E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The source population consists of patients referred to or within the UMC Groningen because they have diagnosed clinically and genetically severe generalized RDEB. |
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E.1.1.1 | Medical condition in easily understood language |
Epidermolysis Bullosa is a genetic skin disease characterized by blistering and chronic wounds of the skin and mucous membranes. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1) To investigate the safety of unrelated cord blood transplantation with additional mesenchymal stromal cell co-infusion, preceeded by reduced toxicity conditioning in patients with severe generalized dystrophic epidermolysis bullosa.
2) To assess clinical improvement of skin with regards to wound healing and blister formation. To study the biology of engraftment of hematopoietic & non-hematopoietic stem cells in skin on a molecular basis with a variety of laboratory techniques. Focus will be on expression of C7 and anchoring fibrils at the dermal-epidermal junction for RDEB-sev-gen before and after transplantation.
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E.2.2 | Secondary objectives of the trial |
1) Sustained full cord blood donor chimerism.
2) Toxicity: acute-GvHD, chronic-GvHD prevention with standard chemotherapy prophylaxis
3) To investigate whether infusion of a single cord blood unit with additional mesenchymal stromal cell co-infusion preceded by the standard “reduced toxicity” conditioning regimen (UMC Utrecht protocol for non malignant disease) will ameliorate the blistering phenotype clinically seen in patients with severe generalized recessive dystrophic epidermolysis bullosa (RDEB-sev-gen).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Diagnosed recessive dystrophic EB, severe generalized type (complete loss of functional type VII collagen by immunofluorescence microscopy and confirmed by molecular analysis).
2) having a single matching (≥ 5/6) umbilical CB unit available with sufficient cell count total NC count > 3 * E7/kg
3) Lansky / Karnofsky > 40
4) Age <18 *( *= Karnofs364 days)
5) Signed Informed Consent
6) Approval by International Expert Advisory Panel (Annex 7) & UMCU kernteam-HCT
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E.4 | Principal exclusion criteria |
1) Creatinine clearance < 40 ml/min
2) Cardiac dysfunction (SF < 30%) (Ejection fraction < 45%), unstable angina, or unstable cardiac arrhythmias
3) Pulmonary function test (for those who can do: age dependent) VC, FEV1 and/ or DOC< 50%
4) Subjects with medical history of evidence of malignancy, including cutaneous squamous cell carcinoma
5) Patients with positive auto-antibodies to type VII collagen Determined with blood sample and salt split skin test (Immunodermatology lab UMCG)
6) Allergy to any of the known constituents found in the investigational products (reduced toxicity chemotherapy drugs, CB and MSC)
7) HIV seropositive infection
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety:
The primary efficacy in this Phase II trial will be based on the safety of the administration of the IMPs in this disease population measured according to Transplantation related mortality (Death associated with the procedure: <40%) at day+100
Biology:
• Clinical improvement of wound healing and shorter time to blister formation
• Punch biopsies: Assessment of protein expression at the dermal-epidermal junction using immunofluorescence (Antigen mapping): Collagen VII deposition at various time points (prior to transplantation, D60, 180, 240, 365, and 730) 6 times during course of the trial, 2 biopsies each time
• Quantitative analysis of the donor cells dermal chimerism (Days: see above, same biopsy is used). Fluorescence in-situ hybridization (FISH)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary efficacy in this Phase II trial will be based on the safety of the administration of the 3 IMPs (reduced intensity conditioning, cord blood transplantation and mesenchymal stromal cells) in this disease population measured according to Non-Relapse mortality (Death associated with the procedure). This will be measured at the classical TRM endpoint for allogeneic stem cell transplantation at day+100.
Biology:
Clinical improvement of wound healing and shorter time to blister formation
Assessment of protein expression at the dermal-epidermal junction: Collagen VII deposition at the DEJ at various time points (D60, 180, 240, 365 and 730)
Quantitative analysis of the donor cells dermal chimerism (Days: see above)
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E.5.2 | Secondary end point(s) |
• Disease specific outcomes: Clinical blister assessment: Suction Blister Time (Electronic Diversities. U.S.A) & Skin Rub Test (Kiritsi et al, 2013 personal communication)
• Acute GVHD (Grade II-IV: Gluckberg Criteria)
• Engraftment: Neutrophils > 500K/uL for 3 consecutive days and Platelet (day 180 > 50 K) engraftment.
• Loss of CB chimerism (<25%) at 6 mths post HSCT
• Event Free Survival (>6 mths follow up). Event defined as: death, graft-failure (<25% total donor chimerism) or relapse.
• Overall Survival
• Chronic GVHD: limited and extensive (Shulman Criteria)
• VOD (Seattle Criteria)
• Mucositis ≥ CTC grade 3
• ISCOREB: Disease specific severity score and quality of life assessment
• Antibody formation (Col7) Blood sample during routine control is used
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Protein expression/skin chimerism assessment: (prior to transplantation, D60, D180, D240, D365, and D730)
Quality of Life/Disease Specific Severity Score: (prior to transplantation, D60, D180, D240, D365 and D730)
Clinical Blister testing (Suction & Rub Test): Prior to transplantation, D180, D365 and D730)
Phenotype improvement: (prior to transplantation, D0, D30, D60, D120, D180, D240, D365, and D730)
Hematologic assessment will be done during admission and by regular control visits |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |