Prevention of Methotrexate Induced Nephrotoxicity and Prolonged Drug Elimination Time With 12 Hours Prehydration
Condition: Methotrexate Induced Nephrotoxicity
Study type: Interventional

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.
    

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.
    

Intervention name(s): 12 hours of prehydration
Intervention type(s): Other
Intervention description(s): 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.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Methotrexate; Nephrotoxicity; Hydration; Acute lymphoblastic leukemia; Non-Hodgkin's lymphoma; Medulloblastoma; Ependymoma; Prolonged elimination time of methotrexate