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

Methotrexate Induced Nephrotoxicity Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00570817
• Other study ID #: 20070009
• Secondary ID: The Danish DataP
• Status: Completed
• Phase: N/A
• First received: December 10, 2007
• Last updated: November 4, 2011
• Start date: June 2007
• Est. completion date: October 2010

Study information

• Verified date: January 2011
• Source: University of Aarhus
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: The Regional Committee on Biomedical Research Ethics
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: October 2010
• Est. primary completion date: October 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 21 Years

Eligibility

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 Design

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Methotrexate Induced Nephrotoxicity

Intervention

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.

Locations

Country	Name	City	State
Denmark	Aarhus University Hospital, Skejby	Aarhus	Aarhus N

Sponsors (3)

Lead Sponsor	Collaborator
University of Aarhus	Danish Child Cancer Foundation, ML Jørgensen og Gunnar Hansens Foundation

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	No
Secondary	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.	No
Secondary	Days of hospitalization in relation to the methotrexate infusion.		Days in relation to the methotrexate infusion and side effects.	No
Secondary	Difference in baseline creatinine to highest serum creatinine between groups.		From initiation of the methotrexate infusion and up til 14 days after.	No
Secondary	Drug exposure measured by area under the curve.		From 23 hours til 66 hours after initiation of the methotrexate infusion.	No
Secondary	Duration and degree of side effects to the methotrexate treatment.		From initiation of the methotrexate infusion and up til on month after.	No
Secondary	Total dosage of leucovorin.		From initiation of the methotrexate infusion and til serum methotrexate concentration is below 0,2 micromol/l.	No