Safety, Efficacy, and Systemic 
Exposure Study followed by a 12-Week Open-label Extension of 
Trifarotene (CD5789) Cream HE1 in Adults and Adolescents with 
Autosomal Recessive Ichthyosis with Lamellar Scale 
AMENDMENT 1 DATE: 
28-Jun-2019 
The undersigned acknowledges possession of and has read the product information 
(e.g., investigator’s brochure) on the IP and has discussed these data with the study monitor. 
Having considered fully all the available information, the undersigned considers that it is ethically 
justifiable to give the IP to selected subjects in his/her care, according to the study protocol. 
He or she agrees to use the study material, including IP, only as specified in the protocol. He or 
she understands that changes cannot be made to the protocol without prior written approval of 
Mayne Pharma LLC. 
He or she understands that any deviation from the protocol may lead to early termination of the 
study. 
He or she agrees to report to Mayne Pharma LLC within time any clinical AE or abnormal 
laboratory value that is serious, whether or not considered related to the administration of IP. 
He or she agrees to comply with Mayne Pharma LLC and regulatory requirements for the 
monitoring and auditing of this study. In addition, he or she agrees that the study will be carried 
out in accordance ICH, the Declaration of Helsinki, and the local laws and regulations relevant to 
the use of new therapeutic agents. 
I, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the study. 
Principal Investigator: 
 
Printed Name: 
 
 
 
Signature: 
 
 
 
Date: 
 
 
 
Investigator’s name and address (stamp) 
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APPENDICES 
A. Regulations and Good Clinical Practice Guidelines 
 
 
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A. Regulations and Good Clinical Practice Guidelines 
1. Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
Refer to the following European Directives (and applicable regulations/guidances): 
• European Directive 2001/20/EC and related guidance documents 
• European Directive 2005/28/EC and related guidance documents> 
2. Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URLs: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf 
 
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PROTOCOL/CLINICAL INVESTIGATION PLAN 
PRODUCT NAME/NUMBER: 
Trifarotene (CD5789) Cream HE1 
PROTOCOL NUMBER: 
18-ICH-001
IND NUMBER: 
<IND Number>
NCT NUMBER:  
NCT03738800
EUDRACT NUMBER: 
2018-003272-12
DEVELOPMENT PHASE: 
2
PROTOCOL TITLE: 
A Phase 2 Randomized, Multicenter, Double-blind, 
Vehicle-controlled, 12-Week, Safety, Efficacy, and 
Systemic Exposure Study followed by a 12-Week 
Open-label Extension of Trifarotene (CD5789) Cream HE1 
in Adults and Adolescents with Autosomal Recessive 
Ichthyosis with Lamellar Scale  
PROTOCOL DATE: 
Final v1.0, 28-Nov-2018 
COORDINATING/PRINCIPAL 
INVESTIGATOR: 
Keith A. Choate, MD 
Department of Dermatology, Yale University School of 
Medicine,  
PO Box 208059 
333 Cedar Street 
New Haven, CT 06520, USA 
phone: +1 203 789 1249 
SPONSORED BY: 
Mayne Pharma LLC 
1240 Sugg Parkway   
Greenville, NC 27834, USA  
+1 984 242 1400
CONTRACT RESEARCH 
ORGANIZATION: 
Premier Research  
One Park Drive, Suite 150 
Durham, NC 27709, USA 
+1 919 627 9100
This study will be performed in compliance with ICH Good Clinical Practices and applicable 
regulatory requirements, including the archiving of essential documents. Information contained in 
this protocol is confidential in nature and may not be used, divulged, published, or otherwise 
disclosed to others except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. Persons to whom this information 
is disclosed should be informed that it is confidential and may not be further disclosed without the 
express permission of Mayne Pharma LLC. 
· pharma 
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Mayne Pharma LLC 
Protocol 18-ICH-00 I 
1. 
APPROVAL SIGNATURES 
PROTOCOL NUMBER: 
18-ICH-001 
Confidential 
PROTOCOL TITLE: 
A Phase 2 Randomized, Multi-center, Double-blind, 
Vehicle-controlled, 12-Week, Safety, Efficacy, and Systemic 
Exposure Study followed by a 12-Week Open-label Extension of 
Trifarotene (CD5789) Cream HEl in Adults and Adolescents with 
Autosomal Recessive Ichthyosis with Lamellar Scale 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge, it 
accurately describes the planned conduct of the study. 
SIGNATURE: 
Ilana Stancovski, PhD 
Chief Scientific Officer 
Mayne Pharma LLC 
(.DocuSigned by: 
I r.....__~ 
l(J 
'Iiti~;1,!;)107AF875E4CE 
Associate Director, Clinical Operations 
Mayne Pharma LLC 
(
DocuSigned by: 
I 7-r~""" 
ll(J 
Signer Name: Joyce Rico 
Signing Reason: I approve this document 
Signing Time: 29-Nov-2018I15:33 EST 
C§(I 
51 8 
Joyce K1co, MD, F AAD 
Consultant Medical Expert 
Premier Research 
{ 
DocuSigned by: 
I ~.,.,,,._,_t-,....._ 
l(J 
Signer Name: Adrienne Kuxhausen 
b
Signing Reason: I approve this document 
_ 
Signing Time: 29-Nov-20161 09:39 EST 
Ad . 
6E6!jlj7C6B9~740819F26B8O5~7gll}ii'CF 
nenne .l.\.uxnausen, 1v1;:, 
Senior Biostatistician 
Premier Research 
28-Nov-2018 
AD-MW-07.06 08-Dec-2017 
DATE: 
Final vl.0 
Page 2 of92 
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Protocol 18-ICH-001 
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2. PROTOCOL SUMMARY 
2.1. Synopsis 
PRODUCT 
NAME/NUMBER 
Trifarotene (CD5789) Cream HE1 
PROTOCOL 
NUMBER 
18-ICH-001 
EUDRACT 
NUMBER 
2018-003272-12 
DEVELOPMENT 
PHASE 
2 
PROTOCOL TITLE 
A Phase 2 Randomized, Multi-center, Double-blind, Vehicle-controlled, 12-Week, 
Safety, and Efficacy, and Systemic Exposure Study followed by a 12-Week Open-label 
Extension of Trifarotene (CD5789) Cream HE1 in Adults and Adolescents with 
Autosomal Recessive Ichthyosis with Lamellar Scale  
INDICATION 
Lamellar ichthyosis 
OBJECTIVES 
Primary: To compare the safety and efficacy of 2 concentrations of trifarotene cream HE1 
versus vehicle in adults and adolescents with moderate to severe autosomal recessive 
ichthyosis with lamellar scale, also known as lamellar ichthyosis (LI) after 12 weeks of 
treatment. 
Secondary:  
• 
To assess systemic exposure to trifarotene and its major metabolites after topical 
application of the investigational product (IP) on up to 90% body surface area (BSA) 
twice weekly. 
• 
To assess safety for up to 24 weeks of dosing with open-label trifarotene cream HE1 
200 µg/g. 
STUDY DESIGN 
This is a 2-cohort, multicenter study in subjects with moderate to severe LI (i.e., 3–4 on 
a 5-point Visual Index for Ichthyosis Severity (VIIS) for scaling where 0 = clear and 4 = 
severe) on at least 2 areas of the 4 body areas assessed (chest/abdomen, back, arms, and 
legs). Adults (Cohort A) and adults and adolescents (Cohort B) will be randomized in a 
double-blind fashion to 1 of 2 doses of trifarotene cream HE1 or vehicle and treated twice 
weekly for 12 weeks. Subjects who complete the randomized, Double-blind Period of the 
study will be eligible to enter a 12-week, Open-label Extension (OLE) Period in which 
additional PK, safety, and efficacy data will be collected. 
Approximately 15 adults (≥18 years old) will be randomized into the first cohort of 
subjects (Cohort A) in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g, trifarotene cream 
HE1 200 µg/g, or vehicle and treated twice weekly for up to 12 weeks. After the initial 
15 subjects complete at least 28 days of treatment, an independent Data Safety Monitoring 
Board (DSMB) will review aggregate safety and tolerability data. If no safety issues are 
identified, both adults and adolescents (ages 12 to 17 years, inclusive) will be allowed to 
enroll in Cohort B. Subjects in Cohort B will be randomized 1:1:1 to trifarotene cream 
HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle and treated twice weekly for 
up to 12 weeks in the same manner as subjects in Cohort A.  
All subjects who complete the 12-week Double-blind Treatment Period will be eligible 
to enroll in the 12-week OLE Period. Subjects in the OLE will receive open-label 
trifarotene cream HE1 200 µg/g twice weekly for up to 12 weeks. 
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After Screening, eligible subjects for Cohort A and B will enter a washout period of up 
to 35 days, during which they must stop using the following prohibited medications: 
a. 
Topical treatments 
Medication 
Washout Period 
Corticosteroids (except inhaled and ophthalmic corticoids) 
2 weeks 
Retinoids (e.g., tretinoin, tazarotene) 
4 weeks 
Vitamin D analogues 
2 weeks 
Immunosuppressants (e.g., tacrolimus) 
2 weeks 
Antracen derivatives, tar and salicylic preparations 
2 weeks 
Keratolytics (such as urea, lactic acid, propylene glycol, 
salicylic acid) except keratolytic shampoo 
- 
b. Systemic treatments 
Medication 
Washout Period 
Retinoids 
8 weeks 
Oral Vitamin A supplementation more than 3500 IU per day 
2 weeks 
Medication interfering with bone activity, e.g., corticosteroids, 
thyroid hormones, cytotoxics, bisphosphonates, calcitonins, 
tetracyclines, quinolones, thiazides, salicylates in long-term 
course, heparin, theophylline, barbiturates, colchicines (except 
Vitamin D analogues taken at stable dose since at least 1 month) 
8 weeks 
QT prolonging drugs 
5 half lives 
Enzymatic inductors (such as rifampicine, phenytoin, 
carbamazepine, phenobarbital, St. John’s Wort) 
3 months 
CYP2C9 and 2C8 inhibitors (not all inclusive: gemfibrozil, 
fluconazole, fluvoxamine, sulfaphenazole, miconazole, 
amiodarone, sertraline, sulfamethoxazole, valproic acid, 
voriconazole, trimethoprim, rosiglitazone, pioglitazone) 
5 half lives 
Study drug will be packaged in 50-g tubes from which up to 36 g of investigational 
product (IP) may be dispensed per application, i.e., the maximum dose per application. 
Study staff will apply the first dose of study drug to each subject in the clinic on Day 1 
after Baseline measurements, and will record the amount of study drug applied.  
Thereafter, each subject will apply approximately the same amount (up to 36 g) of study 
drug as for the first dose on up to 90% of BSA twice weekly, sparing the scalp, inguinal, 
and axillary areas. Subjects will receive an adequate number of tubes to use 1 tube per 
application and will use a new tube for each treatment day. Subjects may use less than the 
full amount of product in a tube. Subjects will record the date and time of study treatment 
administration in the subject diary. 
Local tolerability may differ in subjects with LI compared to healthy subjects, as their 
skin is drier and may be more sensitive. Local tolerability will be followed very carefully 
during the study. Subjects will receive information on study drug use and stopping rules 
and will be instructed to contact the site with any safety/tolerability issues. Study 
personnel will telephone subjects in between scheduled visits (i.e., at Day 7 and Day 45 
in the Double-blind Period; at Day 97 and 134 in the OLE Period) to assess safety; an 
unscheduled clinic visit may be performed, if necessary. During all clinic visits, the 
investigator will assess local tolerability (Scale: 0–3 [none, mild, moderate, severe] for 
stinging/burning, pruritus, erythema) on each body area (chest/abdomen, back, arms, and 
legs) and the following procedures will be followed: 
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- 
If a score of 2 (moderate) is recorded on a local tolerability assessment scale 
(stinging/burning, pruritus, erythema) on any treated area, the study drug will be 
applied on that area only once weekly, until the score is back to <2; 
- 
If a score of 3 (severe) is recorded on a local tolerability assessment scale 
(stinging/burning, pruritus, erythema) on any treated area, the study drug will not 
be applied on that area until the score is back to <3. 
Stopping rules and treatment modification will be defined at the subject level based on 
local tolerability, selected laboratory parameters, and adverse events (AEs). 
All subjects will be provided with diaries in which to record study drug application 
(days/times and any areas of skin not treated [e.g., due to local reactions]) and any AEs, 
including application site reactions and concomitant medications used. Subjects will also 
be advised on permitted emollient(s) use on nontreatment days during the study; use of 
emollient(s) on study drug treatment days within 4 hours of study drug application is 
prohibited. 
Photographs will be taken at Baseline, Day 30 and Day 90 at selected sites with 
photographic capability for subjects who sign a separate photographic informed consent 
form (ICF). 
Samples for pharmacokinetic (PK) analysis will be drawn from all subjects at Baseline 
and at each clinic visit.   
In addition, a PK substudy is to be conducted at a limited number of sites. Participation 
in the PK substudy will be optional and will include at least 30 subjects, 15 adults and 
15 adolescents. Subjects who participate in the PK substudy will come from both study 
cohorts and will undergo serial blood sampling predose and at 1, 2, 4, 8, 12, and 24 hours 
postdose on Day 1 and Day 30. Trough levels will be drawn for these subjects at each of 
the other clinic visits.  
Subjects who complete the Double-blind Treatment Period will have the option to 
continue into the OLE to assess safety for an additional 12-weeks with trifarotene cream 
HE1 200 µg/g twice weekly, on up to 90% of BSA, sparing the scalp, inguinal, and 
axillary areas. During the OLE Period, subjects will return to the site at Weeks 14, 16, 20, 
24, and 26 for safety, tolerability, and efficacy assessments. Blood samples will be drawn 
for clinical laboratory safety tests and PK at Weeks 16 and 24. Study personnel will 
telephone subjects in between scheduled visits (i.e., at Day 97 and Day 134) to assess 
safety; an unscheduled clinic visit may be performed, if necessary.  
PLANNED 
NUMBER OF 
SUBJECTS 
Approximately 120 total subjects; 15 adult subjects in Cohort A and 105 adult and 
adolescent subjects in Cohort B. 
STUDY ENTRY 
CRITERIA 
Inclusion criteria:  
1. For Cohort A: subject is ≥18 years old; for Cohort B: subject is ≥12 years old.  
2. Subject has known diagnosis of LI.  
3. Subject has moderate to severe (VIIS 3-4) LI on at least 2 of the 4 body areas 
assessed (chest/abdomen, back, arms, and legs).  
4. Subject has signed an ICF at Screening before any investigational procedures. 
Subjects <18 years of age (or Age of Majority) must sign an assent form in 
conjunction with an ICF signed by the parent/legal representative. 
5. Subject who is participating in photography has signed a photography ICF. 
6. Subject who is participating in the optional PK substudy has signed a PK ICF. 
7. Subject is not of childbearing potential, i.e., a female who has not yet begun 
menstruating or who is postmenopausal (absence of menstrual bleeding for 1 year 
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before Baseline, without any other medical reason, hysterectomy or bilateral 
oophorectomy),  
OR  
• 
Subject is a woman of childbearing potential (WOCBP) or a male subject with sexual 
partners capable of reproduction who agrees to use 2 effective forms of contraception 
during the study and for at least 1 month after the last study drug application. The 
2 authorized forms of contraception are condom used with 1 of the following 
methods of contraception: 
• bilateral tubal ligation 
• combined oral contraceptives (estrogens and progesterone) or implanted or 
injectable contraceptives with a stable dose for at least 1 month before Baseline 
• hormonal intrauterine device (IUD) inserted at least 1 month before Baseline 
OR 
Agrees to abstain from sex during study participation and for 1 month after the last 
application of study drug and to use a highly effective contraceptive as backup if he 
or she becomes sexually active during the study. 
AND 
Male subjects may not donate sperm during the study and for at least 1 month after 
the last study drug application. 
Note: Subjects who are premenstrual at Screening but begin menses during the study 
should follow the pregnancy testing schedule for WOCBP and must abstain from 
sexual intercourse while in the study and for at least 1 month after the last study drug 
application. 
8. Women of child-bearing potential must be nonlactating and have negative pregnancy 
test results at Screening (serum) and on Day 1 before study drug administration 
(urine). 
9. Subject is reliable and capable of adhering to the protocol and visit schedule, in the 
investigator’s judgment, and has signed informed consent/assent, as applicable. 
10. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin). 
 
Exclusion criteria: 
1. Subject has any variant of ichthyosis other than LI or another disorder of 
keratinization including syndromic ichthyoses.  
2. Subject has a history of or current moderate or severe stinging/burning at Screening. 
3. Subject has an ongoing cutaneous infection or any other significant concomitant skin 
disease (other than the LI) which, in the investigator’s opinion, may interfere with 
the study assessments. 
4. Subject with a known lipid disorder unless well controlled by stable doses of 
lipid-lowering agents for at least 6 months. 
5. Subject was previously treated with trifarotene/CD5789, including the acne 
formulation, or participated in previous studies for ichthyosis.  
6. Subject has known skeletal disease, hypertriglyceridemia, hypercholesterolemia, 
liver disease, or other poorly controlled medical conditions.  
7. Subject has a medical condition that potentially alters bone metabolism (e.g., 
osteoporosis, thyroid dysfunction, Cushing syndrome), Crohn’s disease, or any other 
significant concomitant disease other than LI that, in the investigator’s opinion, may 
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put him or her at risk if he or she takes part in the study, and/or that may interfere 
with the study assessments. 
8. Subject is being treated for major depression disorder. 
9. Subject with positive serology for hepatitis B surface antigen, hepatitis C, or are 
known to be HIV positive or to have AIDS at Screening. 
10. Subject with any of the following laboratory values at Screening: 
a. 
Aspartate aminotransferase or alanine aminotransferase >1.5 × upper limit 
of normal defined by the laboratory 
b. Triglycerides >200 mg/dL 
c. 
Total cholesterol >250 mg/dL 
d. Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women 
e. 
Platelets <150 × 109/L or >400 × 109/L. 
11. Subject has any clinically other significant abnormal laboratory value (hematology, 
chemistry, or urinalysis) at Screening that, in the investigator’s opinion, may put the 
subject at risk if he or she takes part in the study, and/or that may interfere with the 
study assessments. 
12. Subject has a history of long QT syndrome or clinically significant electrocardiogram 
(ECG) abnormalities, including clinically significant conduction disorders or 
significant arrhythmias, QTcF interval >450 ms, PR interval is not between 120 and 
220 ms (inclusive), HR >100 bpm or <50 bpm, QRS interval >110 ms, or QT 
intervals that cannot be consistently analyzed. 
13. Subject has a known allergy or sensitivity to any of the components of the 
investigational products.  
14. Subject has been exposed to excessive ultraviolet (UV) radiations on the treated 
zones within 1 month before Baseline visit or who is planning intensive UV exposure 
during the study (e.g., occupational exposure to the sun, sunbathing, phototherapy, 
etc.). 
15. Subject is inherently sensitive to sunlight. 
16. Subject is presumed to be abusing drugs or alcohol at Screening or Baseline Visits 
based on medical history or current clinical symptoms. 
17. Subject is participating in another interventional clinical trial. 
INVESTIGATIONAL 
PRODUCT 
Name: Trifarotene (CD5789) cream HE1  
Double-blind Period dose, route, frequency: A fixed dose (up to 36 g per dose, determined 
at Visit 2) of 100 µg/g or 200 µg/g applied topically twice weekly on up to 90% BSA  
Open-label Period dose, route, frequency: A fixed dose (up to 36 g per dose, determined 
at Visit 2) of 200 µg/g applied topically twice weekly on up to 90% BSA 
REFERENCE 
PRODUCT(S) 
Name: Vehicle cream 
Double-blind Period dose, route, frequency: A fixed dose (up to 36 g per dose, determined 
at Visit 2) applied topically twice weekly on up to 90% BSA  
TREATMENT 
REGIMENS 
Topical application twice weekly to all affected skin except the scalp, axillae, and inguinal 
area.   
COORDINATING/ 
PRINCIPAL 
INVESTIGATOR 
Keith A. Choate, MD 
Department of Dermatology, Yale University School of Medicine 
New Haven, CT 06520, USA 
PLANNED STUDY 
SITES 
Approximately 40 sites across North America, Europe, Israel, and Australia 
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CRITERIA FOR 
EVALUATION 
Primary efficacy endpoint: The number of subjects in each treatment group who 
experience successful resolution of LI where “success” is defined as clear/almost clear 
overall and at least a 50% reduction from Baseline at Week 12/end-of-treatment (EOT) 
in the Double-blind Period on the overall 16-point VIIS for scaling (i.e., 0-4 points on 
each of the 4 body areas: chest/abdomen, back, arms, and legs).  
Secondary endpoints:  
• 
The difference in mean scores between the active trifarotene cream HE1 and 
vehicle groups in the following assessment indices: 
− 
Investigator’s Global Assessment (0-4) for each body area 
− 
Palm/sole Assessment (Scale: 0–4)  
− 
Individual score for roughness (Scale: 0–4) overall 
• 
Quality of life per Dermatology Life Quality Index (DLQI) 
• 
The difference in proportion of subjects with presence of fissures 
(presence/absence, number of fissures, and pain associated with fissures on a 
0-3 scale) between the active trifarotene cream HE1 and vehicle groups 
Exploratory endpoints:  
• 
The difference in mean ectropion (Ectropion Severity Score [ESS] of 0–8) scores 
between the active trifarotene cream HE1 and vehicle groups 
• 
Quality of life per EQ-5D-5L 
Safety endpoints:  
• 
Reported serious adverse events (SAEs), treatment-emergent AEs (TEAEs), 
and changes in clinical laboratory tests, vital signs, physical examinations, and 
12-lead ECGs  
• 
Local tolerability (Scale: 0–3 [none, mild, moderate, severe], determined by 
the investigator) on each of the 4 body areas (chest/abdomen, back, legs, arms) 
Pharmacokinetic endpoints: Plasma concentrations of CD5789 and its major metabolites 
will be measured. 
STATISTICAL 
METHODS 
Analysis Populations:  
The following are planned for the Double-blind Period of the study: 
The Safety population will be the primary population for analyses of safety and 
tolerability and will comprise all subjects who are randomized to treatment and receive at 
least 1 application of study drug.  
The intent-to-treat (ITT) population will comprise all randomized subjects. 
The modified intent-to-treat (mITT) population comprises all subjects in the safety 
population with at least 1 postbaseline assessment of efficacy in the Double-blind Period. 
This population will be used as the primary population for the analysis of efficacy for the 
Double-blind Period of the study. 
The per protocol (PP) population will be defined prior to database lock and will comprise 
subjects in the mITT population who met all inclusion criteria and no exclusion criteria, 
were compliant with study drug application, and who had no significant protocol 
deviations.  
The PK population includes all subjects in the Safety Population who have at least 
1 plasma sample with quantifiable concentration. The PK population will be used to 
summarize all PK endpoints. 
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The following populations are planned for the OLE period of this study: 
The OLE Safety population: all subjects who complete the 12-week Double-blind 
Treatment Period and receive at least 1 application of study drug in the OLE Period. 
OLE ITT population: all subjects who complete the 12-week Double-blind Period and 
who sign the OLE informed consent. 
The OLE mITT population: all subjects in the OLE safety population with at least 
1 assessment of efficacy after Visit 6. 
The OLE PP population: all subjects in the OLE mITT population who met all inclusion 
criteria and no exclusion criteria, were compliant with study drug application from 
baseline through EOT, and who had no significant protocol deviations throughout the 
study. 
Subject Characteristics and Disposition: Descriptive statistics will be used to summarize 
demographic characteristics (age, sex, ethnicity, and race) and baseline characteristics for 
all enrolled subjects. Medical history, physical examination findings, and vital sign 
measurements for all randomized subjects will be presented in listings. 
Efficacy Analyses: The number and proportion of subjects in each treatment group with 
successful resolution of LI by Week 12/EOT in the Double-blind Period will be presented. 
Generalized estimating equations (GEE) for binary response will be used to model the 
odds of successful resolution of LI with treatment group as a predictor. Other covariates, 
such as baseline VIIS scores, baseline characteristics, and interactions may be included. 
Various correlation matrix structures will be explored to model the within subject 
correlation. Additionally, the difference in mean VIIS score at Week 12/EOT between the 
active trifarotene cream HE1 groups and vehicle group will be analyzed using a 2-sided, 
2-sample Wilcoxon rank-sum test at the 5% significance level; 95% confidence intervals 
will be presented.  
The VIIS scores as well as secondary and exploratory efficacy endpoints will be analyzed 
by visit using descriptive statistics through Week 24. Change from Baseline through 
Week 12 will be presented and analyzed using a mixed model for repeated measures 
(MMRM). The model will include the change from Baseline score as the dependent 
variable, treatment group as a fixed effect, subject as a random effect, and Baseline score 
value as a covariate. Frequencies of results and 95% confidence intervals will also be 
reported, and scores will be analyzed as categorical variables using the Cochran-Mantel-
Haenszel test. For subjects who report having fissures, the number of fissures and pain 
related to fissures will also be presented on a scale of 0–3 (none, mild, moderate, severe). 
Clinical Pharmacology Analyses: Noncompartmental PK analysis will be performed for 
the PK subset of subjects, as data permit. Plasma concentrations of CD5789 and its major 
metabolites will be measured and will be listed by subject. 
Safety Analyses: Safety and tolerability will be assessed based on the incidence of 
reported TEAEs, and SAEs, including relationship to study drug and severity, as well as 
physical examination findings, vital sign measurements (supine systolic blood pressure 
[SBP] and diastolic blood pressure [DBP] and pulse), clinical laboratory results 
(hematology, including serum aminotransferases and serum lipids, coagulation, clinical 
chemistry, and urinalysis) and 12-lead ECGs. Descriptive statistics for observed values 
and change from Baseline will be calculated at each visit within each study period and by 
treatment group within cohort. 
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SAMPLE SIZE 
DETERMINATION 
The first cohort of 15 adult subjects is a reasonable sample size to assess safety and 
tolerability before enrolling adolescents. Accounting for a 20% drop-out/nonevaluable 
rate, a total sample size of 120 subjects randomized in a 1:1:1 ratio to 2 active trifarotene 
cream HE1 arms and a vehicle cream arm will provide >80% power to detect a difference 
between each separate trifarotene cream HE1 arm (32 evaluable subjects) and the vehicle 
cream arm (32 evaluable subjects) using a 2-sample t-test assuming a mean difference of 
at least 1.0 and a standard deviation of 1.4 or lower. This study is not powered to detect a 
difference between the 2 active arms. 
STUDY AND 
TREATMENT 
DURATION 
The sequence and maximum duration of the study will be as follows:  
1. Screening and Washout: Up to 35 days (≥2 weeks washout for topical keratolytics, 
including urea and salicylic acid, and any topical retinoid or retinol [Vitamin A 
derivative], and ≥4 weeks washout for oral Vitamin A). 
2. Double-blind study drug application: Twice weekly for up to 12 weeks.  
3. Optional Open-label Treatment: Twice weekly for up to 12 weeks. 
4. Follow-up: 14 days after last study drug application. 
The maximum study duration for each subject is approximately 229 days 
(33 weeks).  
The maximum treatment duration for each subject is 24 weeks. 
 
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2.2. Schedule of Events  
Table 2-1: 
Schedule of Events for Double-blind Period 
 
Double-blind Treatment Period 
 
Screening 
(-35 days to -1 day) 
Baseline  
(Day 1) 
Telephone 
Visit 
(Day 7) 
Day 14  
± 5 days 
Day 30  
± 7 days 
Telephone 
Visit 
(Day 45) 
Day 60  
± 7 days 
Day 90a,b 
± 7 days (ET) 
Visit 
1 
2 
 
3 
4 
 
5 
6 
Week 
 
1 
 
2 
4 
 
8 
12 
Written informed consent/assent  
X 
 
 
 
 
 
 
Xa 
Assign screening number 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
Physical examinationc  
X 
X 
 
 
 
 
 
X 
VIISd assessment 
X 
X 
 
X 
X 
 
X 
X 
Assign randomization number 
 
X 
 
 
 
 
 
 
IGA assessment 
X 
X 
 
X 
X 
 
X 
X 
Palm/sole assessment 
X 
X 
 
X 
X 
 
X 
X 
Roughness, fissuring assessmente 
X 
X 
 
X 
X 
 
X 
X 
Ectropion score  
X 
X 
 
X 
X 
 
X 
X 
Photographsf 
 
X 
 
 
X 
 
 
X 
Quality of life per Dermatology Life 
Quality Index (DLQI) 
 
X 
 
X 
X 
 
X 
X 
EQ-5D-5L Quality of Life Questionnaire 
 
X 
 
X 
X 
 
X 
X 
Vital signs (blood pressure and pulse)  
X 
X 
 
X 
X 
 
X 
X 
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Double-blind Treatment Period 
 
Screening 
(-35 days to -1 day) 
Baseline  
(Day 1) 
Telephone 
Visit 
(Day 7) 
Day 14  
± 5 days 
Day 30  
± 7 days 
Telephone 
Visit 
(Day 45) 
Day 60  
± 7 days 
Day 90a,b 
± 7 days (ET) 
Visit 
1 
2 
 
3 
4 
 
5 
6 
Week 
 
1 
 
2 
4 
 
8 
12 
Height, weight, and BMI  
 
X 
 
 
 
 
 
X 
12-lead ECGg 
X 
X 
 
 
X 
 
 
X 
Clinical laboratory tests (hematology, 
chemistry, urinalysis)h 
X 
X 
 
 
X 
 
 
X 
Serology (hepatitis B surface antigen, 
hepatitis C) 
X 
 
 
 
 
 
 
 
Pregnancy test for female subjects 
(serum at Screening; urine subsequently)i 
X 
X 
 
 
X 
 
X 
X 
Assign randomization number  
 
X 
 
 
 
 
 
 
PK blood sample collectionj 
 
X 
 
X 
X 
 
X 
X 
Initial study drug application by clinic 
staff and measurementk 
 
X 
 
 
 
 
 
 
Application instructions, advice on 
emollient use 
 
X 
X 
X 
X 
X 
 
 
Dispense study drug and diariesl 
 
X 
 
X 
X 
 
X 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
Tolerability assessment  
 
X 
 
X 
X 
 
X 
X 
Adverse events (and review diaries) 
 
X 
X 
X 
X 
X 
X 
X 
Collect all used/unused study drugm 
 
 
 
X 
X 
 
X 
X 
Provide information about OLE option 
 
 
 
 
X 
X 
X 
 
Abbreviations: BMI = body mass index; DLQI = Dermatology Life Quality Index; ECG = electrocardiogram; ET = early termination; HEENT = head, eyes, ears, 
nose, throat; ICF = informed consent form; IGA = Investigator Global Assessment; OLE = open-label extension; PK = pharmacokinetic; WOCBP = women of 
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childbearing potential; VIIS = Visual Index for Ichthyosis Severity 
a. 
Day 90 procedures should be conducted for subjects who terminate the study early. If a subject discontinues IP, but continues to attend clinic visits, Day 90 
will occur as scheduled. Day 90/Week 12 will be the first visit of the OLE Period for subjects who choose to continue (subjects will have up to 7 days to 
decide to sign the ICF and begin the OLE). Subjects who decide to continue into the OLE will have the following additional procedures: 1) sign informed 
consent; 2) will be weighed; 3) will be instructed on study drug application; 4) will be given new diaries, and 5) will be provided with study drug. 
b. A Follow-up telephone call will be made within 14 days after Day 90 to subjects who choose not to continue into the Open-label Extension. 
c. 
Limited physical examination to include HEENT, cardiorespiratory, abdomen, range of motion.  
d. VIIS: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe for each of 4 body areas: chest/abdomen, back, arms, and legs (possible overall score 
= 16). 
e. 
Roughness (0-4 scale); fissuring assessment: present/absent/number/pain (0-3 scale). 
f. 
Photography will be performed at sites with the capability among subjects who sign a photographic ICF. 
g. ECG to be conducted at Screening, Baseline, Day 30, and Day 90 for all subjects.  
h. Subjects must be fasting (i.e., at least 8 hours) 
i. 
Note: Subjects who are premenstrual at Screening but begin menses during the course of the study should follow the pregnancy testing schedule for WOCBP 
correlating to the visit menses began. 
j. 
Samples for PK will be drawn from all subjects at Baseline and at each clinic visit. At selected sites among subjects who consent to participate in the PK 
substudy, samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1. On Day 30, IP will be applied in the clinic for PK substudy 
subjects, and PK samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose. Trough levels will be drawn when the subjects are in the clinic 
for other study visits (i.e., Day 14, Day 60, and Day 90). 
k. Study staff will apply initial dose of study drug in the clinic after Baseline measurements, and the amount of study drug used will be measured (i.e., 36-g 
tube will be measured before and after application to determine amount used) to determine fixed dose. 
l. 
Study drug provided in 50-g tubes (maximum single application is 36 g). Measure study drug tubes before dispensing; subjects must record days/times of 
study drug application in the diaries and any areas of skin not treated, e.g., due to local reactions). Dispense enough additional study drug until next visit 
(except at Day 90, unless subject consents to continue into OLE). 
m. Confirm study drug compliance by measuring tube weight and reviewing diary.  
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Table 2-2: 
Schedule of Events for Open-label Extension  
 
Open-label Treatment Period 
Follow-up 
 
Telephone 
Visit 
(Day 97)a 
Day 104  
± 5 days 
Day 120  
± 7 days 
Telephone 
Visit 
(Day 134) 
Day 150 
± 7 days 
Day 180  
± 7 days/ET 
Day 194 or 14 days 
after End of 
Open-label Treatment 
Visit 
 
7 
8 
 
9 
10 
11 
Week 
 
14 
16 
 
20 
24 
26 
Informed consenta 
 
 
 
 
 
 
 
Physical examinationb 
 
 
 
 
 
X 
X 
ECG 
 
 
X 
 
 
X 
 
VIISd assessment 
 
X 
X 
 
X 
X 
X 
IGA assessment 
 
X 
X 
 
X 
X 
X 
Palm/sole assessment 
 
X 
X 
 
X 
X 
X 
Roughness, fissuring assessmentd 
 
X 
X 
 
X 
X 
X 
Ectropion score  
 
X 
X 
 
X 
X 
X 
Vital signs (blood pressure and 
pulse)  
 
X 
X 
 
X 
X 
X 
Clinical laboratory tests (hematology, 
chemistry, urinalysis)e 
 
 
X 
 
 
X 
 
Pregnancy test for female subjects 
(urine)f 
 
 
X 
 
X 
X 
X 
PK blood sample collectiong 
 
 
X 
 
 
X 
 
Application instructions, advice on 
emollient useh 
X 
X 
X 
X 
 
 
 
Dispense study drug and diariesi 
 
X 
X 
 
X 
 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
Tolerability assessment  
 
X 
X 
 
X 
X 
 
Adverse events (and review diaries) 
X 
X 
X 
X 
X 
X 
X 
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Open-label Treatment Period 
Follow-up 
 
Telephone 
Visit 
(Day 97)a 
Day 104  
± 5 days 
Day 120  
± 7 days 
Telephone 
Visit 
(Day 134) 
Day 150 
± 7 days 
Day 180  
± 7 days/ET 
Day 194 or 14 days 
after End of 
Open-label Treatment 
Visit 
 
7 
8 
 
9 
10 
11 
Week 
 
14 
16 
 
20 
24 
26 
Collect all used/unused study drugj  
 
X 
X 
 
X 
X 
 
Abbreviations: ECG = electrocardiogram; ET = early termination; HEENT = head, eyes, ears, nose, throat; IGA = Investigator Global Assessment; PK = 
pharmacokinetic; VIIS = Visual Index for Ichthyosis Severity; WOCBP = women of childbearing potential 
a. Subjects will sign the OLE ICF at the Double-blind Day 90/Week 12 Visit or within 7 days thereafter. All efficacy assessments, safety/tolerability 
assessments, including clinical laboratory testing and PK from Day 90/Week 12 will be carried over for the OLE Period and will not be repeated.  
b. Limited physical examination to include HEENT, cardiorespiratory, abdomen, range of motion.  
c. VIIS: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe for each of 4 body areas: chest/abdomen, back, arms, and legs (possible total score = 16). 
d. Roughness (0-4 scale); fissuring assessment: present/absent/number/pain (0-3 scale). 
e. Subjects must be fasting (at least 8 hours) 
f. Note: Subjects who are premenstrual at Screening but begin menses during the course of the study should follow the pregnancy testing schedule for WOCBP 
correlating to the visit menses began. 
g. Samples for PK will be drawn from all subjects at Day 120 and Day 180. 
h. Subjects must record days/times of study drug application in the diaries and any areas of skin not treated (e.g., due to local reactions).  
i. All subjects in the open-label extension will receive trifarotene 200 µg/g. Study drug provided in 50-g tubes (maximum single application is 36 g). Measure 
study drug tubes before dispensing. Dispense enough additional study drug until the next visit (except at Day 180) 
j. Confirm study drug compliance by measuring tube weight and reviewing diary. 
 
 
 
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3. TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES ...................................................................................................2 
2. 
PROTOCOL SUMMARY ........................................................................................................3 
2.1. Synopsis ..........................................................................................................................3 
2.2. Schedule of Events ........................................................................................................11 
3. 
TABLE OF CONTENTS .......................................................................................................16 
3.1. List of In-Text Tables....................................................................................................20 
3.2. List of In-Text Figures ..................................................................................................21 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...........................................22 
5. 
INTRODUCTION ..................................................................................................................24 
5.1. Background and Rationale ............................................................................................24 
5.1.1 CD5789 (Trifarotene) ........................................................................................25 
5.2. Clinical Experience .......................................................................................................25 
5.3. Summary of Potential Risks and Benefits .....................................................................26 
6. 
OBJECTIVES .........................................................................................................................28 
6.1. Primary Objective .........................................................................................................28 
6.2. Secondary Objectives ....................................................................................................28 
7. 
STUDY DESIGN ...................................................................................................................29 
7.1. Overall Study Design and Plan .....................................................................................29 
7.2. Rationale and Discussion of Study Design ...................................................................33 
7.3. Selection of Doses in the Study ....................................................................................33 
7.4. Study Sites .....................................................................................................................33 
7.5. Point of Contact ............................................................................................................33 
7.6. End of Study Definition ................................................................................................34 
8. 
SUBJECT POPULATION .....................................................................................................35 
8.1. Selection of Study Population and Diagnosis ...............................................................35 
8.2. Study Entry Criteria ......................................................................................................35 
8.2.1 Inclusion Criteria ...............................................................................................35 
8.2.2 Exclusion Criteria ..............................................................................................36 
8.3. Premature Subject Withdrawal .....................................................................................37 
8.4. Discontinuation of Study Intervention ..........................................................................37 
8.5. Subject Replacement Criteria ........................................................................................38 
9. 
TREATMENTS ......................................................................................................................39 
9.1. Identification of Investigational Product(s) ..................................................................39 
9.2. Treatments Administered ..............................................................................................39 
9.3. Selection of Timing of Dose for Each Subject..............................................................39 
9.4. Dose Adjustment Criteria ..............................................................................................40 
9.4.1 Stopping Rules ..................................................................................................40 
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9.5. Treatment Compliance ..................................................................................................40 
9.6. Method of Assigning Subjects to Treatment Groups ....................................................41 
9.7. Blinding and Unblinding Treatment Assignment .........................................................41 
9.8. Permitted and Prohibited Therapies ..............................................................................42 
9.8.1 Permitted Therapies ...........................................................................................42 
9.8.2 Prohibited Therapies ..........................................................................................42 
9.8.3 Restrictions ........................................................................................................43 
9.9. Treatment After End of Study .......................................................................................43 
9.10. Dispensing and Storage .................................................................................................43 
9.11. Drug Accountability ......................................................................................................43 
9.12. Labeling and Packaging ................................................................................................44 
9.12.1 Labeling .............................................................................................................44 
9.12.2 Packaging ..........................................................................................................44 
10. STUDY PROCEDURES ........................................................................................................45 
10.1. Study Duration ..............................................................................................................45 
10.1.1 Overall Study Schedule .....................................................................................45 
10.2. Study Periods and Visits ...............................................................................................45 
10.2.1 Screening and Washout .....................................................................................45 
10.2.1.1 Screening Visit (Visit 1)........................................................................45 
10.2.1.2 Washout Period .....................................................................................46 
10.2.2 Double-blind Treatment Period .........................................................................46 
10.2.2.1 Baseline Visit (Visit 2, Day 1) ..............................................................46 
10.2.2.2 Telephone Visit (Day 7) ........................................................................47 
10.2.2.3 Visit 3 (Day 14 ±5 days) .......................................................................47 
10.2.2.4 Visit 4 (Day 30 ±7 days) .......................................................................48 
10.2.2.5 Telephone Visit (Day 45) ......................................................................49 
10.2.2.6 Visit 5 (Day 60 ±7 days) .......................................................................49 
10.2.2.7 Visit 6 (90 ±7 days) or Early Termination ............................................50 
10.2.3 Follow-up Telephone Call (±14 days after Day 90) – Only Subjects Who Do Not 
Continue into Open-label Extension .................................................................51 
10.2.4 Open-label Extension ........................................................................................51 
10.2.4.1 Telephone Visit (Day 97) ......................................................................51 
10.2.4.2 Visit 7 (Week 14; Day 104 ±5 days) .....................................................51 
10.2.4.3 Visit 8 (Week 16; Day 120 ±7 days) .....................................................52 
10.2.4.4 Telephone Visit (Day 134) ....................................................................52 
10.2.4.5 Visit 9 (Week 20; Day 150 ±7 days) .....................................................53 
10.2.4.6 Visit 10 (Week 24; Day 180 ±7 days) or Early Termination ................53 
10.2.4.7 Follow-up Evaluation – Open-Label Period (Week 26/Visit 11) .........54 
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10.3. Assessments ..................................................................................................................54 
10.3.1 Efficacy Variables .............................................................................................54 
10.3.1.1 Visual Index for Ichthyosis Severity – Scaling .....................................54 
10.3.1.2 Investigator’s Global Assessment .........................................................55 
10.3.1.3 Palm/Sole Assessment ..........................................................................55 
10.3.1.4 Individual Score for Roughness ............................................................56 
10.3.1.5 Fissuring Assessment ............................................................................56 
10.3.1.6 Dermatology Life Quality Index ...........................................................56 
10.3.1.7 EQ-5D Quality of Life Questionnaire ...................................................56 
10.3.1.8 Ectropion Severity Score.......................................................................56 
10.3.2 Clinical Pharmacology ......................................................................................57 
10.3.2.1 Pharmacokinetic Analysis Methods ......................................................57 
10.3.2.2 Pharmacokinetic Parameters .................................................................57 
10.3.3 Sample Collection .............................................................................................57 
10.3.4 Safety Variables ................................................................................................58 
10.3.4.1 Clinical Laboratory Safety Assessments ...............................................58 
10.3.4.2 Clinical Examinations ...........................................................................59 
10.3.4.3 Adverse Events......................................................................................60 
11. ADVERSE EVENTS..............................................................................................................61 
11.1. Definitions .....................................................................................................................61 
11.1.1 Adverse Events ..................................................................................................61 
11.1.2 Adverse Drug Reaction .....................................................................................61 
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction ........................................61 
11.1.4 Serious Adverse Events/Drug Reaction ............................................................62 
11.1.5 Significant Adverse Events ...............................................................................62 
11.1.6 Treatment-Emergent Adverse Events ...............................................................62 
11.2. Event Assessment and Follow-up of Adverse Events ..................................................62 
11.2.1 Assessment ........................................................................................................63 
11.2.2 Evaluation ..........................................................................................................64 
11.2.2.1 Severity of Adverse Events ...................................................................64 
11.2.2.2 Seriousness ............................................................................................64 
11.2.2.3 Action(s) Taken .....................................................................................64 
11.2.2.4 Outcome at the Time of Last Observation ............................................65 
11.2.2.5 Adverse Event Relationship to Investigational Product........................65 
11.2.3 Documentation ..................................................................................................65 
11.2.4 Treatment of Adverse Events ............................................................................66 
11.2.5 Follow-up ..........................................................................................................66 
11.2.6 Reporting ...........................................................................................................66 
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11.2.6.1 Serious Adverse Events.........................................................................66 
11.2.6.2 Adverse Drug Reactions .......................................................................68 
11.2.6.3 Nonserious Adverse Events ..................................................................68 
11.3. Special Considerations ..................................................................................................68 
11.3.1 Adverse Events of Special Interest ....................................................................68 
11.3.2 Pregnancy ..........................................................................................................68 
12. DATA SAFETY MONITORING BOARD ...........................................................................69 
13. STATISTICS ..........................................................................................................................70 
13.1. Statistical Analysis ........................................................................................................70 
13.1.1 Analysis Populations .........................................................................................70 
13.1.2 Study Subjects and Demographics ....................................................................71 
13.1.2.1 Disposition and Withdrawals ................................................................71 
13.1.2.2 Protocol Deviations ...............................................................................71 
13.1.2.3 Demographics and Other Baseline Characteristics ...............................71 
13.1.3 Exposure and Compliance .................................................................................72 
13.1.4 Efficacy Analysis ..............................................................................................72 
13.1.4.1 Efficacy Endpoints ................................................................................72 
13.1.4.2 Primary Analysis ...................................................................................72 
13.1.4.3 Secondary Analyses ..............................................................................73 
13.1.4.4 Exploratory Analyses ............................................................................73 
13.1.4.5 Corroborative, Sensitivity, and Other Analyses ....................................73 
13.1.5 Clinical Pharmacology Analyses .......................................................................74 
13.1.5.1 Pharmacokinetics ..................................................................................74 
13.1.6 Safety and Tolerability Analyses ......................................................................74 
13.1.6.1 Local Tolerability ..................................................................................74 
13.1.6.2 Adverse Events......................................................................................74 
13.1.6.3 Clinical Laboratory Evaluations ...........................................................75 
13.1.6.4 Vital Signs .............................................................................................75 
13.1.6.5 Twelve-lead Electrocardiograms ..........................................................75 
13.1.6.6 Physical Examination Findings .............................................................75 
13.1.7 Interim Analysis ................................................................................................75 
13.2. Sample Size Determination ...........................................................................................75 
14. STUDY CONDUCT ...............................................................................................................77 
14.1. Sponsor and Investigator Responsibilities ....................................................................77 
14.1.1 Sponsor Responsibilities ...................................................................................77 
14.1.2 Investigator Responsibilities .............................................................................77 
14.1.3 Confidentiality and Privacy ...............................................................................77 
14.2. Site Initiation .................................................................................................................78 
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14.3. Screen Failures ..............................................................................................................78 
14.4. Study Documents ..........................................................................................................78 
14.4.1 Informed Consent ..............................................................................................79 
14.4.2 Investigator’s Regulatory/Good Clinical Practice Documents .........................79 
14.4.3 Case Report Forms ............................................................................................80 
14.4.4 Source Documents .............................................................................................80 
14.5. Data Quality Control .....................................................................................................80 
14.5.1 Monitoring Procedures ......................................................................................80 
14.5.2 Data Management ..............................................................................................81 
14.5.3 Quality Assurance/Audit ...................................................................................81 
14.6. Study Termination .........................................................................................................82 
14.6.1 Regular Study Termination ...............................................................................82 
14.6.2 Premature Study Termination ...........................................................................82 
14.7. Study Site Closure .........................................................................................................83 
14.7.1 Record Retention ...............................................................................................83 
14.7.2 Sample Retention ..............................................................................................83 
14.8. Changes to the Protocol ................................................................................................84 
14.9. Use of Information and Publication ..............................................................................84 
15. FINAL CLINICAL STUDY REPORT ..................................................................................85 
16. ETHICAL AND LEGAL CONSIDERATIONS ....................................................................86 
16.1. Declaration of Helsinki and Good Clinical Practice .....................................................86 
16.2. Subject Information and Informed Consent and/or Assent ...........................................86 
16.3. Approval by Institutional Review Board and Independent Ethics Committee .............87 
16.4. Finance and Insurance ...................................................................................................87 
17. REFERENCES .......................................................................................................................88 
18. ATTACHMENTS ...................................................................................................................89 
18.1. Investigator’s Agreement ..............................................................................................89 
APPENDICES ...............................................................................................................................91 
A. 
Regulations and Good Clinical Practice Guidelines .....................................................92 
 
 
3.1. List of In-Text Tables 
Table 2-1: 
Schedule of Events for Double-blind Period .....................................................11 
Table 2-2: 
Schedule of Events for Open-label Extension ...................................................14 
Table 9-1: 
Washout Periods for Prohibited Medications ....................................................42 
Table 9-2: 
Amount of Study Drug Needed Per Visit ..........................................................44 
Table 10-1: 
Pharmacokinetic Parameters .............................................................................57 
 
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3.2. List of In-Text Figures 
Figure 7-1: 
Double-blind Study Design ...............................................................................31 
Figure 7-2: 
Open-label Study Design ...................................................................................32 
 
