Back to resultsTo Compare the Efficacy of the Addition of Methotrexate (MTX) to Current Standard Acute Graft-versus-host Disease (GVHD) First-line Treatment With Corticosteroids (MTX-aGVHD)
Primary Purpose
Allogeneic Disease, GVH - Graft Versus Host Reaction, GVHD, Acute
Status
Recruiting
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Methotrexate
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Allogeneic Disease focused on measuring Hematopoietic Stem Cell, Methotrexate, Corticosteroids therapy, Acute GVHD, Allogenic stem cell transplantation
Eligibility Criteria
Inclusion Criteria:
- Adults patients (>=18 years old) with hematological diseases, who develop a first episode of acute GVHD (grade II-IV) requiring systemic therapy
- First allo-SCT, with any type of donor, stem cell source, GVHD prophylaxis or conditioning regimen
- Biopsy of acute GVHD target organ is recommended, but not required. Enrollment should not be delayed awaiting biopsy or pathology results
- The patient must have received no previous systemic immune suppressive therapy for treatment of acute GVHD, except for a maximum 72 hours of prior corticosteroid therapy
- Absolute neutrophil count (ANC) greater than 0.5 G/L
- Platelets count greater than 20 G/L
- Signed informed consent
- Affiliation to a social security system (recipient or assign)
- Women who are of childbearing potential must have a negative serum pregnancy test and agree to use a medically acceptable method of contraception until 6 months after the end of treatment.
Men with a partner of childbearing potential must agree to use a medically acceptable method of contraception until 6 months after the end of treatment.
Exclusion Criteria:
- Hyper-acute GVHD as defined by the MD Anderson's criteria (Saliba, de Lima et al. 2007)
- Flare of GVHD in a patient already on corticosteroid treatment
- Overlap chronic GVHD as defined by the NIH Consensus Criteria (Jagasia, Greinix et al. 2015)
- MTX given within 7 days of enrollment
- Active uncontrolled infection
- Relapsed/persistent malignancy requiring rapid immune suppression withdrawal
- Acute GVHD after donor lymphocytes infusion (DLI)
- Other systemic drugs for GVHD treatment (including extra-corporeal photopheresis)
- If any prior steroid therapy (for indication other than GVHD), treatment at doses > 0.5 mg/kg/day methyl-prednisolone within 7 days prior to onset of acute GVHD
- Patients who are pregnant, breast feeding, or if sexually active, unwilling to use effective birth control for the duration of the study
- Patient on dialysis
- Patients with veno-occlusive disease of the liver or with significant liver abnormalities who in the judgment of the treating physician cannot receive MTX
- Patients requiring after inclusion in the protocol the continuation of one or more of the following medication: probenecide, trimethoprime (alone or in combination with sulfametoxazole), phenylbutazone or yellow fever vaccine
- Patients with a history of intolerance/allergy to MTX
- Hypersensitivity to the active substance or to any of the excipients
Sites / Locations
- Saint Antoine Hospital - Hematology DepartmentRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Methotrexate
Placebo
Arm Description
5mg/Kg/day methotrexate for 4 weeks then 3 mg/m2 every two weeks for 12 weeks 2mg/kg/day PO prednisone prednisone (or 1.6 mg/kg/day IV methylprednisolone) once daily. 10 mg po or iv lederfolin after each MTX administration
Once a week placebo for 4 weeks then every two weeks for 12 weeks 2 mg/kg/day PO prednisone (or 1.6 mg/kg/day IV methylprednisolone) once daily. 10 mg po or iv lederfolin after each placebo administration
Outcomes
Primary Outcome Measures
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization.
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (1).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (2).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (3).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (4).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (5).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (6).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (7).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (8).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (9).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (10)
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (11).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (12).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (13).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (14).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (17).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (18).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (19).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (20).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (21).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (20).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (21).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (22).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (23).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (24).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (25).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (26).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (27).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (28).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (29).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (30).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (31).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (32).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (33).
