Clinical trial NCT03738800: A Safety, Efficacy and Systemic Exposure Study of CD5789 Cream in Adults and Adolescents With Lamellar Ichthyosis
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Lamellar Ichthyosis
Lead sponsor: Mayne Pharma International Pty Ltd
Sponsor class: INDUSTRY
First posted: 2018-11-13
Enrollment: 65
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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 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).

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 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:

    1. Aspartate aminotransferase or alanine aminotransferase \>1.5 × upper limit of normal defined by the laboratory
    2. Total bilirubin \>1.25 × ULN at Screening. Subjects with known Gilbert's syndrome may be included with total bilirubin \>1.25 × ULN
    3. Hemoglobin \<12.5 g/dL for men and \<11.5 g/dL for women
    4. 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.

Primary outcomes:
measure: The Percentage of Subjects in Each Treatment Group Who Experienced Successful Resolution of LI.
timeFrame: 90 Days
Secondary outcomes:
measure: Total 16-point Visual Index for Ichthyosis Severity (VIIS)
timeFrame: 90 Days
measure: The Difference in Mean Scores Using Individual Score for Roughness
timeFrame: 90 Days
measure: The Difference in Mean Scores Using Palm Sole Assessment
timeFrame: 90 Days
measure: The Difference in Proportion of Subjects With Presence of Fissures on Palms Between the Active and Vehicle Groups
timeFrame: 90 Days
measure: Quality of Life Measurement Per Dermatology Life Quality Index (DLQI)
timeFrame: 90 Days
measure: The Difference in Proportion of Subjects With Presence of Fissures on Soles Between the Active and Vehicle Groups
timeFrame: 90 Days
Other outcomes:
measure: The Difference in Mean Ectropion Scores Between the Active and Vehicle Groups
timeFrame: 180 Days
measure: Quality of Life Measurement Per EQ-5D-5L
timeFrame: 180 Days
measure: Incidents of Adverse Events
timeFrame: 180 Days
measure: Measurement of Local Tolerability
timeFrame: 180 Days
measure: Clinical Laboratory Evaluations
timeFrame: 180 Days
measure: Measurement of Vital Signs
timeFrame: 180 Days
measure: Measurement of 12-lead ECG Readings
timeFrame: 180 Days
measure: Physical Examination Findings
timeFrame: 180 Days
measure: Measurement of Area Under the Plasma Concentration Versus Time Curve (AUC)
timeFrame: 180 Days
measure: Measurement of Peak Plasma Concentration (Cmax)
timeFrame: 180 Days
Locations:
city: San Diego
country: United States
facility: TCR Medical Corporation
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Skokie
country: United States
facility: NorthShore University HealthSystem
state: Illinois
city: Indianapolis
country: United States
facility: Dawes Fretzin Clinical Research Group, LLC
state: Indiana
city: Rockville
country: United States
facility: DermAssociates, PC
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: San Antonio
country: United States
facility: Texas Dermatology and Laser Specialists
state: Texas
city: Box Hill
country: Australia
facility: Eastern Health Monash University
city: Brisbane
country: Australia
facility: Veracity Clinical Research
city: Parkville
country: Australia
facility: Royal Children's Hospital
city: Sydney
country: Australia
facility: Premier Specialists Ptd Ltd
city: Toronto
country: Canada
facility: The Hospital for Sick Children
city: Paris
country: France
facility: Dermatologie pédiatrique
city: Rouen
country: France
facility: CHU Charles Nicolle
city: Toulouse
country: France
facility: CHU de Toulouse- Hospital Larrey
city: Berlin
country: Germany
facility: Charite - Universitaetsmedizin Berlin
city: Frankfurt
country: Germany
facility: Universitätsklinkum Frankfurt
city: Hamburg
country: Germany
facility: Kath. Kinderkrankenhaus Wilhelmstift
city: Munich
country: Germany
facility: Ludwig-Maximilians University
city: Rostock
country: Germany
facility: Universitatsmedizin Rostock
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Mc
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Nino Jesus
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra (Madrid)
city: Madrid
country: Spain
facility: Hospital Niño Jesús
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
city: Dnipro
country: Ukraine
facility: Medical Center of Private Enterprise "Dzerkalo"
city: Dnipro
country: Ukraine
facility: Dnipropetrovsk State Hospital of Dermatovenerology
city: Dnipro
country: Ukraine
facility: Medical Center "Family Medicine Clinic"
city: Ternopil'
country: Ukraine
facility: Ternopil Regional Clinical Dermatovenereological Dispensary
city: Uzhhorod
country: Ukraine
facility: TDC PE "Asclepius"
city: Zaporizhzhya
country: Ukraine
facility: Community Institution "Zaporizhzhya Regional Dermatovenereology Clinical Hospital"
city: London
country: United Kingdom
facility: Royal London Hospital Barts Health Nhs Trust
Study officials:
affiliation: Yale University
name: Keith A. Choate, MD
role: PRINCIPAL_INVESTIGATOR
References: