A Phase I Study of Pyrimethamine in Patients With GM2 Gangliosidosis

NCT00679744 | Withdrawn Phase 1

• 3 other identifiers: 3448CL-Pyrimethamine-001FDA OPD Grant: FD-R-03448-01
• Study Type: interventional
• Target: N/A
• Locations: 2 countries
• Sites: 3

Brief Summary

Adult Tay-Sachs disease and Sandhoff diseases are caused by deficiency of an enzyme called β-hexosaminidase A, or Hex A in short. This enzyme is located in a particular cellular component, called lysosomes, inside the brain cells. The reason that Hex A of patients with Adult Tay-Sachs disease or Sandhoff disease is deficient is because this enzyme had gone through mutation, resulting in it not working very well. In healthy people, Hex A efficiently breaks down GM2-ganglioside, which is a by-product from cells of our body. However, patients with Adult Tay-Sachs disease or Sandhoff disease cannot efficiently break down GM2-ganglioside in the body. Therefore, these patients have high levels of this by-product in the brain cells, which causes the brain to be unable to function normally. There is a drug called Pyrimethamine. This drug is used by doctors to treat specific types of infections called malaria and toxoplasmosis. Our laboratory test tube studies have shown that Pyrimethamine can help the Hex A enzyme to function in a normal manner. If Hex A can function normally in presence of Pyrimethamine, this drug should be able restore the brain malfunction of these patients since Hex A can now efficiently break down GM2-ganglioside with Pyrimethamine treatment. Although results from laboratory test tube studies are promising and Pyrimethamine should theoretically restore brain function of these patients, we do not know if Pyrimethamine is safe or if it would actually work in patients. This study is the first study (a Phase I study) of testing Pyrimethamine to treat Adult Tay-Sachs and Sandhoff diseases. The objective of this study is to see if Pyrimethamine is safe in these patients and to see if it can restore the brain function of these patients.

Conditions

G(M2) Ganglioside; Tay-Sachs Disease Ganglioside; Sandhoff Disease Ganglioside

Keywords

Tay-Sachs disease.; Sandhoff disease.; GM2 Gangliosidosis.; β-hexosaminidase deficiency.; Hexosaminidase; Phase I clinical trial.

Outcome Measures

Primary Outcomes (1)

• The primary outcome measure is safety and tolerability, based on conventional laboratory and clinical assessments.

  The primary outcome measure, which is safety and tolerability, will be assessed weekly during the 8-week treatment period and biweekly during the 4-week post-treatment period.

Secondary Outcomes (1)

• The secondary outcome measure is to assess changes in β-hexosaminidase A and B activities in plasma and peripheral blood leukocytes.

  The secondary outcome measure will be assessed weekly during the 4-week treatment period and at the end of the 4-week post-treatment period.

Study Arms (1)

4 dose levels

ACTIVE COMPARATOR

Pyrimethamine at 6.25, 12.5, 25 and 37.5 mg/day will be evaluated sequentially, starting from 6.25 mg/day. Escalation from 6.25 mg/day to 12.5 mg/day, and from 12.5 mg/day to 25 mg/day, will not perform until all patients in the previous dose cohort have been treated for 4 weeks and until results obtained 4 weeks after treatment initiation do not reveal toxicity. Additionally, escalation from 25 mg/day to 37.5 mg/day will not perform until all patients in the 25-mg/day cohort have been treated for 8 weeks, and until results obtained 4 weeks after the 8-week treatment do not reveal toxicity. Dose escalation is considered complete, if 2 patients experience a Grade 3 Adverse Event (AE) or if 1 patient experiences a Grade 4 AE at a particular cohort.

Drug: Pyrimethamine

Interventions

Pyrimethamine DRUG

Pyrimethamine will be given PO once daily for 8 consecutive weeks.

4 dose levels

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: 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 HEX-A or HEX-B genes, which has been shown to respond to Pyrimethamine treatment in previous cell culture experiments (Maegawa et al. 2006).
• Must be 18 years of age or older to participate in the study.
• Able to understand and cooperate with the requirements of the study protocol.
• Mentally competent, have ability to understand and willingness to sign the informed consent form.
• Able to travel to the participating study site.
• Women of child-bearing potential must use accepted contraceptive methods, and must have a negative serum or urine pregnancy test within 2 days 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 be within acceptable range.
• Body weight \>40 kg (88 pounds).

You may not qualify if:

• Serious medical illness, significant cardiac disease that would increase patients' risk for toxicity.
• Any hematologic or related abnormality, especially megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia, atrophic glossitis, hematuria, and disorders of cardiac rhythm, pulmonary eosinophilia, etc.
• Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., active peptic ulcer disease).
• Possible folate deficiency, such as individuals with malabsorption syndrome, alcoholism, or pregnancy, 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 (because Pyrimethamine is a "Pregnancy Category C" product).
• Lactating females because of the potential for serious adverse reactions in nursing infants.
• 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 or to the inactive ingredients (corn and potato starch, lactose, and magnesium stearate).
• Evidence of systemic infection, or anyone who in the opinion of the investigator would not be suitable for the study.
• Test positive for HIV.
• Test positive for hepatitis B or hepatitis C.
• Patients with a history of convulsive disorders, since these patients are very susceptible to the nervous system toxicity of Pyrimethamine.
• Patients receiving any other investigational treatment for any indication within the past 4 weeks prior to initiation of Pyrimethamine treatment.

Sponsors & Collaborators

• Exsar Corporation: lead
• University Hospitals Cleveland Medical Center: collaborator
• NYU Langone Health: collaborator
• The Hospital for Sick Children: collaborator

Study Sites (3)

New York University, School of Medicine, Department of Neurology

New York, New York, 10016, United States

Location

University Hospitals of Cleveland

Cleveland, Ohio, 44106, United States

Location

Division of Clinical & Metabolic Genetics, Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Related Publications (1)

• Maegawa GH, Tropak M, Buttner J, Stockley T, Kok F, Clarke JT, Mahuran DJ. Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis. J Biol Chem. 2007 Mar 23;282(12):9150-61. doi: 10.1074/jbc.M609304200. Epub 2007 Jan 21.

  PMID: 17237499 BACKGROUND

MeSH Terms

Conditions

Tay-Sachs Disease; Sandhoff Disease; Gangliosidoses, GM2

Interventions

Pyrimethamine

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

Study Officials

• Bijan Almassian, Ph.D.

  Exsar Corporation

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Intervention Model: FACTORIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2008
• First Posted: May 19, 2008
• Study Start: May 1, 2008
• Primary Completion: March 1, 2010
• Last Updated: February 25, 2013

Record last verified: 2013-02

Locations

US (2); CA (1)