A Safety, Efficacy and Systemic Exposure Study of CD5789 Cream in Adults and Adolescents With Lamellar Ichthyosis

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2 Randomized, Multicenter, Double-blind, Vehicle Controlled, 90-Day, Safety, Efficacy & Systemic Exposure Study of Trifarotene (CD5789) Cream HE1 in Adults and Adolescents With Autosomal Recessive Ichthyosis With Lamellar Scale

Conditions
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Lamellar Ichthyosis

Intervention / Treatment
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* Drug: CD5789 Cream 200 µg/g
* Drug: CD5789 Cream 100 µg/g
* Drug: CD5789 Cream Vehicle


Participation Criteria
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Eligibility Criteria
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For Cohort A: subject is ≥18 years old; for Cohort B: subject is ≥12 years old. Subject has known diagnosis of LI. Subject has moderate to severe (IGA 3-4) LI on the IGA of LI severity. 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. Subject who is participating in optional photography has signed a photography ICF. 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. 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 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. 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). 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. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin). Exclusion criteria: Subject has any variant of ichthyosis other than LI or another disorder of keratinization, including syndromic ichthyoses. Subject has current moderate or severe stinging/burning at Screening. 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. 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. Subject was previously treated with trifarotene/CD5789 in an acne or ichthyosis study. 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. 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 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. Subject with positive serology for hepatitis B surface antigen, hepatitis C, or are known to be HIV positive or to have AIDS at Screening. Subject with any of the following laboratory values at Screening: Aspartate aminotransferase or alanine aminotransferase >1.5 × upper limit of normal defined by the laboratory Total bilirubin >1.25 × ULN at Screening. Subjects with known Gilbert's syndrome may be included with total bilirubin >1.25 × ULN Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women Platelets <150 × 109/L or >400 × 109/L. 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. 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. 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. Subject has a known allergy or sensitivity to any of the components of the investigational products. 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.). Subject is inherently sensitive to sunlight. Subject is unable or unwilling to stop use of topical or systemic retinoids. Subject is presumed to be abusing drug or alcohol at Screening or Baseline Visits based on medical history or current clinical symptoms. Subject is participating in another interventional clinical trial. Subject is institutionalized. Subject is in any way related to the sponsor, investigator, or site personnel.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CD5789 Cream 200 µg/g<br>CD5789 200 µg/g, topical, 50g | Drug: CD5789 Cream 200 µg/g<br>* A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA<br>|
| Experimental: CD5789 Cream 100 µg/g<br>CD5789 100 µg/g, topical, 50g | Drug: CD5789 Cream 100 µg/g<br>* A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA<br>|
| Placebo Comparator: CD5789 Cream Vehicle<br>CD5789 Cream Vehicle, topical, 50g | Drug: CD5789 Cream Vehicle<br>* A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Subjects in Each Treatment Group Who Experienced Successful Resolution of LI. | The percentage of subjects in each treatment group who experienced 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. | 90 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total 16-point Visual Index for Ichthyosis Severity (VIIS) | 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) where minimum is 0 and maximum is 16 (e.g. 4 points for each of the four body parts). 0 (Clear) No scaling (Almost Clear) Very fine, non-coalescent scales (Mild) Small and thin, non-coalescent scales (Moderate) Large and rather thick scales starting to coalesce (Severe) Very large, adherent, coalescent and very thick scales | 90 Days | 
| The Difference in Mean Scores Using Individual Score for Roughness | The amount of roughness of the skin will be measured on a 5-point scale. 0 (Clear) Smooth skin (Almost Clear) Hardly palpably roughness (Mild) Mild roughness (fine sand paper-like) (Moderate) Moderate, coarse roughness (coarse sand paper-like) (Severe) Very coarse skin (broken cornflakes-like) | 90 Days | 
| The Difference in Mean Scores Using 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 (Almost Clear) Only slight thickening, minimal to no roughness, no fissures (Mild) Some thickening, mild roughness on palpation, few fissures may be present (Moderate) Substantial and diffuse thickening, coarse roughness on palpation may be present, fissures may be present (Severe) Very thickened and rough skin, numerous fissures | 90 Days | 
| The Difference in Proportion of Subjects With Presence of Fissures on Palms Between the Active and Vehicle Groups | 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) at day 90 between the active trifarotene cream HE1 and vehicle groups | 90 Days | 
| Quality of Life Measurement Per Dermatology Life Quality Index (DLQI) | The DLQI, or the Dermatology Quality of Life Index, 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. Responses collected are on a scale of 0-3 depending on the question relevance to the subject. Response (Score) Very much (scored 3) A lot (scored 2) A little (scored 1) Not at all (scored 0) Not relevant (scored 0) A minimum score of 0 and maximum score of 30 is obtained by summing the score of each question. The higher the score, the more quality of life is impaired. 0-1 = no effect at all on patient's life 2-5 = small effect on patient's life 6-10 = moderate effect on patient's life 11-20 = very large effect on patient's life 21-30 = extremely large effect on patient's life | 90 Days | 
| The Difference in Proportion of Subjects With Presence of Fissures on Soles Between the Active and Vehicle Groups | 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) at day 90 between the active trifarotene cream HE1 and vehicle groups | 90 Days |