A Vehicle Controlled Study to Evaluate Safety and Efficacy of Topical TMB-001 for Treatment of Congenital Ichthyosis

Study Overview
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Brief Summary
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The purpose of this study is to investigate the efficacy and safety of two concentrations of topically applied ointment formulation of isotretinoin called TMB-001 (0.05% and 0.1% isotretinoin) in subjects 9 years of age and older for the treatment of congenital ichthyosis (CI), including recessive X-linked ichthyosis (RXLI) and autosomal recessive congenital ichthyosis-lamellar ichthyosis (ARCI-LI) subtypes. Funding Source FDA-OOPD

Detailed Description
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This is a randomized, parallel, double-blind, vehicle-controlled study to evaluate the safety and efficacy of two concentrations of topical TMB-001 for the treatment of CI in subjects with either the ARCI-LI or RXLI subtypes. The duration of treatment will be 12 weeks. Each subject will participate in the study for up to 24 weeks (including up to a 90-day Screening period). Eleven study centers from United States of America and Australia participated in this global study. Each subject participated in the study for up to 24 weeks (including up to a 90-day Screening period). Eligible subjects were randomized (1:1:1) to one of 3 treatment groups: TMB-001, 0.05%, twice daily (bid) TMB-001, 0.1%, bid Vehicle Ointment (Control), 0%, bid Subjects were evaluated on a monthly basis for safety and efficacy results over the 12- week treatment period. Efficacy was determined in 2 ways: VIIS (or Visual Index of Ichthyosis Severity) treatment success (VIIS-50) was defined as ≥ 50% reduction from Baseline for VIIS scaling score for the sum of the scores for 'VIIS body areas' that had a Baseline score ≥ 3). The proportion of subjects achieving VIIS-50 at Visit 6 at Week 12 relative to Baseline was the primary efficacy endpoint and time point used to compare the two active treatments to vehicle. The proportion of subjects achieving IGA (Investigator Global Assessment) treatment success will be the key secondary endpoint. For this endpoint, the IGA score was established as treatment success or treatment failure where treatment success is defined as at least a 2-grade decrease in severity score (for example, severe or score of 4 at baseline to mild or score of 2 at Visit 6) relative to Baseline at Visit 6 at week 12. The safety analyses conducted were extent of exposure, changes in physical examinations and vital signs, blood and urine testing including urine pregnancy testing as indicated, local skin reactions (including burning/stinging, redness, erosions, and swelling) and other adverse events.

Official Title
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A Randomized, Parallel, Double-Blind, Vehicle Controlled Study to Evaluate the Safety and Efficacy of Two Concentrations of Topical TMB-001 for the Treatment of Congenital Ichthyosis

Conditions
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Congenital Ichthyosis

Intervention / Treatment
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* Drug: Isotretinoin
* Other: Vehicle


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is male or female, 9 years of age or older at Visit 2 (Baseline) Subject has provided written informed consent Females of child bearing potential must be surgically sterile or agree to 2 forms of birth control Subject has clinical diagnosis of Congenital Ichthyosis with genetic confirmation of subtype Subject has between 10% and 90% total BSA affected by Congenital Ichthyosis Subject has at least 2 VIIS assessment areas with a scaling score of 3 or greater Exclusion Criteria: Subject has inflammatory skin diseases unrelated to ichthyosis Subject has used other prohibited topical treatments in the assessment areas within certain days from baseline Subject has used systemic retinoids within12 weeks of baseline Subject has untreated secondary infections Subject has lesions suspicious for skin cancer or untreated skin cancers

Ages Eligible for Study
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Minimum Age: 9 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
Interventional Model Description: A Randomized, Parallel, Double-Blind, Vehicle-Controlled Study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Vehicle Ointment (Control)<br>Topical, BID (Twice daily) | Other: Vehicle<br>* Topical Vehicle Ointment<br>|
| Experimental: TMB-001 Ointment, 0.05%<br>Topical, BID ( twice daily) | Drug: Isotretinoin<br>* Topical Isotretinoin ointment<br>* Other names: TMB-001;|
| Experimental: TMB-001 Ointment, 0.1%<br>Topical, BID (Twice daily) | Drug: Isotretinoin<br>* Topical Isotretinoin ointment<br>* Other names: TMB-001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Reduction in Targeted Ichthyosis Severity Using the Visual Index for Ichthyosis Severity Measurement | Number of subjects with Visual Index for Ichthyosis Severity (VIIS) treatment success, defined as 50% or greater decreased in VIIS scaling score | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Reduction in Overall Ichthyosis Severity as Measured With Investigator Global Assessment | Number of subjects with Investigator Global Assessment decrease in disease severity by at least 2 grades | 12 weeks | 
| Change in I-NRS (Itch-Numeric Rating Scale) From Baseline at Week 12 | Mean numeric Change from baseline in Itch-Numeric Rating Scale (I-NRS) at Week 12 for entire population. I-NRS is an 11-point visual analogue scale scored based upon 0 being no itch and 10 being worst itch imaginable. Subjects were asked to grade their itch on such a scale at each visit where I-NRS was administered. A 4-point change from baseline is considered clinically significant | 12 weeks | 
| Change From Baseline in Dermatology Life Quality Index (DLQI) at Week 12 | Change from Baseline in Dermatology Life Quality Index (DLQI) at Week 12 in all adult subjects. The DLQI is validated in all subjects over age 16 years and is a 10-question questionnaire which requests information on how the dermatological condition affects different aspects of their life. Each question is scored on a 0-3 scale (0=no impact, 3=major impact) for a total possible maximal score of 30. Scores over 11 in adults are considered to indicate moderate impairment of quality of life due to the skin disease. A 4-point improvement from baseline is considered clinically significant | 12 weeks |