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Pyrimethamine as a Treatment for Late-Onset GM2-gangliosidosis (Tay-Sachs and Sandhoff Disease)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01102686
Recruitment Status : Completed
First Posted : April 13, 2010
Last Update Posted : February 23, 2012
Information provided by (Responsible Party):
The Hospital for Sick Children

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Gangliosidoses, GM2 Sandhoff Disease Tay-Sachs Disease Drug: Pyrimethamine Drug: Leucovorin Phase 1 Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (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)
Study Start Date : August 2009
Actual Primary Completion Date : November 2010
Actual Study Completion Date : November 2010

Arm Intervention/treatment
Experimental: Pyrimethamine Drug: Pyrimethamine
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/day

Drug: 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.

Primary Outcome Measures :
  1. Efficacy of pyrimethamine [ Time Frame: Baseline, before exposure to pyrimethamine, and Weeks 4, 8, 12, 16 and 18. ]
    Changes in Hex A and Hex B, β-glucuronidase using blood assays

Secondary Outcome Measures :
  1. Pyrimethamine Blood levels [ Time Frame: Weekly (1-18 weeks) ]
  2. Pyrimethamine efficacy [ Time Frame: 6 months ]
    Measurement of GM2 in blood samples

Information from the National Library of Medicine

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Ages Eligible for Study:   17 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • biochemically and genetically confirmed diagnosis of GM2-gangliosidosis caused by β-hexosaminidase deficiency resulting from mutations in the HEXA or HEXB genes;
  • having HEXA or HEXB mutations shown to be responsive to pyrimethamine in vitro;
  • over 17 years of age at the time of study initiation;
  • able to understand and cooperate with the requirements of the study protocol;
  • mentally competent, have the ability to understand and willingness to sign the informed consent form;
  • able to travel to one of the three participating study sites;
  • women of child-bearing potential must use accepted contraceptive methods and must have a negative serum or urine pregnancy test within one week prior to treatment initiation;
  • fertile men must practice effective contraceptive methods during the study period, unless documentation of infertility exists;
  • laboratory values ≤2 weeks prior to randomization must show adequate hematologic, hepatic, renal, and coagulation function; and body weight >40 kg.

Exclusion Criteria:

  • serious medical illness, significant cardiac disease or severe debilitating pulmonary disease;
  • any hematologic abnormality, especially megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia;
  • any active uncontrolled bleeding or any bleeding diathesis (e.g., active peptic ulcer disease);
  • possible folate deficiency, and those receiving therapy (such as phenytoin) affecting folate levels;
  • any complex disease that may confound treatment assessment;
  • pregnant women or women of child-bearing potential not using reliable means of contraception;
  • lactating females;
  • fertile men unwilling to practice contraceptive methods during the study period;
  • unwilling or unable to follow protocol requirements;
  • known hypersensitivity reactions, intolerance or adverse reactions to pyrimethamine;
  • evidence of active infection, or serious infection within the past month;
  • HIV infection;
  • a history of cancer of any type;
  • receiving any other standard or investigational treatment for any indication within the past 4 weeks prior to initiation of pyrimethamine treatment;
  • receiving immunotherapy of any type within the past 4 weeks prior to initiation of pyrimethamine treatment; or any condition or abnormality, which may, in the opinion of the investigator, compromise the safety of patients.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01102686

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Canada, Ontario
The Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Sponsors and Collaborators
The Hospital for Sick Children
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Principal Investigator: Joe T Clarke, MD The Hospital for Sick Children
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Responsible Party: The Hospital for Sick Children Identifier: NCT01102686    
Other Study ID Numbers: 1000013660
First Posted: April 13, 2010    Key Record Dates
Last Update Posted: February 23, 2012
Last Verified: February 2012
Keywords provided by The Hospital for Sick Children:
Late-onset GM2-gangliosidosis
Additional relevant MeSH terms:
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Tay-Sachs Disease
Sandhoff Disease
Gangliosidoses, GM2
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Protective Agents
Physiological Effects of Drugs
Vitamin B Complex
Growth Substances
Antiprotozoal Agents