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

NCT01102686 | Completed Phase 1 DMC

• 1 other identifier: 1000013660
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Gangliosidoses, GM2; Sandhoff Disease; Tay-Sachs Disease

Keywords

Late-onset GM2-gangliosidosis; pyrimethamine

Outcome Measures

Primary Outcomes (1)

• Efficacy of pyrimethamine

  Changes in Hex A and Hex B, β-glucuronidase using blood assays

  Baseline, before exposure to pyrimethamine, and Weeks 4, 8, 12, 16 and 18.

Secondary Outcomes (2)

• Pyrimethamine Blood levels

  Weekly (1-18 weeks)

• Pyrimethamine efficacy

  6 months

Study Arms (1)

Pyrimethamine

EXPERIMENTAL

Drug: Pyrimethamine; Drug: Leucovorin

Interventions

Pyrimethamine DRUG

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

Pyrimethamine

Leucovorin DRUG

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.

Pyrimethamine

Eligibility Criteria

• Age: 17 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• The Hospital for Sick Children: lead

Study Sites (1)

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

MeSH Terms

Conditions

Gangliosidoses, GM2; Sandhoff Disease; Tay-Sachs Disease

Interventions

Pyrimethamine; Leucovorin

Condition Hierarchy (Ancestors)

Gangliosidoses; Sphingolipidoses; 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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Intervention Hierarchy (Ancestors)

Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes

Study Officials

• Joe T Clarke, MD

  The Hospital for Sick Children

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 16, 2009
• First Posted: April 13, 2010
• Study Start: August 1, 2009
• Primary Completion: November 1, 2010
• Study Completion: November 1, 2010
• Last Updated: February 23, 2012

Record last verified: 2012-02

Locations

CA (1)