Prevention of Methotrexate Induced Nephrotoxicity and Prolonged Drug Elimination Time With 12 Hours Prehydration

University of Aarhus

Status: Completed

Conditions: Methotrexate Induced Nephrotoxicity

Treatments: Other: 12 hours of prehydration

Study type: Interventional

Funder types: Other

Identifiers

NCT00570817

20070009

Protection Agency 2007-41-0014

The Danish Data

Details and patient eligibility

About

Infusions with high-dose methotrexate 5 g/m2 or 8 g/m2 are used to treat children with acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, medulloblastoma and ependymoma. Methotrexate is primarily excreted unchanged by the kidney where it can course acute kidney damage resulting in prolonged time of excretion of the drug. Our main hypothesis is that 12 hours of intravenous hydration before the methotrexate infusion is more efficacious in preventing methotrexate induced kidney damage compared to four hours of hydration.

Full description

Infusions with high-dose methotrexate 5 g/m2 or 8 g/m2 are according to the protocol of the Nordic Association for Pediatric Hematology and Oncology 2000 (NOPHO-2000) used to treat children with acute lymphoblastic leukemia (ALL). Treatment with methotrexate 5 g/m2 is also used to treat children with non-Hodgkin lymphoma, medulloblastoma and ependymoma. Methotrexate is primarily excreted unchanged by the kidney where it can course acute nephrotoxicity resulting in prolonged elimination time of the drug. Data from a 10 years retrospective investigation at our pediatric unit show, that in spite of urine alkalinization and intensive hydration the elimination of methotrexate is prolonged in 20-50% of the infusions. The long exposure of a high serum methotrexate concentration is associated with an increased frequency of mucositis and bone marrow suppression. Further more the need of rescue with folic acid is problematic, because it is possibly that it can result in a higher risk of relapse of ALL (Leukemia 2006; Skarby TV). Most ALL protocols prescribe prehydration of 2-6 hours before initiation of the methotrexate infusion and it has never been investigated in a randomized controlled trail if a longer time of prehydration can prevent nephrotoxicity and reduce the risk of prolonged elimination. In our pediatric unit the prehydration is given with a rate of 150 ml/m2/hour with a solution of 5% glucose with 40 mmol sodium bicarbonate/L and 20 mmol potassium chloride/L.

Our main hypothesis is that 12 hours of prehydration is more efficacious in preventing methotrexate induced nephrotoxicity compared to four hours of prehydration. A child enrolled in the study will before half of the methotrexate infusions receive 12 hours of prehydration and before the other half it will receive four hours of prehydration.

Enrollment: 47 patients

Sex: All

Ages: 1 to 21 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Age between 1 and 21 years at the diagnosis of ALL
• Treatment with high-dose methotrexate 5 g/m2 or 8 g/m2 according to the protocol "Nordic Association for Pediatric Hematology and Oncology 2000 (NOPHO-2000)" or the new protocol (NOPHO-2008) to which enrolment begin approx. January 2009.
• Treatment with high-dose methotrexate 5 g/m2 according to the protocol "Treatment Protocol for T-Cell and B-Precursor Cell Lymphoblastic Lymphoma 2002 of the European Inter-group Co-operation on Childhood Non-Hodgkin-Lymphoma (EICNHL)"
• Treatment of medulloblastoma and ependymoma with high-dose methotrexate 5 g/m2 according to the protocol: "(HIT2000)Hirntumorprotokoll der Hrbeitsgruppe für Hirntumoren" from Deutsche Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH).

Exclusion criteria

• Patient or parents not willing to give consent.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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47 participants in 2 patient groups

1

Other group

Description:

The child will receive prehydration at the methotrexate infusions in the following order: At the 1st methotrexate infusion the child will receive 4 hours prehydration. At the 2nd methotrexate infusion the child will receive 12 hours prehydration. At the 3rd methotrexate infusion the child will receive 4 hours prehydration. At the 4th methotrexate infusion the child will receive 12 hours prehydration. At the 5th methotrexate infusion the child will receive 4 hours prehydration. At the 6th methotrexate infusion the child will receive 12 hours prehydration. At the 7th methotrexate infusion the child will receive 4 hours prehydration. At the 8th methotrexate infusion the child will receive 12 hours prehydration.

Treatment:

Other: 12 hours of prehydration

2

Other group

Description:

The child will receive prehydration at the methotrexate infusions in the following order: At the 1st methotrexate infusion the child will receive 12 hours prehydration. At the 2nd methotrexate infusion the child will receive 4 hours prehydration. At the 3rd methotrexate infusion the child will receive 12 hours prehydration. At the 4th methotrexate infusion the child will receive 4 hours prehydration. At the 5th methotrexate infusion the child will receive 12 hours prehydration. At the 6th methotrexate infusion the child will receive 4 hours prehydration. At the 7th methotrexate infusion the child will receive 12 hours prehydration. At the 8th methotrexate infusion the child will receive 4 hours prehydration.

Treatment:

Other: 12 hours of prehydration