G(M2) GangliosidePhase 1NCT00679744
A Phase I Study of Pyrimethamine in Patients With GM2 Gangliosidosis
A Phase 1 study testing Pyrimethamine in people with G(M2) Ganglioside and Tay-Sachs Disease Ganglioside, run by Exsar Corporation at 3 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- G(M2) Ganglioside, Tay-Sachs Disease Ganglioside, Sandhoff Disease Ganglioside
- What is being tested?
- Pyrimethamine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 3 sitesin 2 countries
- Study dates
- May 2008to Mar 2010
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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).
Who cannot join
- 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).
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- 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.
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
United States2 sites
University Hospitals of Cleveland
Cleveland, Ohio, 44106
New York University, School of Medicine, Department of Neurology
New York, New York, 10016
Canada1 site
Division of Clinical & Metabolic Genetics, Hospital for Sick Children
Toronto, Ontario, M5G 1X8
About this study
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)
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.
Read the detailed description
Adult Tay-Sachs (TSD) and Sandhoff disease (SD) result from a deficiency of lysosomal heterodimeric β-hexosaminidase A (Hex A, αβ). These disorders are characterized by progressive neurological deterioration that mainly affects motor, cerebral and spinocerebellar function. They affect fewer than 1000 people in the United States. There is no effective treatment for these diseases.
Substantial evidence supports a disease model for TSD and SD which attributes pathology to decreased or absent Hex A levels in neuronal lysosomes of the brain. The problem in GM2 - gangliosidosis is the inability of the cell to metabolize GM2 gangliosides. When the residual activity of Hex A falls below a critical threshold level, GM2 ganglioside influx into the lysosome (the site of Hex A activity) exceeds the degradation rate and excess substrate continuously accumulates. Consequently, the lysosomes increase in size and number, giving rise to a storage disease.
The majority of the mutations in Hex A affect the ability of the enzyme to obtain and/or retain its native 3-dimensional fold in the endoplasmic reticulum (ER) where intracellular quality control is performed to retain and degrade defective enzymes. Pharmacological chaperones (PC)s are small molecules that can stabilize the native conformation of a mutant enzyme in the ER and allow it to escape the ER's quality control system and its associated degradation pathway (ERAD). PCs have the potential to act as drugs when they can stabilize the native conformation of a mutant enzyme.
In 2006 ExSAR applied for orphan drug designation from the FDA for Pyrimethamine (Pyrimethamine) for the treatment of patients affected with late-onset GM2-gangliosidosis. The application is pending the positive outcome of clinical trials. Pyrimethamine is an FDA-approved drug which readily passes the bloodbrain barrier (BBB). It is currently used to treat malaria and toxoplasmosis. Our in vitro cell-based studies with fibroblasts from these patients show that Pyrimethamine can function as a PC for Hex A and raise intracellular Hex A levels. Our hypothesis is that Pyrimethamine administered to adult TSD and SD patients can improve neurological function and health.
The over objective of the project is to assess the safety and tolerability of the drug. We first conduct a Phase I trial, which is the current study, using Pyrimethamine to treat patients affected with GM2-gangliosidosis. Hex A and B (αβ) activities in plasma and peripheral blood leukocytes will also be measured. The working hypotheses of the Phase I trial are that Pyrimethamine administered according to the regimen of the trial will be tolerated and safe and result in increased Hex A levels in blood and brain.
- Being tested
- Pyrimethamine
- Keywords
- Tay-Sachs disease., Sandhoff disease., GM2 Gangliosidosis., β-hexosaminidase deficiency., Hexosaminidase, Phase I clinical trial.
- Medical subject headings
- Tay-Sachs Disease, Sandhoff Disease, Gangliosidoses, GM2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PyrimethamineDrug
Pyrimethamine will be given PO once daily for 8 consecutive weeks.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Pyrimethamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
The primary outcome measure is safety and tolerability, based on conventional laboratory and clinical assessments.
Measured: 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.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 May 2008 (estimated)
- Study startMay 2008
- Primary completionMar 2010
Why it stopped: Due to lack of funding
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for G(M2) GangliosideStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Exsar Corporation
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- University Hospitals Cleveland Medical Center, NYU Langone Health, The Hospital for Sick Children
- Responsible party
- Sponsor
- Investigators
- Bijan Almassian, Ph.D., Study chair, Exsar Corporation
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00679744
- Sponsor's protocol ID
- 3448
- Other IDs
- CL-Pyrimethamine-001, FDA OPD Grant: FD-R-03448-01
- Status last verified
- Feb 2013
- First submitted
- 15 May 2008
- Last updated
- 25 Feb 2013
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 17237499