| 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.
and/or to
Demonstrate the superiority of MC0518 compared to the first used BAT with respect to overall survival (OS) in adult and adolescent subjects with SR aGVHD until Visit Month 24 |
|
| 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 from the date of randomisation up to the date of the event and before the diagnosis of chronic graft versus host disease (cGvHD)
- 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 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A pilot sub-trial to assess anti-human leukocyte antigen antibodies in adult subjects will be conducted at German trial sites. This pilot sub-trial for Germany is described in an appendix to the protocol.
This pilot sub-trial has now been completed and the results will be presented together with the Clinical Study Report, that will be submitted after the end of trial. |
|
| E.3 | Principal inclusion criteria |
- Subject had a previous allogeneic HSCT as indicated for non-malignant (including inborn errors of metabolism, primary immunodeficiencies, haemoglobinopathies, and bone marrow failure syndromes) or haematological malignant 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 and ≥ 15 kg at the Screening Visit.
-Subject has an estimated life expectancy > 28 days at the Screening Visit (compliance to be re-confirmed at the Baseline Visit).
-Subject, if female and of childbearing potential, agrees to use a highly effective contraceptive measure starting at the Screening Visit and continuing throughout the entire trial period. The definition of women of childbearing potential (WOCBP) and a complete list of highly effective contraceptive measures .are included in an appendix to the protocol.
-Subject, if a fertile male, agrees to sexual abstinence or to use a condom during sexual activity with their female partner of childbearing potential or pregnant partner. Additionally, if their partner is a WOCBP, then their partner has to use an additional highly effective contraceptive method during sexual activity starting at the Screening Visit and continuing throughout the entire trial period. For theThe definition of fertile men and a complete list of highly effective contraceptive measures are included in an appendix to the protocol.
-Subject or parent(s) / legal guardian(s) have read, understood, and signed the informed consent form (and informed assent form, if applicable) according to national regulations. |
|
| 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, mammalian target of rapamycin (mTOR) inhibitors, anti-thymocyte globulin (ATG), mycophenolate mofetil (MMF), methotrexate (MTX), and / or cyclophosphamide before the Screening Visit (compliance to be re-confirmed at the Baseline Visit).
Please Note: In vitro or in vivo graft manipulation to prevent GvHD (eg, T-cell depletion) during HSCT is permitted. Restart of initial prophylaxis with calcineurin inhibitors or mTOR inhibitors after aGvHD onset is permitted.
- 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). |
|
| 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). CR is defined as resolution of aGvHD in all involved organs. PR is defined as improvement in at least 1 stage in 1 or more organs involved with aGvHD symptoms without progression in others.
No response (NR) is defined as the absence of CR or PR. Death before Visit Day 28 will be considered as NR. The addition or change to any further systemic therapy after MC0518 / first used BAT before Visit Day 28 will be considered as NR.
OS until Visit Month 24, defined as the time from the date of randomisation to the date of death due to any cause |
|
| 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.
- 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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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