Gangliosidoses, GM2Phase 1/2NCT01102686
Pyrimethamine as a Treatment for Late-Onset GM2-gangliosidosis (Tay-Sachs and Sandhoff Disease)
A Phase 1/2 study testing Pyrimethamine and Leucovorin in people with Gangliosidoses, GM2 and Sandhoff Disease, run by The Hospital for Sick Children at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 17 years and older
- Conditions the study is for
- Gangliosidoses, GM2, Sandhoff Disease, Tay-Sachs Disease
- What is being tested?
- Pyrimethamine and Leucovorin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteCanada
- Study dates
- Aug 2009to Nov 2010
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
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 17 years and older
- All sexes
- No healthy volunteers
- Child, 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 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;
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- 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.
Who cannot join
- 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;
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Proposed Investigator-Initiated Clinical Trial of Pyrimethamine as a Treatment for Late-Onset GM2-gangliosidosis (Tay-Sachs and Sandhoff Disease)
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.
Read the 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.
- Conditions
- Gangliosidoses, GM2, Sandhoff Disease, Tay-Sachs Disease
- Being tested
- Pyrimethamine, Leucovorin
- Keywords
- Late-onset GM2-gangliosidosis, pyrimethamine
- Medical subject headings
- Gangliosidoses, GM2, Sandhoff Disease, Tay-Sachs Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PyrimethamineDrug
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
LeucovorinDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Pyrimethamine | Experimental | Not described Receives: Drug: Pyrimethamine; Drug: Leucovorin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Efficacy of pyrimethamine
Changes in Hex A and Hex B, β-glucuronidase using blood assays
Measured: Baseline, before exposure to pyrimethamine, and Weeks 4, 8, 12, 16 and 18.
Secondary outcomes (2)
Pyrimethamine Blood levels
Measured: Weekly (1-18 weeks)
Pyrimethamine efficacy
Measurement of GM2 in blood samples
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Apr 2010 (estimated)
- Study startAug 2009
- Primary completionNov 2010
- Study completionNov 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Gangliosidoses, GM2Studies of the same condition, open and under way.
- More trials run by The Hospital for Sick ChildrenThe sponsor's other registered studies.
- 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 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Hospital for Sick Children
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Joe T Clarke, MD, Principal investigator, The Hospital for Sick Children
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01102686
- Sponsor's protocol ID
- 1000013660
- Status last verified
- Feb 2012
- First submitted
- 16 Oct 2009
- Last updated
- 23 Feb 2012
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 23 Feb 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Proposed Investigator-Initiated Clinical Trial of Pyrimethamine as a Treatment for Late-Onset GM2-gangliosidosis (Tay-Sachs and Sandhoff Disease)
- ClinicalTrials.gov ID
- NCT01102686
- Acronym / sponsor ID
- 1000013660
- Conditions
- Gangliosidoses, GM2, Sandhoff Disease, Tay-Sachs Disease
- Keywords
- Late-onset GM2-gangliosidosis, pyrimethamine
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- The Hospital for Sick ChildrenUniversity, hospital or other
- Study start
- Aug 2009
- Primary completion
- Nov 2010 (actual)
- Study completion
- Nov 2010 (actual)
- First posted
- 13 Apr 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Pyrimethamine | Experimental | Drug: Pyrimethamine, Drug: Leucovorin |
Who may qualify
- Ages
- 17 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (9 listed)
- 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;
Key exclusion criteria (15 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PyrimethaminePyrimethamine 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 | Drug | Pyrimethamine |
| LeucovorinTo 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. | Drug | Pyrimethamine |
Primary outcome
Efficacy of pyrimethamine
Time frame: Baseline, before exposure to pyrimethamine, and Weeks 4, 8, 12, 16 and 18.
Changes in Hex A and Hex B, β-glucuronidase using blood assays
2 secondary outcomes
Pyrimethamine Blood levels
Time frame: Weekly (1-18 weeks)
Pyrimethamine efficacy
Time frame: 6 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Feb 2012.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Joe T Clarke, MD principal investigator
The Hospital for Sick Children
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Pyrimethamine and Leucovorin in people with Gangliosidoses, GM2 and Sandhoff Disease, run by The Hospital for Sick Children at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Feb 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Efficacy of pyrimethamine (time frame: Baseline, before exposure to pyrimethamine, and Weeks 4, 8, 12, 16 and 18.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Feb 2012.