E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Graft-versus-Host Disease (GVHD) not responding on regular first line therapy of 2 mg/kg corticosteroids daily. |
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E.1.1.1 | Medical condition in easily understood language |
Acute Graft-versus-Host Disease that does not adequately respond on the regular treatment with corticosteroids. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10068908 |
E.1.2 | Term | AGVHD |
E.1.2 | System Organ Class | 100000004870 |
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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 |
To determine the efficacy with which T-Guard, four weeks after the first infusion (study Day 28) induces an objective clinical response in patients with steroid-resistant acute GVHD. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives:
- To evaluate the overall safety and efficacy of T-Guard during the first 6 months after initiation of therapy.
- To determine the pharmacokinetic profile of T-Guard.
- To determine the immunogenicity of T-Guard
Exploratory objectives:
- To study the specificity and kinetics with which T-Guard depletes T cells and NK cells and ‘resets’ the T-cell compartment.
- To evaluate diagnostic and predictive GHVD biomarkers relative to treatment outcomes.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patients suffering from acute GVHD which is staged as Grade II-IV (Appendix 1) according to the modified Glucksberg Criteria and progressing after 3 days, or not improving after 7 days, of methylprednisolone at a dose of 2 mg/kg per day.
- Age ≥ 18 years.
- Patients or an impartial witness (in case the patient is capable to provide verbal consent but not capable to sign the informed consent) should have given written informed consent.
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E.4 | Principal exclusion criteria |
- Patients receiving concomitant investigational therapeutics for acute GVHD, including investigational agents used for GVHD prophylaxis, at the time of enrollment.
- Patients with signs or symptoms suggestive of chronic GVHD.
- Patients requiring mechanical ventilation, requiring vasopressor support, requiring hemodialysis, having serum creatinine > 266 μmol/l (> 3mg/dl), or having a serum albumin level of 15 g/l or less.
- Patients having uncontrolled infections.
- Patients with current signs or symptoms of active intrapulmonary disease.
- Patients with known hypersensitivity to any of the components of the study drug (murine mAb or RTA).
- Female patients who are pregnant, breast feeding, or, if sexually active, unwilling to use effective birth control for the duration of the study.
- Male patients who are, if sexually active, unwilling to use effective birth control for 30 days after the last infusion.
- Patients participating in a clinical trial with another investigational medicinal product within 30 days prior to providing informed consent.
- Patients whose decision to participate might be unduly influenced by perceived expectation of gain or harm by participation, such as patients in detention due to official or legal order.
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E.5 End points |
E.5.1 | Primary end point(s) |
The acute GVHD response rate at 4 weeks after the first infusion of T-Guard (Day 28), being defined as the fraction of patients showing a complete or partial response (CR plus PR). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Four weeks after initiation of treatment, study Day 28. |
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E.5.2 | Secondary end point(s) |
SECONDARY ENDPOINTS
- The safety and tolerability of T-Guard, as assessed by evaluating DLT´s, adverse and serious adverse events reporting during 6 months after initiation of treatment.
- The proportion of patients receiving a very good partial response (VGPR) of their acute GVHD at 4 weeks after the first infusion (Day 28).
- The acute GVHD relapse rate during 6 months after initiation of treatment.
- The incidence of chronic GVHD during 6 months after initiation of treatment.
- The overall survival and progression-free survival during 6 months after initiation of treatment.
- The pharmacokinetic profile of T-Guard as determined on blood samples drawn during the administration period until 2 days after the last infusion.
- The occurrence and extent of humoral responses against T-Guard (anti-drug-antibodies, ADA) as determined on blood samples drawn at pre-treatment and at 1, 3 and 6 months after the first infusion.
- The occurrence of treatment-induced cytokine release, as determined on blood samples drawn at t = 0 (pre-dose), 1 and 4 hours after starting of each infusion.
EXPLORATORY ENDPOINTS
- The kinetics and specificity of treatment-induced T cell and NK cell depletion as measured on blood samples drawn during the administration period until 2 days after the last dose, and then weekly until 8 weeks, and than at 3 and 6 months after the first infusion.
- The composition and evolution of the T-, B- and NK-cell compartments at pre-treatment and at 4 weeks, 3 and 6 months after the first infusion.
- The composition and evolution of the T-cell receptor (TCR) Vbeta repertoire at pre-treatment and at 4 weeks, 3 and 6 months after the first infusion.
- The identification and evolution of host-reactive T-cell clones at pre-treatment and at 4 weeks, 3 and 6 months after the first infusion.
- The measurement of diagnostic and predictive GVHD biomarkers relative to treatment outcomes, including citrulline, CRP, elafin, IL-8, TNFR1, IL-2Ralfa, HGF, and Reg3alfa as determined on blood samples drawn at at pre-treatment, 2 weeks, and at 1, 3 and 6 months after the first infusion. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The time points are specified under the description of the respective end points at E.5.2 |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Combined Phase Ib/IIa study |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |