Pyrimethamine as a Treatment for Late-Onset GM2-gangliosidosis (Tay-Sachs and Sandhoff Disease)
The objectives of this clinical trial are to assess the safety and tolerability, as well as efficacy, of a stepwise dosing regimen of pyrimethamine, starting at 25 mg/day, given as a single dose daily for 4 weeks in patients affected with chronic Tay-Sachs or Sandhoff variants.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Proposed Investigator-Initiated Clinical Trial of Pyrimethamine as a Treatment for Late-Onset GM2-gangliosidosis (Tay-Sachs and Sandhoff Disease)|
- Efficacy of pyrimethamine [ Time Frame: Baseline, before exposure to pyrimethamine, and Weeks 4, 8, 12, 16 and 18. ] [ Designated as safety issue: No ]Changes in Hex A and Hex B, β-glucuronidase using blood assays
- Pyrimethamine Blood levels [ Time Frame: Weekly (1-18 weeks) ] [ Designated as safety issue: No ]
- Pyrimethamine efficacy [ Time Frame: 6 months ] [ Designated as safety issue: No ]Measurement of GM2 in blood samples
|Study Start Date:||August 2009|
|Study Completion Date:||November 2010|
|Primary Completion Date:||November 2010 (Final data collection date for primary outcome measure)|
Pyrimethamine will be taken orally as a single daily dose of 25 mg/day for 4 weeks, then increasing by 25 mg per dose in three four-week steps, to a final dose of 100 mg/dayDrug: Leucovorin
To eliminate or minimize potential hematologic effects of Pyrimethamine, Leucovorin is to be co-administered with Pyrimethamine at a dose level of 5 mg per day, given when Pyrimethamine is administered.
Patients with late-onset Tay-Sachs or Sandhoff disease will be given increasing doses of Pyr, up to but not exceeding doses used to treat malaria, over a 5-month period. We will follow the effect of the treatment on the levels of Hex A enzyme activity in white blood cells, which are considered to be a reflection of the likely enzyme activity in the brain. We will also follow some other lysosomal enzyme activities to determine if the effect is specific for Hex A. Furthermore, we will examine the effect of the treatment on the levels of GM2-ganglioside in the white blood cells. On the basis of the studies done on cultured skin cells, we expect that treatment with Pyr will increase the levels of Hex A and decrease the accumulation of GM2-ganglioside in the white blood cells.
|The Hospital for Sick Children|
|Toronto, Ontario, Canada, M5G 1X8|
|Principal Investigator:||Joe T Clarke, MD||The Hospital for Sick Children|