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Secondary Outcome Measures
The incidence of severe adverse events within the first 12 months after randomization
The proportion of complete remission (CR), very good partial response (VGPR), partial response (PR), mixed response (MR), no response (NR) and progression at day 28, day 56 and best response within the first 12 months after randomization.
The proportion of GVHD flare within the first 12 months after randomization.
Cumulative incidence of overall and severe chronic GVHD as assessed by NIH Consensus Criteria within the first 12 months after randomization(Jagasia, Greinix et al. 2015, Lee, Wolff et al. 2015).
Incidence of systemic of infection and CMV(cytomegalovirus ) reactivation within 3 months after randomization
Incidence of EBV (Epstein-Barr virus) reactivation and post-transplant lymphoproliferative disease within 12 months after randomization
Cumulative incidence of non-relapse mortality within the first 12 months after randomization.
Corticosteroids-free, disease-free and overall survival within the first 12 months after randomization.
Immune recovery and microbiota: number of patients with complete immune recovery (lymphocytes and dendritic cells) and correction of microbiota dysbiosis within the first 12 months
Quality of Life (QoL)-1
Evaluation by 1 questionnaire: EORTC QLQ-C30 (quality of life questionnaire) (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30)
Quality of Life (QoL)-2
Evaluation by 1 questionnaire: FACT-BMT (Functional Assessment of Cancer Therapy - Bone Marrow Transplant)
Full Information
NCT ID
NCT03371667
First Posted
July 31, 2017
Last Updated
September 6, 2022
Sponsor
Assistance Publique - Hôpitaux de Paris
1. Study Identification
Unique Protocol Identification Number
NCT03371667
Brief Title
To Compare the Efficacy of the Addition of Methotrexate (MTX) to Current Standard Acute Graft-versus-host Disease (GVHD) First-line Treatment With Corticosteroids
Acronym
MTX-aGVHD
Official Title
A Multi-center Randomized in Double-blinded Phase III Study Comparing Standard Care Therapy Alone Versus Corticosteroids and Low-dose Methotrexate (MTX) for the First-line Treatment of Acute Graft-versus-host Disease After Allogeneic Stem Cell Transplantation
Study Type
Interventional
2. Study Status
Record Verification Date
September 2022
Overall Recruitment Status
Recruiting
Study Start Date
August 16, 2018 (Actual)
Primary Completion Date
July 2023 (Anticipated)
Study Completion Date
July 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
Phase III randomized double-blinded trial designed to compare the efficacy of the addition of MTX to current standard acute GVHD first-line treatment with corticosteroids. The protocol will use a novel endpoint for benchmarking interventions based on a composite primary endpoint of GVHD-free and corticosteroids-free survival.
The primary endpoint of the trial will be the assessment of a composite endpoint of graft-versus-host disease-free and corticosteroids-free survival at 12 months after randomization
Detailed Description
This is a phase III randomized, multicenter, double blinded controlled study. Patients who develop clinically meaningful acute GVHD and who meet all other entry criteria will be randomized 1:1 to receive either corticosteroids and placebo ("standard of care", control arm) or the combination of low-dose MTX with corticosteroids as first-line therapy for acute GVHD (MTX; "experimental arm").
The primary analysis of this hypothesis generation study is to estimate the composite endpoint of GVHD-free and corticosteroids-free survival at 12 months after randomization in both treatment arms. In fact, it is more and more established that such composite endpoint is a clinically very relevant one because it represents ideal recovery from allo-SCT (Stem Cell transplantation) (at 1 year after acute GVHD diagnosis) and a measure of cure without ongoing morbidity.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Allogeneic Disease, GVH - Graft Versus Host Reaction, GVHD, Acute, Stem Cell Transplant Complications
Keywords
Hematopoietic Stem Cell, Methotrexate, Corticosteroids therapy, Acute GVHD, Allogenic stem cell transplantation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
102 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Methotrexate
Arm Type
Experimental
Arm Description
5mg/Kg/day methotrexate for 4 weeks then 3 mg/m2 every two weeks for 12 weeks
2mg/kg/day PO prednisone prednisone (or 1.6 mg/kg/day IV methylprednisolone) once daily.
10 mg po or iv lederfolin after each MTX administration
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Once a week placebo for 4 weeks then every two weeks for 12 weeks
2 mg/kg/day PO prednisone (or 1.6 mg/kg/day IV methylprednisolone) once daily.
10 mg po or iv lederfolin after each placebo administration
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Intervention Description
Methotrexate 5 mg/m2 will be given once week for 4 weeks, then 3 mg/m2 every two weeks for 12 weeks. Body surface area will be capped at 2 m2.
Methotrexate will be given as an IV infusion over 15 minutes. All patients will received prednisone 2 mg/kg.day PO (or methylprednisolone 1.6 mg/Kg/day) for 3 days.
For responding patients between day 4 and 28, the dose of prednisone must be at least 0.25 mg/kg/day prednisone (or 0.2 mg/kg/day methylprednisolone).
All patients should receive a folinic acid supplementation 24 hours after each MTX/placebo administration.
Lederfoldin 10 mg po or iv will be administered on days 2, 9, 16 and 23. Lederfoldin 10 mg po or iv will be administered on days 37, 51, 65, 79, 93 and 103.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo 5 mg/m2 will be given once week for 4 weeks, then 3 mg/m2 every two weeks for 12 weeks. Body surface area will be capped at 2 m2.
Placebo will be given as an IV infusion over 15 minutes. All patients will received prednisone 2 mg/kg.day PO (or methylprednisolone 1.6 mg/Kg/day) for 3 days.
For responding patients between day 4 and 28, the dose of prednisone must be at least 0.25 mg/kg/day prednisone (or 0.2 mg/kg/day methylprednisolone).
All patients should receive a folinic acid supplementation 24 hours after each MTX/placebo administration.
Lederfoldin 10 mg po or iv will be administered on days 2, 9, 16 and 23. Lederfoldin 10 mg po or iv will be administered on days 37, 51, 65, 79, 93 and 103.
Primary Outcome Measure Information:
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization.
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at time of inclusion
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (1).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed before start of MTX at the randomization.
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (2).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 8
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (3).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 15
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (4).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 22
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (5).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 28
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (6).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 36
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (7).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 50
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (8).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 56
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (9).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 64
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (10)
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 78
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (11).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 92
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (12).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 102
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (13).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at 5 months after randomization.
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (14).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at 6 months after randomization.
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (17).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at 9 months after randomization .
Title
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (18).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at 12 months after randomization.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (19).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at time of inclusion.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (20).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed before start of MTX at the randomization.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (21).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 8.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (20).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 15.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (21).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 22.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (22).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 28.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (23).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 36
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (24).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 50.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (25).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 56.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (26).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 64.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (27).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 78.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (28).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at D92.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (29).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at Day 102.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (30).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at 5 months after randomization.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (31).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at 6 months after randomization.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (32).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at 9 months after randomization.
Title
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (33).
Description
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day.
Time Frame
Evaluation will be performed at 12 months after randomization.
Secondary Outcome Measure Information:
Title
The incidence of severe adverse events within the first 12 months after randomization
Time Frame
12 months after randomization
Title
The proportion of complete remission (CR), very good partial response (VGPR), partial response (PR), mixed response (MR), no response (NR) and progression at day 28, day 56 and best response within the first 12 months after randomization.
Time Frame
at day 28, day 56 and best response within the first 12 months after randomization.
Title
The proportion of GVHD flare within the first 12 months after randomization.
Time Frame
12 months after randomization
Title
Cumulative incidence of overall and severe chronic GVHD as assessed by NIH Consensus Criteria within the first 12 months after randomization(Jagasia, Greinix et al. 2015, Lee, Wolff et al. 2015).
Time Frame
within the first 12 months after randomization
Title
Incidence of systemic of infection and CMV(cytomegalovirus ) reactivation within 3 months after randomization
Time Frame
within 3 months after randomization
Title
Incidence of EBV (Epstein-Barr virus) reactivation and post-transplant lymphoproliferative disease within 12 months after randomization
Time Frame
within 12 months after randomization
Title
Cumulative incidence of non-relapse mortality within the first 12 months after randomization.
Time Frame
12 months after randomization
Title
Corticosteroids-free, disease-free and overall survival within the first 12 months after randomization.
Time Frame
12 months after randomization
Title
Immune recovery and microbiota: number of patients with complete immune recovery (lymphocytes and dendritic cells) and correction of microbiota dysbiosis within the first 12 months
Time Frame
12 months after randomization
Title
Quality of Life (QoL)-1
Description
Evaluation by 1 questionnaire: EORTC QLQ-C30 (quality of life questionnaire) (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30)
Time Frame
12 Months
Title
Quality of Life (QoL)-2
Description
Evaluation by 1 questionnaire: FACT-BMT (Functional Assessment of Cancer Therapy - Bone Marrow Transplant)
Time Frame
12 Months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Adults patients (>=18 years old) with hematological diseases, who develop a first episode of acute GVHD (grade II-IV) requiring systemic therapy
First allo-SCT, with any type of donor, stem cell source, GVHD prophylaxis or conditioning regimen
Biopsy of acute GVHD target organ is recommended, but not required. Enrollment should not be delayed awaiting biopsy or pathology results
The patient must have received no previous systemic immune suppressive therapy for treatment of acute GVHD, except for a maximum 72 hours of prior corticosteroid therapy
Absolute neutrophil count (ANC) greater than 0.5 G/L
Platelets count greater than 20 G/L
Signed informed consent
Affiliation to a social security system (recipient or assign)
Women who are of childbearing potential must have a negative serum pregnancy test and agree to use a medically acceptable method of contraception until 6 months after the end of treatment.
Men with a partner of childbearing potential must agree to use a medically acceptable method of contraception until 6 months after the end of treatment.
Exclusion Criteria:
Hyper-acute GVHD as defined by the MD Anderson's criteria (Saliba, de Lima et al. 2007)
Flare of GVHD in a patient already on corticosteroid treatment
Overlap chronic GVHD as defined by the NIH Consensus Criteria (Jagasia, Greinix et al. 2015)
MTX given within 7 days of enrollment
Active uncontrolled infection
Relapsed/persistent malignancy requiring rapid immune suppression withdrawal
Acute GVHD after donor lymphocytes infusion (DLI)
Other systemic drugs for GVHD treatment (including extra-corporeal photopheresis)
If any prior steroid therapy (for indication other than GVHD), treatment at doses > 0.5 mg/kg/day methyl-prednisolone within 7 days prior to onset of acute GVHD
Patients who are pregnant, breast feeding, or if sexually active, unwilling to use effective birth control for the duration of the study
Patient on dialysis
Patients with veno-occlusive disease of the liver or with significant liver abnormalities who in the judgment of the treating physician cannot receive MTX
Patients requiring after inclusion in the protocol the continuation of one or more of the following medication: probenecide, trimethoprime (alone or in combination with sulfametoxazole), phenylbutazone or yellow fever vaccine
Patients with a history of intolerance/allergy to MTX
Hypersensitivity to the active substance or to any of the excipients
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mohamad Mohty, PU-PH
Phone
01.49.28.26.20
Email
mohamad.mohty@inserm.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Florent Malard, CCU-AH
Phone
01.49.28.26.20
Email
malardf@yahoo.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mohamad Mohty, PU-PH
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Saint Antoine Hospital - Hematology Department
City
Paris
ZIP/Postal Code
75012
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
mohamad Mohty, PU-PH
Phone
01.49.28.26.20
Email
mohamad.mohty@inserm.fr
First Name & Middle Initial & Last Name & Degree
Florent Malard, CCU-AH
Phone
01.49.28.26.20
Email
malardf@yahoo.fr
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Learn more about this trial
To Compare the Efficacy of the Addition of Methotrexate (MTX) to Current Standard Acute Graft-versus-host Disease (GVHD) First-line Treatment With Corticosteroids
We'll reach out to this number within 24 hrs