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The Effect of Folinic Acid Rescue Following MTX GVHD Prophylaxis on Regimen Related Toxicity and Transplantation Outcome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02506231
Recruitment Status : Unknown
Verified June 2015 by Rabin Medical Center.
Recruitment status was:  Not yet recruiting
First Posted : July 23, 2015
Last Update Posted : July 24, 2015
Sponsor:
Information provided by (Responsible Party):
Rabin Medical Center

Brief Summary:
The purpose of this study is to assess the impact of folinic acid (FA) -rescue following methotrexate (MTX) graft-versus-host disease (GVHD) prophylaxis on regimen related toxicity and transplantation outcomes after allogeneic hematopoietic cell transplantation (alloHCT) in a double blind randomized controlled trial.

Condition or disease Intervention/treatment Phase
Graft vs Host Disease Allogeneic Hematopoietic Cell Transplantation Mucositis Drug: Folinic acid Drug: Placebo Phase 2 Phase 3

Detailed Description:

A regimen consisted on a combination of a calcineurin inhibitor (CNI) with a short course of methotrexate (MTX) is the most widely used regimen for the prevention of GVHD after allogeneic hematopoietic cell transplantation (alloHCT). While the CNI is given in an adjusted dose, based on blood levels, MTX is given at a fixed 3 or 4 doses (15 mg/m2 on day +1, 10 mg/m2 on days +3, +6 +/- day +11). However, its use may be associated with considerable toxicity, including delayed engraftment, hepatotoxicity, nephrotoxicity and particularly oral mucositis (OM). The basis for OM is integrated: conditioning regimen and MTX prophylaxis for acute GVHD. OM has been shown to be associated with increased mortality and morbidity (principally from infection), significant pain, dysgeusia, difficulty speaking, difficulty receiving nutrition, hydration and oral medications, prolonged hospitalization and increased costs of care.

Reducing and even omitting doses of MTX due to regimen related toxicities (mucositis, hepatic and renal toxicities) is common. However, dose reduction of MTX may be associated with increased risk of acute GVHD and early death. Several non-randomized studies have shown that folinic acid (FA, leucovorin) administration may reduce MTX toxicity. Nevertheless, the efficacy and safety of its administration remain controversial. Despite limited and uncontrolled data, the European Group for Blood and Marrow Transplantation (EBMT) and the European LeukemiaNet working group recently recommended the use of FA-rescue and proposed a uniform policy of FA-rescue 24h after each MTX dose: 15mg every 8h after MTX administration on day 1, and every 6h on days 3, 6 and 11. Yet, according to several surveys (including by EBMT-ELN) only half of bone marrow transplantation (BMT) centers use to give post MTX FA-rescue.

The aim of this study is to assess the impact of FA-rescue following MTX GVHD prophylaxis on regimen related toxicity and transplantation outcomes after alloHCT in a double blind randomized controlled trial.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: The Effect of Folinic Acid Rescue Following Methotrexate (MTX) Graft-versus-host Disease (GVHD) Prophylaxis on Regimen Related Toxicity and Transplantation Outcome: a Double Blind Randomized Controlled Study
Study Start Date : October 2015
Estimated Primary Completion Date : October 2017


Arm Intervention/treatment
Experimental: Folinic acid
Patients will be randomly assigned by central randomization in a 1:1 ratio to receive folinic acid (FA) or placebo starting 24h after each MTX dose for 24h. Oral FA 15 mg/dose or placebo will be given every 8h after MTX administration on day 1 (3 doses), and every 6h (4 doses) on days 3 and 6.
Drug: Folinic acid
Other Name: leucovorin

Placebo Comparator: Placebo
Patients will be randomly assigned by central randomization in a 1:1 ratio to receive folinic acid (FA) or placebo starting 24h after each MTX dose for 24h. Oral FA 15 mg/dose or placebo will be given every 8h after MTX administration on day 1 (3 doses), and every 6h (4 doses) on days 3 and 6.
Drug: Placebo



Primary Outcome Measures :
  1. Incidence of severe (grade 3-4) oral mucositis according to the WHO scale [ Time Frame: 30 days ]
    According to the WHO (world health organization) oral mucositis grading scale

  2. Duration (in days) of severe (grade 3-4) oral mucositis according to the WHO scale [ Time Frame: 30 days ]
    According to the WHO (world health organization) oral mucositis grading scale


Secondary Outcome Measures :
  1. Incidence of oral mucositis [ Time Frame: 30 days ]
  2. Grade of oral mucositis [ Time Frame: 30 days ]
    According to the WHO (world health organization) oral mucositis grading scale

  3. Time to neutrophil recovery [ Time Frame: 30 days ]
  4. Time to platelet recovery [ Time Frame: 60 days ]
  5. Adherence to methotrexate schedule [ Time Frame: 14 days ]
    Number of methotrexate doses that were actually given (out of 3 doses on days 1, 3 and 6)

  6. Adherence to methotrexate doses [ Time Frame: 14 days ]
    Actual methotrexate doses given in mg/sqm divided by scheduled doses in mg/sqm X 100

  7. Days of opiate use [ Time Frame: 30 days ]
  8. Days of total parenteral nutrition use [ Time Frame: 100 days ]
  9. Incidence of veno-occlusive disease of the liver (VOD) [ Time Frame: 30 days ]
  10. Severity of veno-occlusive disease of the liver (VOD) [ Time Frame: 30 days ]
    According to the Seattle criteria

  11. Incidence of renal toxicity [ Time Frame: 30 days ]
    Creatinine > 2 mg%

  12. Incidence of hepatic toxicity [ Time Frame: 30 days ]
    total bilirubin > 2 mg%, unless mostly indirect

  13. Incidence of febrile neutropenia [ Time Frame: 30 days ]
  14. Duration of febrile neutropenia [ Time Frame: 30 days ]
  15. Documented infections [ Time Frame: 30 days ]
  16. Time from transplantation to discharge [ Time Frame: 60 days ]
  17. Incidence of acute graft-versus-host disease [ Time Frame: 100 days ]
  18. Severity of acute graft-versus-host disease [ Time Frame: 100 days ]
    According to the consensus grading system

  19. Incidence of chronic graft-versus-host disease [ Time Frame: 24 months ]
  20. Severity of chronic graft-versus-host disease [ Time Frame: 24 months ]
    According to the National Institutes of Health (NIH) consensus criteria

  21. Incidence of relapse [ Time Frame: 24 months ]
  22. Non relapse mortality [ Time Frame: 24 months ]
  23. Disease free survival [ Time Frame: 24 months ]
  24. Overall survival [ Time Frame: 24 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Acute leukemia in complete remission (CR) or myelodysplastic syndrome;
  • First transplantation;
  • Peripheral blood graft;
  • Matched sibling or unrelated donor or one antigen or allelic mismatched sibling or unrelated donor (10/10 or 9/10 human leukocyte antigen match );
  • Myeloablative or reduced intensity preparative regimen;
  • Post-transplant GVHD prophylaxis consisting of a calcineurin inhibitor (CSA or tacrolimus) and methotrexate;
  • Glutamate Pyruvate Transaminase (GPT) < 3 times upper normal limit (UNL) and creatinine ≤ 1.4 mg%;
  • Written informed consent;

Exclusion Criteria:

  • True non-myeloablative preparative regimen (TBI 200 +/- fludarabine);
  • Acute leukemia not in remission;
  • GPT > 3 times upper normal limit or creatinine > 1.4 mg%;
  • Bone marrow, haploidentical or cord blood grafts;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02506231


Contacts
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Contact: Moshe Yeshurun, MD 972-50-4065543 moshey@clalit.org.il
Contact: Liat Shargian, MD 972-54-2394930 LIATSHR@clalit.org.il

Sponsors and Collaborators
Rabin Medical Center
Investigators
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Principal Investigator: Moshe Yeshurun, MD Rabin Medical Center

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Responsible Party: Rabin Medical Center
ClinicalTrials.gov Identifier: NCT02506231    
Other Study ID Numbers: 0197-15-RMC
First Posted: July 23, 2015    Key Record Dates
Last Update Posted: July 24, 2015
Last Verified: June 2015
Keywords provided by Rabin Medical Center:
Allogeneic hematopoietic cell transplantation
GVHD prophylaxis
Methotrexate
Folinic acid
Leucovorin
Mucositis
Additional relevant MeSH terms:
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Mucositis
Graft vs Host Disease
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Mouth Diseases
Stomatognathic Diseases
Immune System Diseases
Leucovorin
Folic Acid
Methotrexate
Levoleucovorin
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Antidotes
Protective Agents
Vitamin B Complex