| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Steroid refractory Acute Graft versus host Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Steroid refractory Acute Graft versus host Disease |
|
| 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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066260 |
| E.1.2 | Term | Acute graft versus host disease |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| 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 |
| The primary objective of this trial is to demonstrate the superiority of MC0518 compared to the first used Best Available Therapy (BAT) with respect to ORR in adult and adolescent subjects with SR aGvHD at Visit Day 28. |
| Démontrer la supériorité du MC0518 par rapport au meilleur traitement disponible (MTD) utilisé en première intention, en termes de taux de réponse global (TRG) chez des adultes et des adolescents présentant la forme aiguë de la maladie du greffon contre l'hôte réfractaire aux stéroïdes (GvH aiguë RS) lors de la Visite du Jour 28 |
|
| E.2.2 | Secondary objectives of the trial |
- Demonstrate the superiority of MC0518 compared with the first used BAT with respect to freedom from treatment failure (FFTF) as defined by the absence of death, malignancy relapse or progression, or addition or change to any further systemic aGvHD immunosuppressive therapy within 6 months of the intervention from the date of randomisation up to the date of the event and before the diagnosis of chronic graft versus host disease (cGvHD)
- Demonstrate the superiority of MC0518 compared with the first used BAT with respect to overall survival (OS) until Visit Month 24
- Compare the efficacy of MC0518 and BAT in further secondary long-term efficacy endpoints and response to treatment
- Investigate the safety of MC0518
- Compare health related quality of life (HRQoL) when treated with MC0518 compared with BAT
|
Démontrer la supériorité du MC0518 par rapport au meilleur traitement disponible (MTD) administré en première intention en termes d'absence d'échec thérapeutique (AET) définie par l'absence de décès, de rechute ou de progression maligne, ou encore d'ajout ou de modification de tout autre traitement immunosuppresseur systémique contre la GvH aiguë dans les 6 mois suivant la participation à l’étude, de la date de la randomisation jusqu’à la date de l'événement, et avant le diagnostic de maladie chronique du greffon contre l’hôte (GvHc)
Démontrer la supériorité du MC0518 par rapport au MTD administré en première intention en termes de survie globale (SG) jusqu'à la Visite du Mois 24
Comparer l'efficacité du MC0518 et du MTD pour d'autres critères d'évaluation de l'efficacité secondaires à long terme, ainsi que la réponse au traitement
Évaluer l'innocuité du MC0518
Comparer la qualité de vie liée à la santé (QVLS) sous traitement par MC0518 par rapport au MTD |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Subject had a previous allogeneic HSCT as indicated for malignant or non-malignant haematological disease, irrespective of human leukocyte antigen match.
- Subject has been clinically diagnosed with Grade II to IV aGvHD at the Screening Visit.
- Subject has experienced failure of previous first line aGvHD treatment (ie, SR aGvHD), defined as:
a. aGvHD progression within 3 to 5 days of therapy onset with ≥ 2 mg/kg/day of prednisone equivalent or
b. failure to improve within 5 to 7 days of treatment initiation with ≥ 2 mg/kg/day of prednisone equivalent or
c. incomplete response after > 28 days of immunosuppressive treatment including at least 5 days with ≥ 2 mg/kg/day of prednisone equivalent.
- Male or female subject who is ≥ 12 years of age at the Screening Visit.
- Subject has an estimated life expectancy > 28 days at the Screening Visit. |
1. Le patient a subi une allogreffe de CSH antérieure indiquée pour une hémopathie maligne ou non maligne, indépendamment de la compatibilité HLA (antigène leucocytaire humain).
2. Le patient a reçu un diagnostic clinique de GvH aiguë de grade II à IV à la visite de sélection (la conformité doit être confirmée de nouveau lors de la visite initiale). Une biopsie des organes impliqués dans la GvH aiguë est encouragée mais n'est pas nécessaire pour la sélection.
3. Le patient a connu un échec de traitement antérieur de première intention contre la GvH aiguë (c'est à dire GvH aiguë RS), qui se définit comme suit :
o progression de la GvH aiguë dans les 3 à 5 jours suivant le début du traitement avec ≥ 2 mg/kg/jour d'équivalent de prednisone ou
o absence d'amélioration dans les 5 à 7 jours suivant le début du traitement avec ≥ 2 mg/kg/jour d'équivalent de prednisone ou
o réponse incomplète après > 28 jours de traitement immunosuppresseur dont au moins 5 jours avec ≥ 2 mg/kg/jour d'équivalent de prednisone.
4. Patient masculin ou féminin âgé de ≥ 12 ans au moment de la visite de sélection.
5. Le patient a une espérance de vie estimée > 28 jours à la visite de sélection (la conformité sera confirmée de nouveau lors de la visite initiale). |
|
| E.4 | Principal exclusion criteria |
- Subject has overt relapse or progression or persistence of the underlying disease at the Screening Visit.
