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

Brief Title

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

Official Title

Proposed Investigator-Initiated Clinical Trial of Pyrimethamine as a Treatment for Late-Onset GM2-gangliosidosis (Tay-Sachs and Sandhoff Disease)

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.
    

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.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Efficacy of pyrimethamine

Secondary Outcome

 Pyrimethamine Blood levels

Condition

Gangliosidoses, GM2

Intervention

Pyrimethamine

Study Arms / Comparison Groups

 Pyrimethamine
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

20

Start Date

August 2009

Completion Date

November 2010

Primary Completion Date

November 2010

Eligibility Criteria

        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.
      

Gender

All

Ages

17 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Joe T Clarke, MD, , 

Location Countries

Canada

Location Countries

Canada

Administrative Informations


NCT ID

NCT01102686

Organization ID

1000013660


Responsible Party

Sponsor

Study Sponsor

The Hospital for Sick Children


Study Sponsor

Joe T Clarke, MD, Principal Investigator, The Hospital for Sick Children


Verification Date

February 2012