To Compare the Efficacy of the Addition of Methotrexate (MTX) to Current Standard Acute Graft-versus-host Disease (GVHD) First-line Treatment With Corticosteroids

NCT ID: NCT03371667

Last Updated: 2024-01-19

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 102 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-08-16
• Study Completion Date: 2024-12-31

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.

Conditions

Allogeneic Disease; GVH - Graft Versus Host Reaction; GVHD, Acute; Stem Cell Transplant Complications

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Methotrexate

• 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

Group Type: EXPERIMENTAL

Methotrexate

Intervention Type: DRUG

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.

Placebo

• 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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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.

Interventions

Methotrexate

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

Placebo

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.

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mohamad Mohty, PU-PH

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Paris

Locations

Saint Antoine Hospital - Hematology Department

Paris, , France

Countries

France

Other Identifiers

2017-002691-98

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PHRC-K 16-150

Identifier Type: -

Identifier Source: org_study_id