Efficacy and Safety Evaluation of Diacerein 1% Ointment in Generalized Epidermolysis Bullosa Simplex: A Randomized, Double-Blind, Vehicle-Controlled Study

Trial ID: 2023-508818-42-00
Protocol: AC-203-EBS-007
Sponsor: Twi Biotechnology Inc.

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Diseases & Conditions

Epidermolysis bullosa

Objectives

The primary objective of this study is to evaluate the **efficacy** of diacerein 1% ointment after 8 weeks of treatment in adult and pediatric patients (aged 6 months and older) with generalized Epidermolysis Bullosa Simplex (EBS), specifically targeting the severe and intermediate subtypes. This objective is clinically relevant as it aims to determine the therapeutic potential of diacerein in managing the symptoms of EBS, a condition characterized by skin fragility and blistering, thereby potentially improving patient outcomes and quality of life.

Secondary objectives include:

Part A: To assess the **safety** of diacerein 1% ointment in the same patient population after 8 weeks of treatment. This is crucial for understanding the risk-benefit profile of the treatment.
Part B: To evaluate the long-term safety of diacerein 1% ointment in subjects with EBS who have previously enrolled and completed Part A of the study. This objective is important for determining the sustainability and safety of prolonged use of the treatment.

Participants

The clinical trial involves a total of **30 participants** diagnosed with **Generalized Epidermolysis Bullosa Simplex (EBS)**, specifically targeting severe and intermediate subtypes. The study population includes both male and female subjects, with an age range starting from 6 months and older, encompassing both pediatric and adult patients. Participants were selected based on a confirmed genetic diagnosis of autosomal dominant mutations in the KRT5 or KRT14 gene, with a requirement of having at least 5% body surface area affected by EBS lesions, excluding hands and feet. The trial includes a vulnerable population, and all participants are required to comply with study protocols, including the use of study medication and reporting of any other medications used. Female participants of childbearing potential must adhere to effective contraception methods and have a negative pregnancy test prior to randomization. The trial aims to evaluate the efficacy of diacerein 1% ointment over an 8-week treatment period.

Plans and Procedures

The clinical trial is designed as an **international, multicenter, randomized, double-blind, parallel group, vehicle-controlled, Phase 2/3 study** with an open-label extension. The primary objective is to evaluate the efficacy of **diacerein 1% ointment** in treating **generalized epidermolysis bullosa simplex (EBS)** over an 8-week period. The trial will involve adult and pediatric patients aged 6 months and older, with severe and intermediate subtypes of EBS. The study is expected to commence recruitment on April 30, 2024, and conclude by March 31, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, genetic diagnosis, and lesion characteristics. Following the screening, eligible participants will be randomized at Visit 2 (Day 1/Baseline A) to receive either the active treatment or placebo. The primary endpoint is the proportion of patients achieving treatment success, defined as a score of 0 or 1 on the Investigator's Global Assessment (IGA) with at least a 2-point reduction from baseline to Week 8 (Visit 5/End of Treatment).

Secondary endpoints include changes in the percentage of body surface area (BSA) affected by EBS lesions, pain and pruritus intensity scores, quality of life, and skin activity scores. Safety endpoints will monitor adverse events, clinical laboratory results, vital signs, and ECG parameters. Participants will be required to attend follow-up visits throughout the study to assess these endpoints and ensure compliance with the study protocol.

The expected length of participant involvement is approximately 8 weeks, with conditions for early termination including non-compliance with study procedures, withdrawal of consent, or adverse events that necessitate discontinuation. Participants and caregivers must agree to adhere to study medication application instructions and report all concurrent medications. Female participants of childbearing potential must use effective contraception and have a negative pregnancy test prior to randomization.

Treatment

The clinical trial involves the use of **AC-203**, an experimental medication formulated as an ointment containing the active substance **diacerein**. The ointment is intended for **topical application** and is administered to participants with generalized Epidermolysis Bullosa Simplex (EBS). The maximum daily dose is 25 grams, with a total maximum dose of 5600 grams over a treatment period of up to 32 weeks. The ointment is produced by TWI Biotechnology, Inc., and is identified by the sponsor product code SUB07060MIG. The trial aims to evaluate the efficacy and safety of this formulation in both adult and pediatric patients aged 6 months and older.

In addition to the experimental treatment, a **vehicle ointment** is used as a placebo control. This placebo is designed to match the AC-203 ointment in appearance and application method but does not contain the active substance diacerein. The vehicle ointment is also applied topically, serving as a comparator to assess the true efficacy of the AC-203 ointment. The use of a placebo control is essential in maintaining the double-blind nature of the study, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thus minimizing bias in the evaluation of outcomes.

Efficacy

The efficacy of Diacerein 1% ointment in the treatment of **Generalized Epidermolysis Bullosa Simplex (EBS)** will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the proportion of patients achieving treatment success on the Investigator's Global Assessment (IGA) of the Treatment Area. Treatment success is defined as a score of 0 or 1, with at least a 2-point reduction from Baseline A (Visit 2/Day 1) to Week 8 (Visit 5/End of Treatment).

Secondary efficacy endpoints include changes from Baseline A to Week 8 in several parameters: the percentage of Body Surface Area (% BSA) affected by EBS lesions, pain intensity scores using the Numeric Rating Scale, pruritus intensity scores also using the Numeric Rating Scale, Quality of Life in Epidermolysis Bullosa (QOLEB) scores, and Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) scores for skin activity. These measurements will be collected and analyzed at specified timepoints to evaluate the treatment's impact on the disease's clinical manifestations.

Inclusion and Exclusion 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
Patient with ≥ 3% BSA of EBS lesions excluding palms and soles 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.

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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)
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 other than steroids, 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 steroids on the EBS lesions within 2 weeks or systemic steroids within 4 weeks, prior to Visit 2 (Day 1/Baseline A). (Note: inhaled and ophthalmic products containing steroids are allowed.)
Patient has been treated with: (a) an approved biologic anti-inflammatory therapy (such as monoclonal antibodies that target to modulate the immune responses) and (b) other immunosuppressive/immunomodulatory therapies or chemotherapy 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.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Recruiting	30 Apr 2024	10
Belgium	Recruiting	30 Apr 2024	4
France	Not Recruiting	30 Apr 2024	3
Greece	Recruiting	30 Apr 2024	4
Ireland	Recruiting	30 Apr 2024	3
Italy	Recruiting	30 Apr 2024	30
Poland	Recruiting	30 Apr 2024	10
Spain	Recruiting	30 Apr 2024	8