An International, Multicenter, Randomized, Double-Blind, Parallel Group, Vehicle-Controlled, Phase 2/3 Study With Open-Label Extension Evaluating the Efficacy and Safety of Diacerein 1% Ointment for the Treatment of Generalized Epidermolysis Bullosa Simplex (EBS)

Study Overview
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Brief Summary
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The proposed Phase 2/3 trial with double-blind and open-label extension phases is an international, multicenter study designed to assess the efficacy and safety of diacerein 1% ointment in patients with generalized EBS.

Detailed Description
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Epidermolysis bullosa simplex (EBS) is a genetic skin disorder characterized by skin fragility and recurrent blister formation, primarily caused by mutations in keratins 5 and 14. EBS has 3 common subtypes based on clinical severity and manifestations: localized EBS, intermediate EBS and severe EBS. Severe EBS and intermediate EBS collectively are also known as generalized EBS due to widespread blistering. Disruption of the keratin 5/14 filament network in basal keratinocytes is a key factor in EBS pathogenesis, compromising skin integrity. The severity of EBS is linked to the extent of keratin mutations disrupting this network, particularly resulting in keratin aggregates in severe cases. Recent studies suggest that mutated keratin proteins can trigger inflammation, exacerbating EBS. Elevated proinflammatory cytokines, like IL-1β and IL-6, are observed in EBS patients, and IFN-γ may mediate inflammation, promoting keratin aggregations. As a result, targeting inflammation is considered a potential therapeutic approach in EBS. AC-203 (diacerein 1% ointment) is a topical formulation of diacerein, well-known for its ability to inhibit IL-1β and other proinflammatory cytokines. Moreover, diacerein and its active metabolite, rhein, have demonstrated ability in reducing keratin aggregates in keratinocytes derived from severe EBS. Taken together, with its anti-inflammatory property and ability to diminish keratin aggregation, AC-203 shows promise in reducing the clinical severity of EBS.

Official Title
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An International, Multicenter, Randomized, Double-Blind, Parallel Group, Vehicle-Controlled, Phase 2/3 Study With Open-Label Extension Evaluating the Efficacy and Safety of Diacerein 1% Ointment for the Treatment of Generalized Epidermolysis Bullosa Simplex (EBS)

Conditions
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Generalized Epidermolysis Bullosa Simplex

Intervention / Treatment
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* Drug: AC-203
* Drug: Vehicle


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is at least 6 months old at Visit 2 (Day 1/Baseline A). Patients has been clinically diagnosed with severe EBS or intermediate EBS, confirmed by documented genetic diagnosis to have autosomal dominant mutations in KRT5 or KRT14 gene. Patients with ≥ 5% BSA of EBS lesions excluding hands and feet at Visit 2 (Day 1/Baseline A). Patient's EBS lesions within the Treatment Area have an IGA score of ≥3 at Visit 2 (Day 1/Baseline A). Patient/caregiver agrees to follow study medication application instructions. Patient (and caregiver/legal guardian) agrees to report use of all prescription and over-the-counter medications, including topical therapies applied to the body, e.g., medical cleansers, bleach cleansers, bleach baths, topical antiseptics, topical disinfectants, etc. for the duration of the study. Patient (and caregiver/legal guardian) is willing and able to comply with all study visits and all the protocol requirements, including completing questionnaires. Patient (and caregiver/legal guardian) is able to provide written informed consent; assent based on age. Female patient of childbearing potential must have a negative pregnancy test prior to randomization. Female patient of childbearing potential is willing to practice highly effective contraception (i.e., pregnancy prevention method with a failure rate of < 1% per year) from Screening throughout the end of the study. Exclusion Criteria: Patient has a clinically significant skin disease other than EBS (e.g., psoriasis, atopic dermatitis, eczema, sun damage, etc.), or a vascular disorder associated with cutaneous erosions/ulcerations, that may confound assessments of efficacy or safety. Patient has a clinically significant underlying medical condition, psychiatric condition (such as major depressive or psychotic disorder, severe intellectual disability, or alcohol or drug use disorder), or requires concomitant medication that based on the investigator's judgement may impair evaluation of the Treatment Area or exposes the patient to an unacceptable risk by study participation. Patient has used any diacerein-containing product within 6 months prior to Visit 2 (Day 1/Baseline A). Patient has had a cutaneous infection in the Treatment Area or use systemic antibiotics within 7 days prior to Visit 2 (Day 1/Baseline A) and prior to Visit 7 (Week 16/Baseline B). Patient has uncontrolled diabetes mellitus (HbA1c ≥ 6.5%), hepatic enzyme abnormalities (alanine aminotransferase or aspartate aminotransferase >2.5 the upper limit of normal (ULN), or total bilirubin >2.0x ULN), or renal abnormalities (estimated glomerular filtration rate [eGFR]< 30 ml/min/1.73 m2) during the Screening period. Patient has a current malignancy, or a history of treatment for a malignancy within 5 years (with the exception of treated non-melanoma cutaneous malignancy e.g., surgically resected with clear margins) prior to Visit 2 (Day 1/Baseline A). Patient is treated with protocol-excluded topical therapies within 2 weeks prior to Visit 2 (Day 1/Baseline A) that might influence the assessment of the Treatment Area throughout the study period. Patient has been treated with topical or systemic corticosteroids within 4 weeks and with other immunosuppressive/immunomodulatory therapies or chemotherapy within 8 weeks prior to Visit 2 (Day 1/Baseline A) and prior to Visit 7 (Week 16/Baseline B). Patient has been treated with an approved or investigational biologic anti-inflammatory therapy (such as monoclonal antibodies that target to modulate the immune responses) within 8 weeks prior to Visit 2 (Day 1/Baseline A). Patient has been treated with any investigational drug or device within 30 days or 5 half-lives, whichever is longer, prior to Visit 2 (Day 1/Baseline A). Patient has a history of allergy or hypersensitivity to any component of study medications, including diacerein or rhein. Patient is pregnant or breastfeeding/lactating. Patient has a planned or anticipated major surgical procedure or other activity that would interfere with their ability to comply with protocol requirements.

Ages Eligible for Study
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Minimum Age: 6 Months

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: Part A AC-203<br>Double-blind, AC-203 Diacerein 1% ointment, QD | Drug: AC-203<br>* The investigational product is formulated as 1% topical ointment<br>|
| Placebo Comparator: Part A Vehicle ointment<br>Double-blind, Vehicle ointment, QD | Drug: Vehicle<br>* Vehicle-only control study medication is the same formulation as investigational product without active ingredient<br>|
| Experimental: Part B AC-203<br>Open-label extension phase, AC-203 Diacerein 1% ointment, QD | Drug: AC-203<br>* The investigational product is formulated as 1% topical ointment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients achieving treatment success on the IGA of the Treatment Area, in which treatment success is defined as a score of 0 or 1 with at least a 2-point reduction | The static IGA is the investigator's visual clinical assessment of the average overall intensity of lesions in the designated Treatment Area at a particular time point. EBS-IGA is a 5-point scale is a 5-point scale (clear=0; almost clear=1; mild=2; moderate=3; severe=4) | from Baseline A (Visit 2/Day 1) to Week 8 (Visit 5/EOT) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in % BSA of EBS lesions in the Treatment Area | The Body Surface Area (BSA) of the Assessment Area will be collected for all lesions included within the Treatment Area using the palmar method | from Baseline A (Visit 2/Day 1) to Week 8 (Visit 5/EOT) | 
| Change in pain intensity score (Numeric Rating Scale for pain) | NRS (Numerical Rating Scale) is a numerical scale that measures the intensity of pain.Scale ranges from 0 to 10, where 0 is no pain and 10 being maximum/ worst imaginable pain. | Baseline A (Visit 2/Day 1) to Week 8 (Visit 5/EOT) | 
| Change in pruritus intensity score (Numeric Rating Scale for pruritus) | NRS (Numerical Rating Scale) is a numerical scale that measures the intensity of pruritus, with 10 being the greatest intensity. 0 is no itch and 10 being maximum// worst imaginable itch. | from Baseline A (Visit 2/Day 1) to Week 8 (Visit 5/EOT) | 
| Change in the QOLEB score | The Life Epidermolysis Bullosa (QOLEB) questionnaire is a valid and reliable, EB-specific QOL measurement tool, for the quantification of QOL in patients with various subtypes of EB, including EBS. It consists of 17 questions with four response choices from not at all to constant | from Baseline A (Visit 2/Day 1) to Week 8 (Visit 5/EOT) | 
| Change in EBDASI score (skin activity) | The EBDASI is a valid and reliable EB-specific outcome measurement tool to assess the overall extent of disease activity and damage in patients with various subtypes of EB, including EBS. Section I (skin), the severity of disease, including erosion/blisters/crusting etc., will be measured at 12 different skin sites. | from Baseline A (Visit 2/Day 1) to Week 8 (Visit 5/EOT). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epidermolysis Bullosa Simplex, EBS