Prevention of Methotrexate Induced Nephrotoxicity and Prolonged Drug Elimination Time With 12 Hours Prehydration - Full Text View

Purpose

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.

Condition	Intervention
Methotrexate Induced Nephrotoxicity	Other: 12 hours of prehydration

Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Crossover Assignment Masking: Open Label Primary Purpose: Prevention
Official Title:	Nephrotoxicity Induced by High-Dose Methotrexate Infusions to Children With Malignant Diseases

Resource links provided by NLM:

MedlinePlus related topics: Leukemia Lymphoma

Drug Information available for: Methotrexate Methotrexate sodium

U.S. FDA Resources

Further study details as provided by University of Aarhus:

Primary Outcome Measures:

Prolonged methotrexate elimination time, defined by serum methotrexate concentrations: > 3,0 micromol/L at 36 hours; > 1,0 micromol/L at 42 hours or > 0,2 micromol/L at 66 hours after initiation of the methotrexate infusion. [ Time Frame: From 36-66 hours after the initiation of methotrexate infusion. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Development of methotrexate induced nephropathy, defined by an increase in serum creatinine by 50% or more compared with the serum creatinine concentration before start of each methotrexate infusion. [ Time Frame: From the initiation of methotrexate infusion until 66 hours after. ] [ Designated as safety issue: No ]
Days of hospitalization in relation to the methotrexate infusion. [ Time Frame: Days in relation to the methotrexate infusion and side effects. ] [ Designated as safety issue: No ]
Difference in baseline creatinine to highest serum creatinine between groups. [ Time Frame: From initiation of the methotrexate infusion and up til 14 days after. ] [ Designated as safety issue: No ]
Drug exposure measured by area under the curve. [ Time Frame: From 23 hours til 66 hours after initiation of the methotrexate infusion. ] [ Designated as safety issue: No ]
Duration and degree of side effects to the methotrexate treatment. [ Time Frame: From initiation of the methotrexate infusion and up til on month after. ] [ Designated as safety issue: No ]
Total dosage of leucovorin. [ Time Frame: From initiation of the methotrexate infusion and til serum methotrexate concentration is below 0,2 micromol/l. ] [ Designated as safety issue: No ]

Enrollment:	47
Study Start Date:	June 2007
Study Completion Date:	October 2010
Primary Completion Date:	October 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1 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.	Other: 12 hours of prehydration 12 hours of prehydration with an infusion rate of 150 ml/m2/hour with a solution of 5% glucose with 40 mmol sodium bicarbonate/L and 20 mmol potassium chloride/L.
2 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.	Other: 12 hours of prehydration 12 hours of prehydration with an infusion rate of 150 ml/m2/hour with a solution of 5% glucose with 40 mmol sodium bicarbonate/L and 20 mmol potassium chloride/L.

Arms

Assigned Interventions

1

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.

Other: 12 hours of prehydration

12 hours of prehydration with an infusion rate of 150 ml/m2/hour with a solution of 5% glucose with 40 mmol sodium bicarbonate/L and 20 mmol potassium chloride/L.

2

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.

Other: 12 hours of prehydration

12 hours of prehydration with an infusion rate of 150 ml/m2/hour with a solution of 5% glucose with 40 mmol sodium bicarbonate/L and 20 mmol potassium chloride/L.

Detailed 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.

Eligibility

Ages Eligible for Study:	1 Year to 21 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00570817

Locations

Denmark
Aarhus University Hospital, Skejby
Aarhus, Aarhus N, Denmark, 8200

Sponsors and Collaborators

University of Aarhus

ML Jørgensen og Gunnar Hansens Foundation

The Danish Child Cancer Foundation

Investigators

Study Director:

Henrik Schrøder, MD

More Information

No publications provided

Responsible Party:	University of Aarhus
ClinicalTrials.gov Identifier:	NCT00570817 History of Changes
Other Study ID Numbers:	20070009, The Danish Data, Protection Agency 2007-41-0014
Study First Received:	December 10, 2007
Last Updated:	November 4, 2011
Health Authority:	Denmark: The Regional Committee on Biomedical Research Ethics

Keywords provided by University of Aarhus:

Methotrexate
Nephrotoxicity
Hydration
Acute lymphoblastic leukemia

Non-Hodgkin's lymphoma
Medulloblastoma
Ependymoma
Prolonged elimination time of methotrexate

Additional relevant MeSH terms:

Methotrexate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
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

ClinicalTrials.gov processed this record on June 18, 2013