- Subject has received the last HSCT for a solid tumour disease.
- Subject has GvHD overlap syndrome at the Screening Visit.
- Subject has received systemic first-line treatment for aGvHD other than steroids and a prophylaxis with other than calcineurin inhibitors, ATG, MMF, MTX, and or cyclophosphamide before the Screening Visit.
- Subject has a known pregnancy (as confirmed by a positive pregnancy test at the Screening Visit) and or is breastfeeding at the Screening Visit.
- Subject has received treatment with any other investigational agent within 30 days or 5 half-lives (whichever is longer) before the Screening Visit (compliance to be confirmed for the period between the Screening Visit and the Baseline Visit at the Baseline Visit). |
- Le patient présente une rechute manifeste ou une progression ou une persistance de la maladie sous-jacente à la visite de selection.
- Le patient a reçu la dernière greffe de CSH pour une tumeur solide.
- Le patient présente un syndrome de chevauchement de la GvH à la visite de selection.
- Le patient a reçu un traitement systémique de première intention autre que des stéroïdes contre la GvH aiguë et une prophylaxie autre que des inhibiteurs de la calcineurine, ATG (globuline antithymocyte), MMF, MTX ou cyclophosphamide avant la visite de sélection.
- La patiente est notoirement enceinte (grossesse confirmée par un test positif lors de la visite de sélection) et ou allaite au moment de la visite de sélection.
- Le patient a reçu un traitement contenant un autre agent expérimental dans les 30 jours ou 5 demi-vies (l'échéance la plus longue prévalant) précédant la visite de sélection (la conformité doit être confirmée pour la période comprise entre la visite de sélection et la visite initiale). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response (OR) as defined by complete response (CR) or partial response (PR) at Visit Day 28 relative to aGvHD status at baseline (Visit Day 1 before the first treatment). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- FFTF until 6 months, defined as the time from the date of randomisation to the date of the event. An event is defined as death, relapse or progression of the underlying disease, or addition or change to any further systemic immunosuppressive aGvHD therapy. The diagnosis of cGvHD is considered to be a competing event.
- OS until Visit Month 24, defined as the time from the date of randomisation to the date of death due to any cause
- aGvHD response at Visit Day 28 assessed by CR, PR, and NR and at Visit Day 60, Visit Day 100, and Visit Day 180 assessed by OR, CR, PR, and NR relative to baseline.
- Change of aGvHD grade at Visit Day 8, Visit Day 15, Visit Day 22, Visit Day 28, Visit Day 60, Visit Day 100, and Visit Day 180 relative to baseline
- Time to response, defined as the time from the date of the first treatment administration to the date of the first response (CR or PR)
- Duration of the response until Visit Month 24, defined as the time from the date of the first OR (CR or PR) to the date of aGvHD assessed as NR compared with the baseline assessment, or the date of addition or change to any further systemic aGvHD therapy, in responders.
- Best OR until Visit Day 28 defined as the achievement of an OR at any time point up to and including Visit Day 28
- Cumulative dose of steroids given for SR-aGvHD from baseline until Visit Day 60 and until Visit Month 24
- Incidence of and time to cGvHD from Visit Day 60 until Visit Month 24
- Incidence of graft failure (GF) from baseline until Visit Month 24
- Incidence of and time to relapse or progression in subjects with underlying malignant disease from randomisation until Visit Month 24
- Event free survival until Visit Month 24, defined as the time from the date of randomisation to the date of the event. An event is defined as GF, relapse or progression of the underlying disease, or death due to any cause.
- Non-relapse mortality (NRM) until Visit Month 24, defined as the time from the date of randomisation to the date of the event. An event is defined as death without previous relapse or progression of the underlying disease. Relapse or progression is considered as a competing event.
- The incidence and severity of all adverse events (AEs) until Visit Day 60 or until 30 days after last administration of trial treatment, whichever is later. Thereafter, the incidence of adverse reactions (ARs) will be documented until Visit Month 24.
- Performance score (Karnofsky / Lansky scale) at Visit Day 8, Visit Day 15, Visit Day 22, Visit Day 28, Visit Day 60, and Visit Day 100 in comparison to the baseline.
- HRQoL measures: EuroQol 5D 5L (EQ 5D 5L) and the Functional Assessment of Cancer Therapy Bone Marrow Transplantation (FACT-BMT) at Visit Day 28, Visit Day 60, Visit Day 100, and Visit Day 180 in comparison to the baseline.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints are evaluated in the various given timepoints during the study. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Best available therapy as defined in the protocol |
|
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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