G(M2) Ganglioside Clinical Trial
Official title:
A Dose-Escalated, Double-Blind, Placebo-Controlled, Randomized Phase I Clinical Trial of Pyrimethamine in Patients Affected With Chronic GM2 Gangliosidosis (Tay-Sachs or Sandhoff Variants)
| Verified date | February 2013 |
| Source | Exsar Corporation |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | United States: Food and Drug Administration |
| Study type | Interventional |
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.
| Status | Withdrawn |
| Enrollment | 0 |
| Est. completion date | |
| Est. primary completion date | March 2010 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years and older |
| Eligibility |
Inclusion Criteria: - Biochemically and genetically confirmed diagnosis of GM2 Gangliosidosis caused by ß-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). Exclusion Criteria: - 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. - A history of cancer of any type, since Pyrimethamine may be carcinogenic. - Patients who have received immunotherapy of any type within the past 4 weeks prior to initiation of Pyrimethamine treatment. - Patients who are receiving antifolic drugs and drugs associated with myelosuppression, or patients who are receiving drugs, when used in combination with Pyrimethamine, have been reported to induce some degree of hepatotoxicity: - Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients. |
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
| Country | Name | City | State |
|---|---|---|---|
| Canada | Division of Clinical & Metabolic Genetics, Hospital for Sick Children | Toronto | Ontario |
| United States | University Hospitals of Cleveland | Cleveland | Ohio |
| United States | New York University, School of Medicine, Department of Neurology | New York | New York |
| Lead Sponsor | Collaborator |
|---|---|
| Exsar Corporation | New York University School of Medicine, The Hospital for Sick Children, University Hospital Case Medical Center |
United States, Canada,
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. Epub 2007 Jan 21. — View Citation
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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. | Yes | |
| Secondary | The secondary outcome measure is to assess changes in ß-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. | No |