 
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4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABBREVIATION 
EXPLANATION 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse events of special interest 
ATC 
anatomical therapeutic chemical 
AUC 
area-under-the-curve 
BMI 
body mass index 
BSA 
body surface area 
CFR 
code of federal regulations 
CI 
confidence interval 
Cmax 
maximum concentration 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
DBP 
diastolic blood pressure 
DLQI 
dermatology life quality index 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
ESS 
ectropion severity score 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GEE 
generalized estimating equations 
HR 
heart rate 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification 
IEC 
independent ethics committee 
IGA  
Investigator’s Global Assessment 
IND 
investigational new drug 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent-to-treat 
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ABBREVIATION 
EXPLANATION 
IUD 
intrauterine device 
IWRS 
interactive web response system 
LI 
lamellar ichthyosis 
MedDRA 
medical dictionary for regulatory activities 
mITT 
modified intent-to-treat 
MMRM 
mixed model of repeated measures 
NCA 
noncompartmental analysis 
OC 
observed case 
OLE 
open-label extension 
PG 
propylene glycol 
PK 
Pharmacokinetic(s) 
PoC 
proof-of-concept 
PP 
per-protocol 
QTc 
QT interval corrected for heart rate 
RARγ 
retinoid acid receptor γ  
RBC 
red blood count 
RR 
respiratory rate 
RXR 
retinoid X receptor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
Tmax 
time of Cmax 
UAE 
unexpected adverse event 
UADR 
unexpected adverse drug reaction 
US 
United States 
UV 
ultraviolet 
VIIS 
Visual Index for Ichthyosis Severity 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
women of child-bearing potential 
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5. INTRODUCTION 
5.1. Background and Rationale 
The ichthyoses comprise a large group of skin scaling disorders with diverse etiology. The 
stereotypic pathophysiology is epidermal hyperplasia and the formation of excess stratum corneum 
accompanied by abnormal (delayed and/or disordered) desquamation, with visible accumulation 
of squames (scales) on the skin’s surface – the clinical hallmark of all the ichthyoses. 
Lamellar ichthyosis (LI) is recognized as a severe form of ichthyosis that persists throughout life. 
During the first postnatal weeks, the hyperkeratotic membrane patients are typically born with is 
gradually shed, and is replaced by scaling and lichenification that involves the entire body 
including the intertriginous areas, palms, soles, and scalp. While usually not life threatening, LI 
can result in disability, partial deafness, poor adaptation to environmental conditions (due to 
hypohydrosis), severe discomfort (pruritus, fissuring of the skin) and significant psychosocial 
impact. 
Lamellar ichthyosis, a member of the nonsyndromic autosomal recessive congenital ichthyosis 
group of ichthyoses, has an incidence of 1 per 100,000–300,000 live births.1 Lamellar ichthyosis 
is undoubtedly a rare disease. 
Therapeutic approaches for LI are mainly based on the use of topical emollients, keratolytic agents 
(urea, lactic acid, salicylic acid), topical retinoids and, in severe cases, oral retinoids.3,3 
Oral retinoid usage in LI is mainly based on case reports and case series.4,5,6,7,8 The mechanism of 
retinoid action involves modulation of keratinocyte differentiation, keratinocyte hyperproliferation 
and tissue infiltration by inflammatory cells. Systemic retinoids (such as acitretin, etretinate, or 
isotretinoin) have been found to be efficacious in the treatment of severe ichthyoses, especially in 
LI.6 
Vahlquist, et al (2008)3 report that by combining 2 or more keratolytic agents and moisturizers in 
the same lipophilic cream base, it is often possible to achieve additive or even synergistic effects 
in LI without the need to use irritating concentrations of either agent alone. In a double-blind trial 
of 4 different cream mixtures in 20 patients with LI, a mixture of 5% lactic acid and 20% propylene 
glycol (PG) in a semi-occlusive cream for 4 weeks twice daily was significantly more effective 
than 20% PG or 5% urea alone in the same vehicle.9 Although the treatments were well tolerated, 
an efficient removal of hyperkeratosis without correcting the underlying biochemical defect in LI 
is likely to deteriorate the patient’s intrinsic barrier problem, because an excessive production of 
corneocytes probably represents a homeostatic response to an ineffective barrier. Indeed, 
transepidermal water loss increased after successful treatment of LI with either topical 
keratolytics9 or oral retinoid.10 Although this may not be noticeable by the patient, even minor 
deteriorations in the barrier function can enhance transcutaneous penetration of active cream 
ingredients or other topically applied chemicals, which is a matter of special concern in children. 
Accordingly, α-hydroxy acids and salicylic acid should not be used at all in babies and only with 
great caution when treating large, eroded skin areas in adult patients.11,12 
Many patients with LI use pumice, foot files, or gentle rubbing of the skin after a hot bath or a 
shower to remove scales and hyperkeratosis. Overnight occlusion of problematic skin areas with 
plastic sheets after applying a thick layer of emollient or keratolytic agents is another way of 
potentiating therapy, especially on the scalp, which is notoriously difficult to treat. Although 
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usually effective, all these remedies may further damage the skin barrier and lead to exaggerated 
epidermal proliferation, erythema, painful erosions and increased trancutaneous penetration.3 
Based on this information, LI has significant unmet medical need for safer and more effective 
therapies. 
5.1.1 CD5789 (Trifarotene) 
CD5789 is a new chemical entity discovered by Galderma R&D SNC and formulated for topical 
application. It is a novel retinoid acid receptor γ (RARγ) agonist, characterized by its high 
specificity to this receptor. CD5789 is selective for RARγ over RARα and RARβ (approximately 
50- and 8-fold, respectively), with no retinoid X receptor (RXR) activity. CD5789 is currently 
under clinical development for the topical treatment of various dermatoses, including acne vulgaris 
and LI. 
The pharmacological retinoid-like properties of CD5789 were confirmed in in vitro and in vivo 
models, showing its interest for its development in the treatment of LI. Therefore, it may have an 
effect on the differentiation and hyperproliferation of keratinocytes, and consequently improve 
hyperkeratotic skin of patients with lamellar ichthyosis. 
Within the overall acne development program at Galderma, CD5789 has been tested in different 
pharmaceutical forms for topical administration. As of 15-Jan-2018, 6 different formulations have 
been evaluated: a solution, a gel and 4 creams (CD5789 cream A, CD5789 cream B, CD5789 
cream HE1 concept and its optimized version, cream HE1), with different concentrations (up to 
400 µg/g). Therefore, several formulations at different CD5789 concentrations have been tested in 
nonclinical and clinical development programs. 
Galderma decided to develop a new cream formulation that might better address the issue of skin 
dryness in patients with LI. This formulation was named “Cream HE1 concept.” It has been 
preliminarily investigated in an exploratory trial in psoriasis at concentrations up to 400 μg/g 
(RD.03.SRE.40204E). In a proof-of-concept study (RD.03.SRE.40181E), positive results were 
also obtained in patients with LI with CD5789 cream (up to 100 µg/g) that was effective in 
decreasing scaling and roughness. Based on these results, a new CD5789 formulation (cream HE1) 
was developed for further clinical investigations in LI. The formulation cream HE1 was developed 
with the objective to obtain a formulation with appropriate stability of the active ingredient and in 
which CD5789 would be homogeneously dissolved in the oily phase at a higher concentration 
compared to the cream formulation used in the acne program. Cream HE1 contains 100, 200, or 
400 μg/g (0.01% [w/w], 0.02% [w/w], 0.04% [w/w], respectively) of CD5789. 
Galderma has granted Mayne Pharma LLC an exclusive license to develop and commercialize 
CD5789 (trifarotene) for LI and other orphan diseases; therefore, the LI indication is no longer 
pursued by Galderma. 
5.2. Clinical Experience 
The cream HE1 differs from the CD5789 cream used to treat acne vulgaris in that it contains fewer 
excipients with drying effects and therefore may be better suited for patients with LI. 
Throughout the 30 clinical studies that comprise the clinical development program for CD5789 
topical products, 1976 subjects were exposed to CD5789. No systemic safety concerns related to 
CD5789 gel or creams, or cream HE1 at doses up to 400 μg/g were reported. The subjects were 
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exposed to a maximal total CD5789 dose of 36 g/day (Investigator’s Brochure for CD5789 
Cutaneous Formulation). 
The CD5789 PK profile was also investigated using cream HE1 (Study GD.03.SRE.103813) in 
36 healthy volunteers of Japanese and non-Japanese origin. Subjects were treated daily on up to 
90% of body surface area (BSA) for 29 days with up to 36 g of cream formulation. Both CD5789 
100 μg/g and 200 μg/g cream HE1 were investigated. Plasma PK assessment demonstrated that 
repeated topical applications of CD5789 cream HE1 resulted in low and similar CD5789 systemic 
levels in all treatment groups. In addition, no systemic safety concerns were raised from this 
healthy volunteer study in which cream HE1 200 μg/g was applied daily under maximal-use 
conditions on almost the full body. In this study, however, the level of irritation resulted in the 
need to decrease the frequency of application to twice weekly (Investigator’s Brochure for CD5789 
Cutaneous Formulation). 
5.3. Summary of Potential Risks and Benefits 
Although the primary objective of this study is safety in the patient population with LI, the 
potential benefits of study participation are that subjects with LI may experience a reduction in 
their LI symptoms as a result of treatment with trifarotene (CD5789) cream HE1. No other benefits 
of participation are anticipated. 
The potential risks of study participation include those associated with exposure to trifarotene 
(CD5789) cream HE1 and the risks of medical evaluation, including venipuncture.  
Animal studies with CD5789 have shown reproductive toxicity in the embryo-fetal studies. 
Despite low systemic levels with the CD5789 concentration of 50 μg/g used in patients with acne, 
CD5789 must not be administered during pregnancy. 
When CD5789 is used in the other formulations and/or for other indications and/or with higher 
concentrations or higher application surface areas, the potential risk of teratogenicity needs to be 
considered as the safety margin may be lower. Depending on the study population and conditions 
mentioned above, or other specific requirements, the appropriate contraception method is 
described in this protocol. 
It is unknown whether CD5789 or its metabolites are excreted in human milk. A risk to the 
newborns/infants cannot be excluded. Lactating women are not eligible for the clinical study. 
Certain cutaneous signs and symptoms of irritation and localized reactions at the application site 
such as erythema, scaling, dryness, stinging/burning, and pruritus may be experienced with use of 
CD5789. Depending upon the severity of these side effects, subjects may be instructed to reduce 
the frequency of application or to discontinue use.  
Trifarotene cream contains propylene glycol that is mildly irritant to the skin, eyes, and mucous 
membranes. Trifarotene (CD5789) cream HE1 also contains butylated hydroxytoluene that may 
cause local skin reactions (e.g., contact dermatitis), or irritation to the eyes and mucous membranes 
and sodium benzoate that is mildly irritant to the skin, eyes, and mucous membranes. 
CD 5789 is mildly irritant to the skin, eyes, and mucous membranes. Therefore, it should not come 
into contact with the eyes, mouth, or mucous membranes.  
There is a potential risk of skin sensitization. If a reaction suggesting sensitivity to trifarotene 
(CD5789) cream HE1 occurs, the use of the trifarotene cream HE1 must be discontinued. 
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There is a potential risk of photosensitivity disorder (sunburn). Excessive exposure to sunlight or 
ultraviolet (UV) radiation (i.e., occupational exposure to the sun, planned holidays in the sun 
during the study, phototherapy, tanning salon) must be avoided during the studies. 
As reported with other topical retinoids, there is a potential risk of pigmentation disorders. 
A summary of the pharmaceutical properties and known potential risks of trifarotene (CD5789) 
cream HE1 is provided in the current version of the investigator brochure (IB). The investigator 
must become familiar with all sections of the trifarotene (CD5789) cream IB before the start of the 
study. 
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6. OBJECTIVES 
6.1. Primary Objective 
The primary objective is to compare the safety and efficacy of 2 concentrations of trifarotene cream 
HE1 versus vehicle in adults and adolescents with moderate to severe autosomal recessive 
ichthyosis with lamellar scale, also known as lamellar ichthyosis (LI) after 12 weeks of treatment. 
6.2. Secondary Objectives 
The secondary objectives are as follows: 
• To assess systemic exposure to trifarotene and its major metabolites after topical 
application of the investigational product (IP) on up to 90% BSA twice weekly. 
• To assess safety for up to 24 weeks of dosing with open-label trifarotene cream HE1 
200 µg/g. 
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7. STUDY DESIGN
7.1. Overall Study Design and Plan 
The first part of this study is a phase 2, randomized, 2-cohort, double-blind, vehicle-controlled, 
multicenter study of the safety, tolerability, PK, and efficacy study of trifarotene cream HE1 
100 µg/g and 200 µg/g in adults and adolescents with LI. Adult and adolescent subjects who 
complete the randomized, double-blind, vehicle-controlled period of the study will be eligible to 
continue into an open-label extension (OLE) period and be treated with trifarotene cream HE1 
200 µg/g for an additional 12 weeks. 
The randomized, double-blind, vehicle-controlled period of the study in subjects with moderate to 
severe LI (i.e., 3–4 on a 5-point Visual Index for Ichthyosis Severity [VIIS] index for scaling where 
0 = clear and 4 = severe on at least 2 of 4 areas of the body: chest/abdomen, back, arms, and legs), 
is designed to compare the safety of 2 doses of trifarotene cream HE1 with that of vehicle in the 
treatment of LI.  
After Screening, eligible subjects for Cohorts A and B will enter a washout period of up to 35 days, 
during which they must stop using prohibited topical and systemic treatments with designated 
washout periods (Table 9-1). 
The first cohort of subjects (Cohort A) will randomize approximately 15 adults (≥18 years old) in 
a 1:1:1 ratio to trifarotene (CD5789) cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or 
vehicle.  
Study drug will be packaged in 50-g tubes from which up to 36 g of IP may be dispensed per 
application, i.e., the maximum dose per application. Study staff will apply the first dose of study 
drug to each subject in the clinic on Day 1 after Baseline measurements, and will record the amount 
of study drug applied (i.e., study staff will measure the 50-g tube before and after the first 
application to determine the fixed dose amount for each subject). Thereafter, subjects will apply 
approximately the same amount (up to 36 g) of study drug as for the first dose on up to 90% of 
BSA twice weekly, sparing the scalp, inguinal, and axillary areas. Subjects will receive an 
adequate number of tubes to use 1 tube per application and will use a new tube for each treatment 
day. Subjects may use less than the full amount of IP in a tube. 
Subjects enrolled in Cohort A will continue treatment for up to 12 weeks. 
After the initial 15 subjects complete at least 28 days of treatment, an independent Data Safety 
Monitoring Board (DSMB) will review aggregate safety and tolerability data. If no safety issues 
are identified, both adults and adolescents (ages 12–17 years, inclusive) will be allowed to enroll 
in Cohort B (up to approximately 105 subjects). Subjects in Cohort B will be randomized 1:1:1 to 
trifarotene cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle and similarly treated 
twice weekly for up to 12 weeks in the same manner as subjects in Cohort A. 
Subjects will be provided with diaries in which to record study drug application (days/times and 
any areas of skin not treated [e.g., due to local reactions]), any application site reactions, adverse 
events (AEs), and concomitant medications used. Subjects will also be advised on permitted 
emollient(s) use on nontreatment days during the study; use of emollient(s) on study drug treatment 
days within 4 hours of study drug application is prohibited. 
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Photographs will be taken at Baseline, Day 30, and Day 90 in the Double-blind Period at selected 
sites with photographic capability for subjects who signed a separate photographic informed 
consent form (ICF). 
Samples for PK will be drawn from all subjects at Baseline and at each clinic visit, as indicated in 
the Schedule of Events (Table 2-1).  
In addition, a PK substudy will be conducted at specific sites with the capability to conduct it. 
Participation in the PK substudy will be optional and will include at least 15 adults and 
15 adolescents. Subjects who participate in the PK substudy will come from both study cohorts 
and will undergo serial blood sampling predose and at 1, 2, 4, 8, 12, and 24 hours postdose on 
Day 1 and Day 30. Trough levels will be drawn for all subjects at specified time points. 
Efficacy will be assessed by the number of subjects in each treatment group who achieve “success” 
defined as clear/almost clear overall and at least a 50% reduction from Baseline at 
Week 12/end-of-treatment (EOT) in the Double-blind Period on the overall 16-point VIIS for 
scaling (i.e., 0-4 points on each of the 4 body areas: chest/abdomen, back, arms, and legs). In 
addition, efficacy criteria include assessment of the Investigator Global Assessment (IGA; scale: 
0-4 for each body area: chest/abdomen, back, legs, and arms), scales for palm/sole, roughness,
fissuring, and the Dermatology Life Quality Index (DLQI), and the EQ-5D-5L Quality of Life
(QoL) Questionnaire. Ectropion Severity Scores (ESS) between the active trifarotene cream HE1
and vehicle groups will be an exploratory endpoint.
Plasma concentrations of CD5789 and its major metabolites will be measured. 
Safety will be assessed by evaluating reported adverse events (AEs), changes in clinical laboratory 
test results, vital sign measurements, physical examinations, 12-lead electrocardiograms (ECGs), 
and local tolerability. 
All AEs observed by the study personnel or reported by the subject during the study (from the time 
of the signing of the informed consent and/or assent through the posttreatment visit) will be 
documented. 
Topical trifarotene cream HE1 was generally well tolerated in recently completed phase 3 pivotal 
and long-term safety studies in subjects aged 9 years and older with acne vulgaris. The local 
tolerability of the trifarotene cream HE1 formulation in subjects with LI is unknown and will be 
monitored during the study. Subjects will receive information on study drug use and stopping rules 
and will be instructed to contact the site with any safety/tolerability issues. Study personnel will 
telephone subjects in between scheduled visits (i.e., at Day 7 and Day 45) to assess safety; an 
unscheduled clinic visit may be performed, if necessary. During all clinic visits, the investigator 
will assess local tolerability (Scale: 0–3 [none, mild, moderate, severe]) on each body area 
(chest/abdomen, back, legs, arms) and will follow the procedures detailed in Section 9.4. 
Subjects who complete the 12-week Double-blind Treatment Period will have an option to 
continue into an OLE Period for an additional 12 weeks with trifarotene cream HE1 200 µg/g. 
During the OLE Period, subjects will return to the site at Weeks 14, 16, 20, 24, and 26. Additional 
PK samples will be drawn at Week 16 and Week 24 from all subjects who continue into the OLE 
Period (Table 2-2). 
Stopping rules and treatment modification will be defined at the subject level based on local 
tolerability, selected laboratory parameters, and AEs; see Section 9.4. 
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Figure 7-1: 
Double-blind Study Design 
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Scre.ening 
28 days oftre~tment 
DS!vlB reviews safety data 
No safety issues 
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Figure 7-2: 
Open-label Study Design 
Double-blind Treatment Period 
Study Day 90/Week 12 (- 7 days) 
= first visit of 
Open-label Extension Period with 
trifarotene 200 µg/g 
Continue through 12 weeks of treatment 
Follow-up Day 192 or 14 days after 
End of Treatment 
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7.2. Rationale and Discussion of Study Design 
The first part of this study is a randomized, double-blind, placebo-controlled study of the safety, 
tolerability, PK, and efficacy study of trifarotene cream HE1 100 µg/g and 200 µg/g in adults and 
adolescents with LI.  
In a previous proof-of-concept study (RD.03.SRE.40181E), subjects with LI applied trifarotene 
50 and 100 µg/g cream to limited areas and results demonstrated a decrease in scaling with good 
safety and tolerance. In a phase 1 study in healthy Japanese and non-Japanese subjects 
(RD.03.SPR.103813), repeated topical applications of trifarotene (CD5789 cream HE1) 100 µg/g 
and 200 µg/g resulted in low and similar CD5789 systemic levels in all the cohorts. These studies 
are fully described in the current Investigational Brochure. 
To ensure safety, this phase 2 study will begin with an initial cohort (Cohort A) of 15 adults 
randomized 1:1:1 to trifarotene cream HE1 100 µg/g, 200 µg/g, or vehicle to be applied twice 
weekly. An independent DSMB will review aggregate safety and tolerability data from the initial 
15 subjects’ first 28 days of treatment. If no safety issues are identified, 105 adults and adolescents 
(ages 12–17 years, inclusive) will be allowed to enroll in Cohort B and randomized to trifarotene 
cream HE1 100 µg/g, trifarotene cream HE1 200 µg/g, or vehicle and treated twice weekly in the 
same manner as subjects in Cohort A. All subjects in the randomized, double-blind portion of the 
study will be treated for up to 12 weeks and data on safety, tolerability, PK, and efficacy collected. 
Adult and adolescent subjects who successfully complete the initial 12 weeks of double-blind 
treatment will have the option to enter an OLE with trifarotene cream HE1 200 ug/g twice weekly 
for up to 12 weeks.  
The OLE will collect additional safety, tolerability, PK, and efficacy data. As designed, this study 
will provide important information on safety, tolerability, and PK with dosing of adolescents and 
adults with LI for up to 6 months.  
The protocol includes appropriate monitoring for safety and tolerability. If subjects develop 
significant local application site reactions or tolerability issues, the protocol includes language for 
reducing the frequency of application or halting study drug application until the symptoms abate. 
7.3. Selection of Doses in the Study 
Based on the results from Study RD.03.SRE.40181E and Study SRE.103813, the doses of 
100 µg/g and 200 µg/g were selected for further investigation in adult and adolescent subjects with 
moderate to severe LI. The PoC study demonstrated efficacious treatment with 100 µg/g in adults. 
The PK and tolerability study showed that, when the frequency of application was reduced from 
daily to twice weekly, the 200 µg/g cream HE1 had good local tolerability. 
Therefore, the current study will use these doses compared with vehicle, applied twice weekly on 
up to approximately 90% BSA in subjects with LI.   
7.4. Study Sites 
The study will take place at approximately 40 sites in North America, Europe, Israel, and Australia. 
7.5. Point of Contact 
A point of contact will be identified to provide information to subjects about where to obtain 
information on the study, the rights of subjects, and whom to contact in case of a study-related 
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injury. This information will be provided in the subject information and informed consent form 
(ICF). 
7.6. End of Study Definition 
A clinical trial is considered completed when the last participant’s last study visit has occurred. 
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8.
SUBJECT POPULATION
8.1. Selection of Study Population and Diagnosis 
Diagnosis of LI for the purposes of this study will be a clinical diagnosis. Although some younger 
subjects may have had genetic testing, older subjects may not.  
While LI is a rare disease and subject enrollment may be challenging, due to possible bias 
introduced by including household members in the same study, it is recommended that only 
1 household member be included in the study to maintain the blind and ensure all assessments are 
independent. 
8.2. Study Entry Criteria 
8.2.1 Inclusion Criteria 
A subject will be eligible for study participation if he or she meets all of the following criteria: 
1. For Cohort A: subject is ≥18 years old; for Cohort B: subject is ≥12 years old.
2. Subject has known diagnosis of LI.
3. Subject has moderate to severe (VIIS 3–4) LI on the at least 2 of the 4 body areas assessed
(chest/abdomen, back, arms, and legs).
4. Subject has signed an ICF at Screening before any investigational procedures. Subjects
<18 years of age (or Age of Majority) must sign an assent form in conjunction with an ICF
signed by the parent/legal representative.
5. Subject who is participating in optional photography has signed a photography ICF.
6. Subject who is participating in the optional PK substudy has signed a PK ICF.
7. Subject is not of childbearing potential, i.e., a female who has not yet begun menstruating or
who is postmenopausal (absence of menstrual bleeding for 1 year before Baseline, without
any other medical reason, hysterectomy or bilateral oophorectomy),
OR
•
Subject is a woman of childbearing potential (WOCBP) or a male subject with sexual partners
capable of reproduction who agrees to use 2 effective forms of contraception during the study
and for at least 1 month after the last study drug application. The 2 authorized forms of
contraception are condom used with 1 of the following methods of contraception:
•
bilateral tubal ligation
•
combined oral contraceptives (estrogens and progesterone) or implanted or injectable
contraceptives with a stable dose for at least 1 month before Baseline
•
hormonal intrauterine device (IUD) inserted at least 1 month before Baseline
OR
Agrees to abstain from sex during study participation and for 1 month after the last application 
of study drug and to use a highly effective contraceptive as backup if he or she becomes 
sexually active during the study. 
AND 
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Male subjects may not donate sperm during the study and for at least 1 month after the last 
study drug application. 
Note: Subjects who are premenstrual at Screening but begin menses during the study should 
follow the pregnancy testing schedule for WOCBP and must abstain from sexual intercourse 
while in the study and for at least 1 month after the last study drug application. 
8. Women of child-bearing potential must be nonlactating and have negative pregnancy test
results at Screening (serum) and on Day 1 before study drug administration (urine).
9. Subject is reliable and capable of adhering to the protocol and visit schedule, in the
investigator’s judgment, and has signed informed consent/assent, as applicable.
10. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin).
8.2.2 Exclusion Criteria 
A subject will be excluded from the study if he or she meets any of the following criteria: 
1. Subject has any variant of ichthyosis other than LI or another disorder of keratinization
including syndromic ichthyoses.
2. Subject has a history of or current moderate or severe stinging/burning at Screening.
3. Subject has an ongoing cutaneous infection or any other significant concomitant skin disease
(other than the LI) which, in the investigator’s opinion, may interfere with the study
assessments.
4. Subject with a known lipid disorder unless well controlled by stable doses of lipid-lowering
agents for at least 6 months.
5. Subject was previously treated with trifarotene/CD5789, including the acne formulation, or
participated in previous studies for ichthyosis.
6. Subject has known skeletal disease, hypertriglyceridemia, hypercholesterolemia, liver disease,
or other poorly controlled medical conditions.
7. Subject has a medical condition that potentially alters bone metabolism (e.g., osteoporosis,
thyroid dysfunction, Cushing syndrome), Crohn’s disease, or any other significant concomitant
disease other than LI that, in the investigator’s opinion, may put him or her at risk if he or she
takes part in the study, and/or that may interfere with the study assessments.
8. Subject is being treated for major depression disorder.
9. Subject with positive serology for hepatitis B surface antigen, hepatitis C, or are known to be
HIV positive or to have AIDS at Screening.
10. Subject with any of the following laboratory values at Screening:
a.
Aspartate aminotransferase or alanine aminotransferase >1.5 × upper limit of normal
defined by the laboratory
b. Triglycerides >200 mg/dL
c.
Total cholesterol >250 mg/dL
d. Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women
e.
Platelets <150 × 109/L or >400 × 109/L.
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11. Subject has any clinically other significant abnormal laboratory value (hematology, chemistry,
or urinalysis) at Screening that, in the investigator’s opinion, may put the subject at risk if he
or she takes part in the study, and/or that may interfere with the study assessments.
12. Subject has a history of long QT syndrome or clinically significant ECG abnormalities,
including clinically significant conduction disorders or significant arrhythmias, QTcF interval
>450 ms, PR interval is not between 120 and 220 ms (inclusive), HR >100 bpm or <50 bpm,
QRS interval >110 ms, or QT intervals that cannot be consistently analyzed.
13. Subject has a known allergy or sensitivity to any of the components of the investigational
products.
14. Subject has been exposed to excessive UV radiations on the treated zones within 1 month
before Baseline visit or who is planning intensive UV exposure during the study (e.g.,
occupational exposure to the sun, sunbathing, phototherapy, etc.).
15. Subject is inherently sensitive to sunlight.
16. Subject is presumed to be abusing drug or alcohol at Screening or Baseline Visits based on
medical history or current clinical symptoms.
17. Subject is participating in another interventional clinical trial.
8.3. Premature Subject Withdrawal 
All subjects will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. The investigator should make every reasonable 
attempt to keep subjects in the study; however, subjects must be withdrawn from the study if they 
withdraw consent to participate. Investigators must attempt to contact subjects who fail to attend 
scheduled visits by telephone or other means to exclude the possibility of an AE being the cause 
of withdrawal. Should this be the cause, the AE must be documented, reported, and followed as 
described in Section 11.2. 
The sponsor reserves the right to request the withdrawal of a subject due to protocol deviations or 
other reasons. 
The investigator also has the right to withdraw subjects from the study at any time for lack of 
therapeutic effect that is intolerable or otherwise unacceptable to the subject, for intolerable or 
unacceptable AEs, intercurrent illness, noncompliance with study procedures, administrative 
reasons, or in the investigator’s opinion, to protect the subject’s best interest. 
If a subject is withdrawn before completing the study, the reason for withdrawal and the date of 
discontinuation will be recorded on the appropriate page of the electronic case report form (eCRF). 
Whenever possible and reasonable, the evaluations that were to be conducted at the completion of 
the study should be performed at the time of premature discontinuation. 
8.4. Discontinuation of Study Intervention 
Discontinuation from study treatment does not mean withdrawal from the study, and the remaining 
study procedures should be completed as indicated in the study protocol (see Section 10.2.4.5). If 
a clinically significant finding is identified (including, but not limited to changes from Baseline) 
after enrollment, the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an AE. 
An investigator may discontinue a participant’s study treatment for any of the following reasons: 
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•
Pregnancy
•
Significant study intervention noncompliance
•
If any clinical AE, laboratory abnormality, or other medical condition or situation occurs
such that continued participation in the study would not be in the best interest of the
participant
•
If the participant meets an exclusion criterion (either newly developed or not previously
recognized) that precludes further study participation
The reason for discontinuation of study treatment will be recorded on the eCRF. Subjects who sign 
the informed consent form and are randomized but do not receive the study intervention may be 
replaced. Subjects who sign the informed consent form, are randomized, and receive the study 
intervention, and subsequently discontinue study treatment, or are withdrawn from the study will 
not be replaced. 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
•
The site will attempt to contact the participant and reschedule the missed visit and counsel
the participant on the importance of maintaining the assigned visit schedule and ascertain
if the participant wishes to and/or should continue in the study.
•
Before a participant is deemed lost to follow-up, the investigator or designee will make
every effort to regain contact with the participant (where possible, 3 telephone calls and, if
necessary, a certified letter to the participant’s last known mailing address or local
equivalent methods). These contact attempts should be documented in the participant’s
medical record or study file.
•
Should the participant continue to be unreachable, he or she will be considered to have
withdrawn from the study with a primary reason of lost to follow-up.
8.5. Subject Replacement Criteria 
Withdrawn subjects will not be replaced. If a substantial number of subjects are withdrawn from 
the study, the sponsor will evaluate the need for developing replacement criteria. 
Randomized subjects withdrawn from the study may not reenter. The subject number for a 
withdrawn subject will not be reassigned to another subject. 
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9.
TREATMENTS
9.1. Identification of Investigational Product(s) 
Trifarotene cream HE1 is a cream containing 100 or 200 μg/g (0.01% [w/w] or 0.02% [w/w], 
respectively) of CD5789 and the following excipients: purified water, propylene glycol, allantoin, 
glycerin, medium-chain triglycerides, polypropylene glycol 15 stearyl ether, cyclomethicone, 
phenoxyethanol, copolymer of acrylamide and sodium acryloyldimethyltaurate, dispersion 40% in 
isohexadecane (simulgel 600 PHA), sodium benzoate, butylated hydroxytoluene, and 
gluconolactone. 
Vehicle contains the same ingredients, without the CD5789. 
Trifarotene cream HE1 and vehicle will be provided in cream form for topical application and will 
be supplied in 50-g tubes from which a maximum of 36 g of IP may be extracted, 
Trifarotene cream HE1 and vehicle will be supplied by G. Production, Inc. (Galderma) in 
Baie-D'Urfé, QC, Canada. 
9.2. Treatments Administered 
For the Double-blind Treatment Period, a fixed dose (determined at Visit 2) of trifarotene cream 
HE1 100 µg/g or 200 µg/g or vehicle cream will be applied topically twice weekly on up to 90% 
BSA of each subject. 
Study staff will apply the first administration of IP in the clinic on Day 1 after Baseline 
measurements, and the amount of IP used will be measured (i.e., 50-g tube will be measured before 
and after application to determine amount used). 
The maximum dose per application is 36 g (i.e., 1 tube). Subjects will receive an adequate number 
of tubes to use 1 tube per application and will use a new tube for each treatment day. Subjects may 
use less than full amount of product in a tube. 
After the Day 1 visit, subjects will apply approximately the same amount (up to 36 g) of study 
drug as for the first dose on up to 90% of BSA twice weekly, sparing the scalp, inguinal, and 
axillary areas. Subjects will continue treatment for up to 12 weeks. 
For the OLE Period, all subjects will receive trifarotene cream HE1 200 µg/g and apply the same 
fixed dose in the same manner as in the Double-blind Period for an additional 12 weeks. 
Subjects should not apply IP on visit days until after the visit. 
9.3. Selection of Timing of Dose for Each Subject 
Subjects will be randomized in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g or 200 µg/g or 
vehicle cream. After Day 1, on which the study staff will apply the first administration of IP in the 
clinic, each subject will apply approximately the same amount of IP on up to 90% of their BSA 
twice weekly. It is suggested that each subject choose 2 specific days per week at least 3 days apart 
on which to apply their IP (e.g., Tuesday and Friday), and maintain that regimen throughout the 
study. 
All subjects will be provided with diaries in which to record study drug application (days/times) 
and any areas of skin not treated (e.g., due to local reactions). 
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If a subject misses an IP application, they should apply the IP as soon as they remember and record 
the date/time in the subject diary, then wait at least 3 days and continue their regimen. 
Subjects should not shower, bathe, or swim for at least 4 hours after IP application. No occlusive 
dressings should be used on areas to which IP is applied. 
Subjects who continue into the Open-label Extension will receive trifarotene cream HE1 200 µg/g 
and apply the same fixed dose in the same manner as in the double-blind period for an additional 
12 weeks. 
9.4. Dose Adjustment Criteria 
Local tolerance will be followed very carefully during the study. Subjects will receive information 
on study drug use and stopping rules and will be instructed to contact the site with any 
safety/tolerability issues. Study personnel will telephone subjects in between scheduled visits (i.e., 
at Day 7 and Day 45) to assess safety; an unscheduled clinic visit may be performed, if necessary. 
During all clinic visits, the investigator will assess local tolerability on a 0–3 scale (0 = none, 1 = 
mild, 2 = moderate, 3 = severe) on each of the 4 body areas (chest/abdomen, back, legs, arms), and 
the following procedures will be followed: 
−
If a score of 2 (moderate) is recorded on a local tolerability assessment scale
(stinging/burning, pruritus, erythema) on any treated area, the study drug will be applied
on this area only once weekly, until the score is back to <2;
−
If a score of 3 (severe) is recorded on a local tolerability assessment scale (stinging/burning,
pruritus, erythema) on any treated area, the study drug will not be applied on that area until
the score is back to <3.
9.4.1
Stopping Rules 
A subject’s treatment in either the Double-blind Period or the Open-label Extension must be 
stopped if any of the following occur: 
•
Subject becomes pregnant or suspects they are pregnant
•
Subject has severe (score of 3) local application site AEs that do not abate with ‘drug
holiday’ and reintroduction of IP.
•
Subject has clinically significant changes in laboratory values (liver function tests,
cholesterol/triglycerides – which may occur with systemic retinoid use)
9.5. Treatment Compliance 
Subjects will be asked to record their twice-weekly applications of IP in the diary during both the 
Double-blind and OLE Periods. Deviations from the planned doses (missed dose or timing) will 
be recorded on the subject’s eCRF. Study personnel will review diaries at each visit and diaries 
will be collected as source documents. Information from subject diaries will be transcribed on the 
appropriate eCRF pages for documentation of subject compliance with the IP. 
Study personnel will assess treatment compliance with IP regimens by weighing IP tubes before 
dispensing and upon return and by questioning the subject, at every post-randomization visit. A 
participant is compliant with study product if he or she takes at least 80% of the scheduled doses 
as assessed by diary entries, supplemented by tube weight. A subject who is not compliant (used 
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80–120% of IP tubes) will be counseled at each visit on the importance of using the IP as 
instructed.  
9.6. Method of Assigning Subjects to Treatment Groups 
In the double-blind, parallel-group, randomized period of the study, subjects who meet study entry 
criteria will be randomly assigned in a 1:1:1 ratio to trifarotene cream HE1 100 µg/g or 200 µg/g 
or vehicle cream. The randomization schedule will be computer generated using a permuted block 
algorithm and will randomly allocate IP to randomization numbers. The randomization numbers 
will be assigned sequentially through a central interactive web response system (IWRS) as subjects 
are entered into the study. Study center will not be a blocking factor in the randomization schedule. 
Premier Research will prepare the randomization schedule before the start of the study. No one 
involved in the study performance will have access to the randomization schedule before the 
official unblinding of treatment assignments. No subject will be randomized into this study more 
than once. 
In the OLE Period, all subjects will receive trifarotene cream HE1 200 µg/g. 
9.7. Blinding and Unblinding Treatment Assignment 
All subjects, investigators, and study personnel involved in the conduct of the Double-blind Period 
of the study, including data management, will be blinded to treatment assignment with the 
exception of a specified unblinded statistician and programmer from Premier Research who will 
have access to the randomization code. The statistician will have access to unblinded data if there 
is an unblinded DSMB review.  
Study personnel will make every effort to safeguard the integrity of the study blind to minimize 
bias in the conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
subject’s treatment assignment. 
Unblinding should be discussed in advance with the medical monitor, if possible. For emergency 
unblinding, study personnel will use the IWRS code. If the investigator is not able to discuss 
treatment unblinding in advance, then he/she must notify the medical monitor as soon as possible 
about the unblinding incident without revealing the subject’s treatment assignment.  
The investigator or designee must record the date and reason for treatment unblinding on the 
appropriate eCRF for that subject. In all cases that are not emergencies, the investigator must 
discuss the event with the medical monitor prior to unblinding the subject’s treatment assignment. 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
that subject’s treatment assignment without unblinding the treatment assignments for the 
remaining subjects in the study. Thus, the overall study blind will not be compromised. If a 
subject’s treatment assignment is unblinded, he/she may or may not be asked to withdraw from 
the study. The investigator will make this decision after consultation with the medical monitor. 
The primary analysis period is the first 12 weeks of treatment (i.e., the Double-blind Period). 
Overall unblinding will take place at the end of the Double-blind Period of the study only after 
database lock has been achieved. A second analysis will take place for endpoints assessed from 
Week 12 through the OLE Period. 
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9.8. Permitted and Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate eCRF. 
All subjects must washout the following medications after enrollment and before randomization: 
Table 9-1: 
Washout Periods for Prohibited Medications 
Medication 
Washout Period 
Topical Treatments 
Corticosteroids (except inhaled and ophthalmic corticoids) 
2 weeks 
Retinoids (e.g. tretinoin, tazarotene) 
4 weeks 
Vitamin D analogues 
2 weeks 
Immunosuppressants (e.g. tacrolimus) 
2 weeks 
Antracen derivatives, tar and salicylic preparations 
2 weeks 
Keratolytics (such as urea, lactic acid, propylene glycol, salicylic acid) except keratolytic 
shampoo 
- 
Systemic treatments 
Retinoids 
8 weeks 
Oral Vitamin A supplementation more than 3500 IU per day 
2 weeks 
Medication interfering with bone activity, e.g., corticosteroids, thyroid hormones, cytotoxics, 
bisphosphonates, calcitonins, tetracyclines, quinolones, thiazides, salicylates in long-term 
course, heparin, theophylline, barbiturates, colchicines (except Vitamin D analogues taken at 
stable dose since at least 1 month) 
8 weeks 
QT prolonging drugs 
5 half lives 
Enzymatic inductors (such as rifampicine, phenytoin, carbamazepine, phenobarbital, St. 
John’s Wort) 
3 months 
CYP2C9 and 2C8 inhibitors (not all inclusive: gemfibrozil, fluconazole, fluvoxamine, 
sulfaphenazole, miconazole, amiodarone, sertraline, sulfamethoxazole, valproic acid, 
voriconazole, trimethoprim, rosiglitazone, pioglitazone) 
5 half lives 
9.8.1 Permitted Therapies 
Subjects will be advised on permitted emollient(s) for use on nontreatment days during the study; 
use of emollient(s) on study drug treatment days within 4 hours of study drug application is 
prohibited.  
Other concomitant medications are allowed (e.g., analgesics, antihistamines), but should be limited 
to those medications considered necessary. All concomitant medications, both prescribed and 
over-the-counter, should be recorded in the eCRF. 
9.8.2 Prohibited Therapies 
The therapies listed in Table 9-1 are prohibited during the study. 
Subjects may not use concomitant keratolytics such as urea, salicylic acid, alpha, or beta 
hydroxyacids. Subjects may not use topical or systemic retinoids. Subjects may not take more than 
3500 IU/day Vitamin A (e.g., as in a multivitamin). 
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Subjects receiving excluded therapies will be ineligible for study enrollment or for continued 
treatment in the study, at the investigator’s discretion with consultation with Mayne Pharma LLC 
and the medical monitor. 
9.8.3 Restrictions 
Subjects should not shower, bathe, or swim within 4 hours of study drug application. No occlusive 
dressings should be applied to areas where study drug was applied.  
Subjects should only use investigator-approved emollients, and should not use them on treatment 
days within 4 hours of study drug application. 
9.9. Treatment After End of Study 
After the end of the study, each subject will be treated according to standard clinical practice. 
9.10. Dispensing and Storage 
The test product supplied by Mayne Pharma LLC is to be used exclusively in the clinical study 
according to the instructions of this protocol. The investigator is responsible for dispensing the IP 
according to the dosage scheme and for ensuring proper storage of the IP. 
The investigator must confirm the receipt of the IP with his or her signature. A copy of this receipt 
must be kept by the investigator and another copy will be stored at Premier Research. Until the IP 
is dispensed to the subjects, it must be stored at 20–25°C (68–77°F), with excursions permitted to 
15–30°C (59–86°F); do not freeze and with the tube kept tightly closed in a securely locked area 
that is not generally accessible. 
The key to the storage area is to be kept by the investigator or designee responsible for the IP. The 
store will be accessible only to those persons authorized by the investigator to dispense the IP. 
9.11. Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the IPs, including the date, quantity, batch or code number, and identification of 
subjects (subject number) who received the IP. The investigator will not supply the IP to any 
person except those named as subinvestigators on the Form Food and Drug Administration 
(FDA) 1572, designated study personnel, and subjects in this study. The investigator will not 
dispense the IP from any study sites other than those listed on the Form FDA 1572. Investigational 
product(s) may not be relabeled or reassigned for use by other subjects. If any of the IP is not 
dispensed, is lost, stolen, spilled, unusable, or is received in a damaged container, this information 
must be documented and reported to the sponsor and appropriate regulatory agencies, as required. 
Each subject will be given enough tubes of study drug to apply up to 1 tube-full (approximately 
36 g of clinical trial material) per treatment day until the next study visit. Tubes will be packed 
2 to a carton, and each subject will receive enough cartons to have the maximum number of tubes 
needed until the next study visit. The number of study drug tubes the subject needs to provide 
enough IP until the next visit is shown in Table 9-2.  
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Table 9-2: 
Amount of Study Drug Needed Per Visit 
Treatment Period 
Number of Cartons 
Number of Tubes 
Double-blind Treatment Period 
Baseline 
3 
6 
Day 14 
4 
8 
Day 30 
6 
12 
Day 60 
6 
12 
OLE Period 
Day 90 
3 
6 
Day 104 
4 
8 
Day 120 
6 
12 
Day 150 
6 
12 
Each carton will be weighed before dispensing and subjects are to bring all cartons and tubes back 
at each study visit, whereupon study staff will weigh them again to estimate study drug use and 
compliance. 
Upon completion of the study, the IP (partly used, unused, and empty tubes) must be left in the 
original packaging and returned to the sponsor or designee for destruction. 
9.12. Labeling and Packaging 
Labeling and packaging of IP will be performed by Catalent Pharma Solutions, Philadelphia, PA, 
USA.  
Tubes will be packaged in cartons comprising 2 tubes each. Tubes will be labeled with inner and 
outer booklet labels, and carton number. Each carton will also be labeled with inner and outer 
booklet labels and numbered.  
9.12.1 Labeling 
The tubes will have a label affixed that meets the applicable regulatory requirements and may 
include, but is not limited to, the following: subject identifier, IP name, lot number, protocol 
number, carton number, caution statement, storage, and sponsor identification. 
Save all empty packaging or packaging containing unused tubes for final disposition by the 
sponsor or contract pharmacy. 
Final labeling will comply with the regulatory requirements of each country where the study will 
be conducted. 
9.12.2 Packaging 
Investigational products will be packaged in high-density polyethylene, 35 × 100 mm tubes 
weighing 50 g from which a maximum of 36 g of IP can be extracted. Trifarotene cream HE1 and 
vehicle will be packaged so as to be blinded to the investigator, the study clinic personnel, and the 
subjects. 
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10. STUDY PROCEDURES
Subjects must provide written informed consent and/or assent before any study-related procedures 
are initiated, including the cessation of prohibited concomitant therapy. 
Subjects who agree to participate in the photography and/or PK substudies must provide written 
informed consent before photographs or serial blood samples are collected. 
For the timing of assessments and procedures throughout the study, refer to the Schedule of 
Events (Section 2.2). Throughout the study, every reasonable effort should be made by study 
personnel to follow the timing of assessments and procedures in the Schedule of Events for each 
subject. If a subject misses a study visit for any reason, the visit should be rescheduled as soon as 
possible. 
10.1. Study Duration 
10.1.1 Overall Study Schedule 
The overall study duration is expected to be approximately 19 months. 
The planned sequence and maximum duration of the study periods will be as follows: 
1. Screening and Washout: up to 35 days to comprise washout of excluded medications
(Table 9-1).
2. Double-blind Treatment: Twice weekly for 12 weeks.
3. Optional Open-label Extension Treatment: Twice weekly for 12 weeks.
4. Follow-up: 14 days after last study drug application.
The maximum treatment duration for each subject is approximately 12 weeks for subjects who 
choose not to continue into the open-label extension period, and 24 weeks for those who choose 
to continue.  
The maximum study duration for each subject is approximately 229 days (33 weeks). 
10.2. Study Periods and Visits 
10.2.1 Screening and Washout 
10.2.1.1 Screening Visit (Visit 1) 
The subject must be screened within 35 days before randomization in the study. The following 
procedures will be performed at Screening: 
1. Obtain written informed consent and/or assent.
2. Assign a screening number when a subject begins screening.
3. Assess inclusion/exclusion criteria.
4. Collect demographic information.
5. Record medical history, including current therapies (e.g., prescription and nonprescription
medications).
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6. Perform a physical examination. 
7. Measure vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and 
pulse). 
8. Perform a 12-lead ECG. 
9. Collect blood and urine for laboratory tests. 
10. Perform serum pregnancy test for WOCBP. 
11. Record VIIS.   
12. Record IGA. 
13. Record palm/sole assessment.  
14. Record assessment of roughness, and fissuring  
15. Record ectropion score. 
Procedures for rescreening subjects who initially fail to meet study entry criteria are described in 
Section 14.3. 
10.2.1.2 Washout Period 
Excluded medications must be washed over the time periods as shown in Table 9-1. The washout 
period is part of the 35-day Screening Period.  
10.2.2 Double-blind Treatment Period  
Eligible subjects who have washed out prohibited medications will be randomized to double-blind 
study drug. 
10.2.2.1 Baseline Visit (Visit 2, Day 1) 
The following procedures will be performed on Day 1 in the study clinic: 
1. Review inclusion/exclusion criteria. 
2. Perform urine pregnancy test for WOCBP. 
3. Collect blood and urine for routine laboratory tests (subject must be fasting; i.e., at least 
8 hours). 
4. Collect a predose PK blood sample (all subjects). 
5. Perform physical examination.  
6. Record concomitant medications and concomitant therapies. 
7. Record VIIS.  
8. Record IGA.  
9. Record palm/sole assessment. 
10. Record assessment of roughness and fissuring.  
11. Record ectropion score.  
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12. Record responses to DLQI and EQ-5D Quality of Life Questionnaires 
13. Record vital signs (blood pressure and pulse).  
14. Measure and record height, weight, and body mass index (BMI).  
15. Perform a 12-lead ECG. 
16. Assign randomization number.  
17. At sites where the photographic substudy is conducted, take photographs of subjects who 
have provided informed consent for the substudy. 
18. Among subjects who consent to participate in the PK substudy, samples will be taken at 1, 
2, 4, 8, 12, and 24 hours postdose on Day 1. 
19. Clinic staff instructs subject on study drug application, applies initial study drug dose and 
measures amount used (i.e., study staff will weigh the 50-g tube before and after the first 
application to determine the fixed dose amount for each subject). 
20. Assess and record local tolerance/AEs. 
21. Dispense study drug and diaries. 
22. Advise subjects regarding permitted emollient(s) for use on nontreatment days; use of 
emollient(s) on study drug treatment days within 4 hours of study drug application is 
prohibited. Remind subjects not to apply IP on visit days until after the visit. 
10.2.2.2 Telephone Visit (Day 7) 
Clinic staff will telephone subject to assess safety and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient(s) on study drug 
treatment days within 4 hours of study drug application is prohibited), and remind subjects not to 
apply IP on visit days until after the visit. An unscheduled clinic visit may be performed, if 
necessary. 
10.2.2.3 Visit 3 (Day 14 ±5 days) 
The following procedures will be performed on Day 14 in the study clinic: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Assess local tolerance. 
4. Record AEs and review diary. 
5. Record VIIS.   
6. Record IGA. 
7. Record palm/sole assessment.  
8. Record assessment of roughness and fissuring. 
9. Record ectropion score. 
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10. Record responses to DLQI and EQ-5D Quality of Life Questionnaires 
11. Collect a PK blood sample (all subjects). 
12. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
13. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) on study drug treatment days 
within 4 hours of study drug application is prohibited. Remind subjects not to apply IP on 
visit days until after the visit.  
14. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
10.2.2.4 Visit 4 (Day 30 ±7 days) 
The following procedures will be performed on Day 30 in the study clinic: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Perform a 12-lead ECG. 
4. Collect blood and urine for routine laboratory tests (subject must be fasting at least 
8 hours). 
5. Collect a PK blood sample (all subjects). 
6. Perform a urine pregnancy test for WOCBP. 
7. Record AEs and review diary. 
8. Assess local tolerance. 
9. Record VIIS. 
10. Record IGA. 
11. Record palm/sole assessment.  
12. Assess roughness and fissuring and record findings. 
13. Record responses to DLQI and EQ-5D Quality of Life Questionnaires 
14. Record ectropion score.  
15. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
16. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) on study drug treatment days 
within 4 hours of study drug application is prohibited. Remind subjects not to apply IP on 
visit days until after the visit.  
17. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
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18. At sites where the optional photographic substudy is conducted, take photographs of 
subjects who have provided informed consent for the substudy. 
19. Among subjects who consent to participate in the PK substudy, IP will be applied in the 
clinic at this visit, and samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours 
postdose.  
20. Provide information about OLE option. 
10.2.2.5 Telephone Visit (Day 45) 
Clinic staff will telephone subject to assess safety and to record concomitant 
medications/therapies. Staff will instruct subject on study drug application, advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient(s) on study drug 
treatment days within 4 hours of study drug application is prohibited), and remind subjects not to 
apply IP on visit days until after the visit. An unscheduled clinic visit may be performed, if 
necessary. Staff will remind subject about OLE option. 
10.2.2.6 Visit 5 (Day 60 ±7 days) 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse).  
3. Record VIIS.   
4. Record IGA. 
5. Record palm/sole assessment.  
6. Assess roughness and fissuring and record findings. 
7. Record ectropion score.  
8. Record responses to DLQI and EQ-5D Quality of Life Questionnaires 
9. Perform a urine pregnancy test for WOCBP. 
10. Collect a PK blood sample (all subjects). 
11. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
12. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
13. Record AEs and review diary. 
14. Assess local tolerance.  
15. Provide information about OLE option. 
 
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10.2.2.7 Visit 6 (90 ±7 days) or Early Termination 
The following procedures will be performed on Day 90 in the study clinic: 
1. Record concomitant medications and concomitant therapies. 
2. Perform a physical examination. 
3. Record vital signs (blood pressure and pulse). 
4. Perform a 12-lead ECG. 
5. Collect blood and urine for routine laboratory tests (subject must be fasting at least 
8 hours). 
6. Collect a PK blood sample (all subjects). 
7. Perform a urine pregnancy test for WOCBP. 
8. Record AEs and review diary. 
9. Assess local tolerance. 
10. Record VIIS. 
11. Record IGA. 
12. Record palm/sole assessment.  
13. Assess roughness and fissuring and record findings. 
14. Record responses to DLQI and EQ-5D Quality of Life Questionnaires 
15. Record ectropion score.  
16. Record responses to DLQI and EQ-5D Quality of Life Questionnaires 
17. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
18. At sites where the optional photographic substudy is conducted, take photographs of 
subjects who have provided informed consent for the substudy. 
For subjects who successfully complete the initial 12 weeks of double-blind treatment and choose 
to continue into the OLE, this visit will be the first visit of that portion of the study. All efficacy 
assessments, safety/tolerability assessments, including clinical laboratory testing, PK from 
Day 90/Week 12 will be carried over to the OLE Period and will not be repeated. Subjects will 
have up to 7 days to decide to enter the OLE; if the subject chooses to continue into OLE, the 
following additional procedures will be done: 
1. Have the subject sign OLE-specific informed consent.  
2. Measure subject’s weight. 
3. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) on study drug treatment days 
within 4 hours of study drug application is prohibited. Remind subjects not to apply IP on 
visit days until after the visit. 
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4. Weigh new study drug tubes and dispense enough additional study drug until next visit 
(only for subjects who choose to continue into the Open-label Extension). 
5. Dispense study diary. 
10.2.3 Follow-up Telephone Call (±14 days after Day 90) – Only Subjects Who Do Not 
Continue into Open-label Extension 
Clinic staff will telephone subjects who choose not to continue into the Open-label Extension 
within 14 days after Day 90 to assess any ongoing AEs.  
10.2.4 Open-label Extension  
Subjects who complete the 12-week Double-blind Treatment Period of the study may choose to 
continue into an optional 12-week Open-label Treatment Period with trifarotene cream HE1 
200 µg/g. During the OLE Period, subjects will return to the site at Weeks 14, 16, 20, 24, and 26. 
Additional PK samples will be drawn at Week 16 and 24 from all subjects who continue into the 
OLE Period.  
10.2.4.1 Telephone Visit (Day 97) 
Clinic staff will telephone subject to assess safety (AEs) and to record concomitant 
medications/therapies. Staff will to instruct subject on study drug application, to advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient(s) on study drug 
treatment days within 4 hours of study drug application is prohibited), and to remind subjects not 
to apply IP on visit days until after the visit. An unscheduled clinic visit may be performed, if 
necessary. 
10.2.4.2 Visit 7 (Week 14; Day 104 ±5 days) 
The following procedures will be performed at this study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Assess and record local tolerance/AEs and review diary. 
4. Record VIIS.   
5. Record IGA. 
6. Record palm/sole assessment.  
7. Record assessment of roughness and fissuring. 
8. Record ectropion score. 
9. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
10. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
11. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) on study drug treatment days 
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within 4 hours of study drug application is prohibited. Remind subjects not to apply IP on 
visit days until after the visit. 
10.2.4.3 Visit 8 (Week 16; Day 120 ±7 days) 
The following procedures will be performed at this study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Assess and record local tolerance/AEs and review diary. 
4. Record VIIS.   
5. Record IGA. 
6. Record palm/sole assessment.  
7. Record assessment of roughness and fissuring. 
8. Record ectropion score. 
9. Perform a 12-lead ECG. 
10. Collect blood and urine for routine laboratory tests. 
11. Perform a urine pregnancy test for WOCBP. 
12. Collect a PK blood sample (all subjects) 
13. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
14. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
15. Instruct subject on study drug application, and advise subjects regarding permitted 
emollient(s) for use on nontreatment days; use of emollient(s) on study drug treatment days 
within 4 hours of study drug application is prohibited. Remind subjects not to apply IP on 
visit days until after the visit 
10.2.4.4 Telephone Visit (Day 134) 
Clinic staff will telephone subject to assess safety (AEs) and to record concomitant 
medications/therapies. Staff will to instruct subject on study drug application, to advise subjects 
regarding permitted emollient(s) for use on nontreatment days (use of emollient(s) on study drug 
treatment days within 4 hours of study drug application is prohibited), and to remind subjects not 
to apply IP on visit days until after the visit. An unscheduled clinic visit may be performed, if 
necessary. 
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10.2.4.5 Visit 9 (Week 20; Day 150 ±7 days) 
The following procedures will be performed at each study clinic visit: 
1. Record concomitant medications and concomitant therapies. 
2. Record vital signs (blood pressure and pulse). 
3. Perform a urine pregnancy test for WOCBP. 
4. Assess and record local tolerance/AEs and review diary. 
5. Record VIIS.   
6. Record IGA. 
7. Record palm/sole assessment.  
8. Record assessment of roughness and fissuring. 
9. Record ectropion score. 
10. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
11. Weigh new study drug tubes and dispense enough additional study drug until next visit, 
and new diary. 
10.2.4.6 Visit 10 (Week 24; Day 180 ±7 days) or Early Termination 
The following procedures will be performed at Week 24 in the study clinic: 
1. Record concomitant medications and concomitant therapies. 
2. Perform a physical examination. 
3. Record vital signs (blood pressure and pulse). 
4. Perform a 12-lead ECG. 
5. Collect blood and urine for routine laboratory tests. 
6. Perform a urine pregnancy test for WOCBP. 
7. Collect a PK blood sample (all subjects) 
8. Assess and record local tolerance 
9. Record AEs and review diary. 
10. Record VIIS. 
11. Record IGA. 
12. Record palm/sole assessment.  
13. Assess roughness and fissuring and record findings. 
14. Record ectropion score.  
15. Collect returned study drug tubes; confirm study drug compliance by weighing returned 
tube contents and reviewing diaries.  
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10.2.4.7 Follow-up Evaluation – Open-Label Period (Week 26/Visit 11) 
At 14 days after the last administration of the IP, the following procedures will be performed: 
1. Perform a physical examination. 
2. Record vital signs (blood pressure and pulse). 
3. Record VIIS.   
4. Record IGA. 
5. Record palm/sole assessment.  
6. Assess roughness and fissuring and record findings. 
7. Record ectropion score.  
8. Perform a urine pregnancy test for WOCBP. 
9. Assess and record AEs occurring since the last evaluation and review diary.  
10. Record any concomitant medications/therapies. 
10.3. Assessments 
The VIIS is a valid measure of disease severity and meets the need for a clinically meaningful 
measure of success for ichthyosis studies. The VIIS scale was developed to generate a reliable 
method to assess ichthyosis clinical severity using solely scale and erythema, which are the only 
findings present in ichthyosis of every genetic cause, and occur either upon skin of normal 
thickness (lamellar subtypes) or upon thickened skin (keratoderma subtypes).13 The VIIS uses a 
5-point index to assess the level of severity of scale and erythema in each of 4 body areas: 
chest/abdomen, back, legs, and arms, for a possible overall total of 16 points (Section 10.3.1.1). 
While retinoid treatment is expected to reduce scale, it may increase erythema; therefore, in this 
study, erythema will be evaluated as part of local tolerability. 
10.3.1 Efficacy Variables 
All efficacy measurements will use scales previously used for dermatological studies or as defined 
in the following sections. 
10.3.1.1 Visual Index for Ichthyosis Severity – Scaling 
The primary endpoint is the number of subjects in each treatment group who experience successful 
resolution of LI where “success” is defined as clear/almost clear overall and at least a 50% 
reduction from Baseline at Week 12/EOT on the overall 16-point VIIS for scaling. 
The investigator will rate the subject’s condition using the 5-point VIIS for each body area 
(chest/abdomen, back, legs, and arms) and an overall score at each time point shown in the 
Schedule of Events (Section 2.2): 
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0 
Clear 
Normal skin; no perceptible scale or smoothening 
1 
Almost clear 
Areas of normal skin intermixed with areas showing 
smoothening (diminished fine skin markings; shininess; 
waxiness) or small scales (visibly separated/fractured 
stratum corneum) 
2 
Mild 
Confluent smoothening (diminished fine skin markings; 
shininess; waxiness) or small scales (visibly 
separated/fractured stratum corneum) 
3 
Moderate 
Confluent scales (visibly separated/fractured stratum 
corneum) including some large (>1cm), thick scales 
4 
Severe 
Confluent, primarily large, thick scales 
10.3.1.2 Investigator’s Global Assessment 
The IGA will be measured on a 5-point scale. 
0 
Clear 
No scaling and no roughness, no fissure 
1 
Almost Clear 
Occasional fine scales, hardly palpable roughness 
(mostly smooth), no fissure 
2 
Mild 
Small and fine scales predominate, no more than a few 
large scales, mild roughness on palpation, few fissures 
may be present 
3 
Moderate 
Large rather thick scales predominate, coarse roughness 
on palpation, few fissures may be present 
4 
Severe 
Large coalescent scales dominate, sharp edges on 
palpation with plate-like hyperkeratosis, many fissures 
may be present 
 
10.3.1.3 Palm/Sole Assessment 
Thickening of the skin on the palms and soles will be measured on a 5-point scale. 
0 Clear 
No thickening, no roughness, no fissure 
1 Almost Clear 
Only slight thickening, minimal to no roughness, no 
fissures 
2 Mild 
Some thickening, mild roughness on palpation, few 
fissures may be present 
3 Moderate 
Substantial and diffuse thickening, coarse roughness on 
palpation may be present, fissures may be present 
4 Severe 
Very thickened and rough skin, numerous fissures 
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10.3.1.4 Individual Score for Roughness 
The amount of roughness of the skin overall will be measured on a 5-point scale. 
0 Clear 
Smooth skin 
1 Almost Clear 
Hardly palpably roughness 
2 Mild 
Mild roughness (fine sand paper-like) 
3 Moderate 
Moderate, coarse roughness (coarse sand paper-like) 
4 Severe 
Very coarse skin (broken cornflakes-like) 
10.3.1.5 Fissuring Assessment 
Fissuring will be assessed by recording the presence or absence of fissures, the number of fissures 
present, and the pain associated with each fissure. The subject will assess pain associated with 
fissures as ranging from 0–3 (none, mild, moderate, severe).  
10.3.1.6 Dermatology Life Quality Index 
The DLQI is a dermatology-specific Quality of Life instrument. It is a simple 10-question validated 
questionnaire with 6 domains (symptoms and feelings, daily activities, leisure, work and school, 
personal relationships, and treatment); higher scores indicate poorer quality of life. The DLQI is 
the most frequently used instrument in studies of randomized controlled trials in dermatology.  
10.3.1.7 EQ-5D Quality of Life Questionnaire 
The EQ-5D is a standardized instrument developed by the EuroQol Group as a measure of health-
related quality of life used in a wide range of health conditions and treatments. The EQ-5D consists 
of a descriptive system and the EQ visual analog scale (VAS).  
The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. The EQ VAS records the subject’s self-rated health on a 
vertical VAS. This can be used as a quantitative measure of health outcome that reflects the 
subject’s own judgement. 
10.3.1.8 Ectropion Severity Score  
The Ectropion Severity Score (ESS), has a maximum score of 8 points. A higher score indicates a 
worse ectropion. The score takes the severity of ectropion in terms of lateral and medial apposition, 
scleral show, conjunctival show, and roundness of the eye into account and gives an indication of 
the functional aspects involved in ectropion by scoring redness, excess tear film, and the position 
of the lacrimal punctum.14 
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10.3.2 Clinical Pharmacology 
10.3.2.1 Pharmacokinetic Analysis Methods  
The pharmacokinetic characterization of drug concentrations for each dose to be profiled will use 
noncompartmental analysis (NCA).  
10.3.2.2 Pharmacokinetic Parameters 
Samples for PK will be drawn from all subjects at Baseline and at each clinic visit for trough 
values.  
Subjects who provide written informed consent to participate in the optional PK substudy will 
provide blood samples for PK analysis predose on Day 1 and at 1, 2, 4, 8, 12, and 24 hours postdose 
on Day 1 and Day 30. 
The PK parameter estimates will be completed using WinNonlin (Pharsight Corporation) software 
using the actual elapsed times from dose administration to sample collection (i.e., not nominal 
time). 
Standard PK parameters assessed will include measures of the extent of absorption using estimates 
of the area-under-the-curve (AUC) and rate-of-absorption using the maximum concentration 
(Cmax) and the time of Cmax (Tmax). Additional details of the parameters and their calculation and 
evaluation will be included in the SAP. 
Table 10-1 shows the PK parameters that will be computed for each subject for samples obtained 
over the planned sampling intervals. 
Table 10-1: 
Pharmacokinetic Parameters 
Parameter 
Description of Parameter 
Cmax 
Maximum (or peak) serum concentration  
Tmax 
Time at which Cmax is observed 
AUC(0-t) 
Area under the plasma concentration-time curve from time 0 to the time of the last 
quantifiable plasma concentration 
AUC(0-inf) 
Area under the plasma concentration-time curve from time 0 to infinity (if data permits) 
t1/2 
Apparent first order terminal elimination half-life 
λz 
Apparent terminal phase rate constant (if data permits) 
10.3.3 Sample Collection 
Samples will be collected at the time points specified in the Schedule of Events (Section 2.2). 
Specimen preparation, handling, shipment, and storage for the complete blood count, chemistry, 
and urinalysis are described in the study laboratory manual. 
Blood 
Each blood sample will be 3 mL/kg in volume. The total amount of blood to be drawn for serial 
PK assessments will be a maximum of 5 mL/kg per subject over a 24-hour period.  
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Urine 
Urinalysis will be performed at central laboratory. Dipstick and urine pregnancy tests will be 
conducted on site.  
10.3.4 Safety Variables 
Safety assessments will include the evaluation of AEs, including local tolerability 
(stinging/burning, pruritus, and erythema), clinical laboratory assessments, vital signs, 12-lead 
ECGs, and physical examinations. 
10.3.4.1 Clinical Laboratory Safety Assessments 
10.3.4.1.1 Clinical Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points specified in the 
Schedule of Events (Section 2.2). 
Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
platelet count (or estimate), white blood cell count including differential 
Serum Chemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, 
creatinine, glucose, sodium, potassium, chloride, bicarbonate, lactate 
dehydrogenase, uric acid, total cholesterol, high-density lipoprotein, low-
density lipoprotein, triglycerides 
Coagulation Panel: prothrombin time, partial thromboplastin time, fibrinogen 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones 
Pregnancy Test: 
for women of childbearing potential only; serum at Screening, urine at 
each other visit. 
Serology 
Hepatitis B surface antigen, and hepatitis C 
 
All blood samples for the clinical laboratory tests must be taken in a fasting state, at least 8 hours 
after the previous drug application.  
Blood and urine samples for hematology, and serum chemistry will be sent to a central laboratory 
for analysis. Urine pregnancy tests and dipstick will be conducted at the study sites. 
10.3.4.1.2 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens in 
both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
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In addition to appropriate handling of subject samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples. Procedures and regulations for the packaging and shipping 
of infectious samples are outlined in the study laboratory manual. The investigator is responsible 
for ensuring that all study samples that are to be transported to another location are packed and 
shipped appropriately according to the applicable regulations.  
Samples for assessment of clinical laboratory tests will be transported to Clinical Reference 
Laboratory (see the study laboratory manual for addresses). 
10.3.4.1.3 Evaluation of Clinical Laboratory Values 
The normal ranges of values for the clinical laboratory assessments in this study will be provided 
by the responsible laboratory and submitted to Mayne Pharma LLC prior to beginning the study. 
They will be regarded as the reference ranges on which decisions will be made. 
If a laboratory value is out of the reference range, it is not necessarily clinically significant. The 
investigator must evaluate the out-of-range values and record his or her assessment of the clinical 
significance in the appropriate eCRF. 
All clinical laboratory values that in the investigator’s opinion show clinically significant or 
pathological changes during or after termination of treatment must be reported as AEs and 
followed, as described in Section 11.2.5. 
All measurements described in this section are recognized standard methods. 
10.3.4.2 Clinical Examinations 
10.3.4.2.1 Vital Signs 
Vital signs, including height and weight (only assessed at Screening), blood pressure and pulse 
will be measured.  
10.3.4.2.2 Twelve-lead Electrocardiogram 
A standard 12-lead ECG will be performed after the subject has been supine for at least 5 minutes. 
All ECG recordings will be identified with the subject number, date, and time of the recording. 
10.3.4.2.3 Physical Examination 
A complete physical examination excluding the genitourinary examination will be performed as 
indicated in the Schedule of Events (Section 2.2). 
10.3.4.2.4 Other Safety Variables 
Local tolerability will be assessed on a 0–3 scale (none, mild, moderate, severe). All application 
site reactions will be recorded as AEs. 
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10.3.4.3 Adverse Events 
The definitions and management of AEs, and any special considerations for AEs, are provided in 
Section 11. 
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11. ADVERSE EVENTS 
11.1. Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not related to the medicinal product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a 
pre-existing condition is considered an AE.) 
Events that occur in subjects treated with control product are also considered AEs. 
11.1.2 Adverse Drug Reaction 
All noxious and unintended responses to an investigational product related to any dose should be 
considered adverse drug reactions (ADRs). 
The phrase “responses to an investigational product” means that a causal relationship between an 
investigational product and an AE is at least a reasonable possibility, i.e., the relationship cannot 
be ruled out. All AEs judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship to an IP qualify as ADRs. 
All AEs for which the judgment of relationship to IP is “possible” or higher will be considered 
ADRs. If a relationship to IP is not provided, then the AE must be treated as if it were “possible.”  
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction 
An expected AE or ADR is one for which the nature or severity is consistent with the known AE 
profile of the product. For a preapproval test product, the known information is contained in the 
IB. For a marketed product, the known information is contained in the current package insert for 
the product. 
An unexpected adverse event (UAE) or unexpected adverse drug reaction (UADR) is one for 
which the nature or severity of which is not consistent with the applicable product information 
(e.g., Investigator’s Brochure [IB] for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product). For example, hepatic necrosis 
would be unexpected (greater severity) if the IB only listed elevated hepatic enzymes or hepatitis. 
Likewise, cerebral thromboembolism and cerebral vasculitis would be unexpected (greater 
specificity) if the IB only listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction constitute unexpected events.  
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11.1.4 Serious Adverse Events/Drug Reaction 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. 
An elective hospital admission to treat a condition present before exposure to the IP, or a 
hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or 
event as an SAE. Further, an overnight stay in the hospital that is only due to transportation, 
organization, or accommodation problems and without medical background does not need 
to be considered an SAE. 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the IP 
during pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject that has 
received an IP is not considered an SAE unless it is suspected that the IP(s) interacted with 
a contraceptive method and led to the pregnancy.  
• is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result 
in hospitalization, development of drug dependency, or drug abuse. The occurrence of 
malignant tumors is also to be considered serious.  
11.1.5 Significant Adverse Events 
Other significant AEs are defined as marked hematological and other laboratory abnormalities 
(other than those meeting the definition of serious) and any events that led to an intervention, 
including withdrawal of test drug, dose reduction, or significant additional concomitant therapy. 
11.1.6 Treatment-Emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening is after the first application 
of IP (trifarotene or vehicle) and not more than 14 days after the last application of IP. 
11.2. Event Assessment and Follow-up of Adverse Events 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care or upon review by a study 
monitor. 
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All reported AEs, including local and systemic AEs not meeting the criteria for SAEs will be 
captured on the appropriate eCRF. Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event. 
All reported AEs occurring while on study must be documented appropriately regardless of 
relationship. All reported AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
Changes in the severity of a reported AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
Study clinic personnel will record all reportable events with start dates occurring any time after 
informed consent is obtained until 14 (for nonserious AEs) or 30 days (for SAEs) after the last day 
of study participation. At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit. Events will be followed for outcome information until resolution or 
stabilization. 
11.2.1 Assessment 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. In addition, 
although local tolerability will be assessed on a 0-3 scale, all application site reactions should be 
recorded as AEs. 
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11.2.2 Evaluation 
11.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as follows: 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.4. 
11.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.4. 
11.2.2.3 Action(s) Taken 
All AEs will be treated/managed according to standard practice. The following actions may be 
taken with regard to the IP. Section 9.4 describes dose adjustment and stopping rules for individual 
subjects. 
Action(s) taken may consist of the following: 
Dose not changed 
An indication that a medication schedule was maintained. 
Dose reduced 
An indication that a medication schedule was modified by subtraction, 
either by changing the frequency, strength, or amount. 
Drug interrupted 
An indication that a medication schedule was modified by temporarily 
terminating a prescribed regimen of medication. 
Drug withdrawn 
An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
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11.2.2.4 Outcome at the Time of Last Observation 
The outcome of an AE at the time of last observation will be classified as follows: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
*Only select fatal as an outcome when the AE results in death. If more than one AE is judged to 
be possibly related to the subject’s death, the outcome of death should be indicated for each such 
AE. Although “fatal” is usually an event outcome, events such as sudden death or unexplained 
death should be reported as SAEs. 
11.2.2.5 Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AE’s relationship to the IP. The categories for 
classifying the investigator’s opinion of the relationship are as follows: 
Not related 
An AE with sufficient evidence to accept that there is no causal relationship 
to IP administration (e.g., no temporal relationship to drug administration, 
because the drug was administered after onset of event; investigation shows 
that the drug was not administered; another cause was proven.) 
Unlikely 
related 
An AE, including laboratory test abnormality, with a temporal relationship to 
IP administration that makes a causal relationship improbable, and in which 
other drugs, events, or underlying disease provide plausible explanations. 
Possibly related An AE with a reasonable time sequence to administration of the IP, but that 
could also be explained by concurrent disease or other drugs or events. 
Information on drug withdrawal may be lacking or unclear. 
Related 
An AE occurring in a causal plausible time relationship to IP administration 
that cannot be attributed to a concurrent disease or other drugs, chemicals, or 
events. The AE relationship to the IP must be assessed separately by the 
investigator and Mayne Pharma LLC. 
 
11.2.3 Documentation 
All AEs that occur within the period of observation for the study must be documented in the eCRF 
with the following information, where appropriate. (The period of observation for the study is 
described in Section 11.2.) 
• AE name or term 
• When the AE first occurred (start date and time) 
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• When the AE stopped (stop date and time or an indication of “ongoing”) 
• Severity of the AE 
• Seriousness (hospitalization, death, etc.) 
• Actions taken 
• Outcome 
• Investigator opinion regarding the AE relationship to the IP(s) 
11.2.4 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. If such treatment constitutes a deviation from the protocol, the subject may be withdrawn 
for treatment but continue to be followed for efficacy and safety in the study. The decision about 
whether the subject may continue in the study will be made by the sponsor after consultation with 
the investigator and/or medical monitor. 
If AEs occur in a subject that are not tolerable, the investigator must decide whether to stop the 
subject’s involvement in the study and/or treat the subject. Special procedures may be 
recommended for the specific IP, such as the collection of a serum sample for determining blood 
concentrations of IP, specific tapering procedures, or treatment regimens, as appropriate. 
It is not necessary to unblind a subject’s treatment assignment in most circumstances, even if an 
SAE has occurred. If unblinding is necessary, see Section 9.6 for a description of the unblinding 
procedures. 
11.2.5 Follow-up 
Any AE will be followed (up to a maximum of 14 days after the last dose of IP) to a satisfactory 
resolution, until it becomes stable, or until it can be explained by another known cause(s) (i.e., 
concurrent condition or medication) and clinical judgment indicates that further evaluation is not 
warranted. All findings relevant to the final outcome of an AE must be reported in the subject’s 
medical record and recorded on the eCRF page.  
11.2.6 Reporting 
11.2.6.1 Serious Adverse Events 
The investigator or designee must report all SAEs promptly to Premier Research within 24 hours 
of first becoming aware of the event by e.g., completing, signing and dating the Serious Adverse 
Event Report Form, verifying the accuracy of the information recorded in the form with the source 
documents and eCRF, and sending the SAE form to the Premier Research by one of the following 
methods:  
Email: globalPV-US@premier-research.com 
Email: PVDS-ROW@premier-research.com 
Fax number: +1 215 972 8765 
Fax number: +421 2 6820 3713 
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This written report should be submitted on the SAE form provided for this purpose. At the time of 
first notification, the investigator or designee should provide the following information, if 
available: 
• Protocol number 
• Reporter (study site and investigator) 
• Suspect IP 
• Subject’s study number 
• Subject’s year of birth 
• Subject’s gender 
• Date of first dose of IP(s) 
• Date of last dose of IP(s), if applicable 
• Adverse event term 
• Date of occurrence of the event 
• A brief description of the event, outcome to date, and any actions taken 
• The seriousness criteria(on) that were met 
• Concomitant medication at onset of the event 
• Relevant medical history information 
• Relevant laboratory test findings 
• Investigator’s opinion of the relationship to IP(s) (“Is there a reasonable possibility that 
the IP caused the SAE? Yes or No?”) 
• Whether and when the investigator was unblinded as to the subject’s treatment 
assignment  
Any missing or additional relevant follow-up information concerning the SAE should be sent to 
the sponsor/sponsor representative via the same contact details above as soon as possible on a 
follow-up SAE Report Form, together with the following minimal information (initial report, 
adverse event, date of occurrence, subject identification (ID), study ID, IP, and site number); this 
will allow the follow-up information to be linked to the initial SAE report.  
Specific information may be requested by the Premier Research Pharmacovigilance Department 
using a follow-up request form or via email communication. 
The investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his or her health authorities, institutional review board 
(IRB)/independent ethics committee (IEC), principal and coordinating investigators, study 
investigators, and institutions. Each investigator is obligated to learn about the reporting 
requirements for investigators in his/her country. The study monitor may be able to assist with 
this. 
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11.2.6.2 Adverse Drug Reactions 
All ADRs should be reported by the investigator in the eCRF.  
Suspected serious ADRs must be reported to the sponsor immediately, regardless of the time 
elapsed since the end of the observation period. 
11.2.6.3 Nonserious Adverse Events 
Nonserious AEs will be recorded in the eCRF and reported by Premier Research to Mayne Pharma 
LLC in aggregate monthly status reports. 
11.3. Special Considerations 
11.3.1 Adverse Events of Special Interest 
Since topical retinoids are associated with local application site AEs, particularly when beginning 
treatment, these events will be followed closely during the study and considered AEs of special 
interest (AESIs). 
11.3.2 Pregnancy 
All WOCBP who participate in the study should be counseled on the need to practice adequate 
birth control and on the importance of avoiding pregnancy during study participation. Women 
should be instructed to contact the investigator or study staff immediately if pregnancy occurs or 
is suspected. 
Pregnancy testing will be conducted prior to administration of the IP on every woman of 
childbearing potential. A woman who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered to be a screening failure. 
A woman who becomes pregnant during IP treatment will be immediately discontinued from study 
treatment. The investigator must report the pregnancy of any woman who becomes pregnant 
during or within 30 days after discontinuing treatment as if it were an SAE within 24 hours of 
learning of the pregnancy, to Premier Research Pharmacovigilance using the Pregnancy Data 
Collection Form via the same fax number and/or email address as for SAE reporting. The 
investigator should contact the designated individual(s) who receive SAE notification and record 
information related to the pregnancy on an SAE and AE form (entering the event temporarily as 
nonserious on both forms) provided by the sponsor or its designee. If a partner of a male study 
subject becomes pregnant, the investigator must report the pregnancy as soon as possible after 
learning of it to the Premier Research Pharmacovigilance using the Pregnancy Data Collection 
Form. A separate pregnant partner ICF will be required. 
Early Termination Visit assessments are required as soon as possible after learning of the 
pregnancy in a study subject. The investigator is also responsible for following the pregnancy until 
delivery or termination. These findings must be reported on the Exposure in Utero form and 
forwarded to the designated individual(s). The event meets the SAE criterion only if it results in a 
spontaneous abortion or a congenital anomaly. 
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12. DATA SAFETY MONITORING BOARD 
Safety oversight will be under the direction of a DSMB composed of individuals with the 
appropriate expertise, including LI. Members of the DSMB should be independent from the study 
conduct and free of conflict of interest, or measures should be in place to minimize perceived 
conflict of interest. The DSMB will operate under a charter that will be finalized prior to the start 
of the study. The DSMB will meet at least 3 times during the conduct of the study: when the study 
begins, when 15 adult subjects have enrolled in Cohort A and have completed at least 28 days of 
treatment, and after 60 subjects have enrolled in the study. 
The DSMB will meet after subjects in Cohort A have completed at least 28 days of double-blind 
treatment to review aggregate safety and tolerability data. The data will remain blinded unless an 
issue or trend arises that requires unblinding. At that time, the DSMB will decide whether Cohort B 
(adults and subjects aged 12–17) may begin enrolling. The DSMB will have the authority to 
recommend to the sponsor that the study be placed on hold or discontinued if serious safety issues 
are discovered. The DSMB will provide its input to Mayne Pharma LLC. 
In case of significant toxicity, the DSMB may choose to review the available safety data and 
recommend stopping recruitment in a particular dose group. If toxicity is observed, the treatment 
assignment for the subject(s) involved may be unblinded by the DSMB at its discretion. 
Stopping rules for individual subjects are in Section 9.4.1. 
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13. STATISTICS 
13.1. Statistical Analysis 
This section presents a summary of the planned statistical analyses. A SAP that describes the 
details of the analyses to be conducted will be written prior to database lock.  
Unless otherwise indicated, all testing of statistical significance will be two-sided, and a difference 
resulting in a P value of ≤ 0.05 will be considered statistically significant.  
Summary statistics will be provided for the variables described below. For continuous variables, 
these statistics will include the number of subjects, mean, standard deviation (SD), median, 
minimum, and maximum. For categorical variables, these statistics will include the number and 
percentage of subjects in each category. 
The primary analysis period is the first 12 weeks of treatment (i.e., the Double-blind Period). 
Overall unblinding will take place at the end of the Double-blind Period of the study only after the 
database is locked. A second analysis will take place for endpoints assessed from Week 12 through 
the OLE Period. The baseline for the safety and efficacy parameters will be measured at Visit 1 or 
Visit 2, per the Schedule of Events for both the Double-blind (Table 2-1) and OLE (Table 2-2) 
Periods. 
13.1.1 Analysis Populations 
The following 5 analysis populations are planned for the Double-blind Period of this study:  
• Safety: all subjects who are randomized to treatment and receive at least 1 application of 
study drug in the Double-blind Period. This population will be the primary population for 
analyses of safety. 
• Intent-to-treat (ITT): all randomized subjects.  
• Modified intent-to-treat (mITT): all subjects in the safety population with at least 
1 postbaseline assessment of efficacy in the Double-blind Period.  
• Per-protocol (PP): subjects in the mITT Population who met all inclusion criteria and no 
exclusion criteria, were compliant with study drug application, and who had no 
significant protocol deviations. 
• Pharmacokinetic: all subjects in the Safety Population who have at least 1 plasma sample 
with quantifiable concentration. This population will be used to summarize all PK 
endpoints. 
The following analysis populations are planned for the OLE Period of this study: 
• OLE Safety: all subjects who complete the 12-week Double-blind Treatment Period and 
receive at least 1 application of study drug in the OLE Period. 
• OLE ITT: all subjects who complete the 12-week Double-blind Treatment Period and 
sign the OLE informed consent. 
• OLE mITT: all subjects in the OLE safety population with at least 1 assessment of 
efficacy after Visit 6. 
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• OLE PP: all subjects in the OLE mITT population who met all inclusion criteria and no 
exclusion criteria, were compliant with study drug application from baseline through 
EOT, and who had no significant protocol deviations throughout the study. 
Inclusion in the analysis populations will be determined prior to database lock. 
If a subject is randomized incorrectly or is administered the incorrect IP, analyses of the ITT and 
mITT populations will be based on the assigned treatment whereas all other analyses will be based 
on the actual treatment received. 
13.1.2 Study Subjects and Demographics 
13.1.2.1 Disposition and Withdrawals 
For the Double-blind Period, the numbers of subjects randomized, completing Week 12 of the 
study, and withdrawing early from the Double-blind Period, along with reasons for withdrawal, 
will be tabulated overall and by randomized treatment group. The number of subjects in each 
analysis population will be reported. The number of subjects completing study milestones will also 
be tabulated by randomized treatment group. This analysis will be conducted for the ITT 
population. 
For the OLE Period, the number of subjects entering the OLE Period, completing the study, and 
withdrawing early, along with reasons for withdrawal, will be tabulated overall. The number of 
subjects in each analysis population will be reported. The number of subjects completing study 
milestones will also be tabulated. This analysis will be conducted for the OLE ITT population. 
13.1.2.2 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol or International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) requirements. The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions are 
to be developed by the site and implemented promptly.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations promptly. All deviations must be addressed in study source documents, and reported to 
Premier Research or Mayne Pharma LLC. Protocol deviations must be sent to the reviewing IRB 
per their policies. The site investigator is responsible for knowing and adhering to the reviewing 
IRB requirements. Further details about the handling of protocol deviations will be included in the 
protocol deviation guidance plan. 
13.1.2.3 Demographics and Other Baseline Characteristics 
These analyses will be conducted for the ITT and OLE ITT populations.  
Demographic variables will include age, sex, race, ethnicity, height, weight, and BMI. Baseline 
subject characteristics will include medical history, physical examination findings, and VIIS score. 
Prior and concomitant medications will be summarized by randomized treatment group, by the 
number and percentage of subjects taking each medication, and classified using World Health 
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Organization Drug Dictionary (WHO-DD) Anatomical Therapeutic Chemical (ATC) classes and 
preferred terms. 
13.1.3 Exposure and Compliance 
Investigational product administration will be summarized in terms of each subject’s dose, and in 
terms of duration of exposure for each period. Descriptive statistics for these quantities, including 
the mean, median, SD, minimum, maximum, and quartiles, will be provided by treatment group. 
Additionally, the number of subjects who are compliant with investigational product will be 
presented by treatment group for the Double-blind Period and overall for the OLE.  
13.1.4 Efficacy Analysis 
The mITT population will be used as the primary population for the primary analysis of efficacy 
at Week 12. All efficacy analyses will be repeated as secondary analyses in the ITT and PP 
populations for the Double-blind Period. Efficacy analyses will also be repeated in the OLE Period 
using the OLE mITT and OLE PP populations. No formal inferential analyses will be conducted 
for efficacy variables in the OLE Period. 
13.1.4.1 Efficacy Endpoints 
Primary efficacy endpoint: The number of subjects in each treatment group who experience 
successful resolution of LI where “success” is defined as clear/almost clear overall and at least a 
50% reduction from Baseline at Week 12/ EOT in the Double-blind Period on the overall 16-point 
VIIS for scaling (i.e., 0-4 points on each of the 4 body areas: chest/abdomen, back, arms, and legs). 
Secondary: The secondary endpoints are as follow: 
• The difference in mean scores between the active trifarotene cream HE1 and 
vehicle groups in the following assessment indices: 
 IGA (Scale: 0-4) for each body area 
 Palm/sole Assessment (Scale: 0–4)  
 Individual score for roughness (Scale: 0–4) overall 
• The difference in proportion of subjects with presence of fissures 
(presence/absence, number of fissures, and pain associated with fissures [on a 0-3 
scale]) between the active trifarotene cream HE1 and vehicle groups  
• Quality of life per Dermatology Life Quality Index (DLQI) 
Exploratory: The exploratory endpoints are as follow: 
• The difference in mean ectropion scores (ESS of 0–8) between the active trifarotene 
cream HE1 and vehicle groups  
• Quality of life per EQ-5D-5L 
13.1.4.2 Primary Analysis 
For the Double-blind Period only, the number and proportion of subjects in each treatment group 
with successful resolution of LI by Week 12/EOT will be presented along with the difference in 
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proportions between each trifarotene cream HE1 group and vehicle. 95% confidence intervals (CI) 
will be provided for proportions. Generalized estimating equations (GEE) for binary response will 
be used to model the odds of successful resolution of LI with treatment group as a predictor. Other 
covariates, such as baseline VIIS scores, baseline characteristics, and interactions may be included. 
Various correlation matrix structures will be explored to model the within subject correlation. 
Additionally, the difference in mean VIIS score at Week 12/EOT between the active trifarotene 
cream HE1 groups and vehicle group will be analyzed using a 2-sided, 2-sample Wilcoxon rank-
sum test at the 5% significance level. The null hypothesis is that the mean of each trifarotene cream 
HE1 group is equal to the mean of the vehicle group.  
Descriptive summaries (such as mean, standard error, median, minimum, and maximum) and the 
changes from baseline will be provided for VIIS scores for both periods.  
13.1.4.3 Secondary Analyses 
Secondary and exploratory efficacy endpoints will be analyzed separately for each period 
(Double-blind and OLE) using descriptive statistics.  
Additionally, for the Double-blind Period only, change from Baseline through Week 12 will be 
presented and analyzed using a mixed model for repeated measures (MMRM). The model will 
include the change from baseline score as the dependent variable, treatment group as a fixed effect, 
subject as a random effect, and baseline score value as a covariate. Frequencies of results and 95% 
CIs will also be reported and scores will be analyzed as categorical variables using the Cochran-
Mantel-Haenszel test. 
For subjects who report having fissures, descriptive summaries of the number of fissures and pain 
related to fissures will also be presented by treatment group and body area for each period. 
The DLQI scores will also be analyzed using descriptive statistics through Week 12. 
13.1.4.4 Exploratory Analyses 
Descriptive summaries and the changes from baseline will be provided for ectropion scores and 
EQ-5D-5L scores by visit for each period. No formal inferential analyses will be conducted for 
exploratory endpoints. 
13.1.4.5 Corroborative, Sensitivity, and Other Analyses 
To assess the effect of missing data on the primary efficacy analysis, a sensitivity analysis will be 
performed using LOCF for the Double-blind Period only. Imputation will not be performed in the 
OLD period.  
For analyses involving study site, if the number of subjects per site is small, sites may be pooled 
for safety and efficacy analysis or omitted from statistical models as the anticipated number of 
subjects per site is small, treatment is self-administered, and the sites are using standardized 
procedures for all assessments. If the distribution of enrollments at sites is such that one or few are 
enrolling a majority of subjects, a subgroup analysis by site may be performed. The final 
determination will be made prior to database lock.  
Details of these analyses will be further detailed in the SAP. 
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13.1.5 Clinical Pharmacology Analyses 
13.1.5.1 Pharmacokinetics 
For noncompartmental analysis, plasma concentrations will be listed and summarized at each time 
point using descriptive statistics. Descriptive statistics reported will include the arithmetic mean, 
SD, CV%, geometric mean, minimum, maximum, and median. Only the range and the median will 
be reported for Tmax, as this is a categorical parameter. The PK parameters will also be 
summarized by treatment using descriptive statistics.  
Individual plasma concentration plots and mean data graphs will be produced using both linear 
and semi-logarithmic scales. Mean data graphs will show plasma concentration profiles by 
treatment group. 
Pharmacokinetic plasma parameter estimates and summaries will be completed for the subjects in 
the PK population. Testing of PK parameters will be outlined in the SAP. 
13.1.6 Safety and Tolerability Analyses 
Safety analyses through Week 12 of the Double-blind Period will be conducted using data from 
the Safety Population and safety analyses in the OLE Period will be conducted using the OLE 
Safety Population (as defined in Section 13.1.1). Safety variables include treatment-emergent AEs, 
clinical laboratory values, vital signs, ECG readings, and physical examination results. No formal 
inferential analyses will be conducted for safety variables in either period. 
13.1.6.1 Local Tolerability 
During all clinic visits, the investigator will assess local tolerability (Scale: 0–3 [none, mild, 
moderate, severe]) on each of the 4 body areas (chest/abdomen, back, legs, arms). Descriptive 
summaries will be presented by period, treatment group, and visit. 
13.1.6.2 Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 20.1 or higher.  
Treatment-emergent AEs are defined as: 
• AEs with onset at the time of or following the start of treatment with IP through the 
Follow-up Visit or Early Termination Visit, whichever occurs first, or 
• AEs starting prior to the start of treatment but increasing in severity or relationship at the 
time of, or following, the start of treatment with IP through the Follow-up Visit or Early 
Termination Visit, whichever occurs first. 
The number and percentage of subjects with AEs will be displayed by each treatment group in the 
Double-blind Period and overall in the OLE by system organ class and preferred term. Summaries 
of AEs by severity and relationship to IP will also be provided. Serious adverse events and AEs 
resulting in discontinuation of IP will be summarized separately in a similar manner. Subject 
listings of AEs, SAEs, and AEs causing discontinuation of IP will be produced. 
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13.1.6.3 Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from baseline values will be presented for clinical laboratory values for each treatment 
group at each time point in each period. 
The number of subjects with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from baseline (shift tables) for each clinical 
laboratory parameter by treatment group and by study visit in each period.  
Laboratory values that are outside the normal range will also be flagged in the data listings and 
presented with the corresponding normal ranges. Any out-of-range values that are identified by 
the investigator as being clinically significant will also be shown in a data listing. 
13.1.6.4 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for systolic blood pressure (SBP), diastolic blood pressure 
(DBP), and pulse for each period. 
The number of subjects with vital signs values categorized as below, within, or above normal 
ranges will be tabulated showing change from baseline (shift tables) for each parameter by period, 
by treatment group and by study visit. Pre and post-treatment values may also be presented with 
an analysis of mean changes from baseline. 
13.1.6.5 Twelve-lead Electrocardiograms 
The number and percentage of subjects with normal and abnormal ECG findings will be 
summarized for each treatment group at each time point in each period. Abnormal results will be 
grouped as clinically significant and not clinically significant. 
A comparison of QT results will be presented. Summary statistics will be displayed by period, by 
treatment group, and by visit for QT and the QT interval corrected for heart rate (QTc) calculated 
using Fridericia’s QT correction methods.  
Descriptive summaries (mean, SD, median, minimum, and maximum) will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTcF interval (Fredericia’s correction 
methods), and HR for each treatment group at each time point in each period. 
13.1.6.6 Physical Examination Findings 
The number and percentage of subjects with normal and abnormal findings in the complete 
physical examination will be displayed for each treatment group in each period. 
13.1.7 Interim Analysis 
No interim analyses are planned.  
13.2. Sample Size Determination 
Accounting for a 20% drop-out/nonevaluable rate, a total sample size of 120 subjects randomized 
in a 1:1:1 ratio to 2 active trifarotene cream HE1 arms and a vehicle cream arm will provide >80% 
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power to detect a difference between each separate trifarotene cream HE1 arm (32 evaluable 
subjects) and the vehicle cream arm (32 evaluable subjects) using a 2-sample t-test assuming a 
mean difference of at least 1.0 and a standard deviation of 1.4 or lower. This study is not powered 
to detect a difference between the 2 active arms. 
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14. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
14.1. Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 16). The sponsor reserves the right to withdraw a subject from the study (Section 8.3), to 
terminate participation of a study site at any time (Section 14.7), and/or to discontinue the study 
(Section 14.6 for US studies/Section 14.6.1 for studies conducted outside of the US). 
Mayne Pharma LLC agrees to provide the investigator with sufficient material and support to 
permit the investigator to conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 18.1), the investigator indicates that he or she 
has read the protocol carefully, fully understands the requirements, and agrees to conduct the study 
in accordance with the procedures and requirements described in this protocol.  
The trial will be conducted in accordance with ICH GCP, and the applicable United States (US) 
Code of Federal Regulations (CFR). The principal investigator will assure that no deviation from, 
or changes to, the protocol will take place without prior agreement from the Investigational New 
Drug (IND) sponsor, funding agency and documented approval from the IRB, except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection and ICH GCP training. 
Investigators should ensure that all persons who are delegated study-related responsibilities are 
adequately qualified and informed about the protocol, the IP(s), and their specific duties within the 
context of the study. Investigators are responsible for providing Mayne Pharma LLC with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
14.1.3 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying study product may inspect all 
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documents and records required to be maintained by the investigator, including, but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. 
The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at Premier Research. This will not include the participant’s contact 
or identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by clinical sites and by Premier Research staff will be secured and password protected. At the end 
of the study, all study databases will be de-identified and archived at the Premier Research 
14.2. Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from the sponsor or its designee that the study can be initiated at the study site. The study site will 
not be authorized for study initiation until: 
1. The study site has received the appropriate IRB/IEC approval for the protocol and the 
appropriate ICF. 
2. All regulatory/GCP documents have been submitted to and approved by the sponsor or its 
designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
14.3. Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study. Subjects may 
only be rescreened once 30 days or more after the original Screening Visit. If a subject is eligible 
to enter the study after having previously failed screening, the subject will be assigned a new 
subject identification number. 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
14.4. Study Documents 
All documentation and material provided by Mayne Pharma LLC for this study are to be retained 
in a secure location and treated as confidential material. 
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14.4.1 Informed Consent 
Consent and assent forms describing in detail the study intervention, study procedures, and risks 
are given to the participant and written documentation of informed consent is required prior to 
starting intervention/administering study intervention. The informed consent and assent forms are 
submitted with this protocol. 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent and assent forms will 
be IRB-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may 
arise. A verbal explanation will be provided in terms suited to the participant’s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research participants. 
Participants will have the opportunity to carefully review the written consent and assent forms and 
ask questions before signing. The participants should have the opportunity to discuss the study 
with their family or surrogates or think about it before agreeing to participate. The participant will 
sign the informed consent or assent document prior to any procedures being done specifically for 
the study. Participants must be informed that participation is voluntary and that they may withdraw 
from the study at any time, without prejudice. A copy of the informed consent and assent document 
will be given to the participants for their records. The informed consent process will be conducted 
and documented in the source document (including the date) and the form signed before the 
participant undergoes any study-specific procedures. The rights and welfare of the participants will 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
14.4.2 Investigator’s Regulatory/Good Clinical Practice Documents 
The regulatory/GCP documents are listed below. 
• Signed original protocol (i.e., Investigator’s Agreement) 
• Curricula vitae of all investigators and subinvestigators 
• Name and address of the laboratories 
• List of laboratory reference ranges, and if available, a quality certificate 
• Form Signature Log/Delegation of Study-related Duties 
• Approved ICF and subject materials 
• FDA1572 and financial disclosure forms, as applicable (US sites) 
• Any other relevant GCP documents 
The regulatory/GCP documents must be received from the investigator and reviewed and approved 
by Mayne Pharma LLC or its designee before the study site can initiate the study and before Mayne 
Pharma LLC will authorize shipment of IP to the study site. Copies of the investigator’s 
regulatory/GCP documents must be retained at the study site in a secure location. Additional 
documents, including a copy of the protocol and applicable amendment(s), the trifarotene 
(CD5789) Cream IB, eCRF completion guidelines, copies of regulatory references, copies of 
IRB/IEC correspondence, and IP accountability records should also be retained as part of the 
investigator’s regulatory/GCP documents. It is the investigator’s responsibility to ensure that 
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copies of all required regulatory/GCP documents are organized, current, and available for 
inspection. 
14.4.3 Case Report Forms 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign an 
ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the study to ensure that the study information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered in the electronic data capture 
(EDC) system according to the completion guidelines provided by the sponsor or its designee. 
The eCRFs must be signed by the investigator or a subinvestigator. These signatures serve to attest 
that the information contained in the eCRF is accurate and true. 
14.4.4 Source Documents 
Information recorded in the EDC system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
Clinical laboratory data required by the protocol will be electronically transferred from the 
central/local laboratory to the sponsor or its designee. A paper copy of the laboratory results will 
be provided to the study site and should be retained with each subject’s source data. 
14.5. Data Quality Control 
Mayne Pharma LLC and its designees will perform quality control checks on this clinical study. 
14.5.1 Monitoring Procedures 
Mayne Pharma LLC and/or its designee will conduct site visits to monitor the study and ensure 
compliance with the protocol, GCP, and applicable regulations and guidelines. The assigned 
clinical research associate(s) (CRA[s]) will visit the investigator and study site at periodic intervals 
and maintain periodic communication. The investigator agrees to allow the CRA(s) and other 
authorized Mayne Pharma LLC personnel access. The CRA(s) will maintain current personal 
knowledge of the study through observation, review of study records and source documentation, 
and discussion of the conduct of the study with the investigator and staff. While on site, the CRA(s) 
will review 
• regulatory documents, directly comparing entries in the EDC system with the source 
documents 
• consenting procedures 
• AE procedures 
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• storage and accountability of IP and study materials 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRF will be provided to the sites. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 18.1), the investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow Mayne Pharma LLC or designee auditors or inspectors from regulatory agencies 
to review records and to assist the inspectors in their duties, if requested.  
For additional information, please refer to the clinical monitoring plan (CMP). 
14.5.2 Data Management 
Mayne Pharma LLC or designee will be responsible for activities associated with the data 
management of this study. The standard procedures for handling and processing records will be 
followed per GCP and Premier Research’s standard operating procedures. A comprehensive data 
management plan (DMP) will be developed, including a data management overview, description 
of database contents, annotated CRF, pre-entry review list, self-evident correction conventions, 
query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries will be provided to the sites. 
14.5.3 Quality Assurance/Audit 
This study will be subject to audit by Mayne Pharma LLC or its designee. Audits may be performed 
to check compliance with GCP guidelines and can include: 
• site audits 
• Trial Master File audits 
• database audits 
• document audits (e.g., protocol and/or clinical study report [CSR]) 
Mayne Pharma LLC or its designee may conduct additional audits on a selection of study sites, 
requiring access to subject notes, study documentation, and facilities or laboratories used for the 
study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB/IEC or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify Mayne Pharma LLC immediately. 
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14.6. Study Termination 
The study may be terminated at Mayne Pharma LLC’s discretion at any time and for any reason. 
The DSMB may recommend discontinuation of the study if they find evidence of unacceptable 
risk to subjects. 
14.6.1 Regular Study Termination 
The end of this study is defined as the date of the last visit of the last subject (last subject out or 
last subject last visit) participating in the study. Within 90 days of the end of the clinical study, 
Mayne Pharma LLC or designee will notify the IECs and regulatory authorities about the regular 
termination of the study as required according to national laws and regulations. 
14.6.2 Premature Study Termination 
The study may be temporarily suspended or terminated prematurely if there is sufficient reasonable 
cause at any time by Mayne Pharma LLC, IECs, regulatory authorities, respective steering 
committees, or the coordinating investigator. A decision to prematurely terminate the study is 
binding to all investigators of all study sites. 
Within 15 days of premature termination of a clinical study, Mayne Pharma LLC or its designee 
will notify the IECs and regulatory authorities about the premature termination as required 
according to national laws and regulations. Mayne Pharma LLC or its designee must clearly 
explain the reasons for premature termination. 
Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigator, funding agency, the IND 
or IDE sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the 
PI will promptly inform study participants, the IRB, and sponsor and will provide the reason(s) for 
the termination or suspension. Study participants will be contacted, as applicable, and be informed 
of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
If the study is terminated prematurely, all investigators have to inform their subjects and take care 
of appropriate follow-up and further treatment of the subjects to ensure protection of the subjects’ 
interests. Study sites may be asked to have all subjects currently participating in the study complete 
all of the assessments for the Follow-up Visit. 
The study might resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB/IEC and/or FDA. 
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14.7. Study Site Closure 
At the end of the study, all study sites will be closed. Mayne Pharma LLC may terminate 
participation of a study site at any time. Examples of conditions that may require premature 
termination of a study site include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate subject enrollment 
14.7.1 Record Retention 
For sites in the US, the investigator shall retain and preserve 1 copy of all data generated in the 
course of the study, specifically including, but not limited to, those defined by GCP as essential 
until 1 of the following occurs: 
• At least 2 years after the last marketing authorization for the IP has been approved or the 
sponsor has discontinued its research with the IP, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development of 
the IP. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor has 30 days to respond to the investigator’s notice, and the 
sponsor has further opportunity to retain such materials at the sponsor’s expense. 
Outside of the US, after completing the study, Mayne Pharma LLC will receive the original eCRFs 
or at least a legible copy and retain the documents for at least 5 years after the completion of the 
study. 
One copy will remain with the investigator. The investigator shall arrange for the retention of the 
subject identification codes, subject files and other source data until at least 5 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or until at least 2 years have elapsed since 
the formal discontinuation of the clinical development of the product. These documents need to be 
retained for a longer period of time if required by applicable regulatory authorities or by agreement 
with the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor shall have 30 days to respond to the investigator’s notice, 
and the sponsor shall have a further opportunity to retain such materials at the sponsor’s expense. 
Copies of these study records (and all study-related documents, including source data) shall be 
kept by the investigator for the maximum period of time permitted by the hospital, institution, or 
private practice. 
14.7.2 Sample Retention 
Blood samples will be used for purposes related to this research. The samples will be stored until 
the sponsor has determined that specimens are no longer needed, and the decision has been made 
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that none of the samples needs to be reanalyzed. In addition, identifiable samples can be destroyed 
at any time at the request of the subject. 
Data collected for this study will be analyzed and stored at Premier Research.  
14.8. Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Mayne Pharma LLC. The protocol amendment must be signed by 
the investigator and approved by the IRB or IEC before it may be implemented. Protocol 
amendments will be filed with the appropriate regulatory agency(s) having jurisdiction over the 
conduct of the study. 
14.9. Use of Information and Publication 
All information concerning trifarotene (CD5789) cream HE1, Mayne Pharma LLC’s operations, 
patent applications, formula, manufacturing processes, basic scientific data, and formulation 
information supplied by Mayne Pharma LLC or its designee to the investigator, and not previously 
published, is considered confidential and remains the sole property of Mayne Pharma LLC. Case 
report forms also remain the property of Mayne Pharma LLC. The investigator agrees to use this 
information for purposes of study execution through finalization and will not use it for other 
purposes without the written consent of the sponsor. 
The information developed in this study will be used by Mayne Pharma LLC in connection with 
the continued development of trifarotene (CD5789) cream HE1 and thus, may be disclosed as 
required to other clinical investigators or government regulatory agencies. 
The information generated by this study is the property of Mayne Pharma LLC. Publication or 
other public presentation of trifarotene (CD5789) cream HE1 data resulting from this study 
requires prior review and written approval of Mayne Pharma LLC. Abstracts, manuscripts, and 
presentation materials should be provided to Mayne Pharma LLC for review and approval at least 
30 days prior to the relevant submission deadline. Data from individual study sites must not be 
published separately. 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition, or publication by the investigator until Mayne Pharma LLC has reviewed and 
commented on such a presentation or manuscript for publication. If applicable, this study will be 
registered at ClinicalTrials.gov, and results information from this study will be submitted to 
ClinicalTrials.gov. 
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15. FINAL CLINICAL STUDY REPORT 
Mayne Pharma LLC will retain ownership of the data. 
The final CSR will be written within 1 year of completion of the clinical part of the study. For 
pediatric studies, the final CSR will be written within 6 months. This report will include a summary 
of the study results based on a statistical evaluation and clinical assessment of the protocol-defined 
endpoints. 
The final CSR may be submitted to the regulatory authorities.  
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16. ETHICAL AND LEGAL CONSIDERATIONS 
16.1. Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry GCP 
E6 (including archiving of essential study documents), the Integrated Addendum to ICH E6 (R2) 
of November 2016, the Declaration of Helsinki, the applicable regulations of the country(ies) in 
which the study is conducted, and with the Commission Directives 2001/20/EC and 2005/28/EC. 
16.2. Subject Information and Informed Consent and/or Assent 
A properly constituted, valid IRB or IEC must review and approve the protocol, the investigator’s 
ICF, and related subject information and recruitment materials before the start of the study. 
It is the responsibility of the investigator to ensure that written informed consent and/or assent is 
obtained from the subject before any activity or procedure is undertaken that is not part of routine 
care. 
According to the Declaration of Helsinki and ICH GCP, subjects must provide their written 
informed assent or consent prior to enrollment in a clinical study and before any protocol-specified 
procedures are performed. Subjects must declare their consent by personally signing and dating 
the ICF. The written ICF will embody the elements of informed consent and/or assent as described 
in the Declaration of Helsinki and will also comply with local regulations.  
Each subject should be made aware by the investigator of the nature of the study (objectives, 
methods, and potential hazards and benefits) and the procedures involved, using the information 
on the ICF. Information should be given in both oral and written form whenever possible and 
deemed appropriate by the IRB/IEC. Subjects, their relatives, or, if necessary, legal representatives 
must be given ample opportunity to inquire about details of the study.  
Subject information and the ICF must be in a language fully comprehensible to the prospective 
subject. The written information must be provided to the subject to give him or her sufficient time 
to understand the information and to prepare questions before being asked for his or her consent. 
The investigator must confirm that the text was understood by the subject. The subject will then 
sign and date the IRB/IEC-approved consent form indicating that he or she has given his or her 
consent to participate in the study. The signature confirms that the consent is based on information 
that has been understood. The form will also be signed by the investigator obtaining the consent 
and annotated with the study subject number. Each subject’s signed ICF must be kept on file by 
the investigator for possible inspection by regulatory authorities, Mayne Pharma LLC, and/or the 
sponsor’s designee. Collection of informed consent and/or assent has to be documented in the 
eCRF. 
Furthermore, the subject will be informed that if he or she wishes to dropout or withdraw (see 
Section 8.3) at any time during the study, this will not have any negative consequences. Subjects 
may be withdrawn by the investigator if any change related to safety or ethics precludes further 
participation in the study. Subjects will be asked to agree to a final assessment in the event of an 
early termination of the study. 
Subjects will be informed that data from their case may be stored in a computer without inclusion 
of their name and that such data will not be revealed to any unauthorized third party. Data will be 
reviewed by the monitor, an independent auditor, and possibly by representatives of regulatory 
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authorities and/or IRBs/IECs. The terms of the local data protection legislation will be applied as 
appropriate. 
16.3. Approval by Institutional Review Board and Independent Ethics Committee 
A valid IRB/IEC must review and approve this protocol before study initiation. Written 
notification of approval is to be provided by the investigator to the sponsor’s or the sponsor’s 
representative before shipment of investigational drug supplies, and will include the date of the 
committee’s approval and the chairperson’s signature. This written approval must follow local 
country requirements. 
Until written approval by the IRB/IEC has been received by the investigator, no subject may 
undergo any procedure not part of routine care for the subject’s condition. 
Protocol amendments must also be reviewed and approved by the IRB/IEC. Written approval from 
the IRB/IEC, or a designee, must be received by Mayne Pharma LLC before implementation.  
16.4. Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator 
and the sponsor. 
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17. REFERENCES 
1. Vahlquist A, Blockhuys S, Steijlen P, 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 Derm. 2014;170(1):173-181. 
2. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited 
ichthyoses: results of the first ichthyosis consensus conference in sorèze 2009. J Am Acad 
Dermatol. 2010;63(4):607–-641. 
3. Vahlquist A, Gånemo A, Virtanen M. Congenital ichthyosis: an overview of current and 
emerging therapies. Acta Derm Venereol. 2008;88(1):4–14. 
4. Blanchet-Bardon C, Nazzaro V, Rognin C, Geiger JM, Puissant A. Acitretin in the 
treatment of severe disorders of keratinization. J Am Acad Dermatol. 1991;24(6):982–986. 
5. Kullavanijaya P and Kulthanan K. Clinical efficacy and side effects of acitretin on the 
disorders of keratinization: a one-year study. J Dermatol. 1993;20:501–506. 
6. Lacour M, Nikhar-Mehta B, Atherton DJ, Harper JI. An appraisal of acitretin therapy in 
children with inherited disorders of keratinization. Br J Dermatol. 1996;134:1023–1029. 
7. Steijlen PM, Van Dooren-Greebe RJ, Van De Kerkhof PCM. Acitretin in the treatment of 
lamellar ichthyosis. Br J Dermatol. 1994;130(2):211–214. 
8. Katugampola RP, Finlay AY. Oral retinoid therapy for disorders of keratinization: single-
centre retrospective 25 years’ experience on 23 patients. Br J Dermatol. 
2006;154(2):267-276. 
9. Gånemo A, Virtanen M, Vahlquist A. Improved topical treatment of lamellar ichthyosis: a 
double‐blind study of four different cream formulations. Br J Derm. 1999;141(6):1027–
1032. 
10. Kiistala R, Lauharanta J, Kanerva L. Transepidermal water loss and sweat gland response 
in lamellar ichthyosis before and during treatment with etretinate: report of three cases. 
Acta Derm Venereol. 1982;62(3):268–270. 
11. Ramirez ME, Youseef WF, Romero RG. Acute percutaneous lactic acid poisoning in a 
child. Pediatr Dermatol. 2006;23(3):282–285. 
12. Chiaretti A, Wismayer DS, Tortorolo L, Piastra M, Polidori G. Salicylate intoxication using 
a skin ointment. Acta Paediatr. 1997;86(3):330–331. 
13. Marukian NV, Deng Y, Gan G, et al. Establishing and validating an ichthyosis severity 
index. J Invest Dermatol. 2017;137(9):1834-1841. 
14. Korteweg SFS, Stenekes MW, van Zyl FE, Werker PMN. Paralytic Ectropion treatment 
with lateral periosteal flap canthoplasty and introduction of the ectropion severity score. 
Plast Reconstr Surg Glob Open. 2014;2(5):e151. 
 
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18. ATTACHMENTS
18.1. Investigator’s Agreement 
PROTOCOL NUMBER: 
18-ICH-001 
PROTOCOL TITLE: 
A Phase 2 Randomized, Multi-center, Double-blind, 
Vehicle-controlled, 12-Week, Safety, Efficacy, and Systemic 
Exposure Study followed by a 12-Week Open-label Extension of 
Trifarotene (CD5789) Cream HE1 in Adults and Adolescents with 
Autosomal Recessive Ichthyosis with Lamellar Scale 
FINAL PROTOCOL 
DATE: 
28-Nov-2018
The undersigned acknowledges possession of and has read the product information on the 
IP and has discussed these data with the study monitor. Having considered fully all the 
available information, the undersigned considers that it is ethically justifiable to give the IP 
to selected subjects in his/her care, according to the study protocol. 
He or she agrees to use the study material, including IP, only as specified in the protocol. He or 
she understands that changes cannot be made to the protocol without prior written approval of 
Mayne Pharma LLC. 
He or she understands that any deviation from the protocol may lead to early termination of the 
study. 
He or she agrees to report to Mayne Pharma LLC within time any clinical AE or abnormal 
laboratory value that is serious, whether or not considered related to the administration of IP. 
He or she agrees to comply with Mayne Pharma LLC and regulatory requirements for the 
monitoring and auditing of this study. 
In addition, he or she agrees that the study will be carried out in accordance ICH, the Declaration 
of Helsinki, and the local laws and regulations relevant to the use of new therapeutic agents. 
I, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the study. 
Principal Investigator: 
Printed Name: 
Signature: 
Date: 
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Investigator’s name and address (stamp) 
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APPENDICES 
A. Regulations and Good Clinical Practice Guidelines 
 
 
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A. Regulations and Good Clinical Practice Guidelines 
1. Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
Refer to the following European Directives (and applicable regulations/guidances): 
• European Directive 2001/20/EC and related guidance documents 
• European Directive 2005/28/EC and related guidance documents> 
2. Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URLs: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf 
 
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SAP_001.pdf: 
 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 1 of 150 
 
   Statistical Analysis Plan 
Sponsor 
Mayne Pharma 
Protocol Title: 
A Phase 2 Randomized, Multicenter, Double-blind, 
Vehicle-controlled, 90-Day, Safety, Efficacy, and 
Systemic Exposure Study followed by a 90-Day 
Open-label Extension of Trifarotene (CD5789) Cream HE1 
in Adults and Adolescents with Autosomal Recessive 
Ichthyosis with Lamellar Scale 
Protocol Number: 
18-ICH-001 
Premier Research PCN: 
MAYN7317 
Document Version: 
Final 2.0 
Document Date:  
09-Nov-2021 
Approvals 
Role 
Signatures 
Date (dd-Mmm-yyyy) 
Biostatistician 
Print Name: Valerie Smith 
 
Sign Name: 
 
 
 
 
 
Mayne Pharma 
Representative 
Print Name: Phoevos Hughes 
 
Sign Name: 
 
 
 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 2 of 150 
 
Document History 
Reasons for Version Final 2.0 
The protocol was amended to version 3.0, and this SAP reflects changes in the protocol. 
Text was added to inform of the study being terminated by Mayne Pharma. 
Summary of Non-Administrative Changes 
• Globally, all references to “Week X” were changed to “Day XX”; e.g., “Week 12” was 
changed to “Day 90”. 
• Figures 1 and 2 (Double-blind and Open-label study designs, respectively) were updated 
according to protocol changes. 
• The Schedule of Events was updated, including the addition of coagulation laboratory 
panel. 
• The lower limit for Analysis Visit 1 was updated to be -97. 
• Table 8 (Ectropion Scoring) was updated to add a maximum score. 
• The derivation of treatment emergent adverse event was updated to match the protocol, 
with the upper limit of the start of the event being at most 14 days after last application of 
study drug. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 3 of 150 
 
Table of Contents 
Approvals ........................................................................................................................................ 1 
Document History ........................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
List of Tables .................................................................................................................................. 5 
List of Figures ................................................................................................................................. 5 
1. 
Overview ............................................................................................................................. 6 
2. 
Study Objectives and Endpoints ......................................................................................... 6 
2.1. 
Study Objectives ........................................................................................................... 6 
2.1.1. Primary Objective ......................................................................................................... 6 
2.1.2. Secondary Objectives.................................................................................................... 6 
2.2. 
Study Endpoints ............................................................................................................ 7 
2.2.1. Safety Endpoints ........................................................................................................... 7 
2.2.2. Efficacy Endpoints ........................................................................................................ 7 
2.2.3. Pharmacokinetic Variables ........................................................................................... 7 
3. 
Overall Study Design and Plan ........................................................................................... 8 
3.1. 
Overall Design .............................................................................................................. 8 
3.2. 
Sample Size and Power ............................................................................................... 10 
3.3. 
Study Population ......................................................................................................... 10 
3.4. 
Treatments Administered ............................................................................................ 10 
3.5. 
Method of Assigning Subjects to Treatment Groups .................................................. 11 
3.6. 
Blinding and Unblinding............................................................................................. 11 
3.7. 
Schedule of Events ...................................................................................................... 11 
4. 
Statistical Analysis and Reporting .................................................................................... 18 
4.1. 
Introduction ................................................................................................................. 18 
4.2. 
Interim Analysis and Data Monitoring ....................................................................... 18 
5. 
Analysis Populations ......................................................................................................... 19 
6. 
General Issues for Statistical Analysis .............................................................................. 20 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 20 
6.1.1. Baseline ....................................................................................................................... 20 
6.1.2. Adjustments for Covariates......................................................................................... 20 
6.1.3. Multiple Comparisons ................................................................................................. 20 
6.1.4. Handling of Dropouts or Missing Data ....................................................................... 20 
6.1.5. Analysis Visit Windows ............................................................................................. 21 
6.1.6. Pooling of Sites ........................................................................................................... 21 
6.1.7. Derived Variables ....................................................................................................... 21 
6.1.8. Data Adjustments/Handling/Conventions .................................................................. 22 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
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7. 
Study Subjects and Demographics.................................................................................... 24 
7.1. 
Disposition of Subjects and Withdrawals ................................................................... 24 
7.2. 
Protocol Violations and Deviations ............................................................................ 24 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 24 
7.4. 
Exposure and Compliance .......................................................................................... 25 
8. 
Efficacy Analysis .............................................................................................................. 25 
8.1. 
Primary Efficacy Analysis .......................................................................................... 25 
8.1.1. Investigator’s Global Assessment (IGA) .................................................................... 25 
8.1.2. Multiple Imputation .................................................................................................... 27 
8.2. 
Secondary Efficacy Analyses ..................................................................................... 28 
8.2.1. Visual Index for Ichthyosis Severity (VIIS) ............................................................... 28 
8.2.2. Individual Score for Roughness .................................................................................. 30 
8.2.3. Palm/Sole Assessment ................................................................................................ 31 
8.2.4. Quality of life per Dermatology Life Quality Index (DLQI) and Children’s 
DLQI (cDLQI) ............................................................................................................ 32 
8.2.5. Fissures ....................................................................................................................... 33 
8.3. 
Exploratory Efficacy Analyses ................................................................................... 33 
8.3.1. Ectropion ..................................................................................................................... 33 
8.3.2. Quality of Life per EQ-5D-5L and EQ-5D-Y ............................................................. 34 
9. 
Safety and Tolerability Analysis ....................................................................................... 34 
9.1. 
Adverse Events ........................................................................................................... 35 
9.1.1. Adverse Events Leading to Withdrawal ..................................................................... 35 
9.1.2. Deaths and Serious Adverse Events ........................................................................... 36 
9.2. 
Clinical Laboratory Evaluations ................................................................................. 36 
9.3. 
Vital Signs ................................................................................................................... 36 
9.4. 
Electrocardiograms ..................................................................................................... 36 
9.5. 
Local Tolerability........................................................................................................ 37 
9.6. 
Physical Examination.................................................................................................. 37 
9.7. 
Concomitant Medication ............................................................................................. 37 
9.8. 
COVID-19 Visit Impact .............................................................................................. 37 
10. 
Changes from Planned Analysis ....................................................................................... 37 
11. 
Other Planned Analysis..................................................................................................... 38 
11.1. Pharmacokinetic Analysis ........................................................................................... 38 
11.2. Photography ................................................................................................................ 39 
12. 
References ......................................................................................................................... 39 
13. 
Tables, Listings, and Figures ............................................................................................ 39 
13.1. Planned Table Descriptions ........................................................................................ 40 
13.2. Efficacy Data .............................................................................................................. 41 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
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13.3. Safety Data .................................................................................................................. 44 
13.4. Pharmacokinetic Data ................................................................................................. 47 
13.5. Planned Listing Descriptions ...................................................................................... 47 
13.6. Planned Figure Descriptions ....................................................................................... 48 
14. 
Tables, Listings, and Listing Shells .................................................................................. 50 
14.1. Standard Layout for all Tables, Listings, and Figures ................................................ 50 
14.2. Planned Table Shells ................................................................................................... 52 
14.3. Planned Listing Shells............................................................................................... 111 
14.4. Planned Figure Shells ............................................................................................... 146 
Appendix 1: Premier Research Library of Abbreviations .......................................................... 147 
 
List of Tables 
Table 1: Schedule of Events for Double-blind Period .................................................................. 12 
Table 2: Schedule of Events for Open-label Extension ................................................................ 16 
Table 3: Analysis Visit Windows ................................................................................................. 21 
Table 4: IGA Scoring Definitions ................................................................................................. 25 
Table 5: VIIS Scoring Definitions ................................................................................................ 28 
Table 6: Roughness Scoring Definitions ...................................................................................... 30 
Table 7: Palm/Sole Scoring Definitions ....................................................................................... 31 
Table 8: Ectropion Scoring ........................................................................................................... 33 
Table 9: Demographic Data Summary Tables and Figures .......................................................... 41 
Table 10: Efficacy Data ................................................................................................................ 41 
Table 11: Safety Data.................................................................................................................... 44 
Table 12: Pharmacokinetic Data ................................................................................................... 47 
Table 13: Planned Listings............................................................................................................ 47 
Table 14: Planned Figures ............................................................................................................ 49 
 
List of Figures 
Figure 1: Double-blind Study Design ............................................................................................. 9 
Figure 2: Open-label Study Design............................................................................................... 10 
Figure 3: Standardized Layout ...................................................................................................... 51 
Figure 4: Planned Table Shells ..................................................................................................... 53 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
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1. 
Overview 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Mayne 
Pharma protocol number 18-ICH-001 (A Phase 2 Randomized, Multi-center, Double-blind, 
Vehicle-controlled, 90-Day, Safety, Efficacy, and Systemic Exposure Study followed by a 90-
Day Open-label Extension of Trifarotene (CD5789) Cream HE1 in Adults and Adolescents with 
Autosomal Recessive Ichthyosis with Lamellar Scale), version 3.0 dated 26-Oct-2020. Reference 
materials for this statistical plan include the protocol and the accompanying sample data 
collection documents. Operational aspects related to collection and timing of planned clinical 
assessments are not repeated in this SAP unless relevant to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials.1 All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association2 and the Royal Statistical Society,3 
for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
Upon sponsor discretion, this study was terminated before the study completed enrollment; 
however, all planned analyses will still occur. Sixty-five (65) subjects were enrolled in the study 
before termination. The statistical plan described hereafter is an a priori plan. It will be 
submitted to file prior to any unblinded inferential or descriptive analysis of data pertaining to 
Mayne Pharma’s study 18-ICH-001. 
2. 
Study Objectives and Endpoints 
2.1. 
Study Objectives 
2.1.1. Primary Objective 
The primary objective is to compare the safety and efficacy of 2 concentrations of trifarotene 
cream HE1 versus vehicle in adults and adolescents with moderate to severe autosomal recessive 
ichthyosis with lamellar scale, also known as lamellar ichthyosis (LI) after 90 days of treatment. 
2.1.2. Secondary Objectives 
The secondary objectives are: 
• To assess systemic exposure to trifarotene and its major metabolites after topical 
application of the investigational product (IP) on up to 90% body surface area (BSA) 
twice weekly. 
• To assess safety for up to 180 days of dosing with open-label trifarotene cream HE1 
200 μg/g. 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
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2.2. 
Study Endpoints 
2.2.1. Safety Endpoints 
The safety endpoints of this study include the following: 
• Reported serious adverse events (SAEs), treatment-emergent AEs (TEAEs), and changes 
in clinical laboratory tests, vital signs, physical examinations, and 12-lead 
electrocardiograms (ECGs) 
• Local tolerability (Scale: 0-3 [none, mild, moderate, severe], determined by the 
investigator) for each body area (chest/abdomen, back, legs, arms, and face/neck). 
2.2.2. Efficacy Endpoints 
2.2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is the proportion of subjects in each treatment group 
who experience successful resolution of LI where “success” is defined as clear/almost clear on 
treated areas and at least a 2-grade change from Baseline at Day 90/end-of-treatment (EOT) in 
the Double-blind Period on the 5-point Investigator Global Assessment (IGA) full body scale.   
2.2.2.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study include the following:  
• The difference in mean scores between the active trifarotene cream HE1 and vehicle 
groups in the following assessment indices from Baseline through Day 90: 
o 5-point Visual Index for Ichthyosis Severity (VIIS) for scaling (overall 16 points 
for scaling, i.e., 0-4 points for 4 body areas: chest/abdomen, back, arms, and legs) 
o Individual score for roughness (Scale: 0–4) overall 
o Palm/sole Assessment (Scale: 0–4) 
o Quality of life per Dermatology Life Quality Index (DLQI) and children’s DLQI 
(cDLQI) 
• The difference in proportion of subjects with presence of fissures on palms/soles 
(presence/absence, number of fissures, and pain associated with fissures on a 0-3 scale) at 
Day 90 between the active trifarotene cream HE1 and vehicle groups 
2.2.2.3. 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints of this study include the following:  
• The difference in mean ectropion (Ectropion Severity Score [ESS] of 0–8) scores 
between the active trifarotene cream HE1 and vehicle groups from Baseline through Day 
90 
• The difference in quality of life per EQ-5D-5L and EQ-5D-Y score between the active 
trifarotene cream HE1 and vehicle groups from Baseline through Day 90 
2.2.3. Pharmacokinetic Variables 
The pharmacokinetic (PK) endpoints of the study include plasma concentrations of CD5789 and 
its major metabolites. 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
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3. 
Overall Study Design and Plan 
3.1. 
Overall Design 
This is a 2-cohort, multicenter study in subjects with moderate to severe LI (i.e., 3–4 on a 5-point 
Investigator’s Global Assessment [IGA] where 0 = clear; 1 = almost clear; 2 = mild; 3 = 
moderate; 4 = severe). Adults (Cohort A) and adults and adolescents (Cohort B) will be 
randomized in a double-blind fashion to 1 of 2 doses of trifarotene cream HE1 or vehicle and 
treated twice weekly for 90 days.  
Approximately 15 adults (≥18 years old) will be randomized into the first cohort of subjects 
(Cohort A) in a 1:1:1 ratio to trifarotene cream HE1 100 μg/g, trifarotene cream HE1 200 μg/g, 
or vehicle and treated twice weekly for up to 90 days. After the initial 15 subjects complete at 
least 28 days of treatment, an independent data safety monitoring board (DSMB) will review 
aggregate safety and tolerability data. 
If no safety issues are identified, both adults and adolescents (ages 12 to 17 years, inclusive) will 
be allowed to enroll in Cohort B. Subjects in Cohort B will be randomized 1:1:1 to trifarotene 
cream HE1 100 μg/g, trifarotene cream HE1 200 μg/g, or vehicle and treated twice weekly for up 
to 90 days in the same manner as subjects in Cohort A. All subjects (Cohort A and Cohort B) 
who complete the randomized, Double-blind Period of the study will be eligible to enter a 
90-day, Open-label Extension (OLE) in which additional PK, safety, and efficacy data will be 
collected. Subjects in the OLE will receive open-label trifarotene cream HE1 200 μg/g twice 
weekly for up to 90 days. A schematic of each period is provided in Figure 1 and Figure 2. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
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Figure 1: Double-blind Study Design 
 
 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
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Figure 2: Open-label Study Design 
 
 
The first cohort of 15 adult subjects is a reasonable sample size to assess safety and tolerability 
before enrolling adolescents. Accounting for a 20% drop-out/nonevaluable rate, a total sample 
size of 120 subjects randomized in a 1:1:1 ratio to 2 active trifarotene cream HE1 arms and a 
vehicle cream arm will provide >80% power to detect a difference between each separate 
trifarotene cream HE1 arm (32 evaluable subjects) and the vehicle cream arm (32 evaluable 
subjects) 2-sided Fisher’s Exact Test assuming a 70% success rate and a 40% success rate, 
respectively. This study is not powered to detect a difference between the 2 active arms. 
3.3. 
Study Population 
This study includes adults and adolescents with moderate to severe autosomal recessive 
ichthyosis with lamellar scale. 
3.4. 
Treatments Administered 
For the Double-blind Treatment Period, a fixed dose (determined at Visit 2) of trifarotene cream 
HE1 100 μg/g or 200 μg/g or vehicle cream will be applied topically twice weekly on up to 90% 
body surface area (BSA) of each subject. Trifarotene cream HE1 is a cream containing 100 or 
200 μg/g (0.01% [w/w] or 0.02% [w/w], respectively) of CD5789. Vehicle contains the same 
ingredients, without the CD5789. Trifarotene cream HE1 and vehicle will be provided in cream 
form for topical application and will be packaged in 50-g tubes from which up to 36 g of 
investigational product (IP) may be dispensed per application, i.e., the maximum dose per 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
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application. Study staff will apply the first dose of study drug to each subject in the clinic on 
Day 1 after baseline measurements, and will record the amount of study drug applied.  
Thereafter, each subject will apply approximately the same amount (up to 36 g) of study drug as 
for the first dose on up to 90% of BSA twice weekly, sparing the scalp, inguinal, and axillary 
areas. Subjects will receive an adequate number of tubes to use 1 tube per application and will 
use a new tube for each treatment day.   
For the OLE, all subjects will receive trifarotene cream HE1 200 μg/g and apply the same fixed 
dose in the same manner as in the Double-blind Period for an additional 90 days. 
If the treatment causes application site reactions, the frequency of application will be reduced or 
interrupted only on the area of concern, as indicated herein. During all clinic visits, the 
investigator will assess local tolerability (Scale: 0-3 [none, mild, moderate, severe]) for 
stinging/burning, pruritus, erythema) for each body area (chest/abdomen, back, arms, legs, and 
face/neck), and the following procedures will be followed: 
• If a score of 2 (moderate) is recorded on a local tolerability assessment scale 
(stinging/burning, pruritus, erythema) on any treated area, the study drug will be applied 
on that area only once weekly, until the score is back to <2. Continue to treat all other 
areas twice weekly provided the score is <2 on those areas. 
• If a score of 3 (severe) is recorded on a local tolerability assessment scale 
(stinging/burning, pruritus, erythema) on any treated area, the study drug will not be 
applied on that area until the score is back to <3 (i.e., “drug holiday”). Continue to treat 
all other areas twice weekly provided the score is <2 on those areas. 
3.5. 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized in a 1:1:1 ratio to trifarotene cream HE1 100 μg/g or 200 μg/g or 
vehicle cream in the Double-blind Period. 
Subjects who continue into the OLE will receive trifarotene cream HE1 200 μg/g and apply the 
same fixed dose in the same manner as in the Double-blind Period for an additional 90 days. 
3.6. 
Blinding and Unblinding 
All subjects, investigators, and study personnel involved in the conduct of the Double-blind 
Period of the study, including data management, will be blinded to treatment assignment with the 
exception of a specified unblinded statistician and programmer from Premier Research who will 
have access to the randomization code. 
The primary analysis period is the first 90 days of treatment (i.e., the Double-blind Period). 
Overall unblinding will take place at the end of the Double-blind Period of the study only after 
database lock has been achieved. A second analysis will take place for endpoints assessed from 
Day 90 through the OLE. 
3.7. 
Schedule of Events 
A detailed schedule of events for the Double-blind period of the study is provided in Table 1. A 
detailed schedule of events for the OLE is provided in Table 2. 


 
Statistical Analysis Plan,  
 
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Table 1: Schedule of Events for Double-blind Period 
 
 
Double-blind Treatment Period 
Screening 
(-97 days to -1 day) 
Washout up to 90 Daysa 
 
Baseline  
(Day 1) 
Telephone 
Visit 
(Day 7) 
Day 14  
± 5 days 
Day 30  
± 7 days 
Telephone 
Visit 
(Day 45) 
Day 60  
± 7 days 
Day 90b,c 
± 7 days 
(ET) 
Visit 
1 
2 
 
3d 
4d 
 
5d 
6d 
Written informed consent/assent  
X 
 
 
 
 
 
 
Xa 
Assign screening number 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
Physical examination  
X 
X e 
 
 
 
 
 
X e 
Vital signs (blood pressure and pulse)  
X 
X 
 
X 
X 
 
X 
X 
Height, weight, and BMI  
X 
 
 
 
 
 
 
Xb 
IGA assessmentf 
X 
X 
 
X 
X 
 
X 
X 
VIISg assessment 
X 
X 
 
X 
X 
 
X 
X 
Roughness assessmenth 
X 
X 
 
X 
X 
 
X 
X 
Palm/sole assessment  
X 
X 
 
X 
X 
 
X 
X 
Palm/sole fissuring assessmenti 
X 
X 
 
X 
X 
 
X 
X 
Ectropion score  
X 
X 
 
X 
X 
 
X 
X 
Photographsj 
 
X 
 
 
X 
 
 
X 
Quality of life per Dermatology Life 
Quality Index (DLQI) 
 
X 
 
X 
X 
 
X 
X 
EQ-5D Quality of Life Questionnaire 
 
X 
 
X 
X 
 
X 
X 
12-lead ECGk 
X 
X 
 
 
X 
 
 
X 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
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Double-blind Treatment Period 
Screening 
(-97 days to -1 day) 
Washout up to 90 Daysa 
 
Baseline  
(Day 1) 
Telephone 
Visit 
(Day 7) 
Day 14  
± 5 days 
Day 30  
± 7 days 
Telephone 
Visit 
(Day 45) 
Day 60  
± 7 days 
Day 90b,c 
± 7 days 
(ET) 
Visit 
1 
2 
 
3d 
4d 
 
5d 
6d 
Clinical laboratory tests (hematology, 
chemistry, urinalysis)l 
X 
X 
 
 
X 
 
 
X 
Serology (hepatitis B surface antigen, 
hepatitis C) 
X 
 
 
 
 
 
 
 
Coagulation panel 
 
X 
 
 
X 
 
 
X 
Pregnancy test for female subjects 
(serum at Screening; urine 
subsequently)m 
X 
X 
 
 
X 
 
X 
X 
Randomization via IWRS 
 
X 
 
 
 
 
 
 
PK blood sample collectionn 
 
X 
 
X 
X 
 
X 
X 
Initial study drug application by clinic 
staff and measuremento 
 
X 
 
 
 
 
 
 
Application instructions, advice on 
emollient and sunscreen use 
 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug and diariesp 
 
X 
 
Xp 
Xp 
 
Xp 
(X)p 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
Tolerability assessment  
 
X 
 
X 
X 
 
X 
X 
Adverse events (and review diaries) 
 
X 
X 
X 
X 
X 
X 
X 
Collect all used/unused study drugq 
 
 
 
X 
X 
 
X 
X 
Provide information about OLE option 
 
 
 
 
X 
X 
X 
X 
Abbreviations: BMI = body mass index; DLQI = Dermatology Life Quality Index; ECG = electrocardiogram; ET = early termination; HEENT = head, eyes, ears, 
nose, throat; ICF = informed consent form; IGA = Investigator’s Global Assessment; IWRS = interactive web response system; OLE = open-label extension; 
PK = pharmacokinetic; WOCBP = women of childbearing potential; VIIS = Visual Index for Ichthyosis Severity 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
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a. 
Upon signing informed consent and entering the Screening Period, subjects will stop using physical and medical treatments for LI, including balneotherapy, 
and begin to washout prohibited topical and systemic treatments with designated washout periods, as applicable. Before asking a subject to enter washout, 
investigators should confirm the subject meets study eligibility criteria, except for LI severity (Inclusion Criterion #3). Washout may be up to 90 days. After 
completing any necessary Washout Period, subjects must return to the site within 35 days before the Baseline Visit within the 97-day Screening Period to 
have their LI severity assessed and study eligibility requirements determined. During washout, subjects may continue their standard ofcare of visible skin 
(face and scalp) for cosmetic reasons and of extremities (palms/soles) to avoid functional consequences on walking or moving their fingers. In the US/EU, 
this may include compounded emollients with keratolytics (alpha or beta hydroxyl acids) and/or urea. The investigator should approve and document these 
standard of care treatments in the electronic case report form (eCRF). If the standard of care treatments of the face and/or palms/soles contain prohibited 
medications, they must be stopped at the Baseline Visit. Subjects may shower, but not bathe or swim, during the Screening Period.  
b. Day 90 procedures should be conducted for subjects who terminate the study early. If a subject discontinues IP, but continues to attend clinic visits, Day 90 
will occur as scheduled. Day 90 will be the first visit of the OLE for subjects who choose to continue. Subjects who decide to continue into the OLE will 
have the following additional procedures: 1) sign informed consent; 2) will be weighed; 3) will be instructed on study drug application; 4) will be given new 
diaries, and 5) will be provided with study drug. 
c. 
A Follow-up telephone call will be made within 14 days after Day 90 to subjects who choose not to continue into the OLE to assess any ongoing adverse 
events. 
d. Although it is preferable to conduct all necessary study assessments in person (onsite visits), this may not be possible as a result of COVID-19-related travel 
restrictions. To ensure the safety of subjects, investigators, and site staff, Visits 3-6 and unscheduled visits may be conducted remotely. Screening and 
baseline visits must be performed onsite only, and must be postponed or scheduled for when onsite visits can be safely conducted. 
e. 
Limited physical examination to include HEENT, cardiorespiratory, abdomen, range of motion.  
f. 
IGA: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe. 
g. VIIS scale for each body area: chest/abdomen, back, legs, and arms, for a possible overall score = 16. 
h. Roughness (0-4 scale);  
i. 
Palm/sole fissuring assessment: present/absent/number/pain (0-3 scale). 
j. 
Photography will be performed at sites with the capability for subjects who sign a photographic ICF. A central reader who will not be an investigator in the 
study will review the photographs to assess consistency of investigator scoring of LI severity as a quality check. 
k. ECG to be conducted at Screening, Baseline, Day 30, and Day 90 for all subjects. Subjects in the PK substudy will also have postdose ECGs at each serial 
blood draw on Day 1 and Day 30. 
l. 
Subjects must be fasting (i.e., at least 8 hours) for clinical laboratory tests, but not for PK blood draws. 
m. Note: Subjects who are premenstrual at Screening but begin menses during the course of the study should follow the pregnancy testing schedule for WOCBP 
correlating to the visit menses began. 
n. Samples for PK will be drawn from all subjects at Baseline and at each clinic visit. At selected sites among subjects who consent to participate in the PK 
substudy, samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose on Day 1. On Day 30, IP will be applied in the clinic for PK substudy 
subjects, and PK samples will be taken predose and at 1, 2, 4, 8, 12, and 24 hours postdose. Trough levels will be drawn when the subjects are in the clinic 
for other study visits (i.e., Day 14, Day 60, and Day 90). Visits for PK must occur at least 24 hours after the last application of the IP to avoid contamination 
of the blood samples with any IP that may have remained in the skin after the last application. 
o. Study staff will apply initial dose of study drug in the clinic after Baseline measurements, and the amount of study drug used will be measured (i.e., 
36-g tube will be measured before and after application to determine amount used). 
p. Study drug provided in 50-g tubes (maximum single application is 36 g). Measure study drug kits (tubes and box, but not leaflets) before dispensing; 
subjects must record days/times of study drug application in the diaries and any areas of skin not treated, e.g., due to local reactions. Dispense enough 
additional study drug until next visit (except at Day 90, unless subject consents to continue into OLE). 


 
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q. Confirm study drug compliance by weighing the studykits (tubes and boxes, but not leaflets) and reviewing diary.  
 
 


 
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Table 2: Schedule of Events for Open-label Extension 
 
Open-label Treatment Perioda 
Follow-up 
 
 
Telephone 
Visit 
(Day 97)a 
Day 104  
± 5 days 
Day 120  
± 7 days 
Telephone 
Visit 
(Day 134) 
Day 150 
± 7 days 
Day 180  
± 7 
days/ET 
Day 194 or 14 days after End of 
Open-label Treatment 
Visit 
 
7a 
8a 
 
9a 
10a 
11a 
Informed consentb 
 
 
 
 
 
 
 
Physical examinationc 
 
 
 
 
 
X 
X 
Vital signs (blood pressure and 
pulse)  
 
 
X 
X 
X 
X 
X 
Record IGAd  
 
X 
X 
 
X 
X 
X 
VIISe assessment 
 
X 
X 
 
X 
X 
X 
Roughness assessmentf 
 
X 
X 
 
X 
X 
X 
Palm/sole assessment 
 
X 
X 
 
X 
X 
X 
Palm/sole fissuring assessment 
 
X 
X 
 
X 
X 
X 
Ectropion score  
 
X 
X 
 
X 
X 
X 
Clinical laboratory tests 
(hematology, chemistry, 
urinalysis)g 
 
 
X 
 
 
X 
 
Pregnancy test for female 
subjects (urine)h 
 
 
X 
 
X 
X 
X 
Coagulation panel 
 
 
X 
 
 
X 
 
12-lead ECG 
 
 
X 
 
 
X 
 
PK blood sample collectioni 
 
 
X 
 
 
X 
 
Application instructions, advice 
on emollient and sunscreen usej 
X 
X 
X 
X 
 
 
 
Dispense study drug and 
diariesk 
 
X 
X 
 
X 
 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 


 
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Open-label Treatment Perioda 
Follow-up 
 
 
Telephone 
Visit 
(Day 97)a 
Day 104  
± 5 days 
Day 120  
± 7 days 
Telephone 
Visit 
(Day 134) 
Day 150 
± 7 days 
Day 180  
± 7 
days/ET 
Day 194 or 14 days after End of 
Open-label Treatment 
Visit 
 
7a 
8a 
 
9a 
10a 
11a 
Tolerability assessment  
 
X 
X 
 
X 
X 
 
Adverse events (and review 
diaries) 
X 
X 
X 
X 
X 
X 
X 
Collect all used/unused study 
drugl  
 
X 
X 
 
X 
X 
 
Abbreviations: ECG = electrocardiogram; ET = early termination; HEENT = head, eyes, ears, nose, throat; ICF = informed consent form; IGA = Investigator’s 
Global Assessment; PK = pharmacokinetic; OLE = open-label extension; VIIS = Visual Index for Ichthyosis Severity; WOCBP = women of childbearing 
potential 
a. Although it is preferable to conduct all necessary study assessments in person (on -site visits), this may not be possible as a result of COVID-19-related travel 
restrictions. To ensure the safety of subjects, investigators, and site staff, Visits 7-11 and unscheduled visits may be conducted remotely. 
b. Subjects will sign the OLE ICF at the Double-blind Day 90 Visit. All efficacy assessments, safety/tolerability assessments, including clinical laboratory 
testing and PK from Day 90 will be carried over for the OLE and will not be repeated.  
c. Limited physical examination to include HEENT, cardiorespiratory, abdomen, range of motion.  
d. IGA: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe  
e. VIIS scale for each body area: chest/abdomen, back, legs, and arms, for a possible overall score = 16. 
f. Roughness (0-4 scale); fissuring assessment on palms/soles: present/absent/number/pain (0-3 scale). 
g. Subjects must be fasting (at least 8 hours) for clinical chemistry testing, but not for PK only blood draws. 
h. Subjects who are premenstrual at Screening but begin menses during the course of the study should follow the pregnancy testing schedule for WOCBP 
correlating to the visit menses began. 
i. Samples for PK will be drawn from all subjects at Day 120 and Day 180. Visits for PK must occur at least 24 hours after the last application of the IP to avoid 
contamination of the blood samples with any IP that may have remained in the skin after the last application. 
j. Subjects must record days/times of study drug application in the diaries and any areas of skin not treated (e.g., due to local reactions).  
k. All subjects in the OLE will receive trifarotene 200 µg/g. Study drug provided in 50-g tubes (maximum single application is 36 g). Measure study drug tubes 
before dispensing. Dispense enough additional study drug until the next visit (except at Day 180). 
l. Confirm study drug compliance by weighing the study kits (tubes and boxes, but not leaflets) dispensed and returned and reviewing diary.


 
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4. 
Statistical Analysis and Reporting 
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher). If the 
use of other software is warranted, the final statistical methodology report will detail what 
software was used for what purposes. 
Continuous (quantitative) variable summaries will include the number of subjects (n) with 
nonmissing values, mean, standard deviation (SD), standard error (SE), median, minimum, and 
maximum.  
Categorical (qualitative) variable summaries will include the frequency and percentage of 
subjects who are in the particular category or each possible value. In general, the denominator 
for the percentage calculation will be based upon the total number of subjects in the study 
population for the treatment groups, unless otherwise specified. The denominator for by-visit 
displays will be the number of subjects in the relevant study population with nonmissing data at 
each study visit. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD, SE) 
will be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified and with the 
following exceptions: a percentage of 0% will not be displayed (i.e., only the count of 0 will be 
displayed), and a percentage of 100% will be displayed with 0 decimal places. 
Unless otherwise indicated, all statistical tests will be conducted at the 0.05 significance level 
using 2-tailed tests, and P values will be reported. Corresponding 95% confidence intervals (CIs) 
will be presented for statistical tests. A P value of ≤0.10 but >0.05 will be considered evidence of 
a trend.  
4.2. 
Interim Analysis and Data Monitoring 
The DSMB will meet after 15 subjects in Cohort A have completed at least 28 days of double-
blind treatment to review aggregate safety and tolerability data (including PK concentration data, 
PK parameters, and ECG results). The safety data will be unblinded. At that time, the DSMB 
will decide whether Cohort B (adults and subjects aged 12–17) may begin enrolling, or if 
additional adult safety data are required before allowing subjects aged 12 – 17 to participate in 
the study. The DSMB will meet again after 60 subjects have enrolled in the study. The sponsor 
may request additional reviews, e.g., should any other findings/issues pertaining to safety emerge 
requiring DSMB review. Details of the DSMB operation will be developed in conjunction with 
the members of the DSMB before the first meeting and will be modified as required. The 
unblinded DSMB outputs will not be seen by anyone except the DSMB and the performing 
statistician. 


 
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The primary analysis period is the first 90 days of treatment (i.e., the Double-blind Period). 
Overall unblinding will take place at the end of the Double-blind Period of the study only after 
database lock has been achieved. The data will be cleaned and frozen and an unblinded analysis 
of the data will be performed. The data will be considered final at this point and no changes to 
these data will be permitted following unblinding with the exception of outcomes and end dates 
of ongoing AEs and concomitant mediations. A second analysis will take place for endpoints 
assessed from Day 90 through the OLE.  
The protocol assumes a 20% dropout/non-evaluable rate. This rate will be continuously 
monitored throughout the COVID-19 pandemic. In the event that this rate dramatically increases, 
a blinded sample size reestimation may be performed to ensure statistical power for the primary 
endpoint is maintained using the assumptions in Section 3.2. 
5. 
Analysis Populations 
 The following 5 analysis populations are planned for the Double-blind Period of this study: 
• Safety: all subjects who are randomized to treatment and receive at least 1 application of 
study drug in the Double-blind Period. This population will be the primary population for 
analyses of safety. Subjects will be analyzed by actual treatment received. 
• Intent-to-treat (ITT): all randomized subjects. This population will be used as the 
primary population for the analysis of efficacy for the Double-blind Period of the study. 
Subjects will be analyzed by randomized treatment. 
• Modified intent-to-treat (mITT): all subjects in the Safety population with at least 
1 postbaseline assessment of efficacy in the Double-blind Period. Subjects will be 
analyzed by randomized treatment. 
• Per-protocol (PP): subjects in the mITT population who met all inclusion criteria and no 
exclusion criteria, were compliant with study drug application, and who had no 
significant protocol deviations. Subjects will be analyzed by actual treatment received. 
• Pharmacokinetic (PK): all subjects in the Safety population who have at least 1 plasma 
sample with quantifiable concentration. This population will be used to summarize all PK 
endpoints. Subjects will be analyzed by actual treatment received. 
The following analysis populations are planned for the OLE of this study: 
• OLE Safety: all subjects who complete the 90-day Double-blind Treatment Period and 
receive at least 1 application of study drug in the OLE.  
• OLE ITT: all subjects who complete the 90-day Double-blind Treatment Period and sign 
the OLE informed consent.  
• OLE mITT: all subjects in the OLE Safety population with at least 1 assessment of 
efficacy after Visit 6. 
• OLE PP: all subjects in the OLE mITT population who met all inclusion criteria and no 
exclusion criteria, were compliant with study drug application from baseline through 
EOT, and who had no significant protocol deviations throughout the study. 
Since all subjects in the OLE are to receive trifarotene cream HE1 200 μg/g, analyses will be by 
actual treatment received. 


 
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Protocol Number 18-ICH-001  
 
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Inclusion in the analysis populations will be determined prior to database lock. Deviations 
related to COVID-19 will also be evaluated in determining PP population eligibility. 
6. 
General Issues for Statistical Analysis 
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
The last nonmissing assessment recorded prior to the first dose of treatment in the Double-blind 
Period will be used as the baseline observation for all calculations of change from baseline, 
including those in the OLE.  
6.1.2. Adjustments for Covariates 
If there is a statistical difference among treatment groups with respect to baseline characteristics, 
that variable may be added to the statistical models as a blocking factor or covariate to determine 
the effect on treatment. Age group and baseline score are planned for inclusion in statistical 
models, unless otherwise indicated. Age group will be categorized as adolescents (ages 12 to 17 
years, inclusive) and adults (≥18 years). 
6.1.3. Multiple Comparisons 
No adjustments will be made for multiple comparisons. All P values for the secondary and 
exploratory endpoints will be provided in the summary tables for informational purposes only. 
6.1.4. Handling of Dropouts or Missing Data 
All possible efforts will be made to ensure that subjects stay in the study and all data are 
collected as scheduled. Withdrawn subjects will not be replaced. If a substantial number of 
subjects are withdrawn from the study, the sponsor will evaluate the need for developing 
replacement criteria. Randomized subjects withdrawn from the study may not reenter. 
Missing endpoint values in this study may result from subjects discontinuing from the study 
prematurely or missing intermediate assessments while remaining on study. To assess the effect 
of missing data on the primary efficacy analysis, a sensitivity analysis will be performed using 
multiple imputation (MI) for the Double-blind Period only. Multiple imputations will be used to 
replace missing IGA outcomes using multiple draws from the posterior predictive distribution 
estimated from the vehicle treatment. The IGA scores will be imputed and then categorized as 
treatment success. 
Sensitivity analyses to investigate robustness to missing data will be performed for the primary 
endpoint as described in Section 8.1.2. 
Missing safety data and data for secondary endpoints will not be imputed. 


 
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6.1.5. Analysis Visit Windows 
Visits will be analyzed as scheduled. Unscheduled and/or repeated measurements will only be 
included if a scheduled measurement is not available and the unscheduled/repeated measurement 
falls within the analysis visit windows as described in Table 3. The windows follow the Schedule 
of Events in Table 1 and Table 2. Unscheduled/repeated measurements will be listed. 
 
Table 3: Analysis Visit Windows  
Visit Target Start Day Lower Limit Upper Limit 
1 
  
-97 
-1 
2 
1 
1 
1 
3 
14 
9 
19 
4 
30 
23 
37 
5 
60 
53 
67 
6 
90 
83 
97 
7 
104 
99 
109 
8 
120 
113 
127 
9 
150 
143 
157 
10 
180 
173 
187 
11 
194 
194 
194 
Visit windows may be extended (as reasonable) so as to accommodate delays for assessments 
due to the COVID-19 pandemic. 
6.1.6. Pooling of Sites 
Not applicable. Site will be omitted from statistical models as the anticipated number of subjects 
per site is small, treatment is self-administered, and the sites are using standardized procedures 
for all assessments. If the distribution of enrollments at sites is such that one or few are enrolling 
a majority of subjects, an ad hoc analysis by site may be performed. 
6.1.7. Derived Variables 
• IGA average score = in protocol version 1.0, IGA was assessed by body area 
(chest/abdomen, back, arms, and legs). Under protocol version 2.0, this was changed to a 
global (overall) assessment. For comparability, the average of the body area IGA results 
will be taken to yield one score for subjects enrolled under protocol version 1.0. Scores 
will range from 0 to 4. Higher scores indicate worse disease. 
• VIIS total score = sum of the individual body area scaling scores, with a range of 0 to 16. 
Each individual item is scored on a scale of 0-4, where 0 = normal skin; no perceptible 
scale or smoothening and 4 = confluent, primarily large, thick scales. Higher scores 
indicate worse scaling. 
• Ectropion total score = sum of the 8 individual item scores (lateral apposition, medial 
apposition, scleral show, conjunctival show, excess tear film, redness of the eye, round 
canthus, punctum lacrimale), with a range of 0 to 8. Each individual item is scored 0 


 
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(nonaffected/no/invisible), 0.5 (≤1 mm/emerging), or 1 (affected/yes/visible). Higher 
scores indicates worse ectropion. 
• DLQI total score = sum of the 10 individual item scores, with a range of 0 to 30. Higher 
scores indicate poorer quality of life. 
• CDLQI total score = sum of the 10 individual item scores, with a range of 0 to 30. Higher 
scores indicate poorer quality of life. 
• Number of doses taken = total number of tubes returned – total number of tubes returned 
unused 
• Number of weeks on study = (last day on study – treatment start date + 1) / 7 
• Number of expected doses = 2 * number of weeks on study  
• Total weight used = total weight of tubes dispensed (grams) – total weight of tubes returned 
(grams) 
• Initial application amount used = tube weight before drug application (grams) – tube weight 
after drug application (grams), as collected on the initial study drug application CRF 
• Compliance by tube weight = total weight used / total weight of tubes dispensed *100% 
• Compliance by number of doses = number of doses taken / number of expected doses * 
100% 
• Change from baseline = value at current time point – value at baseline.  
• TEAE = An AE is defined as treatment emergent if the onset or worsening is at the time of 
or following the start of the first application of study drug (trifarotene or vehicle) through 
the Follow-up Visit or Early Termination Visit, whichever occurs first.. 
6.1.8. Data Adjustments/Handling/Conventions 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings. 
All P values will be displayed in 4 decimals and rounded using standard scientific notation (e.g., 
0.XXXX). If a P value less than 0.0001 occurs it will be shown in tables as <0.0001. 
Adverse events will be coded using the MedDRA version 21.1 thesaurus. Concomitant mediations 
will be coded using the WHO-DD version September 2018. 
A treatment-related AE is any AE with a relationship to the study drug of possibly related and 
related.  


 
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If partial AE or medication dates occur, the convention for replacing missing dates for the 
purpose of statistical analysis is as follows:  
For partial AE and medication start dates: 
• If the year is unknown, then do not impute the date but assign a missing value. 
• If the year is known, but the month or month and day is unknown, then: 
o If the year matches the year of first dose date and the end date (if present) is after 
first dose date, then impute as the month and day of the first dose date. 
o Otherwise, assign 01 January. 
• If the year and month are known, but the day is unknown, then: 
o If the month and year match the month and year of the first dose date, then impute 
as the day of the first dose date. 
o Otherwise, assign 01. 
For partial AE and medication end dates: 
• If the year is unknown, then do not impute the date but assign as missing value. 
• If the year is known, but the month or month and day is unknown, then: 
o If the year matches the year of the last date of the study (date of last contact if 
subject lost to follow-up; date of completion or early termination otherwise), then 
impute as the month and day of the last date of the study. 
o Otherwise, assign 31 December. 
• If the year and month are known, but the day is unknown, then: 
o If the month and year match the month and year of the last date of the study, then 
impute as the day of the last date of the study. 
o Otherwise, assign the last day of the month. 
If partial times occur, the convention is as follows:  
• if the missing time occurs on the day of the first dose and both the hour and minute are 
missing then the time assigned is the time of the first dose, otherwise if both the hour and 
minute are missing and the date is not the date of first dose the time assigned is 12:00;  
• if the date is the same as the date of the first dose and  


 
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o only hour is missing the hour assigned is 12 or the hour of first dose, whichever is 
later; 
o only the minute is missing the minute assigned is 30 or the minute of first dose, 
whichever is later;  
• Otherwise if the date is not the same as the date of first dose, the hour assigned is 12 if 
the hour is missing and the minute assigned is 30 if the minute is missing. 
7. 
Study Subjects and Demographics 
7.1. 
Disposition of Subjects and Withdrawals 
Disposition will include tabulations of the number of subjects randomized into each treatment 
group, the number of subjects completing Day 90 of the study, the number of subjects 
withdrawing early from the Double-blind Period, tabulated reasons for withdrawal from the 
Double-blind Period, and number of subjects in each analysis population. This analysis will be 
conducted on the ITT population. 
Additionally, the number of subjects entering the OLE, completing the study through OLE 
follow up (Day 194), withdrawing early from the OLE, and tabulated reasons for withdrawal 
from the OLE will be presented for the OLE ITT population. 
If a subject discontinues due to COVID-19, those reasons will also be presented. 
7.2. 
Protocol Violations and Deviations 
Major protocol violations, including those due to the impact of COVID-19, as determined by a 
Sponsor blinded review of the data prior to database lock and unblinding of the study, may result 
in the removal of a subject’s data from the PP population.  
All protocol violations will be presented in a data listing, with a flag to indicate if a violation was 
considered major and resulted in the exclusion of the subject from the PP population. 
7.3. 
Demographics and Other Baseline Characteristics 
Summary statistics for age, gender, race, ethnicity, height, weight, BMI, and baseline IGA score 
will be presented by treatment group. See Section 6.1.1 for definition of baseline. 
These analyses will be conducted for the ITT and OLE ITT populations. 
The number and percent of subjects reporting various medical histories, grouped by MedDRA 
system organ class (SOC) and preferred term (PT), will be tabulated by treatment group. This 
analysis will be conducted for the Safety population. 
Prior medications will be summarized by treatment group, by the number and percentage of 
subjects taking each medication, classified using WHO-DDE ATC Class Level 4 and preferred 
term (ATC Class Level 5) and will be presented by treatment group and overall. This analysis 
will be conducted for the Safety population. Prior medications are defined in Section 9.7. 


 
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7.4. 
Exposure and Compliance 
Compliance by tube weight and compliance by number of doses will be summarized by 
treatment group using descriptive statistics. The total weight of tubes dispensed and returned, as 
well as total number of tubes dispensed, returned, and returned unused will also be summarized. 
This analysis will be conducted for the Safety population and for the OLE Safety population. 
A subject is compliant with study product if he or she takes at least 80%-120% of the scheduled 
doses as assessed by number of doses taken reported, supplemented by tube weight and diary 
entries. The number and percentage of subjects who were compliant will be tabulated by 
treatment group for the Double-blind Period and overall for the OLE. Derivations of compliance 
are defined in Section 6.1.7.  
All initial study drug application, drug accountability (dispensed and returned), and subject diary 
data collected will be listed. Changes in treatment administration or treatment dispensation due 
to COVID-19 including start and end dates of change, method of alternative 
administration/dispensation, dosing interruptions, and relevant changes to compliance 
expectations (weights or tube counts) will be documented from the COVID-19 visit impact log.  
8. 
Efficacy Analysis 
All efficacy endpoints will be summarized using the ITT population. The primary analysis will 
be repeated in the mITT and PP populations. 
Summaries of efficacy variables in the OLE will be provided using the OLE ITT. Primary IGA 
summaries will also be provided for the OLE mITT and OLE PP populations. For continuous 
efficacy analyses using MMRM, only formal comparisons of change from baseline will be 
performed in the OLE. No other formal inferential analyses will be conducted for efficacy 
variables in the OLE. 
All efficacy data, regardless of population, will be presented in data listings. 
If alternative methods are used for capturing efficacy assessments (i.e., in person not on site at 
the subject’s home, remotely with visual aid, or remotely via telephone), additional sensitivity or 
subgroup analyses may be performed to assess the potential impact to efficacy analyses. These 
will be delineated as ad hoc analyses in the CSR. 
8.1. 
Primary Efficacy Analysis 
8.1.1. Investigator’s Global Assessment (IGA) 
The 5-point IGA is a measure of disease severity and meets the need for a clinically meaningful 
measure of success for ichthyosis studies. Each level of severity will consider both the severity 
of scaling and the severity of roughness. The investigator will rate the subject’s condition using 
the 5-point scale (0-4), excluding the following areas: knees, elbows, neck, palms, soles, axillae, 
groin, and scalp, where higher scores represent more severe disease. The IGA is collected at all 
clinic visits. The scoring is as follows below in Table 4. 
Table 4: IGA Scoring Definitions 


 
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Score 
Definition 
0 
Clear: No scaling and no roughness 
1 
Almost clear: Occasional fine scales; hardly palpable roughness (mostly smooth) 
2 
Mild: Small and fine scales predominate; no more than a few large scales; mild 
roughness on palpation 
3 
Moderate: Some large scales that may be thick; coarse roughness on palpation 
4 
Severe:  Confluent, primarily large (>1cm) thick scales with plate-like hyperkeratosis 
The primary efficacy endpoint is the proportion of subjects in each treatment group who 
experience successful resolution of LI where “success” is defined as clear/almost clear overall 
and at least a 2-grade change from Baseline at Day 90/EOT in the Double-blind Period on the 5-
point IGA scale. The number and percentage of subjects with treatment success will be 
summarized by treatment group. The primary efficacy endpoint will be analyzed using a logistic 
regression model with treatment, baseline IGA score, and age group as factors. The odds ratios 
and 95% CIs for the odds ratios will be presented. The difference in proportions between the 
active trifarotene cream HEI groups and vehicle cream group, 95% CIs for the differences, and P 
values for the differences in treatment will also be presented. 
The potential for heterogeneity of treatment effects will be assessed by testing treatment-by-
factor interactions. The logistic regression model for the primary analyses will be expanded to 
include the treatment-by-age group interaction. In the event of quasi or complete separation, the 
logistic regression model will use Firth’s penalized maximum likelihood estimation. 
The same logistic regression model will be used to analyze the proportion of subjects with at 
least a 50% reduction in IGA score from baseline as a secondary analysis. 
The change from baseline IGA score will be analyzed using a mixed model for repeated 
measures (MMRM). The MMRM model will include change from baseline in IGA score as the 
dependent variable, treatment, study visit, treatment-by-visit interaction, and age group as fixed 
effects, subject as a random effect, and baseline IGA score as a covariate. All post-baseline study 
visits will be included in the model; however, the primary comparison will be between the active 
trifarotene cream HE1 groups and vehicle at Day 90. An unstructured covariance matrix will be 
used to model the within-subject errors. The Kenward-Roger approximation will be used to 
estimate degrees of freedom. In case of convergence issues, other covariance structures will be 
explored including autoregressive (AR(1)), compound symmetry (CS), and variance components 
(VC) with each model fit to find the covariance structure with the best fit. The fit statistics will 
be compared for all covariance structures; the structure with the smallest Akaike information 
criterion will be retained as the preferred model and noted in the resulting table.  For the OLE 
period, the model will not include treatment or treatment-by-visit interaction since all subjects 
receive the same treatment in the OLE. 
The least squares (LS) mean change from baseline will be presented along with the associated 
95% CI within each treatment group. The overall P value of the model will be presented to test 


 
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the null hypothesis that the change from baseline to subsequent study visit is 0 with a 2-sided 
alternative considering a difference in either direction.  
In comparing treatments (active trifarotene cream HE1 groups minus vehicle), LS mean 
differences in change from baseline will be presented along with associated 95% CIs and P 
values. The null hypothesis that the difference in change from baseline in active trifarotene 
cream HE1 groups minus control vehicle is 0 with a 2-sided alternative considering a difference 
in either direction. Even if a difference from vehicle is observed, as described above, successful 
treatment is defined as clear/almost clear overall (IGA scores of 0 or 1) and at least a 2-grade 
change from baseline. 
The observed value and change from baseline in IGA score will also be summarized 
descriptively by study visit and treatment group using descriptive statistics in addition to the 
above noted models for the Double-blind Period and OLE. Categorical IGA scores will also be 
presented. 
8.1.2. Multiple Imputation 
Multiple imputation (MI) of the primary endpoint will be performed as an analysis of sensitivity 
to missing data in the Double-blind Period only. Following database lock, thorough assessment 
on the extent of missing data due to COVID-19 will be carried out specifically as pertains to the 
primary and secondary endpoints. This will inform decisions around reasonability of imputing 
missing data for secondary endpoints in the Double-blind Period as well. The final determination 
will be documented in the CSR. 
MI assumes that the statistical behavior of drug- and control-treated subjects after discontinuing 
study drug becomes that of the vehicle group. Multiple-imputations will be used to replace 
missing IGA outcomes using multiple draws from the posterior predictive distribution estimated 
from the vehicle treatment group. IGA scores will be imputed and then categorized as treatment 
success according to Section 8.1.1 above. A placebo-based pattern mixture model (PMM) will be 
utilized following the steps outlined in Ratitch B and O’Kelly, M.J. (2011)4. 
Data are processed sequentially by repeatedly calling SAS® PROC MI to impute missing 
outcomes at study visit t = 1, …, T. The following procedure is followed: 
• Initialization (Step 1). Set t = 0 (baseline study visit). 
• Iteration (Step 2). Set t = t + 1. Create a dataset combined records from drug- and 
vehicle-treated subjects with columns for covariates X and outcomes at study visits 1, …, 
t with outcomes for all subjects set to missing at study visit t and set to observed or 
imputed values at study visits 1, …, t-1. 
• Imputation (Step 3). Run placebo-based pattern mixture model in SAS® PROC MI on this 
data to impute missing values for study visit t using previous outcomes for study visit 1 to 
t-1 and baseline covariates. 
o Replace imputed data for all subjects at study visit t with their observed values, 
whenever available. If t < T then go to Step 2, otherwise proceed to Step 4. 
o Repeat steps 1-3, m times with different seed values to create m imputed complete 
datasets. In this analysis, m will be assigned 50. 


 
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• Analysis (Step 4). For each completed dataset use the model as it would have been 
applied had the data been complete for the continuous outcome. The final inference on 
treatment difference is conducted from the multiple datasets, as implemented in SAS® 
PROC MI ANALYZE. 
The steps for this approach are detailed below: 
1. Transpose data horizontally by study visit and impute all non-monotone (intermittent) 
missing data using the Markov Chain Monte Carlo (MCMC) method of PROC MI.  Note 
that this imputation will sample data within each treatment group.  SAS pseudo code is 
provided below.  
PROC MI DATA=example seed = 6654 NIMPUTE = 20 OUT = outdata1; 
 
BY <treatment>; 
 
MCMC chain=multiple impute=monotone; 
 
VAR <treatment> <baseline score>  <visitX score> .. <visit6 score>; 
RUN; 
 
2.  Using the imputed datasets from Step #1 that are now monotone missing (no intermittent 
missing data), a single call to PROC MI (including the MNAR statement) will be utilized 
to impute the monotone missing data.  Within the call to PROC MI, one timepoint is 
imputed at a time. When imputing at time-point t, the imputation step will include all 
vehicle subjects, but only those from the active arms that have a value missing at time-
point t. Subjects with non-missing data that are on active arms will not contribute to the 
estimation for this step. 
Repeat the above step for all timepoints t. Thus, the data for timepoint t+1 uses the data 
imputed from previous timepoints. 
SAS pseudo code is provided below.  SAS accomplishes this iterative process in one step.   
PROC MI DATA=example seed = 2617 NIMPUTE = 1 OUT = outdata1; 
 
BY  _imputation_; 
 
CLASS <treatment>; 
 
MONOTONE REG ( / details); 
 
 
 
 
MNAR MODEL (<v1 score> .. <v6 score> /  
 
 
 
 
 
modelobs=(treatment=(“vehicle”)); 
 
VAR <baseline score> <v1 score> .. <vX score>..<v6 score> ; 
RUN; 
 
3. Pass the output from Step 2 into the model by the imputation variable (coalesce into one 
from each step above). When all missing data are imputed, PROC MIANALYZE will be 
used to combine the parameters from the analyses for inference. 
8.2. 
Secondary Efficacy Analyses 
8.2.1. Visual Index for Ichthyosis Severity (VIIS) 
The investigator will rate the subject’s condition using the 5-point VIIS for each body area 
(chest/abdomen, back, legs, and arms) and an overall score at all clinic visits. The scoring is as 
follows in Table 5. 
Table 5: VIIS Scoring Definitions 


 
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Score 
Definition 
0 
Normal skin; no perceptible scale, or smoothening 
1 
Areas of normal skin intermixed with areas showing smoothening (diminished fine 
skin markings; shininess; waxiness) or small scales (visible separated/fractured 
stratum corneum) 
2 
Confluent smoothening  (diminished fine skin markings; shininess; waxiness) or 
small scales (visible separated/fractured stratum corneum) 
3 
Confluent scales (visibly separated/fractured stratum corneum) including some large 
(>1cm), thick scales 
4 
Confluent, primarily large, thick scales 
The change from baseline VIIS score will be analyzed using an MMRM. The MMRM model 
will include change from baseline in VIIS score as the dependent variable, treatment, study visit, 
treatment-by-visit interaction, and age group as fixed effects, subject as a random effect, and 
baseline VIIS score as a covariate. All post-baseline study visits will be included in the model; 
however, the primary comparison will be between the active trifarotene cream HE1 groups and 
vehicle at Day 90. An unstructured covariance matrix will be used to model the within-subject 
errors. The Kenward-Roger approximation will be used to estimate degrees of freedom. In case 
of convergence issues, other covariance structures will be explored including AR(1), CS, and VC 
with each model fit to find the covariance structure with the best fit. The fit statistics will be 
compared for all covariance structures; the structure with the smallest Akaike information 
criterion will be retained as the preferred model and noted in the resulting table. For the OLE 
period, the model will not include treatment or treatment-by-visit interaction since all subjects 
receive the same treatment in the OLE. 
The LS mean change from baseline will be presented along with the associated 95% CI within 
each treatment group. The overall P value of the model will be presented to test the null 
hypothesis that the change from baseline to subsequent study visit is 0 with a 2-sided alternative 
considering a difference in either direction.  
In comparing treatments (active trifarotene cream HE1 groups minus vehicle), LS mean 
differences in change from baseline will be presented along with associated 95% CIs and P 
values. The null hypothesis that the difference in change from baseline in active trifarotene cream 
HE1 groups minus control vehicle is 0 with a 2-sided alternative considering a difference in either 
direction. 
The observed value and change from baseline in VIIS score will also be summarized 
descriptively by study visit and treatment group using descriptive statistics in addition to the 
above noted model for the Double-blind Period and OLE. 


 
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8.2.2. Individual Score for Roughness 
The amount of roughness of the skin overall will be measured on a 5-point scale at all clinic 
visits. The scoring is as follows in Table 6. 
Table 6: Roughness Scoring Definitions 
Score 
Definition 
0 
Clear: Smooth skin 
1 
Almost clear: Hardly palpable roughness  
2 
Mild: Mild roughness on palpation (fine sand paper-like) 
3 
Moderate: Moderate, coarse roughness (coarse sand paper-like) 
4 
Severe:  Very coarse skin (broken cornflakes-like) 
The change from baseline individual score for roughness will be analyzed using an MMRM. The 
MMRM model will include change from baseline in individual score for roughness as the 
dependent variable, treatment, study visit, treatment-by-visit interaction, and age group as fixed 
effects, subject as a random effect, and baseline individual score for roughness as a covariate. All 
post-baseline study visits will be included in the model; however, the primary comparison will 
be between the active trifarotene cream HE1 groups and vehicle at Day 90. An unstructured 
covariance matrix will be used to model the within-subject errors. The Kenward-Roger 
approximation will be used to estimate degrees of freedom. In case of convergence issues, other 
covariance structures will be explored including AR(1), CS, and VC with each model fit to find 
the covariance structure with the best fit. The fit statistics will be compared for all covariance 
structures; the structure with the smallest Akaike information criterion will be retained as the 
preferred model and noted in the resulting table. For the OLE period, the model will not include 
treatment or treatment-by-visit interaction since all subjects receive the same treatment in the 
OLE. 
The LS mean change from baseline will be presented along with the associated 95% CI within 
each treatment group. The overall P value of the model will be presented to test the null 
hypothesis that the change from baseline to subsequent study visit is 0 with a 2-sided alternative 
considering a difference in either direction.  
In comparing treatments (active trifarotene cream HE1 groups minus vehicle), LS mean 
differences in change from baseline will be presented along with associated 95% CIs and P 
values. The null hypothesis that the difference in change from baseline in active trifarotene 
cream HE1 groups minus control vehicle is 0 with a 2-sided alternative considering a difference 
in either direction. 
The observed value and change from baseline in individual score for roughness will also be 
summarized descriptively by study visit and treatment group using descriptive statistics in 
addition to the above noted model for the Double-blind Period and OLE. 


 
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Protocol Number 18-ICH-001  
 
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Additionally, the proportion of subjects who experience a 2-grade change from baseline to Day 
90 in individual score for roughness will be summarized by treatment group and analyzed using 
a logistic regression model with treatment, baseline individual score for roughness, and age 
group as factors. The odds ratios and 95% CIs for the odds ratios will be presented. The 
difference in proportions between the active trifarotene cream HE1 groups and vehicle cream 
group, 95% CIs for the differences, and P values for the differences in treatment will also be 
presented. 
The potential for heterogeneity of treatment effects will be assessed by testing treatment-by-
factor interactions. The logistic regression model for the analysis will be expanded to include the 
treatment-by-age group interaction. In the event of quasi or complete separation, the logistic 
regression model will use Firth’s penalized maximum likelihood estimation. 
8.2.3. Palm/Sole Assessment 
Thickening of the skin on the palms and soles will be measured on a 5-point scale at all clinic 
visits. The scoring is as follows in Table 7. 
Table 7: Palm/Sole Scoring Definitions 
Score 
Definition 
0 
Clear: No thickening, no roughness, no fissure 
1 
Almost clear: Only slight thickening, minimal to no roughness, no fissures 
2 
Mild: Some thickening, mild roughness on palpation, few fissures may be present 
3 
Moderate: Substantial and diffuse thickening, coarse roughness on palpation may be 
present, fissures may be present 
4 
Severe:  Very thickened and rough skin, numerous fissures 
The change from baseline palm/sole assessment score will be analyzed using an MMRM. The 
MMRM model will include change from baseline in palm/sole assessment score as the 
dependent variable, treatment, study visit, treatment-by-visit interaction, and age group as fixed 
effects, subject as a random effect, and baseline palm/sole assessment score as a covariate. All 
post-baseline study visits will be included in the model; however, the primary comparison will 
be between the active trifarotene cream HE1 groups and vehicle at Day 90. An unstructured 
covariance matrix will be used to model the within-subject errors. The Kenward-Roger 
approximation will be used to estimate degrees of freedom. In case of convergence issues, other 
covariance structures will be explored including AR(1), CS, and VC with each model fit to find 
the covariance structure with the best fit. The fit statistics will be compared for all covariance 
structures; the structure with the smallest Akaike information criterion will be retained as the 
preferred model and noted in the resulting table. For the OLE period, the model will not include 
treatment or treatment-by-visit interaction since all subjects receive the same treatment in the 
OLE. 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
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The LS mean change from baseline will be presented along with the associated 95% CI within 
each treatment group. The overall P value of the model will be presented to test the null 
hypothesis that the change from baseline to subsequent study visit is 0 with a 2-sided alternative 
considering a difference in either direction.  
In comparing treatments (active trifarotene cream HE1 groups minus vehicle), LS mean 
differences in change from baseline will be presented along with associated 95% CIs and 
P values. The null hypothesis that the difference in change from baseline in active trifarotene 
cream HE1 groups minus control vehicle is 0 with a 2-sided alternative considering a difference 
in either direction. 
The observed value and change from baseline in palm/sole assessment score will also be 
summarized descriptively by study visit and treatment group using descriptive statistics in 
addition to the above noted model for the Double-blind Period and OLE. 
Additionally, the proportion of subjects who experience a 2-grade change from baseline to Day 
90 in palm/sole assessment score will be summarized by treatment group and analyzed using a 
logistic regression model with treatment, baseline palm/sole assessment score, and age group as 
factors. The odds ratios and 95% CIs for the odds ratios will be presented. The difference in 
proportions between the active trifarotene cream HE1 groups and vehicle cream group, 95% CIs 
for the differences, and P values for the differences in treatment will also be presented. 
The potential for heterogeneity of treatment effects will be assessed by testing treatment-by-
factor interactions. The logistic regression model for the analysis will be expanded to include the 
treatment-by-age group interaction. In the event of quasi or complete separation, the logistic 
regression model will use Firth’s penalized maximum likelihood estimation. 
8.2.4. Quality of life per Dermatology Life Quality Index (DLQI) and Children’s DLQI 
(cDLQI) 
The DLQI is a dermatology-specific Quality of Life instrument for subjects aged 17 years and 
older. The cDLQI is for subjects aged 12 to 16 years. It is a 10-question validated questionnaire 
with 6 domains: symptoms and feelings, daily activities, leisure, work and school, personal 
relationships, and treatment. Higher scores indicate poorer quality of life. The investigator will 
use his or her judgment of the maturity of the subject to decide which version of the 
questionnaire to use; the same version will be used for the subject throughout the study. 
The change from baseline DLQI/cDLQI score will be analyzed using an MMRM. The MMRM 
model will include change from baseline in DLQI/cDLQI score as the dependent variable, 
treatment, study visit, and treatment-by-visit interactionas fixed effects, subject as a random 
effect, and baseline DLQI/cDLQI score as a covariate. All post-baseline study visits will be 
included in the model; however, the primary comparison will be between the active trifarotene 
cream HE1 groups and vehicle at Day 90. An unstructured covariance matrix will be used to 
model the within-subject errors. The Kenward-Roger approximation will be used to estimate 
degrees of freedom. In case of convergence issues, other covariance structures will be explored 
including AR(1), CS, and VC with each model fit to find the covariance structure with the best 
fit. The fit statistics will be compared for all covariance structures; the structure with the smallest 
Akaike information criterion will be retained as the preferred model and noted in the resulting 
table.  


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
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The LS mean change from baseline will be presented along with the associated 95% CI within 
each treatment group. The overall P value of the model will be presented to test the null 
hypothesis that the change from baseline to subsequent study visit is 0 with a 2-sided alternative 
considering a difference in either direction.  
In comparing treatments (active trifarotene cream HE1 groups minus vehicle), LS mean 
differences in change from baseline will be presented along with associated 95% CIs and P 
values. The null hypothesis that the difference in change from baseline in active trifarotene 
cream HE1 groups minus control vehicle is 0 with a 2-sided alternative considering a difference 
in either direction. 
The observed value and change from baseline in DLQI/cDLQI score will also be summarized 
descriptively by study visit and treatment group using descriptive statistics in addition to the 
above noted model for the Double-blind Period. 
8.2.5. Fissures 
Fissuring will be assessed by recording the presence or absence of fissures, the number of 
fissures present, and the pain associated with each fissure. A fissure is a longitudinal and deep 
crack that separates the stratum corneum and may penetrate down to the dermis, causing pain 
and sometimes bleeding. The subject will assess pain associated with fissures as ranging from 0-
3 (none, mild, moderate, severe). 
The number and proportion of subjects with fissures present on palms or soles along with 95% 
CIs will be summarized by treatment group and study visit. A 2-sided Pearson’s Chi-Square 
Test, or Fisher’s Exact Test, as appropriate, will be performed at the 5% significance level to 
determine whether there is a significant difference between treatment groups. The null 
hypothesis that there is no difference in proportion of subjects with fissures present between 
active trifarotene cream HE1 and vehicle, with a 2-sided alternative considering a difference in 
either direction. The difference in proportions between active trifarotene cream HE1 and vehicle 
(active trifarotene cream HE1 minus vehicle), 95% CIs for the differences, and P values for the 
differences in treatment will also be presented. 
The number of fissures and fissure pain level will be summarized descriptively by body area and 
treatment group. 
8.3. 
Exploratory Efficacy Analyses 
8.3.1. Ectropion 
The Ectropion Severity Score (ESS), has a maximum score of 8 points. A higher score indicates 
a worse ectropion. The score takes the severity of ectropion in terms of lateral and medial 
apposition, scleral show, conjunctival show, and roundness of the eye into account and gives an 
indication of the functional aspects involved in ectropion by scoring redness, excess tear film, 
and the position of the lacrimal punctum. The scoring is as follows in Table 8. 
Table 8: Ectropion Scoring 
 
Points per Item 


 
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0 
0.5 
1 
Lateral apposition 
Nonaffected 
- 
Affected 
Medial apposition 
Nonaffected 
- 
Affected 
Sceral show 
No 
≤ 1 mm 
> 1mm 
Conjunctival show 
No 
- 
Yes 
Excess tear film 
No 
- 
Yes 
Redness of the eye 
No 
- 
Yes 
Round canthus 
No 
- 
Yes 
Punctum lacrimale 
Invisible 
Emerging 
Visible 
Maximum score 
 
 
8 points 
 
The observed value and change from baseline in ectropion score will be summarized 
descriptively by study visit and treatment group using descriptive statistics for the Double-blind 
Period and OLE. 
8.3.2. Quality of Life per EQ-5D-5L and EQ-5D-Y 
The EQ-5D is a measure of health related quality of life. The EQ-5D consists of a descriptive 
system and the EQ visual analog scale (VAS). The EQ-5D-5L is intended for use in adult 
subjects, while the EQ-5D-Y is to be used for children and adolescents. The investigator will use 
his or her judgment of the maturity of the subject to decide which version of the EQ-5D to use; 
the same version will be used for the subject throughout the study. The descriptive system 
comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. The EQ VAS records the subject’s self-rated health on a vertical 0-100 VAS. 
This can be used as a quantitative measure of health outcome that reflects the subject’s own 
judgement. 
The observed value and change from baseline in EQ-5D-5L/EQ-5D-Y score will be summarized 
descriptively by study visit and treatment group using descriptive statistics for the Double-blind 
Period and OLE. 
9. 
Safety and Tolerability Analysis 
Safety variables include treatment-emergent AEs, clinical laboratory values, vital signs, ECG 
readings, local tolerability assessments, and physical examination results. No formal inferential 
analyses will be conducted for safety variables in either period.  


 
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Safety analyses through Day 90 of the Double-blind Period will be conducted using data from 
the Safety population and safety analyses in the OLE will be conducted using the OLE Safety 
population. 
9.1. 
Adverse Events 
All AEs, TEAEs, and SAEs will be coded using the MedDRA dictionary Version 21.1.  
Treatment-emergent AEs are defined as: 
• AEs with onset at the time of or following the start of treatment with study drug 
through 14 days after the last application of study drug, or 
• AEs starting prior to the start of treatment but increasing in severity or relationship at 
the time of, or following, the start of treatment with study drug through the last 
application of study drug. 
The causal relationship of the AE to the study drug is determined by the investigator as Not 
Related, Unlikely Related, Possibly Related, and Related. These will be mapped to Unrelated 
(Not Related or Unlikely Related) and Related (Possibly Related, or Related).  
Adverse event severity grades are reported as mild, moderate, or severe. 
Summaries of incidence rates (frequencies and percentages) of individual TEAEs will be 
presented by SOC, PT, and treatment group for the Double-blind Period and OLE. Such 
summaries will be displayed for all TEAEs, TEAEs by maximum severity, and TEAEs by 
relationship.  
Each subject will be counted only once within each summation level (SOC and PT). If a subject 
experiences more than 1 TEAE within each summation level, the TEAE with the strongest 
relationship or the maximum severity, as appropriate, will be included in the summaries of 
relationship and severity. If a particular event is missing the severity and/or relationship, then the 
strongest possible severity or relationship will be assumed for analysis (severity = severe, 
relationship = related). 
Incidences will be presented by descending frequency of SOC and PT within SOC, and then 
alphabetically within PT where the incidence is the same; this is based on overall subjects then 
alphabetically in case of a tie. 
Missing and partially missing AE start and/or stop dates and times will be imputed, for the 
purpose of statistical analysis, according to the specifications described in Section 6.1.8. 
In the AE data listings, all AEs will be displayed. AEs that are treatment emergent will be 
flagged. 
9.1.1. Adverse Events Leading to Withdrawal 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
study drug, by treatment group, SOC, and PT will be prepared for both the Double-blind Period 
and OLE.  


 
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A data listing of AEs leading to withdrawal of study drug during each period will also be 
provided, displaying details of the event(s) captured on the CRF. 
9.1.2. Deaths and Serious Adverse Events 
Any deaths that occur during the study will be listed. 
Serious adverse events will be listed and also tabulated by SOC and PT and presented by 
treatment group for the Double-blind Period and overall for the OLE. 
9.2. 
Clinical Laboratory Evaluations 
Laboratory tests (clinical chemistry, hematology, coagulation, and quantitative urinalysis) will be 
performed at Screening, Baseline, Day 30, Day 90, Day 120, and Day 180. Results will be 
summarized descriptively by treatment group and study visit as both observed values and change 
from baseline values for the Double-blind Period and OLE. See Section 6.1.1 for the definition 
of baseline. Number and percentage of subjects with abnormal qualitative urinalysis results will 
be provided by treatment group and study visit. 
The number of subjects with clinical laboratory values below, within, or above normal ranges, by 
study visit will be tabulated (shift tables) for each clinical laboratory parameter by treatment 
group. 
Laboratory values will be displayed in the data listings and those that are outside the normal 
range will be flagged and presented along with corresponding normal ranges (if available). A 
separate listing of abnormal laboratory values will be provided. All study visits within a 
parameter for a subject will be presented if at least 1 study visit within that parameter has an 
abnormal result. 
Serology results and pregnancy test results will be listed separately. 
9.3. 
Vital Signs 
Vital signs will be collected at Screening, Baseline, Day 14, Day 30, Day 60, Day 90, Day 120, 
Day 150, Day 180, and Day 194. Descriptive summaries of actual values and changes from 
baseline will be calculated for systolic blood pressure (mmHg), diastolic blood pressure 
(mmHg), and pulse (bpm).   
The number of subjects with vital sign values below, within, or above normal ranges, by study 
visit will be tabulated (shift tables) for each parameter by treatment group.  
These summaries will be presented by study visit and treatment group. See Section 6.1.1 for the 
definition of baseline. 
9.4. 
Electrocardiograms 
12-Lead ECGs will be collected at Screening, Baseline, Day 30, Day 90, Day 120, and Day 180. 
For subjects in the PK substudy, additional ECGs will be performed postdose during serial blood 
sampling on Day 1 and Day 30. Descriptive summaries will be presented for heart rate (bpm), 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
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PR interval (ms), QRS interval (ms), uncorrected QT interval (ms), QTcF (ms). These 
summaries will be presented by study visit and treatment group. 
The number and percentage of subjects with normal and abnormal ECG results will be 
summarized by treatment group and study visit. 
9.5. 
Local Tolerability 
During all clinic visits, the investigator will assess local tolerability (Scale: 0-3 [none, mild, 
moderate, severe]) for each treated body area (chest/abdomen, back, arms, legs, and face/neck).  
Descriptive summaries of the investigator’s assessment of erythema, stinging/burning, and 
pruritus will be presented by body area, period, treatment group, and study visit. 
9.6. 
Physical Examination 
Physical examinations will be performed at Screening, Baseline, Day 90, Day 180, and Day 194. 
The number and percentage of subjects with normal and abnormal findings in the complete 
physical examination will be displayed for each treatment group in each period. 
9.7. 
Concomitant Medication 
Prior and concomitant medications, coded using World Health Organization-Drug Dictionary 
Enhanced (WHO-DDE) (September 2018), will be summarized descriptively by Anatomical 
Therapeutic Chemical (ATC) classification Level 4 and PT (i.e., ATC classification Level 5), if 
applicable, using counts and percentages for the Safety Population.  
Prior medications and concomitant medications will be presented separately. The assignment of 
medications as prior and/or concomitant will be done as follows: 
• Prior medications: Medications that started before the first dose of study drug will be 
considered prior medications whether or not they were stopped before dose.  
• Concomitant medications: Any medications continuing or starting after the first dose of 
study drug through the end of study will be considered to be concomitant.  
If a medication starts prior to the first dose and continues after the first dose it will be considered 
both prior and concomitant. Prior and concomitant medications will also be listed. Prior and 
concomitant medications will be summarized descriptively by treatment using counts and 
percentages. 
9.8. 
COVID-19 Visit Impact 
A listing of the COVID-19 visit impact log will be presented which will display which (if any) 
study visits were impacted by the pandemic. The listing will display if the visit was performed 
and if the visit type was adjusted as well as ths reason(s) for adjustment. 
10. 
Changes from Planned Analysis 
Age was added as a factor for MMRM analyses because the study is enrolling both adults and 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
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adolescents. 
11. 
Other Planned Analysis 
11.1. Pharmacokinetic Analysis 
The pharmacokinetic characterization of drug concentrations for each dose to be profiled will use 
noncompartmental analysis (NCA). 
Samples for PK will be drawn from all subjects at Baseline and at each clinic visit for trough 
values. Subjects who provide written informed consent to participate in the optional PK substudy 
will provide blood samples for PK analysis predose on Day 1 and at 1, 2, 4, 8, 12, and 24 hours 
postdose on Day 1 and Day 30.  
The PK parameter estimates will be completed using WinNonlin (Pharsight Corporation) 
software using the actual elapsed times from dose administration to sample collection (i.e., not 
nominal time).  
Standard PK parameters assessed will include measures of the extent of absorption using 
estimates of the Area under the plasma concentration-time curve from time 0 to the time of the 
last quantifiable plasma concentration (AUC0-t), Area under the plasma concentration-time curve 
from time 0 to infinity (if data permits) (AUC0-inf) and rate-of-absorption using the maximum 
serum concentration (Cmax), the time of Cmax (Tmax), apparent first order terminal elimination 
half-life (t1/2), apparent terminal phase rate constant (λz) (if data permits). 
For noncompartmental analysis, plasma concentrations will be listed and summarized at each 
time point using descriptive statistics. Descriptive statistics reported will include the arithmetic 
mean, SD, CV%, geometric mean, minimum, maximum, and median. Only the range and the 
median will be reported for Tmax, as this is a categorical parameter. The PK parameters will also 
be summarized by treatment using descriptive statistics.  
Individual plasma concentration plots and mean data graphs will be produced using both linear 
and semi-logarithmic scales. Mean data graphs will show plasma concentration profiles by 
treatment group. Pharmacokinetic plasma parameter estimates and summaries will be completed 
for the subjects in the PK population. 
 
 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
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11.2. Photography 
Photography collection dates will be listed. 
12. 
References 
1. US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food 
and Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, 
pages 49583-49598. September 16, 1998. 
2. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm 
3. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014. 
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf. 
4. Ratitich, B. and O’Kelly, M.J. (2011). Implementation of Pattern-Mixture Models Using 
Standard SAS / STAT Procedures. 
13. 
Tables, Listings, and Figures 
All listings, tables, and figures will have a header showing the sponsor company name and 
protocol and a footer showing the version of SAS, the file name and path, and the source of the 
data (CRF page or listing number). 
The following reporting conventions will be adopted for the presentation of study data. These 
conventions will enhance the review process and help to standardize the presentation with 
common notations. 
General Reporting Conventions 
• All tables and data listings will be developed in landscape orientation. 
• Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text will not be used in tables, figures, and data listings unless they add 
significant value to the table, figure, or data listing.  
• Only standard keyboard characters should be used in tables and data listings. Special 
characters, such as nonprintable control characters, printer-specific characters, or font 
specific characters, will not be used on a table, figure, or data listing. 
• All titles will be centered on a page. All footnotes will be left justified and at the bottom 
of a page. 
• Missing values for both numeric and character variables will be presented as blanks in a 
table or data listing. A value of zero may be used if appropriate to identify when the 
frequency of a variable is not observed. 
• 
All date values will be presented as ddmmmyyyy (e.g., 29AUG2011) format.  
• 
If applicable, all observed time values will be presented by using a 24-hour clock 
HH:MM:SS format (e.g., 01:35:45 or 11:26). Seconds should only be reported if they were 
measured as part of the study.  
• Adverse events with missing MedDRA coding will have their system organ class and/or 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
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preferred term presented as “Not Coded” in the tables. The “Not Coded” frequencies will 
be sorted to the end of the tables. This will only be applicable for any deliveries sent 
before database lock (e.g., for dry runs on blinded data). 
• Programming notes may be inserted into the shells, these notes will not appear in the final 
output. 
Population Summary Conventions 
• Population sizes may be presented for each classification factor as totals in the column 
header as (N=xxx), where appropriate. 
• All population summaries for categorical variables will include all categories that were 
planned and for which the subjects may have had a response. Percentages corresponding 
to null categories (cells) will be suppressed; however, counts and percentages of missing 
values may be needed. 
• All population summaries for continuous variables will include: N, mean, SD, median, 
minimum, and maximum. Other summaries (e.g., number missing, 95% CIs) may be used 
as appropriate. The precision of the maximum and minimum will match the maximum 
precision in the data. The mean and median will have 1 additional decimal place. The SD 
will have 2 additional decimal places. 
• All percentages are rounded (where, for example, 0.05% is rounded up to 0.1%) and 
reported to a single decimal point (xx.x%). 
• A percentage of 0% will not be displayed (i.e., only the count of 0 will be displayed), and 
a percentage of 100% will be displayed with 0 decimal places. 
• All P values will be displayed in four decimals and rounded using standard scientific 
notation (e.g., 0.XXXX). If a P value less than 0.0001 occurs it will be shown in tables as 
<0.0001. 
13.1. Planned Table Descriptions 
The following are planned summary tables for protocol number 18-ICH-001. The table numbers 
and page numbers are place holders only and will be determined when the tables are produced. 
 
 
 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
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Table 9: Demographic Data Summary Tables and Figures 
Number Population Title 
Unique/Non-unique 
Table 
14.1.1.1 
ITT 
Summary of Subject Disposition  
Unique 
Table 
14.1.1.2 
OLE ITT 
Summary of Subject Disposition  
Non-unique 
Table 
14.1.2.1 
ITT 
Demographics and Baseline Characteristics  
Unique 
Table 
14.1.2.2 
OLE ITT 
Demographics and Baseline Characteristics  
Non-unique 
Table 
14.1.3 
Safety 
Summary of Medical Histories by System Organ Class and 
Preferred Term 
Unique 
Table 
14.1.4 
Safety 
Summary of Prior Medications by ATC Class Level 4 and 
Preferred Term 
Unique 
Table 
14.1.5.1 
Safety 
Summary of Drug Accountability (Drug Returned and Dispensed) Unique 
Table 
14.1.5.2 
OLE 
Safety 
Summary of Drug Accountability (Drug Returned and Dispensed) Non-unique 
Table 
14.1.5.3 
Safety 
Summary of Treatment Exposure and Compliance 
Unique 
Table 
14.1.5.4 
OLE 
Safety 
Summary of Treatment Exposure and Compliance 
Non-unique 
 
13.2. Efficacy Data 
Table 10: Efficacy Data 
Number Population Title 
Unique/Non-unique 
14.2.1.1.1 ITT 
Primary Analysis: Logistic Regression Analysis of Successful 
Resolution of LI 
Unique 
14.2.1.1.2 OLE ITT 
Proportion of Subjects with Successful Resolution of LI in the 
OLE 
Unique 
14.2.1.2.1 mITT 
Primary Analysis, Sensitivity: Logistic Regression Analysis of 
Successful Resolution of LI 
Non-unique 
14.2.1.2.2 OLE mITT Proportion of Subjects with Successful Resolution of LI in the 
OLE 
Non-unique 
14.2.1.3.1 PP 
Primary Analysis, Sensitivity: Logistic Regression Analysis of 
Successful Resolution of LI 
Non-unique 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
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Number Population Title 
Unique/Non-unique 
14.2.1.3.2 OLE PP 
Proportion of Subjects with Successful Resolution of LI in the 
OLE 
Non-unique 
14.2.1.4 
ITT 
Primary Analysis, Sensitivity: Logistic Regression Analysis of 
Successful Resolution of LI Using Multiple Imputation 
Non-unique 
14.2.1.5.1 ITT 
Logistic Regression Analysis of 50% Reduction in IGA score 
from Baseline 
Non-unique 
14.2.1.5.2 OLE ITT 
Proportion of Subjects with a 50% Reduction in IGA score from 
Baseline 
Non-unique 
14.2.1.6.1 ITT 
MMRM Analysis of Change from Baseline in IGA Score 
Unique 
14.2.1.6.2 OLE ITT 
MMRM Analysis of Change from Baseline in IGA Score 
Non-unique 
14.2.1.7.1 ITT 
Categorical IGA Scores 
Unique 
14.2.1.7.2 OLE ITT 
Categorical IGA Scores 
Non-unique 
14.2.2.1 
ITT 
Secondary Analysis: MMRM Analysis of Change from Baseline 
in VIIS Score 
Non-unique 
14.2.2.2 
OLE ITT 
MMRM Analysis of Change from Baseline in VIIS Score 
Non-unique 
14.2.3.1 
ITT 
Secondary Analysis: MMRM Analysis of Change from Baseline 
in Individual Score for Roughness 
Non-unique 
14.2.3.2 
OLE ITT 
MMRM Analysis of Change from Baseline in Individual Score 
for Roughness 
Non-unique 
14.2.3.3 
ITT 
Logistic Regression Analysis of 2-grade Change in Individual 
Score for Roughness from Baseline 
Non-unique 
14.2.4.1 
ITT 
Secondary Analysis: MMRM Analysis of Change from Baseline 
in Palm/Sole Assessment 
Non-unique 
14.2.4.2 
OLE ITT 
MMRM Analysis of Change from Baseline in Palm/Sole 
Assessment 
Non-unique 
14.2.4.3 
ITT 
Logistic Regression Analysis of 2-grade Change in Palm/Sole 
Assessment from Baseline 
Non-unique 
14.2.5.1 
ITT 
Secondary Analysis: MMRM Analysis of Change from Baseline 
in Dermatology Life Quality Index 
Non-unique 
14.2.5.2 
ITT 
Secondary Analysis: MMRM Analysis of Change from Baseline 
in Children’s Dermatology Life Quality Index 
Non-unique 
14.2.6.1.1 ITT 
Secondary Analysis: Presence of Fissures on Palms or Soles 
Unique 
14.2.6.1.2 OLE ITT 
Presence of Fissures on Palms or Soles 
Unique 
14.2.6.2.1 ITT 
Secondary Analysis: Summary of Number of Fissures and 
Fissure Pain Level 
Unique 
14.2.6.2.2 OLE 
Summary of Number of Fissures and Fissure Pain Level 
Non-unique 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
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Number Population Title 
Unique/Non-unique 
14.2.7.1 
ITT 
Exploratory Analysis: Summary of Change from Baseline in 
Ectropion Score 
Unique 
14.2.7.2 
OLEITT 
Summary of Change from Baseline in Ectropion Score 
Non-unique 
14.2.8.1 
ITT 
Exploratory Analysis: Change from Baseline in EQ-5D-5L 
Non-unique 
14.2.8.2 
ITT  
Exploratory Analysis: Change from Baseline in EQ-5D-Y 
Non-unique 
 
 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
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13.3. Safety Data 
Table 11: Safety Data 
Number 
Population Title 
Unique/Non-unique 
14.3.1.1.1 
Safety 
Overall Summary of Treatment Emergent Adverse Events 
during the Double-blind Period 
Unique 
14.3.1.1.2 
OLE 
Safety 
Overall Summary of Treatment Emergent Adverse Events 
during the OLE 
Non-unique 
14.3.1.2.1 
Safety 
Incidence of Treatment Emergent Adverse Events during the 
Double-blind Period by System Organ Class and Preferred 
Term 
Unique 
14.3.1.2.2 
OLE 
Safety 
Incidence of Treatment Emergent Adverse Events during the 
OLE Period by System Organ Class and Preferred Term 
Non-unique 
14.3.1.3.1 
Safety 
Incidence of Treatment Emergent Adverse Events during the 
Double-blind Period by System Organ Class, Preferred Term, 
and Maximum Severity 
Unique 
14.3.1.3.2 
OLE 
Safety 
Incidence of Treatment Emergent Adverse Events during the 
OLE by System Organ Class, Preferred Term, and Maximum 
Severity 
Non-unique 
14.3.1.4.1 
Safety 
Incidence of Treatment Emergent Adverse Events during the 
Double-blind Period by System Organ Class, Preferred Term, 
and Relationship to Study Drug 
Unique 
14.3.1.4.2 
OLE 
Safety 
Incidence of Treatment Emergent Adverse Events during the 
OLE by System Organ Class, Preferred Term, and 
Relationship to Study Drug 
Non-unique 
14.3.2.1.1 
Safety 
Incidence of Adverse Events Leading to Withdrawal during 
the Double-blind Period by SOC, PT, and Treatment 
Non-unique 
14.3.2.1.2 
OLE 
Safety 
Incidence of Adverse Events Leading to Withdrawal during 
the OLE Period by SOC, PT, and Treatment 
Non-unique 
14.3.2.2.1 
Safety 
Incidence of Serious Adverse Events during the Double-blind 
Period by SOC, PT, and Treatment 
Non-unique 
14.3.2.2.2 
OLE 
Safety 
Incidence of Serious Adverse Events during the OLE by SOC, 
PT, and Treatment 
Non-unique 
14.3.3.1.1 
Safety 
Listing of Adverse Events Leading to Withdrawal during the 
Double-blind Period 
Unique 
14.3.3.1.2 
OLE 
Safety 
Listing of Adverse Events Leading to Withdrawal during the 
Double-blind Period 
Non-unique 
14.3.3.2.1 
Safety 
Listing of Serious Adverse Events during the Double-blind 
Period 
Non-unique 
14.3.3.2.2 
Safety 
Listing of Serious Adverse Events during the OLE 
Non-unique 
14.3.3.3.1 
Safety 
Listing of Deaths during the Double-blind Period 
Non-unique 


 
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Protocol Number 18-ICH-001  
 
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Number 
Population Title 
Unique/Non-unique 
14.3.3.3.2 
Safety 
Listing of Deaths during the OLE 
Non-unique 
14.3.4.1 
Safety 
Listing of Abnormal Laboratory Data 
Unique 
14.3.5.1.1.1 
Safety 
Laboratory Data: Change from Baseline in Clinical Chemistry 
Parameters by Study Visit 
Unique 
14.3.5.1.1.2 
OLE 
Safety 
Laboratory Data: Change from Baseline in Clinical Chemistry 
Parameters by Study Visit 
Non-unique 
14.3.5.1.2.1 
Safety 
Laboratory Data: Shift from Baseline in Clinical Chemistry 
Parameters by Study Visit 
Unique 
14.3.5.1.2.2 
OLE 
Safety 
Laboratory Data: Shift from Baseline in Clinical Chemistry 
Parameters by Study Visit 
Non-unique 
14.3.5.2.1.1 
Safety 
Laboratory Data: Change from Baseline in Hematology 
Parameters by Study Visit 
Non-unique 
14.3.5.2.1.2 
OLE 
Safety 
Laboratory Data: Change from Baseline in Hematology 
Parameters by Study Visit 
Non-unique 
14.3.5.2.2.1 
Safety 
Laboratory Data: Shift from Baseline in Hematology 
Parameters by Study Visit 
Non-unique 
14.3.5.2.2.2 
OLE 
Safety 
Laboratory Data: Shift from Baseline in Hematology 
Parameters by Study Visit 
Non-unique 
14.3.5.3.1.1 
Safety 
Laboratory Data: Change from Baseline in Coagulation 
Parameters by Study Visit 
Non-unique 
14.3.5.3.1.2 
OLE 
Safety 
Laboratory Data: Change from Baseline in Coagulation 
Parameters by Study Visit 
Non-unique 
14.3.5.3.2.1 
Safety 
Laboratory Data: Shift from Baseline in Coagulation 
Parameters by Study Visit 
Non-unique 
14.3.5.3.2.2 
OLE 
Safety 
Laboratory Data: Shift from Baseline in Coagulation 
Parameters by Study Visit 
Non-unique 
14.3.5.4.1.1 
Safety 
Laboratory Data: Change from Baseline in Quantitative 
Urinalysis Parameters by Study Visit 
Non-unique 
14.3.5.4.1.2 
OLE 
Safety 
Laboratory Data: Change from Baseline in Quantitative 
Urinalysis Parameters by Study Visit 
Non-unique 
14.3.5.4.2.1 
Safety 
Laboratory Data: Shift from Baseline in Quantitative 
Urinalysis Parameters by Study Visit 
Non-unique 
14.3.5.4.2.2 
OLE 
Safety 
Laboratory Data: Shift from Baseline in Quantitative 
Urinalysis Parameters by Study Visit 
Non-unique 
14.3.5.4.3.1 
Safety 
Laboratory Data: Summary of Qualitative Urinalysis 
Parameters by Study Visit 
Unique 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
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Number 
Population Title 
Unique/Non-unique 
14.3.5.4.3.2 
OLE 
Safety 
Laboratory Data: Summary of Qualitative Urinalysis 
Parameters by Study Visit 
Non-unique 
14.3.6.1.1 
Safety 
Summary of Vital Signs by Study Visit 
Non-unique 
14.3.6.1.2 
OLE 
Safety 
Summary of Vital Signs by Study Visit 
Non-unique 
14.3.6.2.1 
Safety 
Summary of 12-Lead Electrocardiogram by Study Visit 
Non-unique 
14.3.6.2.2 
OLE 
Safety 
Summary of 12-Lead Electrocardiogram by Study Visit 
Non-unique 
14.3.6.2.3 
Safety 
Summary of 12-Lead Electrocardiogram Interpretation by 
Study Visit 
Unique 
14.3.6.2.4 
OLE 
Safety 
Summary of 12-Lead Electrocardiogram Interpretation by 
Study Visit 
Unique 
14.3.6.3.1 
Safety 
Summary of Local Tolerability Assessments by Study Visit 
Unique  
14.3.6.3.2 
OLE 
Safety 
Summary of Local Tolerability Assessments by Study Visit 
Non-unique 
14.3.6.4.1 
Safety 
Summary of Physical Examination Results by Study Visit 
Unique 
14.3.6.4.2 
OLE 
Safety 
Summary of Physical Examination Results by Study Visit 
Non-unique 
14.3.6.5.1 
Safety 
Summary of Concomitant Medications by ATC Class Level 4 
and Preferred Term 
Non-unique 
14.3.6.5.2 
OLE 
Safety 
Summary of Concomitant Medications by ATC Class Level 4 
and Preferred Term 
Non-unique 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
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13.4. Pharmacokinetic Data 
Table 12: Pharmacokinetic Data 
Number Population Title 
Unique/Non-unique 
14.4.1.1 Safety 
Summary of Pharmacokinetic Concentrations by Study Visit 
Unique  
14.4.1.2 Safety 
Summary of Pharmacokinetic Parameters 
Unique 
13.5. Planned Listing Descriptions 
The following are planned data and patient/subject data listings for protocol number 18-ICH-
001.  
In general, 1 listing will be produced per CRF domain. All listings will be sorted by treatment, 
site, and subject number. All calculated variables will be included in the listings. 
In all listings a blank line will be placed between each subject. Within a data listing, if an item 
appears line after line (e.g., repetition of subject number), then only the first occurrence will be 
displayed. 
In data listings, the information for 1 subject will be kept on 1 page if at all possible, rather than 
splitting a subject’s information across pages. 
Table 13: Planned Listings 
Number Population 
Title 
Unique/Non-unique 
Provide at Topline? 
16.2.1 
All Subjects Subject Disposition 
Unique 
 
16.2.2.1 
All Subjects Inclusion and Exclusion Criteria 
Unique 
 
16.2.2.2 
All Subjects Screen Failures 
Unique 
 
16.2.2.3 
All Subjects Protocol Deviations 
Unique 
 
16.2.3 
All Subjects Analysis Populations 
Unique 
 
16.2.4.1 
All Subjects Subject Demographics 
Unique 
 
16.2.4.2 
All Subjects Informed Consent and Reconsent 
Unique 
 
16.2.4.3 
All Subjects Medical History 
Unique 
 
16.2.5.1 
All Subjects Initial Study Drug Application 
Unique 
 
16.2.5.2 
All Subjects Drug Accountability (Dispensed and 
Returned) 
Unique 
 
16.2.5.3 
All Subjects Subject Diary 
Unique 
 
16.2.5.4.1 All Subjects Pharmacokinetic Sample Collection Unique 
 
16.2.5.4.2 All Subjects Pharmacokinetic Sample Collection 
(Substudy) 
Unique 
 
16.2.5.4.3 PK 
Pharmacokinetic Concentrations 
Unique 
 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
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Number Population 
Title 
Unique/Non-unique 
Provide at Topline? 
16.2.5.4.4 All Subjects Pharmacokinetic Calculated 
Parameters 
Unique 
 
16.2.6.1 
All Subjects Investigator’s Global Assessment 
(IGA) 
Unique 
 
16.2.6.2 
All Subjects Visual Index for Ichthyosis (VIIS) 
Non-unique 
 
16.2.6.3 
All Subjects Roughness Assessment 
Non-unique 
 
16.2.6.4 
All Subjects Palm/Sole Assessment 
Non-unique 
 
16.2.6.5.1 All Subjects Quality of Life per Dermatology 
Life Quality Index (DLQI) 
Non-unique 
 
16.2.6.5.1 All Subjects Quality of Life per Children’s 
Dermatology Life Quality Index 
(DLQI) 
Non-unique 
 
16.2.6.6 
All Subjects Fissuring Assessment 
Unique 
 
16.2.6.7 
All Subjects Ectropion Score 
Non-unique 
 
16.2.6.8 
All Subjects EQ-5D 
Non-unique 
 
16.2.7.1 
All Subjects Adverse Events 
Unique 
 
16.2.8.1 
All Subjects Laboratory Data: Clinical Chemistry Unique 
 
16.2.8.2 
All Subjects Laboratory Data: Hematology 
Non-unique 
 
16.2.8.3 
All Subjects Laboratory Data: Coagulation 
Non-unique 
 
16.2.8.4 
All Subjects Laboratory Data: Urinalysis 
Non-unique 
 
16.2.8.5 
All Subjects Laboratory Data: Serology 
Non-unique 
 
16.2.8.6 
All Subjects Laboratory Data: Pregnancy Tests 
Non-unique 
 
16.2.9.1 
All Subjects Vital Signs 
Non-unique 
 
16.2.9.2 
All Subjects 12-Lead Electrocardiogram 
Non-unique 
 
16.2.9.3 
All Subjects Local Tolerability Assessments 
Unique 
 
16.2.9.4 
All Subjects Physical Examination 
Unique 
 
16.2.9.5 
All Subjects Prior and Concomitant Medications Unique 
 
16.2.9.6 
All Subjects Photography 
Unique 
 
16.2.9.7 
All Subjects Trial Continuation 
Unique 
 
16.2.9.8 
All Subjects Telephone Contact 
Unique 
 
16.2.9.9 
All Subjects COVID-19 Visit Impact Log 
Unique 
 
13.6. Planned Figure Descriptions 
Not applicable. 


 
Statistical Analysis Plan,  
 
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Protocol Number 18-ICH-001  
 
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Table 14: Planned Figures 
Not Applicable.


 
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Protocol Number 18-ICH-001  
 
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14. 
Tables, Listings, and Listing Shells 
14.1. 
Standard Layout for all Tables, Listings, and Figures 
The following standard layout will be applied to all tables, listings, and figures in support of this study. Note that programming notes 
may be added if appropriate after each TLF shell.  
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 51 of 150 
 
Figure 3: Standardized Layout 
Mayne Pharma 
Page xx of xx 
Protocol: 18-ICH-001 
<Version>  
 
<Table, Listing, Figure> xx.x.x 
<Title of Table Listing or Figure> 
<Study Population and if applicable subgroup Description> 
____________________________________________________________________________________________________________ 
 
 
Body of Table, Listing or Figure 
 
 
___________________________________________________________________________________________________________ 
<Note: If directly Applicable> 
Footnote 1 <if applicable>  Recommendation is to keep footnotes to a minimum 
Footnote 2 <if applicable> 
Footnote n <if applicable> 
<pgm path>\<pgm name.sas> 
Executed on DDMONYYYY at hh:mm on data from DDMONYYYY; SAS Version 9.X 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 52 of 150 
 
14.2. 
Planned Table Shells 
See Figure 4 below. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 53 of 150 
 
Figure 4: Planned Table Shells 
Table 14.1.1.1 
Summary of Subject Disposition  
ITT Population 
 
 
Category 
Trifarotene cream HE1 
100 ug/g 
 (N=XXX) 
Trifarotene cream HE1 
200 ug/g 
 (N=XXX) 
Vehicle 
(N=XXX) 
Overall 
(N=XXX) 
 
 
 
 
 
ITT Population 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Safety Population 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
mITT Population 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
PP Population 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
PK Population 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
Completed Continuing 
 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Completed not Continuing to OLE 
 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Ongoing in Double-blind Study 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Early Discontinuation of Medication 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ITT = intent-to-treat; mITT = modified intent-to-treat; OLE = open label extension; PK = pharmacokinetic; PP = per protocol. 
Note: Percentages are n/Number of subjects in the ITT Population within randomized treatment group and overall*100. The ITT population includes all randomized subjects. The Safety 
population includes all subjects who are randomized to treatment and receive at least 1 application of study drug in the Double-blind Period. The mITT population includes all subjects in the 
Safety population with at least 1 postbaseline assessment of efficacy in the Double-blind period. The PP population includes all subjects in the mITT population who met all inclusion criteria and 
no exclusion criteria, were compliant with study drug application, and who had no significant protocol deviations. The PK population includes all subjects in the Safety population who have at 
least 1 plasma sample with quantifiable concentration. Completed continuing represents subjects who completed study visits and Double-blind treatment period (Day 90) and are continuing to 
OLE. Completed not continuing represents subjects who completed study visits and Double-blind treatment period (Day 90) but are not continuing to OLE. Early discontinuation of medication 
represent subjects who did not complete treatment but are not withdrawn from study (i.e., still in follow-up). Early termination from study represents subjects who did not complete study visits or 
complete the Double-blind treatment period. 
SOURCE: Listing 16.2.1 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 54 of 150 
 
Table 14.1.1.1 (cont.) 
Summary of Subject Disposition  
ITT Population 
 
 
Category 
Trifarotene cream HE1 
100 ug/g 
 (N=XXX) 
Trifarotene cream HE1 
200 ug/g 
 (N=XXX) 
Vehicle 
(N=XXX) 
Overall 
(N=XXX) 
 
 
 
 
 
Early Termination from Study 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Reason for Early Termnation: 
 
 
 
 
      Adverse Event 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Intercurrent Illness 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Death 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Lack of Efficacy 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Lost to Follow-up 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Non-compliance with Study Procedures 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Administrative Reasons 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Physician Decision         
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Pregnancy 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Protocol Violation 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Subject Meets an Exclusion Criteria 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Withdrawal by Subject 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Subject Withdrew Consent 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Study Terminated by Sponsor 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Other 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
Blind Broken 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ITT = intent-to-treat; mITT = modified intent-to-treat; OLE = open label extension; PK = pharmacokinetic; PP = per protocol. 
Note: Percentages are n/Number of subjects in the ITT Population within randomized treatment group and overall*100. The ITT population includes all randomized subjects. The Safety 
population includes all subjects who are randomized to treatment and receive at least 1 application of study drug in the Double-blind Period. The mITT population includes all subjects in the 
Safety population with at least 1 postbaseline assessment of efficacy in the Double-blind period. The PP population includes all subjects in the mITT population who met all inclusion criteria and 
no exclusion criteria, were compliant with study drug application, and who had no significant protocol deviations. The PK population includes all subjects in the Safety population who have at 
least 1 plasma sample with quantifiable concentration. Completed continuing represents subjects who completed study visits and Double-blind treatment period (Day 90) and are continuing to 
OLE. Completed not continuing represents subjects who completed study visits and Double-blind treatment period (Day 90) but are not continuing to OLE. Early discontinuation of medication 
represent subjects who did not complete treatment but are not withdrawn from study (i.e., still in follow-up). Early termination from study represents subjects who did not complete study visits or 
complete the Double-blind treatment period. 
SOURCE: Listing 16.2.1 
 
Programming note: Only include the Ongoing in Double-blind Study row when the overall n>0 for that row (i.e. dry runs). 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 55 of 150 
 
Table 14.1.1.2 
Summary of Subject Disposition  
OLE ITT Population 
 
 
Category 
 
 
Trifarotene cream HE1 
200 ug/g 
 (N=XXX) 
 
 
 
 
OLE ITT Population 
 
 
XX (XX.X%) 
OLE Safety Population 
 
 
XX (XX.X%) 
OLE mITT Population 
 
 
XX (XX.X%) 
OLE PP Population 
 
 
XX (XX.X%) 
 
 
 
 
Completed 
 
 
 
XX (XX.X%) 
Ongoing in OLE Study 
 
 
XX (XX.X%) 
Early Discontinuation of Medication 
 
 
XX (XX.X%) 
Early Termination from Study 
 
 
XX (XX.X%) 
   Reason for Early Termnation: 
 
 
 
      Adverse Event 
 
 
XX (XX.X%) 
      Intercurrent Illness 
 
 
XX (XX.X%) 
      Death 
 
 
XX (XX.X%) 
      Lack of Efficacy 
 
 
XX (XX.X%) 
      Lost to Follow-up 
 
 
XX (XX.X%) 
      Non-compliance with Study Procedures 
 
 
XX (XX.X%) 
      Administrative Reasons 
 
 
XX (XX.X%) 
      Physician Decision         
 
 
XX (XX.X%) 
      Pregnancy 
 
 
XX (XX.X%) 
      Protocol Violation 
 
 
XX (XX.X%) 
      Subject Meets an Exclusion Criteria 
 
 
XX (XX.X%) 
      Withdrawal by Subject 
 
 
XX (XX.X%) 
      Subject Withdrew Consent 
 
 
XX (XX.X%) 
      Study Terminated by Sponsor 
 
 
XX (XX.X%) 
      Other 
 
 
XX (XX.X%) 
 
 
 
 
 
 
 
 
Abbreviations: EOT = end of treatment; ITT = intent-to-treat; mITT = modified intent-to-treat; OLE = open label extension; PP = per protocol. 
Note: Percentages are n/Number of subjects in the OLE ITT Population within treatment group and overall*100. All subjects received Trifarotene cream HE1 200 ug/g in the OLE. 
The OLE ITT population includes all subjects who complete the 90-day Double-blind treatment Period and sign the OLE informed consent. The OLE Safety population includes all 
subjects who complete the 90-day Double-blind treatment Period and receive at least 1 application of study drug in the OLE. The OLE mITT population includes all subjects in the 
Safety population with at least 1 assessment of efficacy in after Visit 6 (Day 90). The OLE PP population includes all subjects in the OLE mITT population who met all inclusion 
criteria and no exclusion criteria, were compliant with study drug application from baseline through EOT, and who had no significant protocol deviations throughout the study. 
Completed continuing represents subjects who completed study visits and OLE treatment period. Early discontinuation of medication represent subjects who did not complete 
treatment but are not withdrawn from study (i.e., still in follow-up). Early termination from study represents subjects who did not complete study visits or complete the OLE treatment 
period. 
SOURCE: Listing 16.2.1 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 56 of 150 
 
Table 14.1.2.1 
Summary of Demographics and Baseline Characteristics 
ITT Population 
 
 
Variable 
   Statistic or Category 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
Vehicle 
(N=XX) 
Overall  
(N=XX) 
 
 
 
 
 
Age (years) 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Sex 
 
 
 
 
   Male 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Female 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Child-bearing Age? [1] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
Ethnicity [2] 
 
 
 
 
   Hispanic or Latino 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Not Hispanic or Latino 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Not Applicable 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
Race [2] 
 
 
 
 
   American-Indian or Alaska Native 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Asian 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Black or African-American 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Native Hawaiian or Other Pacific Islander 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   White 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   More than One Race 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Race not Provided 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
Abbreviations: IGA = Investigator’s Global Assessment; SD = standard deviation. 
Note: Percentages are n/Number of subjects in the ITT Population within randomized treatment group and overall*100.   
[1] Only captured for female subjects; percentages are based on the number of female subjects in the Safety Population. 
[2] Not captured in France. 
SOURCE: Listings 16.2.4.1, 16.2.6.1 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 57 of 150 
 
Table 14.1.2.1(cont.) 
Summary of Demographics and Baseline Characteristics 
ITT Population 
 
 
Variable 
   Statistic or Category 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
Vehicle 
(N=XX) 
Overall  
(N=XX) 
 
 
 
 
 
Height (cm) 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Weight (kg) 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Body Mass Index (kg/m2) 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
IGA Score 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
Abbreviations: IGA = Investigator’s Global Assessment; SD = standard deviation. 
Note: Percentages are n/Number of subjects in the ITT Population within randomized treatment group and overall*100.   
[1] Only captured for female subjects; percentages are based on the number of female subjects in the Safety Population. 
[2] Not captured in France. 
SOURCE: Listings 16.2.4.1, 16.2.6.1 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 58 of 150 
 
Table 14.1.2.2 
Summary of Demographics and Baseline Characteristics 
OLE ITT Population 
 
Same shell as Table 14.1.2.1 
Programming note: Only include one column for Trifarotene cream HE1 200 ug/g.  
Update Note: to read “Percentages are n/Number of subjects in the OLE ITT Population within treatment group and overall*100. All subjects received Trifarotene cream HE1 200 ug/g 
in the OLE.” 
 Add OLE = open label extension to Abbreviations. 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 59 of 150 
 
Table 14.1.3 
Summary of Medical Histories by System Organ Class and Preferred Term 
Safety Population 
 
 
System Organ Class 
   Preferred Term 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
Vehicle 
(N=XX) 
Overall  
(N=XX) 
 
 
 
 
 
Subjects with at least 1 Recorded Medical History 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
System Organ Class 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
System Organ Class 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: MedDRA = Medical Dictionary for Regulatory Activities; PT = preferred term; SOC = system organ class. 
Note: Percentages are n/Number of subjects in the Safety population within actual treatment group and overall*100. Medical histories are coded using MedDRA version 
21.1. Subjects were counted once for each system organ class (SOC) and once for each preferred term (PT). Medical history terms are displayed by descending frequency 
of SOC, then PT within SOC, and then alphabetically by PT. 
SOURCE: Listing 16.2.4.3 
Programming note: SOC & PT text should be in title case in table, as shown in the shell. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 60 of 150 
 
Table 14.1.4 
Summary of Prior Medications by ATC Class Level 4 and Preferred Term 
Safety Population 
 
 
ATC Class Level 4 
   Preferred Term (ATC Class Level 5) 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
Vehicle 
(N=XX) 
Overall  
(N=XX) 
 
 
 
 
 
Subjects with at least 1 Prior Medication 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
ATC Class 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
ATC Class 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
    
 
 
 
 
Abbreviations: ATC = Anatomic Therapeutic Chemical; PT = preferred term; WHO-DDE = World Health Organization-Drug Dictionary Enhanced. 
Note: Percentages are n/Number of subjects in the Safety population within actual treatment group and overall*100. Medications were coded using WHO-DDE version March 2019. 
Prior medications are all medications that were started before the first dose of study drug. Medications are displayed by descending frequency of ATC Level 4 classification, by PT 
within ATC, and then alphabetically by PT, based on the overall column. Subjects were counted only once for each ATC and PT. 
SOURCE: Listing 16.2.9.5 
 
Programming note: ATC & PT text should be in title case in table, as shown in the shell.  
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 61 of 150 
 
Table 14.1.5.1 
Summary of Drug Accountability (Drug Returned and Dispensed) 
Safety Population 
 
 
Visit 
  Parameter 
    Statistic 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
Vehicle 
 (N=XX) 
Overall 
 (N=XX) 
 
 
 
 
 
Baseline [1] 
 
 
 
 
  Total Weight of Tubes Dispensed (g) 
 
 
 
 
      n 
XX 
XX 
XX 
XX 
      Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
      Median 
XX.X 
XX.X 
XX.X 
XX.X 
      Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Day 14 
 
 
 
 
  Total Weight of Tubes Dispensed (g) 
 
 
 
 
      n 
XX 
XX 
XX 
XX 
      Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
      Median 
XX.X 
XX.X 
XX.X 
XX.X 
      Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
  Total Number of Tubes Returned 
 
 
 
 
      n 
XX 
XX 
XX 
XX 
      Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
      Median 
XX.X 
XX.X 
XX.X 
XX.X 
      Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: OLE = open label extension. SD = standard deviation. 
Note: Subjects are summarized by actual treatment group. Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the 
Double-blind period. All subjects received Trifarotene cream HE1 200 ug/g in the OLE.  
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
SOURCE: Listings 16.2.5.1, 16.2.5.2, 16.2.5.3 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 62 of 150 
 
Table 14.1.5.1 (cont.) 
Summary of Drug Accountability (Drug Returned and Dispensed) 
Safety Population 
 
 
Visit 
  Parameter 
    Statistic 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
Vehicle 
 (N=XX) 
Overall 
 (N=XX) 
 
 
 
 
 
Day 14 
 
 
 
 
  Total Number of Tubes Returned Unused 
 
 
 
 
      n 
XX 
XX 
XX 
XX 
      Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
      Median 
XX.X 
XX.X 
XX.X 
XX.X 
      Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
  Total Weight of Tubes Returned (g) 
 
 
 
 
      n 
XX 
XX 
XX 
XX 
      Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
      Median 
XX.X 
XX.X 
XX.X 
XX.X 
      Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
 
 
Abbreviation: OLE = open label extension. SD = standard deviation. 
Note: Subjects are summarized by actual treatment group. Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the 
Double-blind period. All subjects received Trifarotene cream HE1 200 ug/g in the OLE.  
SOURCE: Listings 16.2.5.1, 16.2.5.2, 16.2.5.3 
Programming note: Continue for Day 30, Day 60, and Day 90. 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
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 Page 63 of 150 
 
Table 14.1.5.2 
Summary of Drug Accountability (Drug Returned and Dispensed) 
OLE Safety Population 
 
Same shell as Table 14.1.5.1 
Programming note: Only include one column for Trifarotene cream HE1 200 ug/g.  
Continue for Day 104, Day 120, Day 150 and Day 180.  
Update Note: to read “Note: Subjects are summarized by treatment group. All subjects received Trifarotene cream HE1 200 ug/g in the OLE.” 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 64 of 150 
 
Table 14.1.5.3 
Summary of Treatment Exposure and Compliance  
Safety Population 
 
 
Variable  
  Statistic or Category 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
Vehicle 
 (N=XX) 
Overall 
(N=XX) 
 
 
 
 
 
Compliance by Tube Weight (%) [1] 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Compliant  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Not Compliant  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
Compliance by Number of Doses (%) [2] 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
Compliant  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Not Compliant  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: SD = standard deviation. 
Note: Percentages are n/Number of subjects in the Safety population within actual treatment group and overall*100. A subject is compliant with study product if he or she takes at 
least 80%-120% of the scheduled doses as assessed by diary entries, supplemented by tube weight. 
[1] Compliance by tube weight = total weight used / total weight of tubes dispensed *100%, where total weight used = total weight of tubes dispensed (grams) – total weight of tubes 
returned (grams) 
[2] Compliance by number of doses = number of doses taken / number of expected doses * 100%, where number of doses taken = total number of tubes dispensed – total number 
of tubes returned – total number of tubes returned unused, number of expected doses = 2 * number of weeks on study, and number of weeks on study = (last day on study – 
treatment start date + 1) / 7 
SOURCE: Listings 16.2.5.1, 16.2.5.2, 16.2.5.3 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 65 of 150 
 
Table 14.1.5.4 
Summary of Treatment Exposure and Compliance  
OLE Safety Population 
 
Same shell as Table 14.1.5.3 
Programming note: Only include one column for Trifarotene cream HE1 200 ug/g. 
 Update Note: to read “Note: Percentages are n/Number of subjects in the OLE Safety population within treatment group and overall*100. All subjects received Trifarotene cream HE1 
200 ug/g in the OLE.”  
Add OLE = open label extension to Abbreviations. 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 66 of 150 
 
Table 14.2.1.1.1 
Primary Analysis: Logistic Regression Analysis of Successful Resolution of LI 
ITT Population 
 
 
Study Visit 
Trifarotene cream HE1 
100 ug/g 
Trifarotene cream HE1 
200 ug/g 
Overall Trifarotene 
cream HE1 
Vehicle 
   Statistic  
(N = XX) 
(N = XX) 
(N = XX) 
(N = XX) 
 
 
 
 
 
Day 90 
 
 
 
 
   n [1] 
XX 
XX 
XX 
XX 
   Successful Resolution [2] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
   Odds Ratio (Trifarotene cream HE1 vs Vehicle) 
X.XX 
X.XX 
X.XX 
 
   95% CI for Odds Ratio 
(X.XX, X.XX) 
(X.XX, X.XX) 
(X.XX, X.XX) 
 
   P value [3] 
X.XXX 
X.XXX 
X.XXX 
 
 
 
 
 
 
   Difference in Proportion (Trifarotene cream HE1 vs Vehicle) 
X.XX 
X.XX 
X.XX 
 
   95% CI for Proportion Difference 
(X.XX, X.XX) 
(X.XX, X.XX) 
(X.XX, X.XX) 
 
   P value [3] 
X.XXX 
X.XXX 
X.XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: CI = confidence interval; EOT = end of treatment; IGA = Investigator’s Global Assessment; ITT = intent to treat; LI = Lamellar Ichthyosis; OR = odds ratio. 
Note: Percentages are n/Number of subjects in the ITT population within randomized treatment group*100. The 5-point (0 - 4) IGA is a measure of disease severity which 
considers both scaling and roughness. Higher IGA scores represent more severe disease. 
[1] Number of subjects with an IGA assessment at each visit. 
[2] Number of subjects with successful resolution of LI at a visit. Successful resolution is defined as clear/almost clear overall (IGA of 0 or 1, respectively) and at least a 2-
grade change from Baseline on the  
5-point (0 - 4) IGA scale. Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period.  
[3] Estimates for odds ratio, 95% CI for odds ratio, and P value are from a logistic regression model with treatment, baseline IGA score, and age group as factors. The odds 
ratio is the estimate of the odds of having successful resolution of LI for subjects treated with Trifarotene cream HE1 relative to that for subjects treated with vehicle. Age 
group is defined as adolescents (ages 12 to 17 years, inclusive) and adults ≥18 years. 
SOURCE: Listing 16.2.6.1 
 
Programming note: If Firth’s penalized maximum likelihood is used, add ‘Firth’s penalized maximum likelihood estimation is used.’ to end of ‘Note:’ footnote. If the treatment-by-age 
interaction is significant, include it in the logistic regression model and update footnote [3] to include this factor. After Day 90, repeat table for Days 14, 30, and 60. 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 67 of 150 
 
Table 14.2.1.1.2 
Proportion of Subjects with Successful Resolution of LI in the OLE 
OLE ITT Population 
 
 
Study Visit 
 
 
 
Trifarotene cream HE1 
200 ug/g 
   Statistic  
 
 
 
(N = XX) 
 
 
 
 
 
Day 104 
 
 
 
 
   n [1] 
 
 
 
XX 
   Successful Resolution [2] 
 
 
 
XX (XX.X%) 
 
 
 
 
 
Day 120 
 
 
 
 
   n [1] 
 
 
 
XX 
   Successful Resolution [2] 
 
 
 
XX (XX.X%) 
 
 
 
 
 
Day 150 
 
 
 
 
   n [1] 
 
 
 
XX 
   Successful Resolution [2] 
 
 
 
XX (XX.X%) 
 
 
 
 
 
Day 180 
 
 
 
 
   n [1] 
 
 
 
XX 
   Successful Resolution [2] 
 
 
 
XX (XX.X%) 
 
 
 
 
 
Day 194 
 
 
 
 
   n [1] 
 
 
 
XX 
   Successful Resolution [2] 
 
 
 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Abbreviation: CI = confidence interval; EOT = end of treatment; IGA = Investigator’s Global Assessment; ITT = intent to treat; LI = Lamellar Ichthyosis; OLE = open label extension. 
Note: Percentages are n/Number of subjects in the OLE ITT population within treatment group*100. All subjects received Trifarotene cream HE1 200 ug/g in the OLE. The 5-point 
(0 - 4) IGA is a measure of disease severity which considers both scaling and roughness. Higher IGA scores represent more severe disease. 
[1] Number of subjects with an IGA assessment at each visit. 
[2] Number of subjects with successful resolution of LI at a visit. Successful resolution is defined as clear/almost clear overall (IGA of 0 or 1, respectively) and at least a 2-grade 
change from Baseline on the 5-point (0 - 4) IGA scale. Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind 
Period.  
SOURCE: Listing 16.2.6.1 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 68 of 150 
 
 
Table 14.2.1.2.1 
Primary Analysis, Sensitivity: Logistic Regression Analysis of Successful Resolution of LI 
mITT Population 
 
Same shell as Table 14.2.1.1.1 
Programming note: Update Abbreviations to remove ITT and include mITT = modified intent-to-treat.  
Update Note: to read “Note: Percentages are n/Number of subjects in the mITT population within randomized treatment group*100.” 
 
 
 
Table 14.2.1.2.2 
Proportion of Subjects with Successful Resolution of LI in the OLE 
OLE mITT Population 
 
Same shell as Table 14.2.1.1.2 
Programming note: Update Abbreviations to remove ITT and include mITT = modified intent-to-treat and OLE = open label extension.  
Update Note: to read “Note: Percentages are n/Number of subjects in the OLE mITT population within treatment group*100. All subjects received Trifarotene cream HE1 200 ug/g in 
the OLE.” 
 
 
Table 14.2.1.3.1 
Primary Analysis, Sensitivity: Logistic Regression Analysis of Successful Resolution of LI 
PP Population 
 
Same shell as Table 14.2.1.1.1 
Programming note: Update Abbreviations to remove ITT and include PP = per protocol.  
Update Note: to read “Note: Percentages are n/Number of subjects in the PP population within actual treatment group*100.” 
 
 
Table 14.2.1.3.2 
Proportion of Subjects with Successful Resolution of LI in the OLE 
OLE PP Population 
 
Same shell as Table 14.2.1.1.2 
Programming note: Update Abbreviations to remove ITT and include OLE = open label extension and PP = per protocol.  
Update Note: to read “Note: Percentages are n/Number of subjects in the OLE PP population within treatment group*100. All subjects received Trifarotene cream HE1 200 ug/g in the 
OLE.” 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 69 of 150 
 
 
Table 14.2.1.4 
Primary Analysis, Sensitivity: Logistic Regression Analysis of Successful Resolution of LI Using Multiple Imputation 
ITT Population 
 
Same shell as Table 14.2.1.1.1 
Programming note: Update footnote [3] to read “Estimates for odds ratio, 95% CI for odds ratio, and P value are from a logistic regression model with treatment, baseline IGA score, 
and age group as factors. The odds ratio is the estimate of the odds of having successful resolution of LI for subjects treated with Trifarotene cream HE1 relative to that for subjects 
treated with vehicle. Missing values were considered MNAR and imputed using MI with a placebo-based pattern mixture model and then categorized as treatment success. Age group 
is defined as adolescents (ages 12 to 17 years, inclusive) and adults ≥18 years.” 
 
 
 
 
Table 14.2.1.5.1 
Logistic Regression Analysis of 50% Reduction in IGA score from Baseline  
ITT Population 
 
Same shell as Table 14.2.1.1.1 
Programming note: Update “Successful Resolution [2]” row text to read “50% Reduction from Baseline [2]”. 
Update footnote [2] to read “Number of subjects with a 50% reduction in IGA score from baseline at a visit. Baseline is defined as the last non-missing assessment recorded prior to 
the first dose of treatment in the Double-blind Period. Higher IGA scores represent more severe disease.” 
Update [3] to read “Estimates for odds ratio, 95% CI for odds ratio, and P value are from a logistic regression model with treatment, baseline IGA score, and age group as factors. The 
odds ratio is the estimate of the odds of having a 50% reduction in IGA score from baseline for subjects treated with Trifarotene cream HE1 relative to that for subjects treated with 
vehicle. Age group is defined as adolescents (ages 12 to 17 years, inclusive) and adults ≥18 years.”  
 
 
 
Table 14.2.1.5.2 
Proportion of Subjects with a 50% Reduction in IGA score from Baseline  
OLE ITT Population 
 
Same shell as Table 14.2.1.1.2 
Programming note: Update “Successful Resolution [2]” row text to read “50% Reduction from Baseline [2]”. 
Update Note: to read “Note: Percentages are n/Number of subjects in the OLE ITT population within treatment group*100. All subjects received Trifarotene cream HE1 200 ug/g in the 
OLE.” 
Update footnote [2] to read “Number of subjects with a 50% reduction in IGA score from baseline at a visit. Baseline is defined as the last non-missing assessment recorded prior to 
the first dose of treatment in the Double-blind Period. Higher IGA scores represent more severe disease.” 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 70 of 150 
 
Table 14.2.1.6.1 
MMRM Analysis of Change from Baseline in IGA Score 
ITT Population 
 
 
Study Visit 
Trifarotene cream HE1 
100 ug/g 
 (N=XXX) 
 
Trifarotene cream HE1 
200 ug/g 
 (N=XXX) 
   Statistic [1] 
Observed 
CFB 
 
Observed 
CFB 
 
 
 
 
 
 
Baseline [2] 
 
 
 
 
 
   n 
XXX 
 
 
XXX 
 
   Mean (SD) 
XX.XX (XX.XXX) 
 
 
XX.XX (XX.XXX) 
 
   Median 
XX.XX 
 
 
XX.XX 
 
   Min, Max 
XX.X, XX.X 
 
 
XX.X, XX.X 
 
 
 
 
 
 
 
Day 14 
 
 
 
 
 
   n 
XXX 
XXX 
 
XXX 
XXX 
   Mean (SD) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
   Median 
XX.XX 
XX.XX 
 
XX.XX 
XX.XX 
   Min, Max 
XX.X, XX.X 
XX.X, XX.X 
 
XX.X, XX.X 
XX.X, XX.X 
 
 
 
 
 
 
   LS Mean (SE) CFB 
 
X.XX (X.XXX) 
 
 
X.XX (X.XXX) 
   95% CI for LS Mean CFB 
 
(X.XX, X.XX) 
 
 
(X.XX, X.XX) 
   P value for CFB = 0 
 
X.XXXX 
 
 
X.XXXX 
 
 
 
 
 
 
   Comparison vs. Vehicle 
 
 
 
 
 
      Difference in LS Mean (SE) 
 
X.XX (X.XXX) 
 
 
X.XX (X.XXX) 
      95% CI for Difference in LS Mean 
 
(X.XX, X.XX) 
 
 
(X.XX, X.XX) 
      P value for Difference 
 
X.XXXX 
 
 
X.XXXX 
 
 
 
 
 
 
    
 
 
 
 
 
Abbreviations: CFB = change from baseline; CI = confidence interval; IGA = Investigator’s Global Assessment; ITT = intent to treat; LS = least-squares; MMRM = mixed model for 
repeated measures; SD = standard deviation; SE = standard error. 
Note: Subjects are summarized by randomized treatment group. The 5-point (0 - 4) IGA is a measure of disease severity which considers both scaling and roughness. Higher IGA 
scores represent more severe disease. 
[1] LS mean CFB, LS mean differences (Trifarotene cream HE1 - vehicle), 95% CIs, and P values were obtained from a mixed model for repeated measures (MMRM) with change 
from baseline in IGA score as the repeated dependent variable, fixed effect terms for baseline IGA score, treatment, study visit, treatment-by-study visit interaction, and age group 
as independent variables. An unstructured covariance matrix was used to model the within-subject correlation. Age group is defined as adolescents (ages 12 to 17 years, inclusive) 
and adults ≥18 years. 
[2] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
SOURCE: Listing 16.2.6.1 
 
Programming note: If the unstructured covariance structure does not converge, use other structures as outlined in the SAP section 8.1 and update the footnote accordingly. Include 
Days 30, 60, and 90 as well. Rows will be the same as what is displayed for Day 14. Repeat Table for Overall Trifarotene cream HE1 and Vehicle columns. 
Vehicle column will not have Comparison vs. Vehicle row cells populated. 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 71 of 150 
 
Table 14.2.1.6.2 
MMRM Analysis of Change from Baseline in IGA Score 
OLE ITT Population 
 
Programming note: Update Note: to read “Subjects are summarized by treatment group. All subjects received Trifarotene cream HE1 200 ug/g in the OLE.” 
Only include one set of columns for Trifarotene cream HE1 200 ug/g. 
Do not include Comparison vs. Vehicle rows. 
Baseline [2], Days 104, 120, 150, 180, and 194 will be displayed. 
Update footnote [1] to read “LS mean CFB, 95% CIs, and P values were obtained from a mixed model for repeated measures (MMRM) with change from baseline in IGA score as the 
repeated dependent variable, fixed effect terms for baseline IGA score, study visit, and age group as independent variables. An unstructured covariance matrix was used to model the 
within-subject correlation. Age group is defined as adolescents (ages 12 to 17 years, inclusive) and adults ≥18 years.” 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 72 of 150 
 
Table 14.2.7.1.1 
Categorical IGA Scores  
ITT Population 
 
 
Study Visit 
   Category 
Trifarotene 
cream HE1 
100 ug/g 
(N=XX) 
Trifarotene 
cream HE1 
200 ug/g 
(N=XX) 
Overall 
Trifarotene 
cream HE1 
 (N=XX) 
Vehicle 
(N=XXX) 
 
 
 
 
 
Baseline [1] 
 
 
 
 
  0 = Clear 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  1 = Almost clear 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  2 = Mild 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  3 = Moderate 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  4 = Severe 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
Day 14 
 
 
 
 
  0 = Clear 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  1 = Almost clear 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  2 = Mild 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  3 = Moderate 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  4 = Severe 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 90 
 
 
 
 
  0 = Clear 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  1 = Almost clear 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  2 = Mild 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  3 = Moderate 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  4 = Severe 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: IGA = Investigator’s Global Assessment; ITT = intent to treat; 
Note: Percentages are n/Number of subjects in the ITT population within randomized treatment group*100. The 5-point (0 - 4) IGA is a measure of disease severity which considers 
both scaling and roughness. Higher IGA scores represent more severe disease. 
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
SOURCE: Listing 16.2.6.1 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 73 of 150 
 
Table 14.2.1.7.2 
Categorical IGA Scores 
OLE ITT Population 
 
Programming note: Update Note: to read “Percentages are n/Number of subjects in the OLE ITT population within treatment group*100. All subjects received Trifarotene cream HE1 
200 ug/g in the OLE.” 
Only include one set of columns for Trifarotene cream HE1 200 ug/g. 
Baseline [2], Days 104, 120, 150, 180, and 194 will be displayed. 
Add OLE = open label extension to Abbreviations. 
 
 
 
Table 14.2.2.1 
Secondary Analysis: MMRM Analysis of Change from Baseline in VIIS Score 
ITT Population 
 
Same shell as Table 14.2.1.6.1 
 
Programming note: Update Note: to read “Note: Subjects are summarized by randomized treatment group. The VIIS is scored on a 5-point (0 - 4) scale by body area 
(chest/abdomen, back, legs, and arms). Higher VIIS scores represent worse scaling.”  
Update [1] to read “LS mean CFB, LS mean differences (Trifarotene cream HE1 - vehicle), 95% CIs, and P values were obtained from a mixed model for repeated measures (MMRM) 
with change from baseline in VIIS score as the repeated dependent variable, fixed effect terms for baseline VIIS score, treatment, study visit, treatment-by-study visit interaction, and 
age group as independent variables. An unstructured covariance matrix was used to model the within-subject correlation. Age group is defined as adolescents (ages 12 to 17 years, 
inclusive) and adults ≥18 years.”  
Remove IGA and add VIIS= Visual Index for Ichthyosis Severity to Abbreviations. 
Update SOURCE: to Listing 16.2.6.2 
 
 
 
 
Table 14.2.2.2 
MMRM Analysis of Change from Baseline in VIIS Score 
OLE ITT Population 
 
Same shell as Table 14.2.2.1 
Update Note: to read “Subjects are summarized by treatment group. All subjects received Trifarotene cream HE1 200 ug/g in the OLE.” 
Only include one set of columns for Trifarotene cream HE1 200 ug/g. 
Do not include Comparison vs. Vehicle rows. 
Baseline [2], Days 104, 120, 150, 180, and 194 will be displayed. 
Update footnote [1] to read “LS mean CFB, 95% CIs, and P values were obtained from a mixed model for repeated measures (MMRM) with change from baseline in IGA score as the 
repeated dependent variable, fixed effect terms for baseline IGA score,  study visit, and age group as independent variables. An unstructured covariance matrix was used to model the 
within-subject correlation. Age group is defined as adolescents (ages 12 to 17 years, inclusive) and adults ≥18 years.” 
Update SOURCE: to Listing 16.2.6.2 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 74 of 150 
 
Table 14.2.3.1 
Secondary Analysis: MMRM Analysis of Change from Baseline in Individual Score for Roughness 
ITT Population 
 
Same shell as Table 14.2.1.6.1 
 
Programming note: Update Note: to read “Note: Subjects are summarized by randomized treatment group. The individual score for roughness measures the amount of roughness of 
the skin overall and is scored on a 5-point (0 - 4) scale. Higher scores indicate more severe roughness.” 
Update footnote [1] to read “LS mean CFB, LS mean differences (Trifarotene cream HE1 - vehicle), 95% CIs, and P values were obtained from a mixed model for repeated measures 
(MMRM) with change from baseline in individual score for roughness as the repeated dependent variable, fixed effect terms for baseline individual score for roughness, treatment, 
study visit, treatment-by-study visit interaction, and age group as independent variables. An unstructured covariance matrix was used to model the within-subject correlation. 
[2] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. Age group is defined as adolescents (ages 12 to 17 
years, inclusive) and adults ≥18 years.” 
Update SOURCE: to Listing 16.2.6.3 
 
 
Table 14.2.3.2 
MMRM Analysis of Change from Baseline in Individual Score for Roughness 
OLE ITT Population 
 
Same shell as Table 14.2.1.6.1 
Update Note: to read “Subjects are summarized by treatment group. All subjects received Trifarotene cream HE1 200 ug/g in the OLE. The individual score for roughness measures 
the amount of roughness of the skin overall and is scored on a 5-point (0 - 4) scale. Higher scores indicate more severe roughness.” 
Only include one set of columns for Trifarotene cream HE1 200 ug/g. 
Do not include Comparison vs. Vehicle rows. 
Baseline [2], Days 104, 120, 150, 180, and 194 will be displayed. 
Update footnote [1] to read “LS mean CFB, 95% CIs, and P values were obtained from a mixed model for repeated measures (MMRM) with change from baseline in individual score 
for roughness as the repeated dependent variable, fixed effect terms for baseline individual score for roughness, study visit, and age group as independent variables. An unstructured 
covariance matrix was used to model the within-subject correlation. Age group is defined as adolescents (ages 12 to 17 years, inclusive) and adults ≥18 years.” 
Update SOURCE: to Listing 16.2.6.3 
 
 
Table 14.2.3.3 
Logistic Regression Analysis of 2-grade Change in Individual Score for Roughness from Baseline  
ITT Population 
 
Same shell as Table 14.2.1.1.1 
Programming note: Update “Successful Resolution [2]” row text to read “2-grade Change from Baseline [2]”. 
Update Note: to read “Note: Percentages are n/Number of subjects in the ITT population within randomized treatment group*100. The individual score for roughness measures the 
amount of roughness of the skin overall and is scored on a 5-point (0 - 4) scale. Higher scores indicate more severe roughness.” 
Update footnote [2] to read “Number of subjects with a 2-grade change in individual score for roughness from baseline at a visit. Baseline is defined as the last non-missing 
assessment recorded prior to the first dose of treatment in the Double-blind Period. Higher scores indicate more severe roughness.” 
Update [3] to read “Estimates for odds ratio, 95% CI for odds ratio, and P value are from a logistic regression model with treatment, baseline individual score for roughness, and age 
group as factors. The odds ratio is the estimate of the odds of having a 2-grade change in individual score for roughness from baseline for subjects treated with Trifarotene cream HE1 
relative to that for subjects treated with vehicle. Age group is defined as adolescents (ages 12 to 17 years, inclusive) and adults ≥18 years.” 
Update SOURCE: to Listing 16.2.6.3 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 75 of 150 
 
 
Table 14.2.4.1 
Secondary Analysis: MMRM Analysis of Change from Baseline in Palm/Sole Assessment 
ITT Population 
 
Same shell as Table 14.2.1.6.1 
 
Programming note: Update Note: to read “Note: Subjects are summarized by randomized treatment group. Thickening of the skin on the palms and soles will be measured on a 5-
point (0 - 4) scale. Higher scores indicate more severe thickening.” 
Update footnote [1] to read “LS mean CFB, LS mean differences (Trifarotene cream HE1 - vehicle), 95% CIs, and P values were obtained from a mixed model for repeated measures 
(MMRM) with change from baseline in palm/sole assessment score as the repeated dependent variable, fixed effect terms for baseline palm/sole assessment score, treatment, study 
visit, treatment-by-study visit interaction, and age group as independent variables. An unstructured covariance matrix was used to model the within-subject correlation. 
[2] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. Age group is defined as adolescents (ages 12 to 17 
years, inclusive) and adults ≥18 years.” 
Update SOURCE: to Listing 16.2.6.4 
 
 
 
Table 14.2.4.2 
MMRM Analysis of Change from Baseline in Palm/Sole Assessment 
OLE ITT Population 
 
Same shell as Table 14.2.1.6.1 
 
Update Note: to read “Subjects are summarized by treatment group. All subjects received Trifarotene cream HE1 200 ug/g in the OLE. Thickening of the skin on the palms and soles 
will be measured on a 5-point (0 - 4) scale. Higher scores indicate more severe thickening.” 
Only include one set of columns for Trifarotene cream HE1 200 ug/g. 
Do not include Comparison vs. Vehicle rows. 
Baseline [2], Days 104, 120, 150, 180, and 194 will be displayed. 
Update footnote [1] to read “LS mean CFB, 95% CIs, and P values were obtained from a mixed model for repeated measures (MMRM) with change from baseline in palm/sole 
assessment score as the repeated dependent variable, fixed effect terms for baseline palm/sole assessment score, study visit, and age group as independent variables. An 
unstructured covariance matrix was used to model the within-subject correlation. Age group is defined as adolescents (ages 12 to 17 years, inclusive) and adults ≥18 years.” 
Update SOURCE: to Listing 16.2.6.4 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 76 of 150 
 
Table 14.2.4.3 
Logistic Regression Analysis of 2-grade Change in Palm/Sole Assessment from Baseline  
ITT Population 
 
Same shell as Table 14.2.1.1.1 
 
Programming note: Update “Successful Resolution [2]” row text to read “2-grade Change from Baseline [2]”. 
Update Note: to read “Note: Percentages are n/Number of subjects in the ITT population within randomized treatment group*100. Thickening of the skin on the palms and soles will be 
measured on a 5-point (0 - 4) scale. Higher scores indicate more severe thickening.” 
Update footnote [2] to read “Number of subjects with a 2-grade change in palm/sole assessment score from baseline at a visit. Baseline is defined as the last non-missing assessment 
recorded prior to the first dose of treatment in the Double-blind Period. Higher scores indicate more severe roughness.” 
Update [3] to read “Estimates for odds ratio, 95% CI for odds ratio, and P value are from a logistic regression model with treatment, baseline palm/sole assessment score, and age 
group as factors. The odds ratio is the estimate of the odds of having a 2-grade change in palm/sole assessment score from baseline for subjects treated with Trifarotene cream HE1 
relative to that for subjects treated with vehicle. Age group is defined as adolescents (ages 12 to 17 years, inclusive) and adults ≥18 years.” 
Update SOURCE: to Listing 16.2.6.4 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 77 of 150 
 
Table 14.2.5.1 
Secondary Analysis: MMRM Analysis of Change from Baseline in Dermatology Life Quality Index 
ITT Population 
 
Same shell as Table 14.2.1.6.1 
 
Programming note: Update Note: to read “Note: Subjects are summarized by randomized treatment group. DLQI total score is derived as the sum of the 10 individual item scores, 
with a range of 0 to 30. Higher scores indicate poorer quality of life.” 
Update footnote [1] to read “LS mean CFB, LS mean differences (Trifarotene cream HE1 - vehicle), 95% CIs, and P values were obtained from a mixed model for repeated measures 
(MMRM) with change from baseline in DLQI score as the repeated dependent variable, fixed effect terms for baseline DLQI score, treatment, study visit, and treatment-by-study visit 
interaction as independent variables. An unstructured covariance matrix was used to model the within-subject correlation. 
[2] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period.” 
Update SOURCE: to Listing 16.2.6.5.1 
 
 
 
Table 14.2.5.2 
Secondary Analysis: MMRM Analysis of Change from Baseline in Children’s Dermatology Life Quality Index 
ITT Population 
 
Same shell as Table 14.2.1.6.1 
 
Programming note: Update Note: to read “Note: Subjects are summarized by randomized treatment group. cDLQI total score is derived as the sum of the 10 individual item scores, 
with a range of 0 to 30. Higher scores indicate poorer quality of life.” 
Update footnote [1] to read “LS mean CFB, LS mean differences (Trifarotene cream HE1 - vehicle), 95% CIs, and P values were obtained from a mixed model for repeated measures 
(MMRM) with change from baseline in cDLQI score as the repeated dependent variable, fixed effect terms for baseline cDLQI score, treatment, study visit, and treatment-by-study visit 
interaction as independent variables. An unstructured covariance matrix was used to model the within-subject correlation. 
[2] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period.” 
Update SOURCE: to Listing 16.2.6.5.2 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 78 of 150 
 
Table 14.2.6.1.1 
Secondary Analysis: Presence of Fissures on Palms or Soles 
ITT Population 
 
 
Study Visit 
   Category/Statistic [1] 
Trifarotene 
cream HE1 
100 ug/g 
(N=XX) 
Trifarotene 
cream HE1 
200 ug/g 
(N=XX) 
Overall 
Trifarotene 
cream HE1 
 (N=XX) 
Vehicle 
(N=XXX) 
 
 
 
 
 
Baseline [2] 
 
 
 
 
  Fissures Present 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  No Fissures Present 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
Day 14 
 
 
 
 
  Fissures Present 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  No Fissures Present 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
   Comparison vs. Vehicle 
 
 
 
 
      Difference in Percentage of Fissures Present 
XX.X 
XX.X 
XX.X 
 
      95% CI for Difference in Percentage of Fissures Present 
(XX.X, XX.X) 
(XX.X, XX.X) 
(XX.X, XX.X) 
 
      P value for Difference  
X.XXXX 
X.XXXX 
X.XXXX 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 90 
 
 
 
 
  Fissures Present 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  No Fissures Present 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
   Comparison vs. Vehicle 
 
 
 
 
      Difference in Percentage of Fissures Present 
XX.X 
XX.X 
XX.X 
 
      95% CI for Difference in Percentage of Fissures Present 
(XX.X, XX.X) 
(XX.X, XX.X) 
(XX.X, XX.X) 
 
      P value for Difference  
X.XXXX 
X.XXXX 
X.XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CI = confidence interval; ITT = intent-to-treat. 
Note: Percentages are n/Number of subjects in the ITT population within randomized treatment group*100. 
[1] P value from 2-sided Pearson’s Chi-Square test. Difference is calculated Trifarotene cream HE1 - vehicle. 
[2] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
SOURCE: Listing 16.2.6.6 
 
Programming Note: If cell counts are <5, use Fisher’s Exact Test and update footnote [1] accordingly. Include all study visits (Days 14, 30, and 60). 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 79 of 150 
 
Table 14.2.6.1.2 
Presence of Fissures on Palms or Soles 
OLE ITT Population 
 
 
Study Visit 
   Category/Statistic  
 
 
 
Trifarotene cream HE1 
200 ug/g 
 
 
 
 
 
Baseline [1] 
 
 
 
 
  Fissures Present 
 
 
 
XX (XX.X%) 
  No Fissures Present 
 
 
 
XX (XX.X%) 
 
 
 
 
 
Day 104 
 
 
 
 
  Fissures Present 
 
 
 
XX (XX.X%) 
  No Fissures Present 
 
 
 
XX (XX.X%) 
 
 
 
 
 
Day 120 
 
 
 
 
  Fissures Present 
 
 
 
XX (XX.X%) 
  No Fissures Present 
 
 
 
XX (XX.X%) 
 
 
 
 
 
Day 150 
 
 
 
 
  Fissures Present 
 
 
 
XX (XX.X%) 
  No Fissures Present 
 
 
 
XX (XX.X%) 
 
 
 
 
 
Day 180 
 
 
 
 
  Fissures Present 
 
 
 
XX (XX.X%) 
  No Fissures Present 
 
 
 
XX (XX.X%) 
 
 
 
 
 
Day 194 
 
 
 
 
  Fissures Present 
 
 
 
XX (XX.X%) 
  No Fissures Present 
 
 
 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CI = confidence interval; ITT = intent-to-treat; OLE = open label extension. 
Note: Percentages are n/Number of subjects in the OLE ITT population within treatment group*100. All subjects received Trifarotene cream HE1 200 ug/g in the OLE. 
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
SOURCE: Listing 16.2.6.6 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 80 of 150 
 
Table 14.2.6.2.1 
Secondary Analysis: Summary of Number of Fissures and Fissure Pain Level 
ITT Population 
 
Body Area: Palms 
 
Study Visit 
   Category/Statistic  
Trifarotene 
cream HE1 
100 ug/g 
(N=XX) 
Trifarotene 
cream HE1 
200 ug/g 
(N=XX) 
Overall 
Trifarotene 
cream HE1 
 (N=XX) 
Vehicle 
(N=XXX) 
 
 
 
 
 
Baseline [1] 
 
 
 
 
  Number of Fissures 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
  Fissure Pain Level 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
    None 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
    Mild 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
    Moderate  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
    Severe 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
… 
 
 
 
 
 
 
 
 
 
Day 90 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  Number of Fissures 
 
 
 
 
   n 
XX 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
   Median 
XX.X 
XX.X 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
 
 
 
 
 
  Fissure Pain Level 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
    None 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
    Mild 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
    Moderate  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
    Severe 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CI = confidence interval; ITT = intent-to-treat. 
Note: Percentages are n/Number of subjects in the ITT population within randomized treatment group*100. 
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
SOURCE: Listing 16.2.6.6 
 
Programming note: Repeat for Body Area: Soles. Include all study visits (Days 14, 30, and 60). 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 81 of 150 
 
Table 14.2.6.2.2 
Summary of Number of Fissures and Fissure Pain Level 
OLE ITT Population 
Same shell as Table 14.2.6.2.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. 
Update Note: to read “Note: Percentages are n/Number of subjects in the OLE ITT population within treatment group*100. All subjects received Trifarotene cream HE1 200 ug/g in the 
OLE.” 
Baseline [2], Days 104, 120, 150, 180, and 194 will be displayed. 
Add OLE = open label extension to Abbreviations. 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 82 of 150 
 
Table 14.2.7.1 
Exploratory Analysis: Summary of Change from Baseline in Ectropion Score 
ITT Population 
 
 
Study Visit 
Trifarotene cream HE1 
100 ug/g 
 (N=XXX) 
 
Trifarotene cream HE1 
200 ug/g 
 (N=XXX) 
   Statistic  
Observed 
CFB 
 
Observed 
CFB 
 
 
 
 
 
 
Baseline [1] 
 
 
 
 
 
   n 
XXX 
 
 
XXX 
 
   Mean (SD) 
XX.XX (XX.XXX) 
 
 
XX.XX (XX.XXX) 
 
   Median 
XX.XX 
 
 
XX.XX 
 
   Min, Max 
XX.X, XX.X 
 
 
XX.X, XX.X 
 
 
 
 
 
 
 
Day 14 
 
 
 
 
 
   n 
XXX 
XXX 
 
XXX 
XXX 
   Mean (SD) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
   Median 
XX.XX 
XX.XX 
 
XX.XX 
XX.XX 
   Min, Max 
XX.X, XX.X 
XX.X, XX.X 
 
XX.X, XX.X 
XX.X, XX.X 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 90 
 
 
 
 
 
   n 
XXX 
XXX 
 
XXX 
XXX 
   Mean (SD) 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
 
XX.XX (XX.XXX) 
XX.XX (XX.XXX) 
   Median 
XX.XX 
XX.XX 
 
XX.XX 
XX.XX 
   Min, Max 
XX.X, XX.X 
XX.X, XX.X 
 
XX.X, XX.X 
XX.X, XX.X 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
Abbreviations: CFB = change from baseline; ITT = intent to treat; SD = standard deviation. 
Note: Subjects are summarized by randomized treatment group. Ectropion total score is derived as the sum of the 8 individual item scores (lateral apposition, medial apposition, 
scleral show, conjunctival show, excess tear film, redness of the eye, round canthus, punctum lacrimale), with a range of 0 to 8. Each individual item is scored 0 
(nonaffected/no/invisible), 0.5 (≤ 1 mm/emerging), or 1 (affected/yes/visible). Higher scores indicates worse ectropion. 
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
SOURCE: Listing 16.2.6.7 
 
Programming note: Include Days 30, and 60 as well. Repeat Table for Overall Trifarotene cream HE1 and Vehicle columns. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 83 of 150 
 
Table 14.2.7.2 
Summary of from Baseline in Ectropion Score 
OLE ITT Population 
 
Same shell as 14.2.7.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. 
Update Note: to read “Note: Percentages are n/Number of subjects in the OLE ITT population within treatment group*100. All subjects received Trifarotene cream HE1 200 ug/g in the 
OLE.” 
Baseline [2], Days 104, 120, 150, 180, and 194 will be displayed. 
Add OLE = open label extension to Abbreviations. 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 84 of 150 
 
Table 14.2.8.1 
Exploratory Analysis: Change from Baseline in EQ-5D-5L 
ITT Population 
 
Same Shell as Table 14.2.7.1 
 
Programming Note: Headers will be as follows. Repeat for the following Parameters: Self-Care, Usual Activities, Pain/Discomfort, Anxiety/Depression, and Your Health Today. 
 
Parameter: Mobility 
Study Visit 
Trifarotene cream HE1 
100 ug/g 
 (N=XXX) 
 
Trifarotene cream HE1 
200 ug/g 
 (N=XXX) 
   Statistic  
Observed 
CFB 
 
Observed 
CFB 
 
Update Note: to read “Subjects are summarized by randomized treatment group. The EQ-5D is a measure of health related quality of life. The EQ-5D consists of a descriptive system 
and the EQ visual analog scale (VAS). The EQ-5D-5L is intended for use in adult subjects. The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. The EQ VAS records the subject’s self-rated health on a vertical 0-100 VAS. Add VAS = visual analog scale to Abbreviations. Update 
SOURCE: to Listing 16.2.6.8 
 
 
 
Table 14.2.8.2 
Exploratory Analysis: Change from Baseline in EQ-5D-Y 
ITT Population 
 
Same Shell as Table 14.2.7.1 
 
Programming Note: Headers will be as follows. Repeat for the following Parameters: Taking Care of Myself, Doing Usual Activities, Having Pain or Discomfort, Feeling Worried, Sad 
or Unhappy, Number Subject Indicated on Scale. 
 
Parameter: Mobility 
Study Visit 
Trifarotene cream HE1 
100 ug/g 
 (N=XXX) 
 
Trifarotene cream HE1 
200 ug/g 
 (N=XXX) 
   Statistic  
Observed 
CFB 
 
Observed 
CFB 
 
Update Note: to read “Subjects are summarized by randomized treatment group. The EQ-5D is a measure of health related quality of life. The EQ-5D consists of a descriptive system 
and the EQ visual analog scale (VAS). The EQ-5D-Y is to be used for children and adolescents. The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. The EQ VAS records the subject’s self-rated health on a vertical 0-100 VAS. Add VAS = visual analog scale to Abbreviations. Update 
SOURCE: to Listing 16.2.6.8 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 85 of 150 
 
Table 14.3.1.1.1 
Overall Summary of Treatment Emergent Adverse Events during the Double-blind Period 
Safety Population 
 
 
 
Trifarotene cream 
HE1 
100 ug/g 
Trifarotene cream 
HE1 
200 ug/g 
Overall 
Trifarotene cream 
HE1 
Vehicle 
Overall 
Category 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
 
 
 
 
 
 
Subjects with at least 1 TEAE 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
Subjects with an SAE 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
Maximum Severity of TEAE [1] 
 
 
 
 
 
      Mild 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Moderate 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Severe 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
Relationship of TEAE [2] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Related 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Not Related 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
Subjects with a TEAE Leading to Discontinuation of 
Study Drug 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
Subjects with an AE leading to Death 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; CRF = case report form; MedDRA = Medical Dictionary for Regulatory Activities; SAE = serious adverse event; TEAE = treatment emergent 
adverse event. 
  
Note: Percentages are n/Number of subjects in the Safety Population within actual treatment group and overall*100. AEs were coded using MedDRA version 21.1. A TEAE is any 
AE with an onset at the time of or following the start of treatment with study drug through the Follow-up Visit or Early Termination Visit, whichever occurs first. This will include any 
AE starting prior to the start of treatment but increasing in severity or relationship at the time of, or following, the start of treatment with study drug through the Follow-up Visit or 
Early Termination Visit, whichever occurs first.  
[1] Subjects are counted only once at the worst severity. If a severity designation is missing, it will be considered as severe. 
[2] Subjects are counted only once at the strongest possible relationship. If a relationship designation is missing, the AE will be considered as related. This relationship is 
categorized for summarization as follows: Related = Related and Possibly Related; Not Related = Not Related and Unlikely Related. 
SOURCE: Listing 16.2.7.1 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 86 of 150 
 
Table 14.3.1.1.2 
Overall Summary of Treatment Emergent Adverse Events during the OLE 
OLE Safety Population 
 
Same shell as Table 14.3.1.1.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. 
Update Note: to read “Note: Percentages are n/Number of subjects in the OLE Safety population within treatment group*100. All subjects received Trifarotene cream HE1 200 ug/g in 
the OLE.” Add OLE = open label extension to Abbreviations. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 87 of 150 
 
Table 14.3.1.2.1 
Incidence of Treatment Emergent Adverse Events during the Double-blind Period by System Organ Class and Preferred Term 
Safety Population 
 
 
System Organ Class 
   Preferred Term 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
Overall 
Trifarotene cream HE1 
(N=XX) 
Vehicle 
(N=XX) 
Overall 
(N=XX) 
 
 
 
 
 
 
Subjects with at least 1 TEAE 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
System Organ Class 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
System Organ Class 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; PT = preferred term; SOC = system organ class; TEAE = treatment emergent adverse 
event. 
Note: Percentages are n/Number of subjects in the Safety Population within actual treatment group and overall*100. AEs were coded using MedDRA version 21.1. A TEAE is any 
AE with an onset at the time of or following the start of treatment with study drug through the Follow-up Visit or Early Termination Visit, whichever occurs first. This will include any 
AE starting prior to the start of treatment but increasing in severity or relationship at the time of, or following, the start of treatment with study drug through the Follow-up Visit or 
Early Termination Visit, whichever occurs first. Subjects are counted once for each system organ class (SOC) and once for each preferred term (PT). AEs are displayed by 
descending frequency of SOC, then PT within SOC, and then alphabetically by PT.  
SOURCE: Listing 16.2.7.1 
 
 
 
Table 14.3.1.2.2 
Incidence of Treatment Emergent Adverse Events during the OLE by System Organ Class and Preferred Term 
OLE Safety Population 
 
Same shell as 14.3.1.2.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. 
Update Note: to read “Note: Percentages are n/Number of subjects in the OLE Safety population within treatment group*100. All subjects received Trifarotene cream HE1 200 ug/g in 
the OLE.” Add OLE = open label extension to Abbreviations. 
  
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 88 of 150 
 
Table 14.3.1.3.1 
Incidence of Treatment Emergent Adverse Events during the Double-blind Period by System Organ Class, Preferred Term, and Maximum Severity 
Safety Population 
 
 
System Organ Class 
   Preferred Term 
      Severity 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
Overall 
Trifarotene cream HE1 
(N=XX) 
Vehicle 
(N=XX) 
Overall 
(N=XX) 
 
 
 
 
 
 
Subjects with at least 1 TEAE 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Mild 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Moderate 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Severe 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
System Organ Class 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Mild 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Moderate 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Severe 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
   Preferred Term 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Mild 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Moderate 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Severe 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
   Preferred Term 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Mild 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Moderate 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Severe 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; PT = preferred term; SOC = system organ class; TEAE = treatment emergent adverse 
event. 
Note: Percentages are n/Number of subjects in the Safety Population within actual treatment group and overall*100. AEs were coded using MedDRA version 21.1. A TEAE is any 
AE with an onset at the time of or following the start of treatment with study drug through the Follow-up Visit or Early Termination Visit, whichever occurs first. This will include any 
AE starting prior to the start of treatment but increasing in severity or relationship at the time of, or following, the start of treatment with study drug through the Follow-up Visit or 
Early Termination Visit, whichever occurs first. Subjects are counted once for each system organ class (SOC) and once for each preferred term (PT) at the maximum severity. The 
severity shown is the greatest severity reported for a particular subject (Severe > Moderate > Mild). AEs with a missing severity were counted as Severe. AEs are displayed by 
descending frequency of SOC, then PT within SOC, and then alphabetically by PT.  
SOURCE: Listing 16.2.7.1 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 89 of 150 
 
Table 14.3.1.3.2 
Incidence of Treatment Emergent Adverse Events during the OLE by System Organ Class, Preferred Term, and Maximum Severity 
OLE Safety Population 
 
Same shell as 14.3.1.3.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. 
Update Note: to read “Note: Percentages are n/Number of subjects in the OLE Safety population within treatment group*100. All subjects received Trifarotene cream HE1 200 ug/g in 
the OLE.” Add OLE = open label extension to Abbreviations. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 90 of 150 
 
Table 14.3.1.4.1 
Incidence of Treatment Emergent Adverse Events during the Double-blind Period by System Organ Class, Preferred Term, and Relationship to Study Drug 
Safety Population 
 
 
System Organ Class 
   Preferred Term 
      Relationship [1] 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
Overall 
Trifarotene cream HE1 
(N=XX) 
Vehicle 
(N=XX) 
Overall 
(N=XX) 
 
 
 
 
 
 
Subjects with at least 1 TEAE 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Related 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Not Related 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
System Organ Class 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Related 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Not Related 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
   Preferred Term 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Related 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Not Related 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
   Preferred Term 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Related 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
      Not Related 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; PT = preferred term; SOC = system organ class; TEAE = treatment emergent adverse 
event. 
Note: Percentages are n/Number of subjects in the Safety Population within actual treatment group and overall*100. AEs were coded using MedDRA version 21.1. A TEAE is any 
AE with an onset at the time of or following the start of treatment with study drug through the Follow-up Visit or Early Termination Visit, whichever occurs first. This will include any 
AE starting prior to the start of treatment but increasing in severity or relationship at the time of, or following, the start of treatment with study drug through the Follow-up Visit or 
Early Termination Visit, whichever occurs first. Subjects are counted once for each system organ class (SOC) and once for each preferred term (PT) at the greatest relationship 
category. The relationship shown is the greatest relationship reported for a particular subject (Related > Not Related). AEs with a missing relationship were counted as Related. AEs 
are displayed by descending frequency of SOC, then PT within SOC, and then alphabetically by PT.  
[1] Related = Related and Possibly Related; Not Related = Not Related and Unlikely Related. 
SOURCE: Listing 16.2.7.1 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 91 of 150 
 
Table 14.3.1.4.2 
Incidence of Treatment Emergent Adverse Events during the OLE by System Organ Class, Preferred Term, and Relationship to Study Drug 
OLE Safety Population 
 
Same shell as 14.3.1.4.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. 
Update Note: to read “Note: Percentages are n/Number of subjects in the OLE Safety population within treatment group*100. All subjects received Trifarotene cream HE1 200 ug/g in 
the OLE.” Add OLE = open label extension to Abbreviations. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 92 of 150 
 
 
Table 14.3.2.1.1 
Incidence of Adverse Events Leading to Withdrawal during the Double-blind Period by SOC, PT, and Treatment 
Safety Population 
 
Same shell as Table 14.3.1.2.1 
 
Programming note: Update first row text to “Subjects with at least 1 TEAE Leading to Withdrawal.” 
 
 
 
Table 14.3.2.1.2 
Incidence of Adverse Events Leading to Withdrawal during the OLE by SOC, PT, and Treatment 
OLE Safety Population 
 
Same shell as Table 14.3.1.2.2 
 
Programming note: Update first row text to “Subjects with at least 1 TEAE Leading to Withdrawal.” 
 
 
 
 
Table 14.3.2.2.1 
Incidence of Serious Adverse Events during the Double-blind Period by SOC, PT, and Treatment 
Safety Population 
 
Same shell as Table 14.3.1.2.1 
 
Programming note: Update first row text to “Subjects with at least 1 SAE.” Add SAE = serious adverse event to abbreviations. 
 
 
 
Table 14.3.2.2.2 
Incidence of Serious Adverse Events during the OLE by SOC, PT, and Treatment 
OLE Safety Population 
 
Same shell as Table 14.3.1.2.2 
 
Programming note: Update first row text to “Subjects with at least 1 SAE.” Add SAE = serious adverse event to abbreviations. 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 93 of 150 
 
Table 14.3.3.1.1 
Listing of Adverse Events Leading to Withdrawal during the Double-blind Period 
Safety Population 
 
Randomized Treatment: XXXXXXXXXXXXXXX 
Subject 
ID 
TEAE? [1] 
System Organ Class/ 
   Preferred Term/ 
      Verbatim Term 
Start Date/Time (Study Day)/ 
   End Date/Time (Study Day) 
Severity/ 
   Relationship to Study Drug 
Outcome 
 
Serious?/ 
  Criteria Met 
Action Taken/ 
Other Action Taken? 
 
 
 
 
 
 
XXXXX 
XXX 
XXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXXXXX 
      XXXXXXXXXXXXX 
DDMMMYYYY/HH:MM (X)/ 
   DDMMMYYYY/HH:MM (X) 
XXXXXXXXX/ 
   XXXXXXXXXX 
XXXXXXXXX XX 
XXXXXXXXX/  
XXXXXXXXX 
 
 
 
 
 
 
 
XXXXX 
XX 
XXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXXXXX 
      XXXXXXXXXXXXX 
DDMMMYYYY/HH:MM (X)/ 
   DDMONYYYY/HH:MM (X) 
XXXXXXXXX/ 
   XXXXXXXXXX 
XXXXXXXXX   XX 
XXXXXXXXX/  
XXXXXXXXX 
 
XXX 
XXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXXXXX 
      XXXXXXXXXXXXX 
DDMMMYYYY/HH:MM (X)/ 
   Ongoing 
XXXXXXXXX/ 
   XXXXXXXXXX 
XXXXXXXXX/ XXX/ 
   XXXXXXXXX 
XXXXXXXXX/  
XXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; TEAE = treatment emergent adverse event. 
Note: Study day is calculated relative to the date of first dose of study drug. AEs were coded using MedDRA version 21.1. 
[1] A TEAE is any AE with an onset at the time of or following the start of treatment with study drug through the Follow-up Visit or Early Termination Visit, whichever occurs first. This 
will include any AE starting prior to the start of treatment but increasing in severity or relationship at the time of, or following, the start of treatment with study drug through the Follow-
up Visit or Early Termination Visit, whichever occurs first. 
 
Programming note: If time missing, display “- -:- -”. If Serious? is Yes, concatenate all serious criteria marked as Yes with a semicolon. If Other Action Taken? Is Yes, concatenate 
Medication Required, Relevant Procedure, Procedure Specify, Other, or Other Specify with a colon as applicable. If no events meet the criteria for display, present “No events are 
reported.” SOC & PT text should be in proper case in table. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 94 of 150 
 
Table 14.3.3.1.2 
Listing of Adverse Events Leading to Withdrawal during the OLE 
OLE Safety Population 
 
Same shell as Table 14.3.3.1.1 
 
Programming note: Add OLE = open label extension to Abbreviations. 
 
 
 
Table 14.3.3.2.1 
Listing of Serious Adverse Events during the Double-blind Period 
Safety Population 
 
Same shell as Table 14.3.3.1.1 
 
 
Table 14.3.3.2.2 
Listing of Serious Adverse Events during the OLE 
OLE Safety Population 
 
Same shell as Table 14.3.3.1.1 
 
Programming note: Add OLE = open label extension to Abbreviations. 
 
 
Table 14.3.3.3.1 
Listing of Deaths during the Double-blind Period 
Safety Population 
 
Same shell as Table 14.3.3.1.1 
 
 
 
Table 14.3.3.3.1 
Listing of Deaths during the OLE 
OLE Safety Population 
 
Same shell as Table 14.3.3.1.1 
 
Programming note: Add OLE = open label extension to Abbreviations. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 95 of 150 
 
Table 14.3.4.1 
Listing of Abnormal Laboratory Data 
Safety Population and OLE Safety Population 
 
Randomized Treatment: XXXXXXXXXXX 
Subject ID 
Parameter Category 
Parameter (unit) 
Study 
Visit 
Date/Time of 
Assessment 
(Study Day) 
Standard 
Results 
Standard 
Reference 
Range 
[1] 
Standard 
Reference 
Range 
Flag 
 
 
 
 
 
 
 
 
XXXXX 
Chemistry 
Albumin (unit) 
XXXXXX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
XX – YY 
 
 
 
 
XXXXXX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
XX – YY 
XXX 
 
 
 
XXXXXX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
XX – YY 
 
 
 
 
XXXXXX 
 
ND 
 
 
 
 
 
XXXXXX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
XX – YY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AL = abnormal-low; AH = abnormal-high; ND = not done. 
Note: Study day is calculated relative to the date of first dose of study drug. Assessments marked as Not Done are not presented. 
[1] Reference range is used to identify potentially clinically significant laboratory values. 
 
Programming note: include all parameter categories and parameters. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 96 of 150 
 
Table 14.3.5.1.1.1 
Laboratory Data: Change from Baseline in Clinical Chemistry Parameters by Study Visit  
Safety Population 
 
Parameter: XXXXXXX (unit) 
Study Visit 
   Statistic 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
 
 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
 
Overall 
Trifarotene cream HE1 
 (N=XX) 
Observed 
CFB 
 
Observed 
CFB 
 
Observed 
CFB 
 
 
 
 
 
 
 
 
 
Baseline [1] 
 
 
 
 
 
 
 
 
   n 
XX 
 
 
XX 
 
 
XX 
 
   Mean (SD) 
XX.X (XX.XX) 
 
 
XX.X (XX.XX) 
 
 
XX.X (XX.XX) 
 
   Median 
XX.X 
 
 
XX.X 
 
 
XX.X 
 
   Min, Max 
XX, XX 
 
 
XX, XX 
 
 
XX, XX 
 
 
 
 
 
 
 
 
 
 
Day 30 
 
 
 
 
 
 
 
 
   n 
XX 
XX 
 
XX 
XX 
 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
 
XX.X (XX.XX) 
XX.X (XX.XX) 
 
XX.X (XX.XX) 
XX.X (XX.XX) 
   Median 
XX.X 
XX.X 
 
XX.X 
XX.X 
 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
 
XX, XX 
XX, XX 
 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
 
Day 90 
 
 
 
 
 
 
 
 
   n 
XX 
XX 
 
XX 
XX 
 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
 
XX.X (XX.XX) 
XX.X (XX.XX) 
 
XX.X (XX.XX) 
XX.X (XX.XX) 
   Median 
XX.X 
XX.X 
 
XX.X 
XX.X 
 
XX.X 
XX.X 
   Min, Max 
XX, XX 
XX, XX 
 
XX, XX 
XX, XX 
 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
 
Repeat for all clinical chemistry parameters. 
 
 
Abbreviation: CFB = change from baseline; SD = standard deviation. 
Note: Subjects are summarized by actual treatment group and overall.  
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
SOURCE: Listing 16.2.8.1 
 
Programming note: Repeat table for Vehicle and Overall columns.  
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 97 of 150 
 
 
Table 14.3.5.1.1.2 
Laboratory Data: Change from Baseline in Clinical Chemistry Parameters by Study Visit  
OLE Safety Population 
 
Same shell as Table 14.3.5.1.1.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. Update Note: to read “Subjects are summarized by treatment group. All subjects received 
Trifarotene cream HE1 200 ug/g in the OLE.” Visits will be Baseline, Day 120, and Day 180. Add OLE = open label extension to Abbreviations. 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 98 of 150 
 
Table 14.3.5.1.2.1 
Laboratory Data: Shift from Baseline in Clinical Chemistry Parameters by Study Visit  
Safety Population 
 
Parameter: XXXXXXX 
 
Baseline [1] 
 
Trifarotene cream HE1 100 ug/g (N=XX) 
Study Visit 
Low 
Normal 
High 
Missing 
   Category 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
Day 30 
 
 
 
 
   Low 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   High 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Missing 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
Day 90 
 
 
 
 
   Low 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   High 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Missing 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
Continue for other parameters. Sort alphabetically by parameter. 
 
 
Note: Note: Percentages are n/Number of subjects in the Safety Population within actual treatment group and overall*100.   
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
SOURCE: Listing 16.2.8.1 
 
Programming note: Repeat table for Trifarotene cream HE1 200 ug/g, Overall Trifarotene cream HE1, Vehicle, and Overall treatment groups.  
 
 
 
Table 14.3.5.1.2.2 
Laboratory Data: Shift from Baseline in Clinical Chemistry Parameters by Study Visit  
OLE Safety Population 
 
Same shell as Table 14.3.5.1.2.1 
 
Programming note: Only include Trifarotene cream HE1 200 ug/g. Update Note: to read “Subjects are summarized by treatment group. All subjects received Trifarotene cream HE1 
200 ug/g in the OLE.” Visits will be Baseline, Day 120, and Day 180. Add OLE = open label extension to Abbreviations. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 99 of 150 
 
Table 14.3.5.2.1.1 
Laboratory Data: Change from Baseline in Hematology Parameters by Study Visit  
Safety Population 
 
Same shell as Table 14.3.5.1.1.1 
 
Programming note: Update SOURCE: to Listing 16.2.8.2 
 
 
 
 
Table 14.3.5.2.1.2 
Laboratory Data: Change from Baseline in Hematology Parameters by Study Visit  
OLE Safety Population 
 
Same shell as Table 14.3.5.1.1.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. Update Note: to read “Subjects are summarized by treatment group. All subjects received 
Trifarotene cream HE1 200 ug/g in the OLE.”  Visits will be Baseline, Day 120, and Day 180. Add OLE = open label extension to Abbreviations. Update SOURCE: to Listing 16.2.8.2 
 
 
 
 
Table 14.3.5.2.2.1 
Laboratory Data: Shift from Baseline in Hematology Parameters by Study Visit  
Safety Population 
 
Same shell as Table 14.3.5.1.2.1 
 
Programming note: Update SOURCE: to Listing 16.2.8.2 
 
 
 
 
Table 14.3.5.2.2.2 
Laboratory Data: Shift from Baseline in Hematology Parameters by Study Visit  
OLE Safety Population 
 
Same shell as Table 14.3.5.1.2.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. Update Note: to read “Subjects are summarized by treatment group. All subjects received 
Trifarotene cream HE1 200 ug/g in the OLE.”  Visits will be Baseline, Day 120, and Day 180. Add OLE = open label extension to Abbreviations. Update SOURCE: to Listing 16.2.8.2 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 100 of 150 
 
Table 14.3.5.3.1.1 
Laboratory Data: Change from Baseline in Coagulation Parameters by Study Visit  
Safety Population 
 
Same shell as Table 14.3.5.1.1.1 
 
Programming note: Update SOURCE: to Listing 16.2.8.3 
 
 
 
 
Table 14.3.5.3.1.2 
Laboratory Data: Change from Baseline in Coagulation Parameters by Study Visit  
OLE Safety Population 
 
Same shell as Table 14.3.5.1.1.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. Update Note: to read “Subjects are summarized by treatment group. All subjects received 
Trifarotene cream HE1 200 ug/g in the OLE.”  Visits will be Baseline, Day 120, and Day 180. Add OLE = open label extension to Abbreviations. Update SOURCE: to Listing 16.2.8.3 
 
 
 
 
Table 14.3.5.3.2.1 
Laboratory Data: Shift from Baseline in Coagulation Parameters by Study Visit  
Safety Population 
 
Same shell as Table 14.3.5.1.2.1 
 
Programming note: Update SOURCE: to Listing 16.2.8.3 
 
 
 
 
Table 14.3.5.3.2.2 
Laboratory Data: Shift from Baseline in Coagulation Parameters by Study Visit  
OLE Safety Population 
 
Same shell as Table 14.3.5.1.2.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. Update Note: to read “Subjects are summarized by treatment group. All subjects received 
Trifarotene cream HE1 200 ug/g in the OLE.”  Visits will be Baseline, Day 120, and Day 180. Add OLE = open label extension to Abbreviations. Update SOURCE: to Listing 16.2.8.3 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 101 of 150 
 
Table 14.3.5.4.1.1 
Laboratory Data: Change from Baseline in Quantitative Urinalysis Parameters by Study Visit  
Safety Population 
 
Same shell as Table 14.3.5.1.1.1 
 
Programming note: Update SOURCE: to Listing 16.2.8.4 
 
 
 
 
Table 14.3.5.4.1.2 
Laboratory Data: Change from Baseline in Quantitative Urinalysis Parameters by Study Visit  
OLE Safety Population 
 
Same shell as Table 14.3.5.1.1.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. Update Note: to read “Subjects are summarized by treatment group. All subjects received 
Trifarotene cream HE1 200 ug/g in the OLE.”  Visits will be Baseline, Day 120, and Day 180. Add OLE = open label extension to Abbreviations. Update SOURCE: to Listing 16.2.8.4 
 
 
 
 
Table 14.3.5.4.2.1 
Laboratory Data: Shift from Baseline in Quantitative Urinalysis Parameters by Study Visit  
Safety Population 
 
Same shell as Table 14.3.5.1.2.1 
 
Programming note: Update SOURCE: to Listing 16.2.8.4 
 
 
 
 
Table 14.3.5.4.2.2 
Laboratory Data: Shift from Baseline in Quantitative Urinalysis Parameters by Study Visit  
OLE Safety Population 
 
Same shell as Table 14.3.5.1.2.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. Update Note: to read “Subjects are summarized by treatment group. All subjects received 
Trifarotene cream HE1 200 ug/g in the OLE.”  Visits will be Baseline, Day 120, and Day 180. Add OLE = open label extension to Abbreviations. Update SOURCE: to Listing 16.2.8.4 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 102 of 150 
 
Table 14.3.5.4.3.1 
Laboratory Data: Summary of Qualitative Urinalysis Parameters by Study Visit  
Safety Population 
 
Parameter: XXXXXXX (unit) 
 
 
Study Visit 
   Category 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
Overall 
Trifarotene cream HE1 
(N=XX) 
Vehicle 
(N=XX) 
Overall 
(N=XX) 
 
 
 
 
 
 
Baseline [1] 
 
 
 
 
 
   Category 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
Day 30 
 
 
 
 
 
   Category 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
Day 90 
 
 
 
 
 
   Category 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are n/Number of subjects in the ITT population within randomized treatment group and overall*100. 
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
SOURCE: Listing 16.2.8.4 
 
 
Table 14.3.5.4.3.2 
Laboratory Data: Summary of Qualitative Urinalysis Parameters by Study Visit  
OLE Safety Population 
 
Same shell as Table 14.3.5.4.3.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. Update Note: to read “Subjects are summarized by treatment group. All subjects received 
Trifarotene cream HE1 200 ug/g in the OLE.”  Visits will be Baseline, Day 120, and Day 180. Add OLE = open label extension to Abbreviations. 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 103 of 150 
 
Table 14.3.6.1.1 
Summary of Vital Signs by Study Visit  
Safety Population 
 
Same shell as Table 14.3.5.1.1.1 
 
Programming note: Visits include Baseline [1], Days 14, 30, 60, and 90. Parameters include weight (kg), BMI (kg/m2), systolic blood pressure (mmHg), and diastolic blood pressure 
(mmHg). Include derivation of BMI in Note: Body Mass Index (BMI) = weight (kg) / [height (m)]2. Update SOURCE: to Listings 16.2.9.1 
 
 
 
 
Table 14.3.6.1.2 
Summary of Vital Signs by Study Visit  
OLE Safety Population 
 
Same shell as Table 14.3.5.1.1.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. Update Note: to read “Subjects are summarized by treatment group. All subjects received 
Trifarotene cream HE1 200 ug/g in the OLE.” Visits include Baseline [1], Days 120, 180, and 194. Parameters include weight (kg), BMI (kg/m2), systolic blood pressure (mmHg), and 
diastolic blood pressure (mmHg). Include derivation of BMI in Note: Body Mass Index (BMI) = weight (kg) / [height (m)]2. Add OLE = open label extension to Abbreviations. Update 
SOURCE: to Listings 16.2.9.1 
‘ 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 104 of 150 
 
Table 14.3.6.2.1 
Summary of 12-Lead Electrocardiogram by Study Visit  
Safety Population 
 
Same shell as Table 14.3.5.1.1.1 
 
Programming note: Visits include Baseline [1], Days 30 and 90. Parameters include heart rate (bpm), PR interval (ms), QRS interval (ms), uncorrected QT interval (ms), and QTcF 
(ms). Update SOURCE: to Listings 16.2.9.2 
 
 
 
 
Table 14.3.6.2.2 
Summary of 12-Lead Electrocardiogram by Study Visit  
OLE Safety Population 
 
Same shell as Table 14.3.5.1.1.1 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. Update Note: to read “Subjects are summarized by treatment group. All subjects received 
Trifarotene cream HE1 200 ug/g in the OLE.” Visits include Baseline [1], Days 120 and 180. Parameters include heart rate (bpm), PR interval (ms), QRS interval (ms), uncorrected QT 
interval (ms), and QTcF (ms). Add OLE = open label extension to Abbreviations. Update SOURCE: to Listings 16.2.9.2 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 105 of 150 
 
Table 14.3.6.2.3 
Summary of 12-Lead Electrocardiogram Interpretation by Study Visit 
Safety Population 
 
 
 
 
Study Visit 
   Category 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
Overall 
Trifarotene cream HE1 
(N=XX) 
Vehicle 
(N=XX) 
Overall 
(N=XX) 
 
 
 
 
 
 
Baseline [1] 
 
 
 
 
 
   Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Abnormal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
Day 30 
 
 
 
 
 
   Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Abnormal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
Day 90 
 
 
 
 
 
   Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Abnormal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are n/Number of subjects in the Safety population within actual treatment group and overall*100.  
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
SOURCE: Listing 16.2.9.2 
 
 
Table 14.3.6.2.4 
Summary of 12-Lead Electrocardiogram Interpretation by Study Visit 
OLE Safety Population 
 
Same shell as Table 14.3.6.2.3 
 
Programming note: Only include one set of columns for Trifarotene cream HE1 200 ug/g. Update Note: to read “Subjects are summarized by treatment group. All subjects received 
Trifarotene cream HE1 200 ug/g in the OLE.” Visits include Baseline [1], Days 120 and 180.


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 106 of 150 
 
Table 14.3.6.3.1 
Summary of Local Tolerability Assessments by Study Visit  
Safety Population 
 
Study Visit: XXXXX 
 
 
Body Area 
  Assessment 
   Score 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
Overall 
Trifarotene cream HE1 
(N=XX) 
Vehicle 
(N=XX) 
Overall 
(N=XX) 
 
 
 
 
 
 
 Chest/Abdomen 
 
 
 
 
 
   Erythema 
 
 
 
 
 
     None 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Mild 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Moderate 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Severe 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
   Stinging/Burning 
 
 
 
 
 
     None 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Mild 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Moderate 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Severe 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
   Pruritus 
 
 
 
 
 
     None 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Mild 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Moderate 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Severe 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are n/Number of subjects in the Safety population within actual treatment group and overall*100.  
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
SOURCE: Listing 16.2.9.3 
 
Programming note: Continue for Back, Arms, and Legs. Visits will be Baseline [1], Day 14, Day 30, Day 60, and Day 90. 
 
 
 
Table 14.3.6.3.2 
Summary of Local Tolerability Assessments by Study Visit  
OLE Safety Population 
 
Same shell as Table 14.3.6.3.1 
Programming note: Continue for Back, Arms, and Legs. Visits will be Baseline [1], Day 104, Day 120, and Day 150. Update Note: to read “Note: Percentages are n/Number of 
subjects in the OLE Safety population within treatment group*100. All subjects received Trifarotene cream HE1 200 ug/g in the OLE.” Add OLE = open label extension to 
Abbreviations. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 107 of 150 
 
Table 14.3.6.4.1 
Summary of Physical Examination Results by Study Visit  
Safety Population 
 
Study Visit: XXXXX 
 
 
Body System 
  Result 
   Clinically 
Significant? 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
Overall 
Trifarotene cream HE1 
(N=XX) 
Vehicle 
(N=XX) 
Overall 
(N=XX) 
 
 
 
 
 
 
 Body System 1 
 
 
 
 
 
   Not Done 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Abnormal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Yes 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     No 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 Body System 2 
 
 
 
 
 
   Not Done 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Abnormal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Yes 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     No 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are n/Number of subjects in the Safety population within actual treatment group and overall*100.  
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
SOURCE: Listing 16.3.9.4 
 
Programming note: Continue for all body systems. Visits will be Baseline [1] and Day 90. 
 
 
 
Table 14.3.6.4.2 
Summary of Physical Examination Results by Study Visit  
OLE Safety Population 
 
Same shell as Table 14.3.6.4.1 
Programming note: Visits will be Day 180 and Day 194. Update Note: to read “Note: Percentages are n/Number of subjects in the OLE Safety population within treatment group*100. 
All subjects received Trifarotene cream HE1 200 ug/g in the OLE.” Add OLE = open label extension to Abbreviations. 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 108 of 150 
 
Table 14.3.6.5.1 
Summary of Concomitant Medications during the Double-blind Period by ATC Class Level 4 and Preferred Term 
Safety Population 
 
Same shell as Table 14.1.4 
 
Programming note: Update Note: to read “Note: Percentages are n/Number of subjects in the Safety population within actual treatment group and overall*100. Medications were 
coded using WHO-DDE version March 2019. Concomitant medications are any medications continuing or starting after the first dose of study drug through the end of study. 
Medications are displayed by descending frequency of ATC Level 4 classification, by PT within ATC, and then alphabetically by PT, based on the overall column. Subjects were 
counted only once for each ATC and PT. Include an additional column for Overall Trifarotene cream HE1. 
 
 
 
 
Table 14.3.6.5.2 
Summary of Concomitant Medications during the OLE by ATC Class Level 4 and Preferred Term 
Safety Population 
 
Same shell as Table 14.1.4 
 
Programming note: Update Note: to read “Note: Percentages are n/Number of subjects in the OLE Safety population within treatment group*100. All subjects received Trifarotene 
cream HE1 200 ug/g in the OLE. Medications were coded using WHO-DDE version March 2019. Concomitant medications are any medications continuing or starting after the first 
dose of study drug through the end of study. Medications are displayed by descending frequency of ATC Level 4 classification, by PT within ATC, and then alphabetically by PT, based 
on the overall column. Subjects were counted only once for each ATC and PT. Include an additional column for Overall Trifarotene cream HE1. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 109 of 150 
 
Table 14.4.1.1 
Summary of Pharmacokinetic Concentrations by Study Visit  
PK Population  
 
Study Visit 
Statistic 
 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
 
 
 
 
Day 1, Pre-Dose 
 
 
 
     n 
 
XX 
XX 
     Mean (SD) 
 
XX.X (XX.X) 
XX.X (XX.X) 
     Geometric Mean 
 
XX.X 
XX.X 
     Median 
 
XX.X 
XX.X 
     Min, Max 
 
XX, XX 
XX, XX 
     %CV 
 
XX.X 
XX.X 
 
 
 
 
Day 1, 1 hour Post-Dose 
 
 
 
     n 
 
XX 
XX 
     Mean (SD) 
 
XX.X (XX.X) 
XX.X (XX.X) 
     Geometric Mean 
 
XX.X 
XX.X 
     Median 
 
XX.X 
XX.X 
     Min, Max 
 
XX, XX 
XX, XX 
     %CV 
 
XX.X 
XX.X 
 
 
 
 
 Day 1, 2 Hours Post-Dose 
 
 
 
     n 
 
XX 
XX 
     Mean (SD) 
 
XX.X (XX.X) 
XX.X (XX.X) 
     Geometric Mean 
 
XX.X 
XX.X 
     Median 
 
XX.X 
XX.X 
     Min, Max 
 
XX, XX 
XX, XX 
     %CV 
 
XX.X 
XX.X 
… 
 
 
 
 
 
 
 
 
 
Abbreviation: BLQ = below limit of quantification; PK = pharmacokinetic; SD = standard deviation. 
Note: Values below the lower limit of quantification (<BLQ) have been set to zero in the calculation of the summary statistics.  
SOURCE: Listing 16.2.5.4.1, 16.2.5.4.2, 16.2.4.3 
 
Programming note: Time points will be pre-dose, 1, 2, 4, 8, 12, and 24 hours post dose on Day 1 and Day 30. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 110 of 150 
 
Table 14.4.1.2 
Summary of Pharmacokinetic Parameters  
PK Population  
 
Study Visit 
Statistic 
 
Trifarotene cream HE1 
100 ug/g 
(N=XX) 
Trifarotene cream HE1 
200 ug/g 
(N=XX) 
 
 
 
 
AUC(0-t) (ng/mL*hr) 
 
 
 
     n 
 
XX 
XX 
     Mean (SD) 
 
XX.X (XX.X) 
XX.X (XX.X) 
     Geometric Mean 
 
XX.X 
XX.X 
     Median 
 
XX.X 
XX.X 
     Min, Max 
 
XX, XX 
XX, XX 
     %CV 
 
XX.X 
XX.X 
 
 
 
 
 
 
 
 
Cmax (ng/mL) 
 
 
 
     n 
 
XX 
XX 
     Mean (SD) 
 
XX.X (XX.X) 
XX.X (XX.X) 
     Geometric Mean 
 
XX.X 
XX.X 
     Median 
 
XX.X 
XX.X 
     Min, Max 
 
XX, XX 
XX, XX 
     %CV 
 
XX.X 
XX.X 
 
 
 
 
Tmax 
 
 
 
   Median 
 
XX.X 
XX.X 
   Min, Max 
 
XX, XX 
XX, XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: AUC = area under the plasma concentration-time curve; BLQ = below limit of quantification; Cmax = peak plasma concentration; CV = coefficient of variation; λz = 
apparent terminal phase rate constant; PK = pharmacokinetic; SD = standard deviation; t1/2= first order termination half-life; Tmax = time of Cmax. 
SOURCE: Listing 16.2.5.4.4 
 
Programming note: Continue for AUC0-inf, t1/2, λz, if data permit. If not, do not include in abbreviations. 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 111 of 150 
 
14.3. 
Planned Listing Shells 
Listing 16.2.1 
Subject Disposition 
All Subjects 
 
Randomized Treatment: XXXXXXXXX 
 
 
Double-blind Period 
 
OLE 
Subject 
ID 
Date Informed 
Consent Signed 
Subject 
Status 
Date of 
Completion/ 
Discontinuation 
(Study Day) 
Reason for Early 
Termination 
Was the Blind 
Broken 
For This 
Subject? 
 
Subject 
Status 
Date of 
Completion/ 
Discontinuation 
(Study Day) 
Reason for Early 
Termination 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY  
XXXXXX 
DDMMMYYYY 
(XX) 
 
 
 
XXXXXX 
DDMMMYYYY 
(XX) 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY  
XXXXXX 
DDMMMYYYY 
(XX) 
 
 
 
XXXXXX 
DDMMMYYYY 
(XX) 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY  
XXXXXX 
DDMMMYYYY 
(XX) 
XXXXXXXX: XXXXXX 
 
 
XXXXXX 
DDMMMYYYY 
(XX) 
XXXXXXXX: XXXXXX 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY  
XXXXXX 
DDMMMYYYY (X) 
XXXXXX 
 
 
XXXXXX 
DDMMMYYYY (X) 
XXXXXX 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY  
XXXXXX 
DDMMMYYYY 
(XX) 
XXXXXXXXXXXXXX 
XXX; 
XXXXXX; 
XXXXX 
 
XXXXXX 
DDMMMYYYY 
(XX) 
XXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: OLE = open label extension. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. 
             
Programming Note: Subject status will be completed continuing, completed not continuing, or early termination. If reason for early termination is AE, Physician Decision, Protocol 
Violation, or Other, concatenate the specify text as follows: “Other: XXXXXXXXX”. If reason for early termination is lost to follow-up, concatenate with date of last contact and 
comments as follows: “Lost to follow-up; date of last contact: DDMMMYYYY; XXXXX”. If reason for early termination is death, concatenate with comment, cause of death and date of 
death as follows: “Lost to follow-up; XXXXX; date of death: DDMMMYYYY; comment: XXXX”.  
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 112 of 150 
 
Listing 16.2.2.1 
Inclusion and Exclusion Criteria  
All Subjects 
 
Randomized Treatment: XXXXXXX 
Subject ID 
Assessment Date 
(Study Day) 
Met All Inclusion Criteria? 
Inclusion Criteria 
 Number(s) Not Met [1] 
Met Any Exclusion Criteria? 
Exclusion Criteria 
 Number(s) Met [2] 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY (XX) 
Yes 
 
No 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY (XX) 
Yes 
 
No 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY (XX) 
Yes 
 
No 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY (XX) 
No 
XX 
No 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY (XX) 
Yes 
 
No 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY (XX) 
Yes 
 
Yes 
XX; XX 
 
 
 
 
 
 
 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. 
[1] XX = XXXXXXXXXXXXXXXXXXXXXXXX. 
[2] XX = XXXXXXXXXXXXXXXXXX; XX = XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX. 
Programming note: If more than 1 inclusion or exclusion criterion number exists, concatenate with a comma as shown above. Decode any relevant criteria in the footnotes as shown 
in the example. If no criteria are present for a column, remove the [1] and/or [2] from the column header.  
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 113 of 150 
 
Listing 16.2.2.2 
Screen Failures  
All Subjects 
 
 
 
 
 
Subject ID 
Date of Screen Failure 
(Study Day) 
Reason for Screen Failure 
Other Reason for Screen Failure 
 
 
 
 
XXXXXX 
DDMMMYYYY (XX) 
XXXXXX 
XXXXXXXXXXXXXXX 
 
 
 
 
XXXXXX 
DDMMMYYYY (XX) 
XXXXXX 
 
 
 
 
 
XXXXXX 
DDMMMYYYY (XX) 
XXXXXX 
 
 
 
 
 
XXXXXX 
DDMMMYYYY (XX) 
XXXXXX 
XXXXXXXXXXXXX 
 
 
 
 
XXXXXX 
DDMMMYYYY (XX) 
XXXXXX 
 
 
 
 
 
XXXXXX 
DDMMMYYYY (XX) 
XXXXXX 
 
 
 
 
 
 
 
 
 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 114 of 150 
 
Listing 16.2.2.3 
Protocol Deviations 
All Subjects 
 
 
Randomized Treatment: XXXXXXXXXXX 
Subject 
ID 
Date Identified 
(Study Day) 
Event Date 
(Study Day) 
Study 
Visit 
Event Type 
Violation 
Level 
Description 
Action/Resolution 
Reportable to IRB? 
Excluded from PP 
Population? 
 
 
 
 
 
 
XXXXXX DDMMMYYYY
(XX) 
DDMMMYYYY
 (XX) 
XXXXXX XXXXXXXXXXX 
MAJOR XXXXXXX 
XXXXXXX 
XXX; 
DDMMMYYYY; 
XXXXX 
XXX 
 
DDMMMYYYY
 (XX) 
DDMMMYYYY
 (XX) 
XXXXXX XXXXXXXXXXXXXX MINOR XXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXX 
XXX 
 
 
 
 
 
 
XXXXXX DDMMMYYYY
 (XX) 
DDMMMYYYY
 (XX) 
XXXXXX XXXXXXXXXXXX 
MINOR XXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXX 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX DDMMMYYYY
 (X) 
DDMMMYYYY
 (X) 
XXXXXX XXXXXXXXXXXX 
MAJOR XXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXX
XX 
Abbreviation: IRB = institutional review board; PP = per protocol. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. 
Programming note: the structure of this listing may change depending on the information in the protocol deviations file. If Reportable to IRB is yes, concatenate IRB Submission Date 
and IRB Submission Comments fields with a semicolon. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 115 of 150 
 
Listing 16.2.3 
Analysis Populations 
All Subjects 
 
 
Subject 
Randomization 
Actual 
Analysis Populations 
 
ID 
Date 
Number 
Treatment 
Treatment 
ITT/ 
OLE ITT 
 [1] 
mITT/ 
OLE 
mITT 
[2] 
PP/ 
OLE 
PP 
[3] 
Safety/ 
OLE 
Safety 
[4] 
PK 
[5] 
Primary Reason(s) for 
Exclusion 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY 
XXXX 
XXXXXXXXXXXX 
XXXXXXXXXXXX 
Yes 
Yes 
No 
Yes 
No 
PP: Subject had a 
significant protocol 
violation. 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY 
XXXX 
XXXXXXXXXX 
XXXXXXXXXX 
Yes 
Yes 
Yes 
Yes 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY 
XXXX 
XXXXXXXXXX 
XXXXXXXXXX 
No 
Yes 
No 
Yes 
No 
Safety: Subject did not 
receive at least one 
application of study 
drug. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ITT = intent-to-treat; mITT = modified intent-to-treat; OLE = open label extension; PK= pharmacokinetic; PP = per protocol. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. 
[1] The ITT population includes all randomized subjects. The OLE ITT population includes all subjects who complete the 90-day Double-blind Treatment Period and sign the OLE 
informed consent. 
[2] The mITT includes all subjects in the Safety population with at least 1 post baseline assessment of efficacy in the Double-blind Period. The OLE mITT population includes all 
subjects in the OLE Safety population with at least 1 assessment of efficacy after Visit 6. 
[3] The PP Population includes subjects in the mITT population who met all inclusion criteria and no exclusion criteria, were compliant with study drug application, and who had no 
significant protocol deviations. The OLE PP population includes all subjects in the OLE mITT population who met all inclusion criteria and no exclusion criteria, were compliant with 
study drug application from baseline through EOT, and who had no significant protocol deviations throughout the study. 
[4] The Safety Population includes all subjects who are randomized to treatment and receive at least 1 application of study drug in the Double-blind Period. The OLE Safety 
population includes all subjects who complete the 90-day Double-blind Treatment Period and receive at least 1 application of study drug in the OLE. 
[5] The PK Population includes all subjects in the Safety population who have at least 1 plasma sample with quantifiable concentration. 
 
Programming note: Concatenate all reasons for exclusion with a colon.  
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 116 of 150 
 
Listing 16.2.4.1 
Subject Demographics 
All Subjects 
 
Randomized Treatment: XXXXXXX 
Subject 
ID 
Date of 
Birth 
Age 
(years) 
QOL 
Questionnaires 
Used 
Sex 
Child-
Bearing 
Potential? 
Ethnicity 
Race 
Weight 
(kg) 
Height 
(cm) 
BMI 
(mg/m2) [1] 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYY 
XX 
XXXX 
XXXX 
No 
XXXXXXX 
XXXXXXX 
XX.X 
XX.X 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYY 
XX 
XXXXXX 
XXXXXX 
No 
XXXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYY 
XX 
XXXXXX 
XXXXXX 
Yes  
XXXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYY 
XX 
XXXX 
XXXX 
No 
XXXXXXX 
XXXXX 
XX.X 
XX.X 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYY 
XX 
XXXXXX 
XXXXXX 
No 
XXXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYY 
XX 
XXXX 
XXXX 
Yes 
XXXXXX 
XXXXXX 
XX.X 
XX.X 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: BMI = body mass index; QOL =quality of life. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All 
subjects received Trifarotene cream HE1 200 ug/g in the open label extension period. Height and weight are values obtained at screening.  
[1] BMI = weight (kg) / [height (m)]2. 
 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 117 of 150 
 
Listing 16.2.4.2 
Informed Consent and Reconsent 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXX 
 
 
 
 
Subject 
ID 
Screened 
Previously? 
Previous 
Subject 
Number 
Protocol Version 
of Initial 
Consent/Assent 
Date Informed 
Consent/Assent 
Signed 
Consent to 
PK Sub-
study? 
Signed 
Photographic 
ICF? 
Re-consent 
to Later 
Protocol 
Version 2.0? 
Date 
Reconsent 
Date of 
Assent  
Date OLE  
Informed 
Consent/Assent 
Signed 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
No 
 
X.X 
DDMMMYYY 
No 
No 
Yes 
DDMMMYYY 
DDMMMYYY 
DDMMMYYY 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
No 
 
X.X 
DDMMMYYY 
No 
No 
Yes 
DDMMMYYY 
DDMMMYYY 
DDMMMYYY 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
Yes  
XXXXXXX 
X.X 
DDMMMYYY 
Yes  
Yes  
Yes  
DDMMMYYY 
DDMMMYYY 
DDMMMYYY 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
No 
 
X.X 
DDMMMYYY 
No 
No 
Yes 
DDMMMYYY 
DDMMMYYY 
DDMMMYYY 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
No 
 
X.X 
DDMMMYYY 
No 
No 
Yes 
DDMMMYYY 
DDMMMYYY 
DDMMMYYY 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
Yes 
XXXXXXX 
X.X 
DDMMMYYY 
Yes 
Yes 
Yes 
DDMMMYYY 
DDMMMYYY 
DDMMMYYY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ICF = informed consent form; OLE =open label extension; PK = pharmacokinetic. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. 
 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 118 of 150 
 
Listing 16.2.4.3 
Medical History 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
 
System Organ Class/ 
 
 
   Preferred Term/ 
Start Date (Study Day)/ 
 Subject ID 
      Verbatim Term 
   End Date (Study Day)/ 
 
 
 
XXXXXX 
XXXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXX/ 
      XXXXXXXXXXXXX 
DDMMMYYYY (X)/ 
   DDMMMYYYY (X) 
 
 
 
 
XXXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXX/ 
XXXXXXXXXXXXX 
--MMMYYYY/ 
   Ongoing 
 
 
 
 
XXXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXX/ 
  XXXXXXXXXXXXX 
DDMMMYYYY (X)/ 
   Ongoing 
 
 
 
XXXXXX 
XXXXXXXXXXXXXXXXXX/ 
    XXXXXXXXXXXXXXXX/ 
  XXXXXXXXXXXXXXX 
DDMMMYYYY (X)/ 
   DDMMMYYYY (X) 
 
 
 
 
 
 
 
 
 
 
Abbreviation: MedDRA = Medical Dictionary for Regulatory Activities. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. Medical history was coded using MedDRA version 
21.1. Only subjects with any medical history recorded are listed.  
 
Programming note: SOC & PT text should be in title case in table. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 119 of 150 
 
Listing 16.2.5.1 
Initial Study Drug Application 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
Subject ID 
Was Study Drug 
Applied? 
Date of Application 
 (Study Day) 
Time of Administration 
Tube Weight Before 
Drug Application (grams) 
Tube Weight After  
Drug Application (grams) 
Amount Used 
(grams) 
 
 
 
 
 
 
 
XXXXXX 
XXX 
DDMMMYYYY 
 (X) 
HH:MM (X) 
XXX 
XXX 
XXX 
 
 
 
 
 
 
 
XXXXXX 
XX; XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXX 
DDMMMYYYY 
 (X) 
HH:MM (X) 
XXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. 
 
Programming Note: If drug was not applied, concatenate reason in cell with a semicolon. 
  
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 120 of 150 
 
Listing 16.2.5.2 
Drug Accountability (Dispensed and Returned) 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
Subject 
ID 
Study 
Visit 
Was Study Drug 
Dispensed at this 
Visit? 
Dispensation 
Date 
 (Study Day) 
Tube Weight  
of Tubes 
Dispensed 
(grams) 
Kit ID 
Dispensed 
Was Study 
Drug 
Returned at 
this Visit? 
Return Date 
 (Study Day) 
Number 
of Tubes 
Returned  
Number 
of Tubes 
Returned 
Unused 
Tube 
Weight  
of Tubes 
Returned 
(grams) 
Kits 
Returned 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
XXX 
DDMMMYYYY 
 (X) 
XXX 
XXX 
XXX 
DDMMMYYYY 
 (X) 
XXX 
XXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
XX; XXXXX 
 
 
 
XX; XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
XXX 
DDMMMYYYY 
 (X) 
XXX 
XXX 
XXX 
DDMMMYYYY 
 (X) 
XXX 
XXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. 
 
Programming Note: If drug was not dispensed/returned at a visit, concatenate reason in cell with a semicolon. 
 
  
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 121 of 150 
 
Listing 16.2.5.3 
Subject Diary 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
Subject 
ID 
Study 
Visit 
Was Diary Data 
Collected at this 
Visit? 
Dose 
Number 
Date of Dose 
(Study Day) 
Day of the 
Week 
Time Drug 
Taken 
Areas of Skin 
Treated 
Areas Not 
Treated 
Reasons 
Cream 
Reaction 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
XXX 
XX 
DDMMMYYYY 
 (X) 
XXXXXXXX 
HH:MM 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
 
 
 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
XX; XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
XXX 
XX 
DDMMMYYYY 
 (X) 
XXXXXX 
HH:MM 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
 
 
 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
 
 
 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. 
 
Programming Note: If diary data was not collected at this visit, concatenate reason in cell with a semicolon. Include all body areas not treated. If body area not treated or reason is 
other, concatenate specify field in cell with a semicolon.  
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 122 of 150 
 
Listing 16.2.5.4.1 
Pharmacokinetic Sample Collection 
PK Population 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
subject ID 
Was the Sample Collected? 
Reason 
Date Collected 
(Study Day) 
 
 
 
 
XXXXXX 
XXXXXXX 
XXXXXXX 
DDMMMYYYY (X) 
 
XXXXXXX 
XXXXXXX 
DDMMMYYYY (X) 
 
XXXXXXX 
XXXXXXX 
DDMMMYYYY (X) 
 
XXXXXXX 
XXXXXXX 
DDMMMYYYY (X) 
 
 
 
 
XXXXXX 
XXXXXXX 
XXXXXXX 
DDMMMYYYY (X) 
 
 
 
 
 
 
 
 
Abbreviation: PK = pharmacokinetic. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug.  
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 123 of 150 
 
Listing 16.2.5.4.2 
Pharmacokinetic Sample Collection (Substudy) 
PK Population 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
subject ID 
Initial Study Drug 
Application? 
Date Collected 
(Study Day) 
Time 
Timepoints 
Sample Collected? 
Date/Time Collected 
(Study Day) 
 
 
 
 
 
 
 
XXXXXX 
XXX 
DDMMMYYYY (X) 
HH:MM 
XXXXXXX 
XXX 
DDMMMYYYY/HH:MM (X) 
 
XXX 
DDMMMYYYY (X) 
HH:MM 
XXXXXXX 
XXX 
DDMMMYYYY/HH:MM (X) 
 
XX 
DDMMMYYYY (X) 
HH:MM 
XXXXXXX 
XXX 
DDMMMYYYY/HH:MM (X) 
 
XX 
DDMMMYYYY (X) 
HH:MM 
XXXXXXX 
XXX 
DDMMMYYYY/HH:MM (X) 
 
 
 
 
 
 
 
XXXXXX 
XX 
DDMMMYYYY (X) 
HH:MM 
XXXXXXX 
XXX 
DDMMMYYYY/HH:MM (X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: PK = pharmacokinetic. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug.  
 
Programming Note: If sample was not collected, concatenate reason in cell with a semicolon. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 124 of 150 
 
 
 
 
Listing 16.2.5.4.3 
Pharmacokinetic Concentrations 
PK Population 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
subject ID 
Study Visit 
Time In-Clinic Dose 
Taken 
Time Point 
Was Sample Collected? 
Date/Time Sample 
Collected 
(Study Day) 
Concentration 
(unit) 
 
 
 
 
 
 
XXXXXX 
XXXXXXX 
HH:MM 
XXXXXXX 
Yes 
DDMMMYYYY/HH:MM 
(X) 
X.XX 
 
XXXXXXX 
HH:MM 
XXXXXXX 
Yes 
DDMMMYYYY/HH:MM 
(X) 
X.XX 
 
XXXXXXX 
HH:MM 
XXXXXXX 
Yes 
DDMMMYYYY/HH:MM 
(X) 
X.XX 
 
XXXXXXX 
HH:MM 
XXXXXXX 
No; XXXXXXXX 
 
 
 
 
 
 
 
XXXXXX 
XXXXXXX 
HH:MM 
XXXXXXX 
Yes 
DDMMMYYYY/HH:MM 
(X) 
X.XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: BLQ = below the limit of quantification; PK = pharmacokinetic. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects 
received Trifarotene cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. Any results that 
are BLQ (i.e., <0.xx) are displayed as BLQ in the listing. 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 125 of 150 
 
Listing 16.2.5.4.4 
Pharmacokinetic Calculated Parameters 
PK Population  
 
Randomized Treatment: XXXXXXXXX 
 
 
 
Subject ID 
AUC0-t 
(unit) 
Cmax 
(unit) 
Tmax 
(unit) 
AUC0-inf 
(unit) 
t1/2 
(unit) 
λz 
(unit) 
 
 
 
 
 
 
 
XXXXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
 
 
 
 
 
 
XXXXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: AUC = area under the plasma concentration-time curve; Cmax = peak plasma concentration; CV = coefficient of variation; λz = apparent terminal phase rate constant. 
PK = pharmacokinetic; SD = standard deviation; t1/2= first order termination half-life; Tmax = time of Cmax. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. 0-t represents time from 0 to the time of the last 
quantifiable plasma concentration. 
 
Programming note: the number of decimal places depends on the raw data. The above parameters are expected, however the final parameters provided by the pharmacokineticist 
will be listed. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 126 of 150 
 
Listing 16.2.6.1 
Investigator’s Global Assessment (IGA) 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
 Subject 
ID 
Was 
Assessment 
Performed? 
Study Visit 
Assessment Date 
(Study Day) 
Body Area [1] 
Result 
Baseline [2] 
CFB [3] 
% CFB [4] 
Successful 
Resolution of 
LI?   
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXX 
XXXXXX 
DDMMMYYYY 
(XX) 
XXXXXX 
X 
X 
X 
X 
XXX 
 
 
 
 
XXXXXX 
X 
X 
X 
X 
XX 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXX 
XXXXXX 
DDMMMYYYY 
(XX) 
 
X 
X 
X 
X 
XXX 
 
 
 
 
 
XX 
XX 
XX 
XX 
XX 
 
 
 
 
 
XX 
XX 
XX 
XX 
XXX 
 
 
 
 
 
XX 
XX 
XX 
XX 
XXX 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XX; XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CFB = change from baseline; IGA = Investigator’s Global Assessment; LI = Lamellar Ichthyosis. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. The 5-point (0 - 4) IGA is a measure of disease 
severity which considers both scaling and roughness. Higher IGA scores represent more severe disease. Successful resolution is defined as clear/almost clear overall and at least 
a 2-grade change from Baseline on the 5-point (0 - 4) IGA scale. 
[1] Body area only for subjects enrolled under protocol version 1.0. 
[2] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period.  
[3] CFB is calculated as Result – Baseline. 
[4] % CFB is calculated as Change from baseline / Result at baseline * 100. 
 
Programming note: If assessment was not performed, concatenate reason with a semicolon. CFB, % CFB and Successful Resolution of LI columns will not be populated for Baseline 
rows. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 127 of 150 
 
Listing 16.2.6.2 
Visual Index for Ichthyosis (VIIS) 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
 Subject ID 
Was Assessment 
Performed? 
Study Visit 
Assessment Date 
(Study Day) 
Body Area  
Scaling Score 
Baseline [2] 
CFB [3] 
% CFB [4] 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXX 
XXXXXX 
DDMMMYYYY 
(XX) 
Chest/Abdomen 
X 
X 
X 
X 
 
 
 
 
Back 
X 
X 
X 
X 
 
 
 
 
Arms 
X 
X 
X 
X 
 
 
 
 
Legs 
XX 
XX 
XX 
XX 
 
 
 
 
Total  
XX 
XX 
XX 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XX; XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CFB = change from baseline; VIIS = .Visual Index for Ichthyosis. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. The VIIS is scored on a 5-point (0 - 4) scale by body 
area (chest/abdomen, back, legs, and arms). Higher VIIS scores represent worse scaling.  
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period.  
[2] CFB is calculated as Result – Baseline. 
[3] % CFB is calculated as Change from baseline / Result at baseline * 100. 
 
Programming note: If assessment was not performed, concatenate reason with a semicolon. CFB and % CFB columns will not be populated for Baseline rows. 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 128 of 150 
 
Listing 16.2.6.3 
Roughness Assessment 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
 Subject ID 
Was Assessment 
Performed? 
Study Visit 
Assessment Date 
(Study Day) 
Overall Score for 
Roughness 
Baseline [2] 
CFB [3] 
% CFB [4] 
2-grade 
CFB?   
 
 
 
 
 
 
 
 
 
XXXXXX 
XXX 
XXXXXX 
DDMMMYYYY 
(XX) 
X 
X 
X 
X 
XXX 
 
 
 
 
X 
X 
X 
X 
XX 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXX 
XXXXXX 
DDMMMYYYY 
(XX) 
X 
X 
X 
X 
XXX 
 
 
 
 
XX 
XX 
XX 
XX 
XX 
 
 
 
 
XX 
XX 
XX 
XX 
XXX 
 
 
 
 
XX 
XX 
XX 
XX 
XXX 
 
 
 
 
 
 
 
 
 
XXXXXX 
XX; XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CFB = change from baseline. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. The individual score for roughness measures the 
amount of roughness of the skin overall and is scored on a 5-point (0 - 4) scale. Higher scores indicate more severe roughness.  
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period.  
[2] CFB is calculated as Result – Baseline. 
[3] % CFB is calculated as Change from baseline / Result at baseline * 100. 
 
Programming note: If assessment was not performed, concatenate reason with a semicolon. CFB and % CFB columns will not be populated for Baseline rows. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 129 of 150 
 
Listing 16.2.6.4 
Palm/Sole Assessment 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
 Subject ID 
Was Assessment Performed? 
Study Visit 
Assessment Date 
(Study Day) 
Body Area  
Assessment 
Baseline [2] 
CFB [3] 
% CFB [4] 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXX 
XXXXXX 
DDMMMYYYY 
(XX) 
Palms 
X 
X 
X 
X 
 
 
 
 
Soles 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXX 
XXXXXX 
DDMMMYYYY 
(XX) 
Palms 
XX 
XX 
XX 
XX 
 
 
 
 
Soles 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XX; XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CFB = change from baseline. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. Thickening of the skin on the palms and soles will be 
measured on a 5-point (0 - 4) scale. Higher scores indicate more severe thickening.  
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period.  
[2] CFB is calculated as Result – Baseline. 
[3] % CFB is calculated as Change from baseline / Result at baseline * 100. 
 
Programming note: If assessment was not performed, concatenate reason with a semicolon. CFB and % CFB columns will not be populated for Baseline rows. 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 130 of 150 
 
Listing 16.2.6.5.1 
Quality of Life per Dermatology Life Quality Index (DLQI) 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
 Subject ID 
Was Assessment 
Performed? 
Study Visit 
Assessment Date 
(Study Day) 
Item  
Score 
Baseline [2] 
CFB [3] 
% CFB 
[4] 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXX 
XXXXXX 
DDMMMYYYY 
(XX) 
1. Over the last week, how itchy, sore, painful 
or stinging has your skin been? 
X 
X 
X 
X 
 
 
 
 
2. Over the last week, how embarrassed or self 
conscious have you been 
because of your skin? 
X 
X 
X 
X 
 
 
 
 
… 
 
 
 
 
 
 
 
 
10. Over the last week, how much of a problem 
has the treatment for your skin 
been, for example by making your home 
messy, or by taking up time? 
XX 
XX 
XX 
XX 
 
 
 
 
Total Score 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XX; XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CFB = change from baseline; DLQI = Quality of Life per Dermatology Life Quality Index. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. DLQI total score is derived as the sum of the 10 
individual item scores, with a range of 0 to 30. Higher scores indicate poorer quality of life. 
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period.  
[2] CFB is calculated as Result – Baseline. 
[3] % CFB is calculated as Change from baseline / Result at baseline * 100. 
 
Programming note: If assessment was not performed, concatenate reason with a semicolon. CFB and % CFB columns will not be populated for Baseline rows. 
 
 
 
Listing 16.2.6.5.2 
Quality of Life per Children’s Dermatology Life Quality Index (cDLQI) 
All Subjects 
 
Same shell as Listing 16.2.6.5.1 
 
Programming note: If update to cDLQI throughout footnotes and abbreviations. 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 131 of 150 
 
Listing 16.2.6.6 
Fissuring Assessment 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
 Subject ID 
Was Assessment 
Performed? 
Study Visit 
Assessment Date 
(Study Day) 
Fissures Present on Palms or 
Soles?  
Body Area 
Number of 
Fissures 
Fissure Pain Level 
 
 
 
 
 
 
 
 
XXXXXX 
XXX 
XXXXXX 
DDMMMYYYY 
(XX) 
XXX 
Palms 
XX 
XXXXX 
 
 
 
 
 
Soles 
XX 
XXXXX 
 
 
 
 
 
 
 
 
XXXXXX 
XXX 
XXXXXX 
DDMMMYYYY 
(XX) 
XXX 
Palms 
XX 
XXXXXXXX 
 
 
 
 
 
Soles 
XX 
XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XX; XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug.  
 
Programming note: If assessment was not performed, concatenate reason with a semicolon. 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 132 of 150 
 
Listing 16.2.6.7 
Ectropion Score 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
 Subject ID 
Was Assessment Performed? 
Study Visit 
Assessment Date 
(Study Day) 
Item  
Score 
Baseline [2] 
CFB [3] 
% CFB [4] 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXX 
XXXXXX 
DDMMMYYYY 
(XX) 
Lateral apposition 
XX 
XX 
XX 
XX 
 
 
 
 
Medial apposition 
XX 
XX 
XX 
XX 
 
 
 
 
Scleral show 
XX 
XX 
XX 
XX 
 
 
 
 
Conjunctival show 
XX 
XX 
XX 
XX 
 
 
 
 
Excess tear film 
XX 
XX 
XX 
XX 
 
 
 
 
Redness of the eye 
XX 
XX 
XX 
XX 
 
 
 
 
Round canthus 
XX 
XX 
XX 
XX 
 
 
 
 
Punctum lacrimate 
XX 
XX 
XX 
XX 
 
 
 
 
Total Score 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CFB = change from baseline. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. Ectropion total score is derived as the sum of the 8 
individual item scores (lateral apposition, medial apposition, scleral show, conjunctival show, excess tear film, redness of the eye, round canthus, punctum lacrimale), with a range 
of 0 to 8. Each individual item is scored 0 (nonaffected/no/invisible), 0.5 (<= 1 mm/emerging), or 1 (affected/yes/visible). Higher scores indicates worse ectropion.  
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period.  
[2] CFB is calculated as Result – Baseline. 
[3] % CFB is calculated as Change from baseline / Result at baseline * 100. 
 
Programming note: If assessment was not performed, concatenate reason with a semicolon. CFB and % CFB columns will not be populated for Baseline rows. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 133 of 150 
 
Listing 16.2.6.8 
EQ-5D 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXXX 
 Subject ID 
Was Assessment 
Performed? 
Study Visit 
Assessment Date 
(Study Day) 
Item  
Score 
Baseline [2] 
CFB [3] 
% CFB [4] 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXX 
XXXXXX 
DDMMMYYYY 
(XX) 
Mobility 
XX 
XX 
XX 
XX 
 
 
 
 
Self-care 
XX 
XX 
XX 
XX 
 
 
 
 
Usual Activities 
XX 
XX 
XX 
XX 
 
 
 
 
Pain/Discomfort 
XX 
XX 
XX 
XX 
 
 
 
 
Anxiety Depression 
XX 
XX 
XX 
XX 
 
 
 
 
Your Health Today 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
 
 
 
XXXXXX 
XX; XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CFB = change from baseline; VAS = visual analog scale. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. The EQ-5D is a measure of health related quality of 
life. The EQ-5D consists of a descriptive system and the EQ visual analog scale (VAS). The EQ-5D-5L is intended for use in adult subjects. The descriptive system comprises 5 
dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ VAS records the subject’s self-rated health on a vertical 0-100 VAS.  
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period.  
[2] CFB is calculated as Result – Baseline. 
[3] % CFB is calculated as Change from baseline / Result at baseline * 100. 
 
Programming note: If assessment was not performed, concatenate reason with a semicolon. CFB and % CFB columns will not be populated for Baseline rows. 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 134 of 150 
 
Listing 16.2.7.1 
Adverse Events 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXX 
Subject 
ID 
TEAE? [1] 
System Organ Class/ 
   Preferred Term/ 
      Verbatim Term 
Start Date/Time (Study Day)/ 
   End Date/Time (Study Day) 
Severity/ 
   Relationship to Study Drug 
Outcome 
 
Serious?/ 
  Criteria Met 
Action Taken/ 
Other Action Taken? 
 
 
 
 
 
 
XXXXX 
XXX 
XXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXXXXX 
      XXXXXXXXXXXXX 
DDMMMYYYY/HH:MM (X)/ 
   DDMMMYYYY/HH:MM (X) 
XXXXXXXXX/ 
   XXXXXXXXXX 
XXXXXXXXX XX 
XXXXXXXXX/  
XXXXXXXXX 
 
 
 
 
 
 
 
XXXXX 
XX 
XXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXXXXX 
      XXXXXXXXXXXXX 
DDMMMYYYY/HH:MM (X)/ 
   DDMONYYYY/HH:MM (X) 
XXXXXXXXX/ 
   XXXXXXXXXX 
XXXXXXXXX   XX 
XXXXXXXXX/  
XXXXXXXXX 
 
XXX 
XXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXXXXX 
      XXXXXXXXXXXXX 
DDMMMYYYY/HH:MM (X)/ 
   Ongoing 
XXXXXXXXX/ 
   XXXXXXXXXX 
XXXXXXXXX/ XXX/ 
   XXXXXXXXX 
XXXXXXXXX/  
XXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; TEAE = treatment emergent adverse event. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. AEs were coded using MedDRA version 21.1. 
[1] A TEAE is any AE with an onset at the time of or following the start of treatment with study drug through the Follow-up Visit or Early Termination Visit, whichever occurs first. This 
will include any AE starting prior to the start of treatment but increasing in severity or relationship at the time of, or following, the start of treatment with study drug through the Follow-
up Visit or Early Termination Visit, whichever occurs first. 
 
Programming note: If time missing, display “- -:- -”. If Serious? is Yes, concatenate all serious criteria marked as Yes with a semicolon. If no events meet the criteria for display, 
present “No events are reported.” SOC & PT text should be in proper case in table. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 135 of 150 
 
Listing 16.2.8.1 
Laboratory Data: Clinical Chemistry 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXX 
Subject ID 
Parameter 
(unit) 
Study 
Visit 
Date/Time of 
Assessment 
(Study Day) 
Standard 
Results 
Standard 
Reference 
Range 
[1] 
Standard 
Reference Range 
Flag 
CFB 
[2] 
%CFB 
[3] 
Accession 
Number 
Comments 
 
 
 
 
 
 
 
 
 
 
 
XXXXX 
Albumin (unit) 
XXXXXX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
XX – YY 
 
 
 
XXXXXXX 
 
 
 
XXXXXX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
XX – YY 
XXX 
XXX 
XXX 
XXXXXXX 
 
 
 
XXXXXX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
XX – YY 
 
XXX 
XXX 
XXXXXXX 
 
 
 
XXXXXX 
 
ND 
 
 
 
 
 
XXXXXXX 
 
 
XXXXXX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
XX – YY 
 
XXX 
XXX 
XXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; AL = abnormal-low; AH = abnormal-high; CFB = change from baseline; CS = clinically significant; NCS = not clinically significant; ND = not 
done. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. 
[1] Reference range is used to identify potentially clinically significant laboratory values. 
[2] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
[2] CFB is calculated as Result – Baseline. 
[3] % CFB is calculated as Change from baseline / Result at baseline * 100. 
 
Programming note: update abbreviations to reflect actual data. If test was not done, set results to ND. For reference range flag, concatenate AL or AH with clinical significant like “XX-
YY” (e.g., AL-CS). CFB and %CFB columns will be blank for Baseline. Include all parameters. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 136 of 150 
 
Listing 16.2.8.2 
Laboratory Data: Hematology 
All Subjects 
 
Same shell as Listing 16.2.8.1 
 
 
 
 
Listing 16.2.8.3 
Laboratory Data: Coagulation  
All Subjects 
 
Same shell as Listing 16.2.8.1 
 
 
 
 
 
Listing 16.2.8.4 
Laboratory Data: Urinalysis 
All Subjects 
 
Same shell as Listing 16.2.8.1 
 
 
 
Listing 16.2.8.5 
Laboratory Data: Serology  
All Subjects 
 
Same shell as Listing 16.2.8.1 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 137 of 150 
 
 
Listing 16.2.8.6 
Laboratory Data: Pregnancy Tests 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXX 
Subject ID 
Sample Type  
Was Sample for Urine/Serum 
Pregnancy Test Collected? 
Date of 
Collection 
(Study Day) 
Result 
 
 
 
 
 
XXXXX 
XXXXXX  
XXX 
DDMMMYYYY 
 (X) 
XXXXXXX 
 
 
 
 
 
XXXXX 
XXXXXX  
XXX 
DDMMMYYYY 
 (X) 
XXXXXXX 
 
 
 
 
 
XXXXX 
XXXXXX  
XX; XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. 
 
Programming note: If sample not collected, concatenate reason in cell with a semicolon. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 138 of 150 
 
Listing 16.2.9.1 
Vital Signs 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXX 
Subject ID 
Parameter (unit) 
Study 
Visit 
Date/Time Collected 
 (Study Day) 
Result 
CFB [2] 
%CFB [3] 
 
 
 
 
 
 
 
XXXXX 
Pulse (bpm) 
XXXXXX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
 
 
 
 
XXXXXX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
XXX 
XXX 
 
 
XXXXXX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
XXX 
XXX 
 
 
 
 
 
 
 
XXXXX 
XXXXXX 
XXXXXX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CFB = change from baseline. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. 
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
[2] CFB is calculated as Result – Baseline. 
[3] % CFB is calculated as Change from baseline / Result at baseline * 100. 
 
Programming note: CFB and %CFB columns will be blank for Baseline. Include all parameters. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 139 of 150 
 
Listing 16.2.9.2 
12-Lead Electrocardiogram 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXX 
Subject ID 
Parameter (unit) 
Study 
Visit 
Timepoint 
Was ECG Performed at this Time 
point? 
Date/Time Collected 
 (Study Day) 
Result 
CFB [2] 
%CFB [3] 
 
 
 
 
 
 
 
 
 
XXXXX 
Pulse (bpm) 
XXXXXX 
XXXXXX 
XX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
 
 
 
 
XXXXXX 
XXXXXX 
XX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
XXX 
XXX 
 
 
XXXXXX 
XXXXXX 
XX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
XXXXX 
XXXXXX 
XXXXXX 
XXXXXX 
XX 
DDMMMYYYY/ 
HH:MM (X) 
XX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CFB = change from baseline; ECG= electrocardiogram. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. 
[1] Baseline is defined as the last non-missing assessment recorded prior to the first dose of treatment in the Double-blind Period. 
[2] CFB is calculated as Result – Baseline. 
[3] % CFB is calculated as Change from baseline / Result at baseline * 100. 
 
Programming note: If ECG was not performed, concatenate reason in cell with a semicolon.


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 140 of 150 
 
Listing 16.2.9.3 
Local Tolerability Assessments 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXX 
 Subject ID 
Was Assessment Collected? 
Study Visit 
Date Assessment Collected 
(Study Day) 
Body Area 
Assessment 
Score 
 
 
 
 
 
 
 
XXXXXX 
XXX 
XXXXXXXX 
DDMMMYYYY 
(X) 
Face/Neck 
Erythema 
XXXXX 
 
 
 
 
 
Stinging/Burning 
XXXXX 
 
 
 
 
 
Pruritus 
XXXXX 
 
 
 
 
XXXXX 
XXXXXXXXX 
XXXXX 
 
 
 
 
XXXXX 
XXXXXXXXX 
XXXXX 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. 
 
Programming note: If assessment was not collected, concatenate reason in cell with a semicolon. 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 141 of 150 
 
Listing 16.2.9.4 
Physical Examination 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXX 
Subject 
ID 
Was Exam 
Performed? 
Study 
Visit 
Exam Date 
(Study Day) 
Body System 
Result 
Abnormal 
Findings 
Clinically 
Significant? 
 
 
 
 
 
 
 
 
XXXXXX 
XXX 
XXXXXXX 
DDMMMYYYY 
(-X) 
General Appearance 
Normal 
 
 
 
 
 
 
Integumentary 
Abnormal 
XXXXXXXX 
No 
 
 
 
 
Head, Ears, Eyes, 
Nose, Throat 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind 
period. All subjects received Trifarotene cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date 
of first dose of study drug. 
 
Programming note: if physical examination was not performed, concatenate reason with a semicolon.  
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 142 of 150 
 
Listing 16.2.9.5 
Prior and Concomitant Medications 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXX 
Subject ID 
Prior/ 
Concomitant 
[1] 
Indication 
ATC Class (Level 4)/ 
   Preferred Term (ATC Level 5)/ 
      Verbatim Term 
Start Date/Time (Study Day)/ 
   End Date/Time (Study Day) 
Dose (unit) 
Route/ 
   Frequency 
 
 
 
 
 
 
 
XXXXXX 
Prior 
XXXXXXX 
XXXXXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXX/ 
      XXXXXXXXXXXXX 
DDMMMYYYY/hh:mm (X)/ 
   DDMMMYYYY/hh:mm (X) 
XXX (XXX) 
 
XXXXXXXX/ 
   XXXXXXX 
 
Both 
XXXXXXX 
XXXXXXXXX/ 
   XXXXXXXXXXXXXXX/ 
      XXXXXXXXXXX 
--MMMYYYY/--:-- (X)/ 
   Ongoing 
XXX (XXX) 
XXXXXXXX/ 
   XXXXXXX 
 
Concomitant 
XXXXXXX 
XXXXXXXXX/ 
   XXXXXXXXXXXXXX/ 
      XXXXXXXXXXXXXXXXX 
DDMMMYYYY/hh:mm (X)/ 
   DDMMMYYYY/hh:mm (XX) 
XXX (XXX) 
XXXXXXXX/ 
   XXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ATC = anatomic therapeutic chemical; NA = not applicable; WHO-DDE = World Health Organization-Drug Dictionary Enhanced. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects 
received Trifarotene cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. Medications 
were coded using WHO-DDE version March 2019.  
[1] “Prior” medications are all medications that were started before the first dose of study medication. “Concomitant” medications are medications continuing or 
starting after the first dose through the end of study. “Both” indicates medication that was started before the first dose and continued during the study. 
 
Programming note: If Dose unit, Route or Frequency is Other, display other specify text only (i.e., do not display “Other: XXXXXX” but just “XXXXXX “). Sort by subject, start 
date/time, end date/time, ATC level 4 & PT. ATC & PT text should be in title case in table, as shown in the shell. Ensure proper WHO-DDE version is printed in footnote. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 143 of 150 
 
Listing 16.2.9.6 
Photography 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXX 
Subject ID 
Was Photography Collected? 
Collection Date 
(Study Day) 
 
 
 
XXXXXX 
XXX 
DDMMMYYYY (XX) 
 
 
 
XXXXXX 
XXX 
DDMMMYYYY (XX) 
 
 
 
XXXXXX 
XXX 
DDMMMYYYY (XX) 
 
 
 
XXXXXX 
XXX 
DDMMMYYYY (XX) 
 
 
 
XXXXXX 
XX 
 
 
 
 
XXXXXX 
XXX 
DDMMMYYYY (XX) 
 
 
 
 
 
 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or 
vehicle in the double-blind period. All subjects received Trifarotene cream HE1 200 ug/g in the open label extension 
period. Study day is calculated relative to the date of first dose of study drug. 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 144 of 150 
 
Listing 16.2.9.7 
Trial Continuation 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXX 
 
Subject ID 
Study Visit 
Continuing to 
 Next Visit? 
Continuing with  
Drug Administration? 
Continuing to OLE? 
 
 
 
 
 
XXXXXX 
XXXXXX 
XXX 
XXX 
XXX 
 
 
 
 
 
XXXXXX 
XXXXXX 
XXX 
XXX 
XXX 
 
 
 
 
 
XXXXXX 
XXXXXX 
XXX 
XXX 
XXX 
 
 
 
 
 
XXXXXX 
XXXXXX 
XXX 
XXX 
XXX 
 
 
 
 
 
XXXXXX 
XXXXXX 
XX 
XX 
XX 
 
 
 
 
 
XXXXXX 
XXXXXX 
XXX 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
Abbreviation: OLE = open label extension. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period.  
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 145 of 150 
 
Listing 16.2.9.8 
Telephone Contact 
All Subjects 
 
Randomized Treatment: XXXXXXXXXXXXXXX 
 
 
Subject ID 
Study Visit 
Contacted to Assess New 
AEs/SAEs? 
Contact Date 
(Study Day) 
Report Any New or Worsening 
AEs/SAEs? 
Report Any New Concomitant 
Medications? 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
XXX 
DDMMMYYYY (XX) 
XXX 
XXX 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
XXX 
DDMMMYYYY (XX) 
XXX 
XXX 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
XXX 
DDMMMYYYY (XX) 
XXX 
XXX 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
XXX 
DDMMMYYYY (XX) 
XXX 
XXX 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
XX; XXXXX 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXXXXX 
XXX 
DDMMMYYYY (XX) 
XXX 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: AE = adverse event; OLE = open label extension; SAE = serious adverse event. 
Note: Subjects were randomized to either Trifarotene cream HE1 100 ug/g, Trifarotene cream HE1 200 ug/g, or vehicle in the double-blind period. All subjects received Trifarotene 
cream HE1 200 ug/g in the open label extension period. Study day is calculated relative to the date of first dose of study drug. 
 
 
 
 
Listing 16.2.9.9 
COVID-19 Impact Log 
All Subjects 
 
Programming Note: The structure of this listing will be determined prior to database lock, when the log is finalized. 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 146 of 150 
 
14.4. 
Planned Figure Shells 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 147 of 150 
 
Appendix 1: Premier Research Library of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse events special interest 
AIC 
Akaike information criterion 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical 
BLQ 
beneath limit of quantification 
BMI 
body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
CFB 
Change from baseline 
CFR 
code of federal regulations 
CI 
confidence intervals 
CRF 
case report form 
CRO 
contract research organization 
CS 
clinically significant 
CSR 
clinical study report 
DBP 
diastolic blood pressure 
DEA 
drug enforcement administration 
DIA 
drug information association 
DOB 
date of birth 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 148 of 150 
 
Abbreviation 
Definition 
EC 
ethics committee 
ECG 
electrocardiogram 
EMA 
European medicines agency 
EOS 
End of study 
ET 
Early termination 
FAS 
Full analysis set 
FDA 
food and drug administration 
FOCP 
Females of childbearing potential 
FPC 
Follow-up phone call 
HR 
heart rate 
IC or ICF 
informed consent or informed consent form 
ICH 
international council for harmonization  
ID 
identification 
IND 
investigational new drug 
IRB 
institutional review board 
LS 
Least squares 
MAR 
Missing at random 
MedDRA 
medical dictionary for regulatory activities 
mg 
milligram 
MI 
Multiple imputation 
MI 
Metacognitive index 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 149 of 150 
 
Abbreviation 
Definition 
MMRM 
mixed effect model repeat measurement 
MNAR 
Missing not at random 
ms 
millisecond 
N 
number 
NA 
not applicable 
NCS 
non-clinically significant 
OLE 
Open-label extension 
PD 
protocol deviation 
PE 
physical examination 
PK 
pharmacokinetic 
PKAP 
pharmacokinetic analysis plan 
POC 
Point of care 
PP 
per-protocol 
QD 
Once daily 
QOL 
quality of life 
REML 
Restricted maximum likelihood 
RR 
respiratory rate or relative rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS®  
a software system used for data analysis 
SBP 
systolic blood pressure 


 
Statistical Analysis Plan,  
 
Sponsor Mayne Pharma  
 
Protocol Number 18-ICH-001  
 
PCN Number MAYN7317 
AD-ST-33.05  Effective date: 22-Jan-2018 
Version Final 2.0    |    09-Nov-2021    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 150 of 150 
 
Abbreviation 
Definition 
SD 
standard deviation 
SDQ 
Symptoms of Depression Questionnaire 
SF 
screen failure 
SM 
Study medication 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
USA 
United States of America 
UTC 
universal coordinated time 
WHO 
world health organization 
WHO-DDE 
world health organization drug dictionary enhanced