Clinical trial NCT03371667: To Compare the Efficacy of the Addition of Methotrexate (MTX) to Current Standard Acute Graft-versus-host Disease (GVHD) First-line Treatment With Corticosteroids
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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: 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
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2017-12-13
Enrollment: 102
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization.
timeFrame: Evaluation will be performed at time of inclusion
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (1).
timeFrame: Evaluation will be performed before start of MTX at the randomization.
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (2).
timeFrame: Evaluation will be performed at Day 8
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (3).
timeFrame: Evaluation will be performed at Day 15
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (4).
timeFrame: Evaluation will be performed at Day 22
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (5).
timeFrame: Evaluation will be performed at Day 28
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (6).
timeFrame: Evaluation will be performed at Day 36
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (7).
timeFrame: Evaluation will be performed at Day 50
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (8).
timeFrame: Evaluation will be performed at Day 56
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (9).
timeFrame: Evaluation will be performed at Day 64
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (10)
timeFrame: Evaluation will be performed at Day 78
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (11).
timeFrame: Evaluation will be performed at Day 92
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (12).
timeFrame: Evaluation will be performed at Day 102
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (13).
timeFrame: Evaluation will be performed at 5 months after randomization.
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (14).
timeFrame: Evaluation will be performed at 6 months after randomization.
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (17).
timeFrame: Evaluation will be performed at 9 months after randomization .
measure: Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (18).
timeFrame: Evaluation will be performed at 12 months after randomization.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (19).
timeFrame: Evaluation will be performed at time of inclusion.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (20).
timeFrame: Evaluation will be performed before start of MTX at the randomization.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (21).
timeFrame: Evaluation will be performed at Day 8.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (20).
timeFrame: Evaluation will be performed at Day 15.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (21).
timeFrame: Evaluation will be performed at Day 22.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (22).
timeFrame: Evaluation will be performed at Day 28.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (23).
timeFrame: Evaluation will be performed at Day 36
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (24).
timeFrame: Evaluation will be performed at Day 50.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (25).
timeFrame: Evaluation will be performed at Day 56.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (26).
timeFrame: Evaluation will be performed at Day 64.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (27).
timeFrame: Evaluation will be performed at Day 78.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (28).
timeFrame: Evaluation will be performed at D92.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (29).
timeFrame: Evaluation will be performed at Day 102.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (30).
timeFrame: Evaluation will be performed at 5 months after randomization.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (31).
timeFrame: Evaluation will be performed at 6 months after randomization.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (32).
timeFrame: Evaluation will be performed at 9 months after randomization.
measure: Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (33).
timeFrame: Evaluation will be performed at 12 months after randomization.
Secondary outcomes:
measure: The incidence of severe adverse events within the first 12 months after randomization
timeFrame: 12 months after randomization
measure: 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.
timeFrame: at day 28, day 56 and best response within the first 12 months after randomization.
measure: The proportion of GVHD flare within the first 12 months after randomization.
timeFrame: 12 months after randomization
measure: 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).
timeFrame: within the first 12 months after randomization
measure: Incidence of systemic of infection and CMV(cytomegalovirus ) reactivation within 3 months after randomization
timeFrame: within 3 months after randomization
measure: Incidence of EBV (Epstein-Barr virus) reactivation and post-transplant lymphoproliferative disease within 12 months after randomization
timeFrame: within 12 months after randomization
measure: Cumulative incidence of non-relapse mortality within the first 12 months after randomization.
timeFrame: 12 months after randomization
measure: Corticosteroids-free, disease-free and overall survival within the first 12 months after randomization.
timeFrame: 12 months after randomization
measure: 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
timeFrame: 12 months after randomization
measure: Quality of Life (QoL)-1
timeFrame: 12 Months
measure: Quality of Life (QoL)-2
timeFrame: 12 Months
Other outcomes:
Locations:
city: Paris
country: France
facility: Saint Antoine Hospital - Hematology Department
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Mohamad Mohty, PU-PH
role: PRINCIPAL_INVESTIGATOR
References: