| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Lamellar ichthyosis (LI)
Autosomal Recessive Ichthyosis with Lamellar Scale |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023686 |
| E.1.2 | Term | Lamellar ichthyosis |
| E.1.2 | System Organ Class | 100000004850 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
• 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. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| 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. For the subjects in the PK substudy, postdose ECGs will be performed at each serial blood draw on Day 1 and Day 30. |
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| E.3 | Principal 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 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). |
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| E.4 | Principal 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:
a. Aspartate aminotransferase or alanine aminotransferase >1.5 × upper limit of normal (ULN) defined by the laboratory
b. Total bilirubin >1.25 x ULN at screening. Subjects with known Gilbert’s syndrome may be included with total bilirubin >1.25 x 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 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 who 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary time point is Day 90 for double blind and day 194 for open label part of the study
|
|
| E.5.2 | Secondary end point(s) |
• 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) 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 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
secondary and exploratory efficacy endpoints as well as PK endpoints will be presented for all study visits (Day 1,14,30,60,90 and 104,120,150,180,194). Safety endpoints will be monitored throughout the entire study.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Double-blind 90-Day study followed by 90-Day Open-label extension study |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Israel |
| Ukraine |
| United States |
| France |
| Germany |
| Spain |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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