Clinical trial NCT06073132: 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)
Official title: 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) [EBShield Study]
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Generalized Epidermolysis Bullosa Simplex
Keywords: Epidermolysis Bullosa Simplex
EBS
Lead sponsor: TWi Biotechnology, Inc.
Sponsor class: INDUSTRY
First posted: 2023-10-10
Enrollment: 80
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Patient is at least 6 months old at Visit 2 (Day 1/Baseline A). (Note: Enrollment of patients under 4 in the EU is pending approval of the safety review for 10 patients aged 4-12.)
2. 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.
3. Patient with ≥ 3% BSA of EBS lesions excluding palms and soles at Visit 2 (Day 1/Baseline A).
4. Patient's EBS lesions within the Treatment Area have an IGA score of ≥3 at Visit 2 (Day 1/Baseline A).
5. Patient/caregiver agrees to follow study medication application instructions.
6. 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.
7. Patient (and caregiver/legal guardian) is willing and able to comply with all study visits and all the protocol requirements, including completing questionnaires.
8. Patient (and caregiver/legal guardian) is able to provide written informed consent; assent based on age.
9. Female patient of childbearing potential must have a negative pregnancy test prior to randomization.
10. 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:

1. 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.
2. 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.
3. Patient has used any diacerein-containing product within 6 months prior to Visit 2 (Day 1/Baseline A).
4. 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).
5. 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.
6. 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).
7. 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.
8. 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.)
9. 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).
10. 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).
11. Patient has a history of allergy or hypersensitivity to any component of study medications, including diacerein or rhein.
12. Patient is pregnant or breastfeeding/lactating.
13. Patient has a planned or anticipated major surgical procedure or other activity that would interfere with their ability to comply with protocol requirements.

Primary outcomes:
measure: 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
timeFrame: from Baseline A (Visit 2/Day 1) to Week 8 (Visit 5/EOT)
Secondary outcomes:
measure: Change in % BSA of EBS lesions in the Treatment Area
timeFrame: from Baseline A (Visit 2/Day 1) to Week 8 (Visit 5/EOT)
measure: Change in pain intensity score
timeFrame: Baseline A (Visit 2/Day 1) to Week 8 (Visit 5/EOT)
measure: Change in pruritus intensity score
timeFrame: from Baseline A (Visit 2/Day 1) to Week 8 (Visit 5/EOT)
measure: Change in EBDASI score (skin activity)
timeFrame: from Baseline A (Visit 2/Day 1) to Week 8 (Visit 5/EOT).
measure: Change in the QOLEB score
timeFrame: from Baseline A (Visit 2/Day 1) to Week 8 (Visit 5/EOT)
Other outcomes:
Locations:
city: Rancho Santa Margarita
country: United States
facility: Mission dermatology Center
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Miami
country: United States
facility: Pediatric Center of Excellence (PCE) - Miami Pediatric Endocrinology, LLC
state: Florida
city: Chicago
country: United States
facility: Northwestern University - Lurie Childrens's Hospital
state: Illinois
city: Stony Brook
country: United States
facility: Stony Brook Dermatology
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Childrens Hospital
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: San Antonio
country: United States
facility: Texas Dermatology and Laser Specialists
state: Texas
city: Kogarah
country: Australia
facility: Premier Specialists
city: Randwick
country: Australia
facility: Sydney Children's Hospital
city: Salzburg
country: Austria
facility: Universitaetsklinik fuer Dermatologie und Allergologie
city: Leuven
country: Belgium
facility: UZ Leuven
city: Paris
country: France
facility: Hopital Necker-Enfants Malades
city: Thessaloniki
country: Greece
facility: Hospital of Skin and Venereal Diseases of Thessaloniki
city: Muddenahalli
country: India
facility: Sri Madhusudan Sai Institute of Medical Science
state: Karnataka
city: Chandigarh
country: India
facility: Postgraduate Institute of Medical Education and Research (PGIMER)
city: Dublin
country: Ireland
facility: Children's Health Ireland
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Bologna
country: Italy
facility: IRCCS, AOUBO, Policlinico Sant'Orsola
city: Milan
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano
city: Modena
country: Italy
facility: Università degli Studi di Modena e Reggio Emilia (UNIMORE)
city: Rome
country: Italy
facility: Istituto Dermopatico dell'Immacolata (IDI) - Istituto di
city: Rome
country: Italy
facility: UOS "Centro delle Dermatosi Croniche Complesse e Genodermatosi" UOC Dermatologia
city: Seoul
country: Korea, Republic of
facility: Gangnam Severane Hospital
city: Kuala Lumpur
country: Malaysia
facility: Hospital Tunku Azizah (Hospital Wanita Dan Kanak-kanak Kuala Lumpur)
city: Iloilo
country: Philippines
facility: Iloilo Doctors Hospital
city: Mandaluyong
country: Philippines
facility: Health Cube Medical Clinics
city: Muntinlupa
country: Philippines
facility: Asian Hospital
city: Warsaw
country: Poland
facility: OT.CO Clinic Osipowicz & Turkowski
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Abu Dhabi
country: United Arab Emirates
facility: Sheikh Khalifa Medical City (SKMC)
city: London
country: United Kingdom
facility: Great Ormond Street Hospital (GOSH) for Children NHS Foundation Trust - Somers Clinical Research Facility (CRF)
city: Solihull
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust (UHB)
Study officials:
References: