Familial Amyotrophic Lateral SclerosisPhase 1/2NCT01083667
SOD1 Inhibition by Pyrimethamine in Familial Amyotrophic Lateral Sclerosis (ALS)
A Phase 1/2 study testing Pyrimethamine in people with Familial Amyotrophic Lateral Sclerosis, run by Weill Medical College of Cornell University at 5 sites in 4 countries.
Trial summary
The objective of this study will be to evaluate the safety, tolerability and effect on SOD1 levels by pyrimethamine in patients with familial amyotrophic lateral sclerosis. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Familial Amyotrophic Lateral Sclerosis
- What is being tested?
- Pyrimethamine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 32 participants
- Where
- 5 sitesin 4 countries
- Study dates
- Nov 2009to May 2016
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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
- Subjects with definite, probable, or laboratory supported probable ALS will be eligible.
- ALS diagnosed as probable, laboratory supported probable or definite according to the World Federation of Neurology El Escorial criteria [Brooks et al. 2000]
- Age 18 or older
- Capable of providing informed consent and complying with trial procedures
- SOD1 mutation confirmation by study team
- Not taking Riluzole (Rilutek) or on a stable dose for 30 days
- Not taking Coenzyme QR10R or on a stable dose and brand for 30 days
- Absence of exclusion criteria
Who cannot join
- History or evidence of malabsorption syndromes
- Exposure to any experimental agent within 30 days of onset of this protocol
- Women who are pregnant or planning to become pregnant
- Women of childbearing potential not practicing contraception
- Women who are breastfeeding
- Enrollment in another research study within 30 days of or during this trial
Show all 19Show fewer
- Alcoholism
- Patients taking phenytoin (Dilantin) or other therapy affecting folate levels
- Dementia (MMSE <22)
- Seizure disorder
- Folate deficiency
- Megaloblastic anemia
- Cardiovascular disorder/arrhythmia
- Impaired kidney function, defined as creatinine levels of 2.5 x ULN
- Impaired liver function, defined as AST or ALT of 3 X ULN
- Advanced ALS patients, defined as those with any of the following: forced vital capacity <60% (use of BIPAP is allowed); tracheostomy; or mechanical ventilation
- Use of any of the following medications: cytosine, arabinoside, methotrexate, daunorubicin, sulfonamides, zidovudine, lorazepam, coumadin, sulfamethoxazole, and trimethoprim
- Patients taking Lithium within 30 days of or during this trial
- Incapable of providing informed consent and complying with trial procedures
Trial locations and contacts
5 sites in 4 countries.
5 sites in 4 countries
United States2 sites
Methodist Neurological Institute
Houston, Texas, 77030
Weill Cornell Medical Center/New York Presbyterian Hospital
New York, New York, 10021
About this study
Official title: Phase I/II Study of SOD1 Inhibition by Pyrimethamine in Familial ALS
The objective of this study will be to evaluate the safety, tolerability and effect on SOD1 levels by pyrimethamine in patients with familial amyotrophic lateral sclerosis.
Read the detailed description
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing relentlessly progressive weakness of the arms, legs and respiratory muscles that is uniformly fatal. There are approximately 30,000 patients living with ALS in the United States. There is no treatment. The cause is uncertain in most patients. However, 3% of patients (< 1000 in number) have a familial form of ALS (FALS), phenotypically identical to the sporadic illness, that is caused by a mutation in the gene coding for the free radical scavenging enzyme copper/zinc superoxide dismutase (SOD1). Inserting the SOD1 mutant gene into mice causes them to develop a disease closely resembling ALS.
Inhibiting expression of the SOD1 gene prevents animals from developing the disease. Increasing or decreasing the number of mutated genes proportionately speeds or slows the progression of the disease. Therefore, reducing SOD1 levels in patients with SOD1 associated FALS may be a promising therapeutic approach. Through an extensive in vitro screening program for medications having the ability to reduce SOD1 levels, several molecules that reduce SOD1 protein levels are known. One of the most potent molecules is pyrimethamine, an FDA approved medication used for the treatment of malaria and toxoplasmosis. Pyrimethamine dramatically reduces SOD1 levels in mice and our preliminary studies show similar findings in humans. Our study's primary objective is to determine if familial ALS patients taking pyrimethamine will show a decline in SOD1 levels in the CSF by 15% or more. We will also determine if SOD1 and pyrimethamine are present in the blood and if the SOD-1 levels decline over the course of the study. We will also evaluate the safety and tolerability of pyrimethamine in patients with FALS. Secondary objectives will be to determine dose optimization for maximal SOD1 level reduction and tolerability of medication. We will also assess the feasibility of proceeding to phase II/III studies using pyrimethamine. Change in ALS-FRS, Appel ALS score and quality of life will also be measured. A clinical effect realized in patients with FALS associated with an SOD1 mutation may serve as an important foundation toward finding a treatment for sporadic ALS.
- Conditions
- Familial Amyotrophic Lateral Sclerosis
- Being tested
- Pyrimethamine
- Keywords
- ALS, Familial ALS, SOD1 Gene Mutation
- Medical subject headings
- Amyotrophic Lateral Sclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PyrimethamineDrug
Also called Daraprim
Open Label, dose escalating,
| Study group | Role | What they receive |
|---|---|---|
| Pyrimethamine | Experimental | Open label. Only one arm will receive the intervention. Receives: Drug: Pyrimethamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mean Change in SOD1 CSF
Reported change in mean SOD1 CSf from baseline to visit 6 (week 18) and end of study for all subjects who completed the measure
Measured: baseline, Visit 6 week 18, end of study
Secondary outcomes (1)
Appel ALS Score
an objective and timed measurement of strength and function of subjects including muscle testing, respiratory function and fine motor function, all summed together for a total value, and is measured at baseline, visit 2, visit 6 and end of study. The scale ranges from 30 in a healthy person to to 164 in a maximally impaired person; an increase in score indicates progression and is expected in disease progression.
Measured: Week 0, 6, 18, and end of study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Mar 2010 (estimated)
- Study startNov 2009
- Primary completionDec 2014
- Study completionMay 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Familial Amyotrophic Lateral SclerosisStudies of the same condition, open and under way.
- More trials run by Weill Medical College of Cornell UniversityThe 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 32 participants (actual)
Sponsor and investigators
- Lead sponsor
- Weill Medical College of Cornell University
- Sponsor type
- University, hospital or other
- Collaborators
- Muscular Dystrophy Association
- Responsible party
- Principal investigator, Dr. Dale J. Lange, Weill Medical College of Cornell University
- Investigators
- Dale J. Lange, M.D., Principal investigator, Hospital for Special Surgery/Weill Cornell Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01083667
- Sponsor's protocol ID
- 0903010259
- Status last verified
- May 2017
- First submitted
- 17 Dec 2009
- Last updated
- 19 Jun 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 19 Jun 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Study of SOD1 Inhibition by Pyrimethamine in Familial ALS
- ClinicalTrials.gov ID
- NCT01083667
- Acronym / sponsor ID
- 0903010259
- Conditions
- Familial Amyotrophic Lateral Sclerosis
- Keywords
- ALS, Familial ALS, SOD1 Gene Mutation
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 32 participants (actual)
- Lead sponsor
- Weill Medical College of Cornell UniversityUniversity, hospital or other
- Collaborators
- Muscular Dystrophy Association
- Study start
- Nov 2009
- Primary completion
- Dec 2014 (actual)
- Study completion
- May 2016 (actual)
- First posted
- 10 Mar 2010 (estimated)
- Results
- Posted 19 Jun 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The objective of this study will be to evaluate the safety, tolerability and effect on SOD1 levels by pyrimethamine in patients with familial amyotrophic lateral sclerosis.
Detailed description
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing relentlessly progressive weakness of the arms, legs and respiratory muscles that is uniformly fatal. There are approximately 30,000 patients living with ALS in the United States. There is no treatment. The cause is uncertain in most patients. However, 3% of patients (< 1000 in number) have a familial form of ALS (FALS), phenotypically identical to the sporadic illness, that is caused by a mutation in the gene coding for the free radical scavenging enzyme copper/zinc superoxide dismutase (SOD1). Inserting the SOD1 mutant gene into mice causes them to develop a disease closely resembling ALS.
Inhibiting expression of the SOD1 gene prevents animals from developing the disease. Increasing or decreasing the number of mutated genes proportionately speeds or slows the progression of the disease. Therefore, reducing SOD1 levels in patients with SOD1 associated FALS may be a promising therapeutic approach. Through an extensive in vitro screening program for medications having the ability to reduce SOD1 levels, several molecules that reduce SOD1 protein levels are known. One of the most potent molecules is pyrimethamine, an FDA approved medication used for the treatment of malaria and toxoplasmosis. Pyrimethamine dramatically reduces SOD1 levels in mice and our preliminary studies show similar findings in humans. Our study's primary objective is to determine if familial ALS patients taking pyrimethamine will show a decline in SOD1 levels in the CSF by 15% or more. We will also determine if SOD1 and pyrimethamine are present in the blood and if the SOD-1 levels decline over the course of the study. We will also evaluate the safety and tolerability of pyrimethamine in patients with FALS. Secondary objectives will be to determine dose optimization for maximal SOD1 level reduction and tolerability of medication. We will also assess the feasibility of proceeding to phase II/III studies using pyrimethamine. Change in ALS-FRS, Appel ALS score and quality of life will also be measured. A clinical effect realized in patients with FALS associated with an SOD1 mutation may serve as an important foundation toward finding a treatment for sporadic ALS.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Pyrimethamine | Experimental | Drug: PyrimethamineOpen label. Only one arm will receive the intervention. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Subjects with definite, probable, or laboratory supported probable ALS will be eligible.
Key exclusion criteria (19 listed)
- History or evidence of malabsorption syndromes
- Exposure to any experimental agent within 30 days of onset of this protocol
- Women who are pregnant or planning to become pregnant
- Women of childbearing potential not practicing contraception
- Women who are breastfeeding
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 |
|---|---|---|
| PyrimethamineAlso: DaraprimOpen Label, dose escalating, | Drug | Pyrimethamine |
Primary outcome
Mean Change in SOD1 CSF
Time frame: baseline, Visit 6 week 18, end of study
Reported change in mean SOD1 CSf from baseline to visit 6 (week 18) and end of study for all subjects who completed the measure
1 secondary outcome
Appel ALS Score
Time frame: Week 0, 6, 18, and end of study
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Jun 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Undecided
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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.
Dale J. Lange, M.D. principal investigator
Hospital for Special Surgery/Weill Cornell Medical Center
5 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Pyrimethamine in people with Familial Amyotrophic Lateral Sclerosis, run by Weill Medical College of Cornell University at 5 sites in 4 countries.
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 8 inclusion and 19 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 19 Jun 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in United States, Germany, Italy, Sweden. 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?
Yes. Results are posted in the registry (first posted 19 Jun 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Mean Change in SOD1 CSF (time frame: baseline, Visit 6 week 18, end of study). 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 19 Jun 2017.