E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Steroid-refractory chronic graft-versus-host-disease. |
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E.1.1.1 | Medical condition in easily understood language |
A complication of bone marrow transplants in which donor T cells contained in the graft attack the host's tissues.Treatment with corticosteroids has failed to control this attack. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Biological Phenomena [G16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066261 |
E.1.2 | Term | Chronic graft versus host disease |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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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 |
To evaluate the clinical and immunological impact of donor Treg infusion (DTI) in patients with steroid-refractory chronic GVHD
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E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Signed informed consent.
•Grafts from HLA-identical siblings or HLA-matched unrelated donor (1 of 10 HLA-mismatch is allowed).
•≥ 18 years of age.
•Steroid-refractory or steroid-resistant chronic GVHD defined as:
-development of 1 or more new sites of disease while being treated for chronic GVHD,
-progression of existing sites of disease while receiving treatment for chronic GVHD,
-failure to improve despite at least 1 month of standard treatment for chronic GVHD.
•Severe chronic GVHD and contra-indication to the use of steroids.
•GFR > 25 mL/min.
•No alemtuzumab administration in the last 6 years.
•Karnofsky performance score ≥ 70%.
•DLCO > 35% and no need of supplemental continuous oxygen. |
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E.4 | Principal exclusion criteria |
•Prior failure of rapamycine as treatment for chronic GVHD
•Contra-indication to the use of rapamycin.
•HIV seropositivity.
•Fungal infection with radiological progression after treatment
•Other uncontrolled infection.
•Progression of the hematological malignancy.
•Active post-transplant microangiopathy or previous microangiopathy while on rapamycine.
•Uncontrolled hypertriglyceridemia |
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E.5 End points |
E.5.1 | Primary end point(s) |
To assess the safety of a combination of donor Treg infusion and rapamycine administration in patients with steroid-refractory chronic GVHD.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Monitoring throughout the whole trial |
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E.5.2 | Secondary end point(s) |
1.To assess the efficiency of Treg selection with the Clinimacs procedure.
2.To assess the response rate of chronic GVHD (defined using the NIH criteria) to donor Treg infusion + rapamycine.
3.To compare response rate of chronic GVHD in patients given Treg infusion + rapamycine (DTI arm) versus in those given rapamycine without Treg infusion (control arm; vide infra).
4.To compare the incidence of viral, bacterial, fungal and parasitic infection in patients given Treg infusion + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra).
5.To compare overall survival, progression-free survival and relapse incidence in patients given Treg infusion + rapamycine (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra).
6.To assess the impact of 3-4 weeks rapamycine administration on percentage and absolute counts of Treg and conventional T cells.
7.To compare immunological changes in patients given Treg infusion + rapamycine (DTI arm) versus in those given rapamycine without Treg infusion (control arm; vide infra).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-The day after that of the donor's blood sampling.
2-at 1, 2, 3, 6 and 12 mths after rapamycine.
3-The day of inclusion (1ts day of rapamycine).
•3 to 4 wk after rapamycine (but before DTI).
•4-5 wk after rapamycine (control arm).
•3 wk after DTI (DTI arm) or 6-7 wk after rapamycine onset (control arm).
•3, 6 and 12 mth after rapamycine.
4-Monitoring throughout the whole trial
5-Monitoring throughout the whole trial
6-Between week 3 and 4 after rapamycine.
7-The day of inclusion (or the first day of rapamycine).
•3 to 4 wk after rapamycine (but before DTI).
•1 week after DTI (DTI arm) or 4-5 wk after rapamycine (control arm).
•3 wk after DTI (DTI arm) or 6-7 wk after rapamycine (control arm).
•3, 6 and 12 mth after rapamycine. |
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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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | No |
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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•10 patients will be included in the DTI arm which will be stopped when 4 patients experience nonrelapse mortality within 90 days of inclusion or experience GVHD progression within 90 days of inclusion. •Up to 25 patients will be included in the rapamycine arm (control arm). This arm will be closed if ≥ 4/10, ≥8/20 or ≥10/25 patients die of nonrelapse causes the first 90 days and ≥ 4/10, ≥8/20 or ≥10/25 patients experienced chronic GVHD progression within the first 90 days after inclusion.
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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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |