A Safety and Tolerability Study of Topical PAT-001 in Congenital Ichthyosis

Study Overview
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Brief Summary
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Congenital ichthyosis (CI) is a large, heterogeneous family of inherited skin disorders of cornification resulting from an abnormality of skin keratinization, such as scaling and thickening of the skin. Treatment options include keratolytic agents, which can abruptly lead to extensive shedding or peeling of scales. PAT-001 primarily acts as a keratolytic agent; thus, making it a potential drug candidate for the treatment of skin disorders associated with hyperkeratinization, such as CI. The current study intends to evaluate the safety and tolerability of PAT-001 in patients with CI of either the Lamellar or X-Linked subtypes.

Detailed Description
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The management of CI is a life-long endeavor, which remains largely symptomatic (i.e., emollients with or without keratolytics agents) and commonly focused on reducing scaling and/or skin lubrication with both systemic and topical treatments. A first-line therapy includes hydration and lubrication accomplished by creams and ointments containing low concentrations of salt, urea, or glycerol, which increase the water-binding capacity of the horny layer. Addition of keratolytics agents are used to decrease corneocyte cohesiveness, to promote desquamation, and to dissolve keratins and lipids (e.g., α-hydroxy acids, salicylic acid, high dose urea, propylene glycol, N-acetylcysteine, and retinoids). Systemic retinoid treatment is reserved for those patients refractory to topical agents because of long-term adverse effects and teratogenicity. This is a two part, Phase 2, multicenter, proof-of-concept (POC) study of the safety and tolerability of PAT-001 for the treatment of Congenital ichthyosis (CI) in patients ages 12 years of age and older. Part 1 will be a double-blind, randomized, vehicle controlled, bilateral comparison of two treatments (PAT-001 [0.1% or 0.2%] vs. vehicle) for eight (8) weeks. Part 2 will be a double-blind, active only treatment comparison of the two PAT-001 concentrations (0.1% or 0.2%) for an additional four (4) weeks. Subjects will have the option to participate in the pharmacokinetics (PK) portion of the study.

Official Title
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A Randomized, Bilateral Comparison, Vehicle-Controlled, Safety and Tolerability Study of Topical PAT-001 for the Treatment of Congenital Ichthyosis

Conditions
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Congenital Ichthyosis

Intervention / Treatment
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* Drug: PAT-001, 0.1%
* Drug: PAT-001, 0.2%
* Drug: Vehicle for PAT-001 0.1%
* Drug: Vehicle for PAT-001 0.2%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of either sex aged 12 years or older. Females of childbearing potential should use appropriate contraception. Women of childbearing potential must have a negative pregnancy test at screening and baseline visits. Patient and legal representative(s), if applicable, has provided written informed consent. Patient has congenital ichthyosis of either lamellar or X-Linked subtype. Patient has two contralateral comparable Treatment Areas (e.g., each arm is affected and treatments areas can be applied equally). Patient is, except for their ichthyosis, in good general health. Exclusion Criteria: Patient is pregnant or breast feeding, or is planning to become pregnant during the study. Patient has inflammatory skin disease unrelated to ichthyosis. Patient is currently using concomitant retinoid therapy, within two weeks (topical) or 12 weeks (oral) of Visit 2/Baseline. Patient is currently taking concomitant immunosuppressive drugs, including systemic corticosteroids, within two weeks of Visit 2/Baseline. Patient is currently enrolled in an investigational drug or device study. Patient has used an investigational drug or investigational device treatment within 30 days prior to Visit 2/Baseline. Patient is unable to communicate or cooperate with the investigator due to language problems, impaired cerebral function, or physical limitations. Patient is known to be noncompliant or is unlikely to comply with the requirements of the study protocol (e.g., due to alcoholism, drug dependency, mental incapacity) in the opinion of the investigator.

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: PAT-001 0.1%<br>Part 1: Bilateral comparison. Patients will have two comparable Treatment Areas: PAT-001, 0.1% (e.g., left side) and Vehicle, 0.0% (e.g., right side). This comparison lasts from Weeks 0-8 Part 2: Patients will apply only PAT-001, 0.1% to both Treatment Areas from Weeks 8-12. | Drug: PAT-001, 0.1%<br>* PAT-001 is a topical ointment. PAT-001, 0.1% contains 0.1% of active drug.<br>* Other names: PAT-001;|
| Experimental: PAT-001 0.2%<br>Part 1: Bilateral comparison. Patients will have two comparable Treatment Areas: PAT-001, 0.2% (e.g., left side) and Vehicle, 0.0% (e.g., right side). This comparison lasts from Weeks 0-8 Part 2: Patients will apply PAT-001, 0.2% to both Treatment Areas. | Drug: PAT-001, 0.2%<br>* PAT-001 is a topical ointment. PAT-001, 0.2% contains 0.2% of active drug.<br>* Other names: PAT-001;|
| Placebo Comparator: Vehicle for PAT-001 0.1% arm<br>Part 1: Bilateral comparison. Patients will have two comparable Treatment Areas: PAT-001, 0.1% (e.g., left side) and Vehicle, 0.0% (e.g., right side). The application of vehicle only lasts from Weeks 0-8. | Drug: Vehicle for PAT-001 0.1%<br>* Vehicle topical ointment contains 0.0% of active drug and is color matched to the active test article, PAT-001 0.1%.<br>* Other names: Vehicle;|
| Placebo Comparator: Vehicle for PAT-001 0.2% arm<br>Part 1: Bilateral comparison. Patients will have two comparable Treatment Areas: PAT-001, 0.2% (e.g., left side) and Vehicle, 0.0% (e.g., right side). The application of vehicle only lasts from Weeks 0-8. | Drug: Vehicle for PAT-001 0.2%<br>* Vehicle topical ointment contains 0.0% of active drug and is color matched to the active test article, PAT-001 0.2%.<br>* Other names: Vehicle;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) in Part 1 of Trial (Weeks 0-8) | The number of participants with AEs will be assessed by the investigator and the incidence (severity and causality) of any local and systemic AEs will be reported. | Day 0 through Day 57 (Weeks 0-8) | 
| Incidence of Local Skin Reactions (LSRs) in Participants Treated With PAT-001 0.1%, 0.2% and/or Vehicle | LSRs including burning/stinging, pain, and pruritus (itch) will be assessed in each Treatment Area using a four-point ordinal scale where 0=none, 1=mild, 2=moderate, and 3=severe (based on the investigator's evaluation of the skin reaction) at each clinic visit to allow a comparison between Treatment Groups and Test Articles. Only LSRs that require medical intervention (e.g., prescription medication) or require withholding or reduction in dosing frequency of the test articles will be documented in this LSR Table. Any LSRs that are not listed here will be recorded as AEs. | Up to Day 84 (Weeks 0-12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Improvement to State of Clear, Almost Clear or Mild in the Investigator's Global Assessment (IGA) Using a Five-point Scale at Day 57 (Part 1) | Overall severity of ichthyosis will be graded using a five-point scale Investigator Global Assessment (IGA) based upon a 5 point scale going from 0=clear., 1=almost clear, 2=mild, 3=moderate to 4=severe. Scoring is based upon investigator evaluation. This is a static morphological scale that refers to a point in time and not a comparison to Baseline. | Up to Day 57 | 
| Number of Participants Achieving an Improvement of at Least 1 Point Score in the Individual Clinical Signs/Symptoms of Erythema, Scaling, Fissuring and Papulation/Lichenification Using a Five-point Scale | Overall severity of erythema (redness), scaling , fissuring (cracks in skin), and papulation/lichenification (skin thickening, increased pigmentation and/or exaggerated skin lines, formation of papules) will be graded using a five-point scale from 0=clear, 1=almost clear, 2=mild, 3=moderate to 4=severe. This is a static morphological scale that refers to a point in time and not a comparison to Baseline. This scoring is based upon investigator discretion. | Up to Day 57 (Weeks 0-8) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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X-linked, lamellar