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

Nephrotoxicity Induced by High-Dose Methotrexate Infusions to Children With Malignant Diseases

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.

Study Overview

• Status: Completed
• Conditions: Methotrexate Induced Nephrotoxicity
• Intervention / Treatment: Other: 12 hours of prehydration

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.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Not Applicable

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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.
Other: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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.	From 36-66 hours after the initiation of methotrexate infusion.

Secondary Outcome Measures

Outcome Measure	Time Frame
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.	From the initiation of methotrexate infusion until 66 hours after.
Days of hospitalization in relation to the methotrexate infusion.	Days in relation to the methotrexate infusion and side effects.
Difference in baseline creatinine to highest serum creatinine between groups.	From initiation of the methotrexate infusion and up til 14 days after.
Drug exposure measured by area under the curve.	From 23 hours til 66 hours after initiation of the methotrexate infusion.
Duration and degree of side effects to the methotrexate treatment.	From initiation of the methotrexate infusion and up til on month after.
Total dosage of leucovorin.	From initiation of the methotrexate infusion and til serum methotrexate concentration is below 0,2 micromol/l.

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Danish Child Cancer Foundation; ML Jørgensen og Gunnar Hansens Foundation
• Investigators: Study Director: Henrik Schrøder, MD

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: December 10, 2007
• First Submitted That Met QC Criteria: December 10, 2007
• First Posted (Estimate): December 11, 2007

Study Record Updates

• Last Update Posted (Estimate): November 6, 2011
• Last Update Submitted That Met QC Criteria: November 4, 2011
• Last Verified: January 1, 2011

More Information

Terms related to this study

• Keywords: Methotrexate; Non-Hodgkin's lymphoma; Hydration; Medulloblastoma; Ependymoma; Acute lymphoblastic leukemia; Nephrotoxicity; Prolonged elimination time of methotrexate
• Other Study ID Numbers: 20070009; The Danish Data; Protection Agency 2007-41-0014