A double-blind, randomized, placebo-controlled, interventional, multicenter, phase III clinical trial to investigate the safety and efficacy of ABCB5-positive mesenchymal stromal cells (ABCB5+ MSCs) on epidermolysis bullosa (EB)
- Trial ID
- 2022-500266-10-00
- Protocol
- allo-APZ2-EB-III
- Sponsor
- Rheacell GmbH & Co. KG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase III clinical trial is to evaluate the **safety** and **efficacy** of intravenously administered allo-APZ2-OTS in subjects with **Recessive Dystrophic Epidermolysis Bullosa (RDEB)** compared to a placebo. This investigation is clinically significant as RDEB is a severe genetic skin disorder characterized by fragile skin that blisters easily, leading to significant morbidity. The trial also includes a baseline-controlled open-label arm to assess the safety and efficacy of allo-APZ2-OTS in subjects with **Junctional Epidermolysis Bullosa (JEB)** and in RDEB subjects under 1 year of age. The study aims to provide insights into potential therapeutic benefits and safety profiles of allo-APZ2-OTS, which could lead to improved management strategies for these debilitating conditions.
Participants
The clinical trial involves a total of **48 participants** diagnosed with **Recessive Dystrophic Epidermolysis Bullosa (RDEB)** or **Junctional Epidermolysis Bullosa (JEB)**. The study population includes both male and female subjects, ranging from birth onwards, with a confirmed diagnosis through genetic testing or skin biopsy with immunofluorescence mapping. Participants are required to have a minimum body weight of 5 kg and meet specific health criteria, including hematological, hepatic, renal, and pulmonary parameters. The trial population was selected based on these health assessments and the presence of a target wound of 5-50 cm², less than 9 months old, and without signs of acute infection. The study includes vulnerable populations, and all participants or their legal representatives provided informed consent. Women of childbearing potential are required to have a negative pregnancy test and, along with male participants and their partners, must agree to use highly effective contraceptive methods throughout the trial duration.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, interventional, multicenter, phase III study. The primary objective is to evaluate the safety and efficacy of **allo-APZ2-OTS**, a cell suspension for injection, in subjects with **recessive dystrophic epidermolysis bullosa** (RDEB) and **junctional epidermolysis bullosa** (JEB). The trial includes an additional baseline-controlled open-label arm for specific subgroups. The estimated duration of the trial is from January 31, 2023, to April 28, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as genetic testing or skin biopsy results, and specific laboratory values. The trial will include multiple follow-up visits to assess primary and secondary endpoints, such as wound closure and changes in disease activity, until Month 17. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 11 months.
Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the protocol, or if the investigator deems it necessary for safety reasons. The trial will monitor various safety endpoints, including the frequency of adverse events and immunogenicity assessments. The study aims to provide comprehensive data on the therapeutic potential of allo-APZ2-OTS in treating these rare genetic conditions.
Treatment
The clinical trial involves the administration of **allo-APZ2-OTS**, a cell suspension for injection containing **allogeneic skin-derived ABCB5-positive dermal mesenchymal stromal cells**. This investigational product is administered intravenously with a maximum daily dose of 2,000,000 dosage forms and a total maximum dose of 16,000,000 dosage forms over a treatment period of 11 days. The product is classified as a biological substance and is designated as an orphan drug for the treatment of recessive dystrophic epidermolysis bullosa (RDEB).
**Solu-Decortin® H 10 mg** is a solution for injection/infusion containing **prednisolone sodium succinate**. It is administered intravenously with a maximum daily and total dose of 1000 mg over 11 days. This chemical substance is used as an auxiliary treatment in the trial.
**Loratadine 5 mg/5 ml Syrup** is an oral solution containing **loratadine**. It is administered orally with a maximum daily and total dose of 5 mg over 11 days. This chemical substance serves as an auxiliary treatment in the study.
**Neoclarityn 0.5 mg/ml oral solution** contains **desloratadine** and is administered orally. The maximum daily and total dose is 45 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**Tavegil Injektionslösung 2 mg/2 ml** is a solution for injection containing **clemastine fumarate**. It is administered intravenously with a maximum daily and total dose of 2 ml over 11 days. This chemical substance is used as an auxiliary treatment.
**Pipolphen 25 mg/ml oldatos injekció** is a solution for injection containing **promethazine hydrochloride**. It is administered intravenously with a maximum daily and total dose of 100 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**Dibondrin - Ampullen** is a solution for injection containing **diphenhydramine hydrochloride**. It is administered intravenously with a maximum daily and total dose of 400 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**Methylprednisolone 1000 mg powder and solvent for solution for injection/infusion** contains **methylprednisolone**. It is administered intramuscularly with a maximum daily and total dose of 1 g over 11 days. This chemical substance is used as an auxiliary treatment.
**Fexofenadine Hydrochloride 120 mg Film-coated tablets** contain **fexofenadine hydrochloride**. They are administered orally with a maximum daily and total dose of 120 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**Efcortesol Injection** is a solution for injection containing **hydrocortisone sodium phosphate**. It is administered intravenously with a maximum daily and total dose of 200 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**Lorastad 10 mg, tabletten** contain **loratadine**. They are administered orally with a maximum daily and total dose of 10 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**Synopen 20 mg/2 ml otopina za injekciju** is a solution for injection containing **chloropyramine hydrochloride**. It is administered intravenously with a maximum daily and total dose of 0.2 mg/kg over 11 days. This chemical substance is used as an auxiliary treatment.
**Trimeton 10 mg/1 ml soluzione iniettabile** is a solution for injection containing **chlorphenamine maleate**. It is administered intravenously with a maximum daily and total dose of 40 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**Rupatadine 1 mg/ml oral solution** contains **rupatadine**. It is administered orally with a maximum daily and total dose of 10 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**Xyzal 5 mg film-coated tablets** contain **levocetirizine dihydrochloride**. They are administered orally with a maximum daily and total dose of 5 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**POLARAMINE 5 mg/1 ml, solution injectable** is a solution for injection containing **dexchlorpheniramine maleate**. It is administered intravenously with a maximum daily and total dose of 5 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**Rupafin 10 mg Tablets** contain **rupatadine**. They are administered orally with a maximum daily and total dose of 10 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**Cetirizine dihydrochloride 10 mg film-coated tablets** contain **cetirizine dihydrochloride**. They are administered orally with a maximum daily and total dose of 10 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**Neoclarityn 5 mg film-coated tablets** contain **desloratadine**. They are administered orally with a maximum daily and total dose of 5 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**Xyzal 0.5 mg/ml oral solution** contains **levocetirizine dihydrochloride**. It is administered orally with a maximum daily and total dose of 5 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**Zirtek 1 mg/ml oral solution** contains **cetirizine dihydrochloride**. It is administered orally with a maximum daily and total dose of 20 mg over 11 days. This chemical substance is used as an auxiliary treatment.
**Placebo-OTS (cryomedium RGD10)** is used as a placebo in the trial. It does not contain any active substance and serves as a comparator to evaluate the efficacy of the investigational product.
Efficacy
The efficacy of the clinical trial investigating the use of ABCB5-positive mesenchymal stromal cells (ABCB5+ MSCs) for the treatment of **recessive dystrophic epidermolysis bullosa (RDEB)** will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the proportion of subjects with RDEB aged 1 year or older who achieve complete target wound closure at Month 6, with closure confirmed two weeks later. Secondary efficacy endpoints will be evaluated for each study population, including RDEB subjects aged 1 year or older, RDEB subjects younger than 1 year, and subjects with junctional epidermolysis bullosa (JEB). These secondary endpoints include the proportion of subjects achieving complete target wound closure at each post-baseline visit, changes in overall wound burden, duration of target wound closure, time to complete target wound closure from baseline, and changes in pain and itch severity using validated scales such as FPS-R, FLACC, and ItchyQuant. Additionally, changes in overall disease activity and damage will be assessed using the EBDASI scores, and quality of life will be measured using the CDLQI. Serum levels of inflammation markers and the development of new wounds will also be monitored.
Data collection for these endpoints will occur at each post-baseline visit until Month 17, with the main analysis focusing on data obtained until Month 6b. Optional assessments for RDEB subjects include changes in C7 expression, presence of ABCB5+ MSCs, and immune cell presence on skin biopsies. The trial will also monitor safety endpoints, including Anti-Human Leukocyte Antigen (Anti-HLA) antibody levels, potential immune reactions, frequency of adverse events, and overall survival. These assessments will be conducted at specified time points, such as Month 6a and Month 12, and in response to any immune reactions. The trial is designed to provide comprehensive data on the efficacy and safety of the investigational treatment in the specified patient populations.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female subjects from birth with a diagnosis of RDEB or JEB confirmed by genetic testing or by a skin biopsy with immunofluorescence mapping (IFM). A minimal body weight of at least 5 kg is required;
- Subject is eligible to participate in this clinical trial based on general health condition assessed by the following specific lab values: a. Hematology: Absolute neutrophil count > 1000/mm3 and platelet count > 150,000/mcL; b. Hepatic: AST and ALT < 2x the upper limit of normal for age; c. Renal: Creatinine < 2x the upper limit of normal for age; d. Pulmonary: Oxygen saturation > 92% on room air and without supplemental oxygen requirement;
- Subject with a target wound meeting the following criteria: 5-50 cm2, and < 9 months, no signs of acute infection;
- Patient/legal representative understands the nature of the procedure and provide written informed consent/assent prior to any clinical trial procedure;
- Women of childbearing potential must have a negative urine pregnancy test at Visit 1. Women of childbearing potential, male participants, and their partner must be willing to use highly effective contraceptive methods during the course of the entire clinical trial.
Exclusion Criteria
- Signs and/or a history of skin precancerous and cancerous lesions at screening or any current tumor diseases, including squamous cell carcinoma and basal cell carcinoma;
- Known chronic lung disease;
- Clinically significant laboratory values for coagulation and thrombocytes at screening;
- Thromboembolic events of any grade in medical history;
- Immunoreactions of any grade in medical history;
- Any known allergies to components of the IP* or premedication;
- Patient/legal representative anticipated to be unwilling or unable to comply with the requirements of the protocol;
- Pregnant or lactating women;
- Current or previous (within 30 days of screening) treatment with another IP, or participation and/or under follow-up in another interventional clinical trial;
- Previous participation in this clinical trial** (except for screening failures);
- Clinically significant or unstable concurrent disease or other clinical contraindications like an uncontrolled or poorly controlled mental health condition of the subject and/or his/her legal representative that could impact on patient’s safety or interfere with study compliance such as inability to attend scheduled study visits;
- Employees of the sponsor, or employees or relatives of the investigator.
- *IP: Ringer lactate, glucose, DMSO ** Except for subjects enrolled under protocols issued before 2024. Re-screening may only be performed after a thorough benefit/risk assessment performed by the investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 31 Jan 2023 | 5 |
 Croatia | Not Recruiting | 31 Jan 2023 | 7 |
 Denmark | Not Recruiting | 31 Jan 2023 | 7 |
 France | Not Recruiting | 31 Jan 2023 | 12 |
 Germany | Not Yet Recruiting | 31 Jan 2023 | 15 |
 Greece | Not Recruiting | 31 Jan 2023 | 5 |
 Hungary | Not Recruiting | 31 Jan 2023 | 8 |
 Italy | Not Recruiting | 31 Jan 2023 | 20 |
 The Netherlands | Not Recruiting | 31 Jan 2023 | — |
 Poland | Not Recruiting | 31 Jan 2023 | 8 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Xyzal 0.5 mg/ml oral solution | Other | ORAL SOLUTION | ORAL USE | 5 | 11 | PRD435720 |
Neoclarityn 5 mg film-coated tablets | Other | FILM-COATED TABLETS | ORAL USE | 5 | 11 | PRD8926174 |
Efcortesol Injection | Other | INJECTION | INTRAVENOUS | 200 | 11 | PRD2781738 |
Xyzal 5 mg film-coated tablets | Other | FILM-COATED TABLETS | ORAL USE | 5 | 11 | PRD439495 |
Rupafin 10 mg Tablets | Other | TABLETS | ORAL USE | 10 | 11 | PRD330326 |
Solu-Decortin® H 10 mg | Other | SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS | 1000 | 11 | PRD374241 |
Rupatadine 1 mg/ml oral solution | Other | ORAL SOLUTION | ORAL USE | 10 | 11 | PRD9567664 |
Pipolphen 25 mg/ml oldatos injekció | Other | 25 MG/ML | INTRAVENOUS USE | 100 | 11 | PRD2047445 |
Zirtek 1 mg/ml oral solution | Other | ORAL SOLUTION | ORAL USE | 20 | 11 | PRD439896 |
Trimeton 10 mg/1 ml soluzione iniettabile | Other | SOLUZIONE INIETTABILE | INTRAVENOUS USE | 40 | 11 | PRD2984511 |