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

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ClinicalTrials.gov Identifier: NCT03738800
Recruitment Status : Not yet recruiting
First Posted : November 12, 2018
Last Update Posted : February 18, 2019
Sponsor:
Information provided by (Responsible Party):
Mayne Pharma International Pty Ltd

Brief Summary:
This is 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 cream in adults and adolescents with autosomal recessive ichthyosis with lamellar scale

Condition or disease Intervention/treatment Phase
Lamellar Ichthyosis Drug: CD5789 Cream 200 µg/g Drug: CD5789 Cream 100 µg/g Drug: CD5789 Cream Vehicle Phase 2

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 12 weeks. Subjects who complete the randomized, double-blind portion of the study will be eligible to enter a 12 week, 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 12 weeks. 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 12 weeks in the same manner as subjects in Cohort A.

All subjects who complete 12 weeks of double-blind study treatment will be eligible to enroll in a 12-week open-label extension. Subjects in the open-label extension will receive active twice weekly for up to 12 weeks.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2 Randomized, Multicenter, Doubleblind, Vehicle Controlled, 12 Week, Safety, Efficacy & Systemic Exposure Study Followed by a 12 Week Open-label Extension of CD5789 in Adults and Adolescents With Autosomal Recessive Ichthyosis With Lamellar Scale
Estimated Study Start Date : February 21, 2019
Estimated Primary Completion Date : February 10, 2020
Estimated Study Completion Date : June 4, 2020


Arm Intervention/treatment
Experimental: CD5789 Cream 200 µg/g
CD5789 200 µg/g, topical, 50g
Drug: CD5789 Cream 200 µg/g
A fixed dose (determined at Visit 1) of 200 µg/g applied topically twice weekly to up to 90% BSA

Experimental: CD5789 Cream 100 µg/g
CD5789 100 µg/g, topical, 50g
Drug: CD5789 Cream 100 µg/g
A fixed dose (determined at Visit 1) of 100 µg/g applied topically twice weekly to up to 90% BSA

Placebo Comparator: CD5789 Cream Vehicle
CD5789 Cream Vehicle, topical, 50g
Drug: CD5789 Cream Vehicle
A fixed dose (determined at Visit 1) applied topically twice weekly, up to 36 g per dose up to 90% BSA




Primary Outcome Measures :
  1. The number of subjects in each treatment group who experience successful resolution of LI. [ Time Frame: 12 weeks ]
    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 Outcome Measures :
  1. The difference in mean scores using Palm Sole Assessment [ Time Frame: 12 weeks ]

    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

  2. The difference in mean scores using Individual score of scaling [ Time Frame: 12 weeks ]

    The amount of scaling will be measured on a 5-point scale. 0 (Clear) No scaling

    1. (Almost Clear) Very fine, non-coalescent scales
    2. (Mild) Small and thin, non-coalescent scales
    3. (Moderate) Large and rather thick scales starting to coalesce
    4. (Severe) Very large, adherent, coalescent and very thick scales

  3. The difference in mean scores using Individual score for roughness [ Time Frame: 12 weeks ]

    The amount of roughness of the skin 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)

  4. Quality of life measurement per Dermatology Life Quality Index (DLQI) [ Time Frame: 12 weeks ]

    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


  5. The difference in proportion of subjects with presence of fissures between the active and vehicle groups [ Time Frame: 12 weeks ]
    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).


Other Outcome Measures:
  1. The difference in mean ectropion scores between the active and vehicle groups [ Time Frame: 24 weeks ]

    The Ectropion Severity Score (ESS), is a proven system to be reliable and sensitive to the presence of ectropion and has a maximum score of 8 points (0-8). 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 A point scale of 0=Nonaffected, 0.5=Emerging, 1= Affected is assigned to 8 observations.

    • Lateral apposition
    • Medial apposition
    • Sceral show
    • Conjunctival show
    • Excess team film
    • Redness of the eye
    • Round canthus
    • Punctum lacrimale

  2. Quality of life measurement per EQ-5D-5L [ Time Frame: 24 weeks ]

    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). Descriptive system of health-related quality of life states consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) each of which can take 1 of 5 responses.

    1. no problem
    2. slight problems
    3. moderate problems
    4. severe problems
    5. extreme problems It should be noted that the numerals 1-5 have no arithmetic properties and should not be used as a cardinal score. The EQ VAS records the respondent's self-rated health on a 20 cm vertical, visual analogue scale with endpoints labelled 100-'the best health you can imagine' and 0-'the worst health you can imagine'. This information can be used as a quantitative measure of health as judged by the individual respondents.

  3. Incidents of adverse events [ Time Frame: 24 weeks ]
    The number of subjects with AEs will be collected for each treatment group

  4. Measurement of local tolerability [ Time Frame: 24 weeks ]
    Local tolerability will be assessed on a 0-3 scale (none, mild, moderate, severe).

  5. Clinical Laboratory Evaluations [ Time Frame: 24 weeks ]
    The number of subjects with clinical laboratory values categorized as below (vital signs, 12 lead electrocardiogram, Physical Exam), within, or above normal ranges will be evaluated (changes from baseline for each clinical laboratory parameter by treatment group and by study visit).

  6. Measurement of vital signs [ Time Frame: 24 weeks ]
    Blood pressure (systolic blood pressure [SBP], diastolic blood pressure [DBP] and pulse will be measured. Measurement of actual values and changes from baseline will be calculated. Vital signs The number of subjects with vital signs values categorized as below, within, or above normal ranges (change from baseline for each parameter by period, by treatment group and by study visit).

  7. Measurement of 12-lead ECG Readings [ Time Frame: 24 weeks ]
    The number of subjects with normal and abnormal ECG findings will be measured for each treatment group at each time point for QT and the QT interval corrected for heart rate (QTc) calculated using Fridericia's QT correction methods.

  8. Physical examination findings [ Time Frame: 24 weeks ]
    The number of subjects with normal and abnormal findings in the complete physical examination for each treatment group. This is a limited physical examination to include HEENT, cardiorespiratory, abdomen, and range of motion.

  9. Measurement of area under the plasma concentration versus time curve (AUC) [ Time Frame: 24 weeks ]
    Measurement of the extent of absorption using estimates of the area-under-the-curve (AUC).

  10. Measurement of peak plasma concentration (Cmax) [ Time Frame: 24 weeks ]
    Measurement of therate-of-absorption using the maximum concentration (Cmax) and the time of Cmax (Tmax).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 body areas assess (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 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:

  • 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 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 or pruritus 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 human immunodeficiency virus antibody 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. Triglycerides >200 mg/dL
    3. Total cholesterol >250 mg/dL
    4. Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women
    5. 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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03738800


Contacts
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Contact: Phoevos Hughes, JD 9193096970 phoevos.hughes@maynepharma.com
Contact: Alicia Alton 252-945-0183 alicia.alton@maynepharma.com

Sponsors and Collaborators
Mayne Pharma International Pty Ltd
Investigators
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Principal Investigator: Keith A. Choate, MD Yale University

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Responsible Party: Mayne Pharma International Pty Ltd
ClinicalTrials.gov Identifier: NCT03738800     History of Changes
Other Study ID Numbers: 18-ICH-001
First Posted: November 12, 2018    Key Record Dates
Last Update Posted: February 18, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Ichthyosis
Ichthyosis, Lamellar
Skin Abnormalities
Congenital Abnormalities
Infant, Newborn, Diseases
Keratosis
Skin Diseases
Ichthyosiform Erythroderma, Congenital
Skin Diseases, Genetic
Genetic Diseases, Inborn
Trifarotene
Dermatologic Agents