SOD1 Inhibition by Pyrimethamine in Familial Amyotrophic Lateral Sclerosis (ALS)
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
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
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Pyrimethamine Open label. Only one arm will receive the intervention. |
Drug: Pyrimethamine
Open Label, dose escalating,
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Mean Change in SOD1 CSF [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
Secondary Outcome Measures
- Appel ALS Score [Week 0, 6, 18, and end of study]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
- 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
Exclusion Criteria:
-
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
-
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Weill Cornell Medical Center/New York Presbyterian Hospital | New York | New York | United States | 10021 |
| 2 | Methodist Neurological Institute | Houston | Texas | United States | 77030 |
| 3 | Universitäts- und Rehabilitationskliniken Ulm | Ulm | Germany | ||
| 4 | Milano Neurological Institute | Milan | Italy | ||
| 5 | Umea University | Umea | Sweden |
Sponsors and Collaborators
- Weill Medical College of Cornell University
- Muscular Dystrophy Association
Investigators
- Principal Investigator: Dale J. Lange, M.D., Hospital for Special Surgery/Weill Cornell Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 0903010259
Study Results
Participant Flow
| Recruitment Details | Patient were recruited from all sites and referrals received from other physicians. Subjects also contacted sites from ClinicalTrials.gov posting |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Pyrimethamine |
|---|---|
| Arm/Group Description | Open label. Only one arm will receive the intervention. Pyrimethamine: Open Label, dose escalating, |
| Period Title: Overall Study | |
| STARTED | 32 |
| COMPLETED | 22 |
| NOT COMPLETED | 10 |
Baseline Characteristics
| Arm/Group Title | Pyrimethamine |
|---|---|
| Arm/Group Description | Open label. Only one arm will receive the intervention. Pyrimethamine: Open Label, dose escalating, |
| Overall Participants | 32 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
31
96.9%
|
| >=65 years |
1
3.1%
|
| Age (years) [Mean (Full Range) ] | |
| Mean (Full Range) [years] |
48
|
| Sex: Female, Male (Count of Participants) | |
| Female |
16
50%
|
| Male |
16
50%
|
| Region of Enrollment (participants) [Number] | |
| United States |
20
62.5%
|
| Italy |
8
25%
|
| Germany |
4
12.5%
|
Outcome Measures
| Title | Mean Change in SOD1 CSF |
|---|---|
| Description | Reported change in mean SOD1 CSf from baseline to visit 6 (week 18) and end of study for all subjects who completed the measure |
| Time Frame | baseline, Visit 6 week 18, end of study |
Outcome Measure Data
| Analysis Population Description |
|---|
| 24 subjects completed up to visit 6 and 21 subjects for final study visit. Reported is the change in SOD1 CSF from baseline to week 36. |
| Arm/Group Title | Pyrimethamine |
|---|---|
| Arm/Group Description | Open label. Only one arm will receive the intervention. Pyrimethamine: Open Label, dose escalating, |
| Measure Participants | 22 |
| Mean (95% Confidence Interval) [ng/ml] |
6.8
|
| Title | Appel ALS Score |
|---|---|
| Description | 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. |
| Time Frame | Week 0, 6, 18, and end of study |
Outcome Measure Data
| Analysis Population Description |
|---|
| 22 subjects completed to visit 9 and had a final score for Appel Score. Reported is the mean change from Baseline to week 36 |
| Arm/Group Title | Pyrimethamine |
|---|---|
| Arm/Group Description | Open label. Only one arm will receive the intervention. Pyrimethamine: Open Label, dose escalating, |
| Measure Participants | 22 |
| Number (95% Confidence Interval) [units on a scale] |
18
|
Adverse Events
| Time Frame | AE's were collected over the course of the study and up to 30 days following the last dose taken. | |
|---|---|---|
| Adverse Event Reporting Description | CTCAE version 4.0 was used to assess the severity of AE's experienced during the study. This uses a grading system (referring to the severity) to assess the AEs. The CTCAE v4.0 displays Grades 1-5 with unique clinical descriptions of severity for each AE based on this general guideline: G1 Mild AE, G2 Moderate AE, G3 Severe or medically significant but not immediately life-threatening, G4 Life-threatening, G5 Death related to AE. SAE reporting per criteria od clinicaltrials.gov | |
| Arm/Group Title | Pyrimethamine | |
| Arm/Group Description | Open label. Only one arm will receive the intervention. Pyrimethamine: Open Label, dose escalating, | |
All Cause Mortality |
||
| Pyrimethamine | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/32 (0%) | |
Serious Adverse Events |
||
| Pyrimethamine | ||
| Affected / at Risk (%) | # Events | |
| Total | 1/32 (3.1%) | |
| Infections and infestations | ||
| Pneumonia | 1/32 (3.1%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Pyrimethamine | ||
| Affected / at Risk (%) | # Events | |
| Total | 14/32 (43.8%) | |
| Infections and infestations | ||
| Upper respiratory infection | 4/32 (12.5%) | 4 |
| Metabolism and nutrition disorders | ||
| Nausea | 14/32 (43.8%) | 14 |
| Diarrhea | 6/32 (18.8%) | 6 |
| weight loss | 3/32 (9.4%) | 3 |
| decreased appetite | 2/32 (6.3%) | 2 |
| Musculoskeletal and connective tissue disorders | ||
| Pain | 5/32 (15.6%) | 5 |
| Nervous system disorders | ||
| Headache | 13/32 (40.6%) | 13 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dale Lange |
|---|---|
| Organization | HSS/WCMC |
| Phone | 6467978917 |
| langed@hss.edu |
- 0903010259