Graft vs Host DiseasePhase 2/3NCT02506231
The Effect of Folinic Acid Rescue Following MTX GVHD Prophylaxis on Regimen Related Toxicity and Transplantation Outcome
A Phase 2/3 study testing Folinic acid in people with Graft vs Host Disease and Allogeneic Hematopoietic Cell Transplantation, run by Rabin Medical Center.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Graft vs Host Disease, Allogeneic Hematopoietic Cell Transplantation, Mucositis
- What is being tested?
- Folinic acid
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 160 participants
- Where
- No sites listed yet
- Study dates
- Oct 2015to Oct 2017
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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;
Who cannot join
- 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;
Trial locations and contacts
No sites are listed yet.
About this study
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
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.
Read the 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.
- Being tested
- Folinic acid, Placebo
- Keywords
- Allogeneic hematopoietic cell transplantation, GVHD prophylaxis, Methotrexate, Folinic acid, Leucovorin, Mucositis
- Medical subject headings
- Graft vs Host Disease, Mucositis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Folinic acidDrug
Also called leucovorin
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Folinic acid | Experimental | 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. Receives: Drug: Folinic acid |
| Placebo | Placebo comparator | 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of severe (grade 3-4) oral mucositis according to the WHO scale
According to the WHO (world health organization) oral mucositis grading scale
Measured: 30 days
Duration (in days) of severe (grade 3-4) oral mucositis according to the WHO scale
According to the WHO (world health organization) oral mucositis grading scale
Measured: 30 days
Secondary outcomes (24)
Incidence of oral mucositis
Measured: 30 days
Grade of oral mucositis
According to the WHO (world health organization) oral mucositis grading scale
Measured: 30 days
Time to neutrophil recovery
Measured: 30 days
Time to platelet recovery
Measured: 60 days
Adherence to methotrexate schedule
Number of methotrexate doses that were actually given (out of 3 doses on days 1, 3 and 6)
Measured: 14 days
Adherence to methotrexate doses
Actual methotrexate doses given in mg/sqm divided by scheduled doses in mg/sqm X 100
Measured: 14 days
Days of opiate use
Measured: 30 days
Days of total parenteral nutrition use
Measured: 100 days
Incidence of veno-occlusive disease of the liver (VOD)
Measured: 30 days
Severity of veno-occlusive disease of the liver (VOD)
According to the Seattle criteria
Measured: 30 days
Incidence of renal toxicity
Creatinine > 2 mg%
Measured: 30 days
Incidence of hepatic toxicity
total bilirubin > 2 mg%, unless mostly indirect
Measured: 30 days
Incidence of febrile neutropenia
Measured: 30 days
Duration of febrile neutropenia
Measured: 30 days
Documented infections
Measured: 30 days
Time from transplantation to discharge
Measured: 60 days
Incidence of acute graft-versus-host disease
Measured: 100 days
Severity of acute graft-versus-host disease
According to the consensus grading system
Measured: 100 days
Incidence of chronic graft-versus-host disease
Measured: 24 months
Severity of chronic graft-versus-host disease
According to the National Institutes of Health (NIH) consensus criteria
Measured: 24 months
Incidence of relapse
Measured: 24 months
Non relapse mortality
Measured: 24 months
Disease free survival
Measured: 24 months
Overall survival
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jul 2015 (estimated)
- Study startOct 2015
- Primary completionOct 2017 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Graft vs Host DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 160 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Rabin Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Moshe Yeshurun, MD, Principal investigator, Rabin Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02506231
- Sponsor's protocol ID
- 0197-15-RMC
- Status last verified
- Jun 2015
- First submitted
- 13 Jul 2015
- Last updated
- 24 Jul 2015
- Results posted
- No
- Data monitoring committee
- No
Publications
Yeshurun M, Rozovski U, Pasvolsky O, Wolach O, Ram R, Amit O, Zuckerman T, Pek A, Rubinstein M, Sela-Navon M, Raanani P, Shargian-Alon L. Efficacy of folinic acid rescue following MTX GVHD prophylaxis: results of a double-blind, randomized, controlled study. Blood Adv. 2020 Aug 25;4(16):3822-3828. doi: 10.1182/bloodadvances.2020002039.
PubMed 32790844
Study at a glance
From the registry record, last updated by the sponsor on 24 Jul 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02506231
- Acronym / sponsor ID
- 0197-15-RMC
- Keywords
- Allogeneic hematopoietic cell transplantation, GVHD prophylaxis, Methotrexate, Folinic acid, Leucovorin, Mucositis
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 160 participants (estimated)
- Lead sponsor
- Rabin Medical CenterUniversity, hospital or other
- Study start
- Oct 2015
- Primary completion
- Oct 2017 (estimated)
- First posted
- 23 Jul 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Folinic acid | Experimental | Drug: Folinic acidPatients 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. |
| Placebo | Placebo comparator | Drug: PlaceboPatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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;
Key exclusion criteria (4 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Folinic acidAlso: leucovorin | Drug | Folinic acid |
| Placebo | Drug | Placebo |
Primary outcome
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
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
24 secondary outcomes
Incidence of oral mucositis
Time frame: 30 days
Grade of oral mucositis
Time frame: 30 days
Time to neutrophil recovery
Time frame: 30 days
Time to platelet recovery
Time frame: 60 days
Adherence to methotrexate schedule
Time frame: 14 days
Adherence to methotrexate doses
Time frame: 14 days
Days of opiate use
Time frame: 30 days
Days of total parenteral nutrition use
Time frame: 100 days
Incidence of veno-occlusive disease of the liver (VOD)
Time frame: 30 days
Severity of veno-occlusive disease of the liver (VOD)
Time frame: 30 days
Incidence of renal toxicity
Time frame: 30 days
Incidence of hepatic toxicity
Time frame: 30 days
Incidence of febrile neutropenia
Time frame: 30 days
Duration of febrile neutropenia
Time frame: 30 days
Documented infections
Time frame: 30 days
Time from transplantation to discharge
Time frame: 60 days
Incidence of acute graft-versus-host disease
Time frame: 100 days
Severity of acute graft-versus-host disease
Time frame: 100 days
Incidence of chronic graft-versus-host disease
Time frame: 24 months
Severity of chronic graft-versus-host disease
Time frame: 24 months
Incidence of relapse
Time frame: 24 months
Non relapse mortality
Time frame: 24 months
Disease free survival
Time frame: 24 months
Overall survival
Time frame: 24 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Jul 2015.
- Derived from this study: PubMed 32790844Yeshurun M, Rozovski U, Pasvolsky O, Wolach O, Ram R, Amit O, Zuckerman T, Pek A, Rubinstein M, Sela-Navon M, Raanani P, Shargian-Alon L. Efficacy of folinic acid rescue following MTX GVHD prophylaxis: results of a double-blind, randomized, controlled study. Blood Adv. 2020 Aug 25;4(16):3822-3828. doi: 10.1182/bloodadvances.2020002039.
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Graft vs Host Disease
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Moshe Yeshurun, MD principal investigator
Rabin Medical Center
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Folinic acid in people with Graft vs Host Disease and Allogeneic Hematopoietic Cell Transplantation, run by Rabin Medical Center.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 24 Jul 2015. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Moshe Yeshurun, MD (972-50-4065543, moshey@clalit.org.il), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of severe (grade 3-4) oral mucositis according to the WHO scale (time frame: 30 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02506231, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jul 2015.