E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Steroid refractory gastro-intestinal acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation |
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E.1.1.1 | Medical condition in easily understood language |
Medical complication not treatable with steroids following the receipt of transplanted tissue from a genetically different person. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Evaluation of the gastrointestinal response (Complete Response (CR) and Very Good Partial Response (VGPR)) at D28 of steroid refractory (SR) gastro-intestinal (GI) acute graft-versus-host disease (aGVHD) patients treated with allogeneic Fecal Microbiota Transfer (FMT). |
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E.2.2 | Secondary objectives of the trial |
• Evaluation of overall aGVHD response (CR and VGPR)
• Evaluation of overall and best response rates (CR, VGPR and Partial Response (PR)) for GI and overall aGVHD
• Evaluation of the durable overall response rate
• Evaluation of the duration of response
• Evaluation of safety within 24 hours after FMT as well as overall safety.
• Evaluation of feasibility of allogeneic FMT procedure and acceptance by the patient
• Evaluation of clinical safety and performance of MaaT Pharma’s medical device
• Evaluation of the number of patients receiving the full treatment sequence (3 FMTs)
• Evaluation of FMT activity and/or impact on:
- Steroid-free, progression-free survival, relapse of the initial disease, GVHD-free survival, GVHD and relapse-free survival, overall survival 0
- Infectious disorders
- Multi-Drug Resistant Bacteria (MDRB) carriage
- Clinical symptoms of skin/liver aGVHD associated with SR-GI-aGVHD
- Stool evaluation (volume of diarrhea, Bristol stool chart)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients who develop a first episode of Grade III or IV aGVHD (= gastrointestinal Stages 2 to 4) with gut predominance if other organs involved (Przepiorka D, 1995), resistant to a first-line therapy with steroids,
2. Age ≥ 18 years old
3. Allo-HSCT with any type of donor, stem cell source, GVHD prophylaxis or conditioning regimen
4. Patients able to have a minimum of 12 hours discontinuation of systemic antibiotics in order to perform the allogeneic FMT (for patients who require antibiotics, using antibiotics that have limited impact on the gut microbiota should be considered in priority. The complete list of recommended and not recommended antibiotics is in Appendix 6)
5. Signature of informed and written consent by the subject or by the subject’s legally acceptable representative for patients under guardianship or trusteeship
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E.4 | Principal exclusion criteria |
1. Grade IV hyper-acute GVHD as defined by the MD Anderson’s criteria (Saliba RM, 2007)
2. Overlap chronic GVHD as defined by the NIH Consensus Criteria (Jagasia MH, 2015)
3. Acute GVHD after donor lymphocytes infusion (DLI)
4. Relapsed/persistent malignancy requiring rapid immune suppression withdrawal
5. Active uncontrolled infection according to the attending physician
6. Current or past veno-occlusive disease or other uncontrolled complication unless otherwise agreed in writing by the sponsor.
7. Systemic drugs other than corticosteroids for GvHD treatment, including extra-corporeal photopheresis (ECP), unless treatments began before or concomitantly with corticosteroid treatment. New therapies after corticosteroids are a definitive non-inclusion criterium.
Drugs for GVHD prevention (e.g., calcineurin inhibitors, Mycophenolate mofetil (MMF), ECP…), are allowed as long as treatment began before or concomitantly with the corticosteroid treatment.
8. Absolute neutrophil count < 0.5 x 109 /L
9. Absolute platelet count < 10 000
10. Patient with negative IgG EBV serology
11. Current or past evidence of toxic megacolon, bowel obstruction or gastrointestinal perforation on abdominal X-ray
12. Known allergy or intolerance to trehalose or maltodextrin
13. Vulnerable patients such as: minors, persons deprived of liberty, persons in Intensive Care Unit unable to provide informed consent prior to the intervention
14. Pregnancy: positive urinary or blood test in females of childbearing potential; lactation; absence of effective contraceptive method for females of childbearing potential throughout the entire duration of the study
15. Other ongoing interventional protocol that might interfere with the current study’s primary endpoint.
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy of FMT in the treatment of SR-GI-aGVHD at D28 post inclusion (V4):
Number and proportion of patients achieving GI aGVHD response by D28, defined as Complete Response or Very Good Partial Response.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1) Efficacy of FMT in the treatment of overall aGVHD at D28 post inclusion (V4)
2) Evaluation of overall and best response rates (CR, VGPR and Partial Response (PR)) for both GI and overall aGVHD
3) Evaluation of the durable overall response rate
4) Evaluation of the duration of response
5) Safety of FMT in patients with SR-GI-aGVHD
6) Feasibility of allogeneic FMT procedure and acceptability by the Patient
Number of patients receiving 3 FMTs
8) Clinical safety and performance of MaaT Pharma’s medical device (Directive 9342 CE, med dev 2.7.1)
9) Evaluation of FMT activity and/or impact on steroid-free, progression-free survival, relapse of the initial disease, GVHD-free survival, GVHD and relapse-free survival and overall survival
10) Evaluation of FMT activity and/or impact on infectious disorders
11) Evaluation of FMT activity and/or impact on MDRB carriage
12) Evaluation of FMT activity and/or impact on clinical symptoms of skin/liver aGVHD associated with SR-GI-aGVHD
13) Stool evaluation (volume of diarrhea, Bristol stool chart)
14) Evaluation of microbiota reconstitution
15) Chronic GVHD incidence and severity
16) Assessment of a microbiota signature (Exploratory)
17) Impact of FMT on the immune system (Exploratory) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
D28 post inclusion (V4), M3 (V5) M6 (V6) and M12 (V7) |
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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 | No |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 24 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 24 |
E.8.9.2 | In all countries concerned by the trial days | 0 |