Study Purpose:
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.Study Status:
Not recruiting
Disease:
Familial Amyotrophic Lateral Sclerosis
Study Type:
Interventional
Type of Intervention:
Drug
Intervention Name:
Pyrimethamine
Placebo:
Phase:
Phase 1/Phase 2
Study Chair(s)/Principal Investigator(s):
Dale J. Lange, M.D., Hospital for Special Surgery/Weill Cornell Medical Center
Clinicaltrials.gov ID:
Neals Affiliated?
No
Coordinating Center Contact Information
Weill Medical College of Cornell University
1305 York Avenue
New York, New York, 10021 United States
Full Study Summary:
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 Sponsor:
Weill Medical College of Cornell University
Participant Duration:
9 months
Estimated Enrollment:
32
Estimated Study Start Date:
10 / 31 / 2009
Estimated Study Completion Date:
05 / 01 / 2016
Posting Last Modified Date:
06 / 19 / 2017
Date Study Added to neals.org:
03 / 10 / 2010
Minimum Age:
18 Years
Maximum Age:
N/A
Inclusion Criteria:- Subjects with definite, probable, or laboratory supported probable ALS will be eligible.
1. ALS diagnosed as probable, laboratory supported probable or definite according to the World Federation of Neurology El Escorial criteria [Brooks et al. 2000]
2. Age 18 or older
3. Capable of providing informed consent and complying with trial procedures
4. SOD1 mutation confirmation by study team
5. Not taking Riluzole (Rilutek) or on a stable dose for 30 days
6. Not taking Coenzyme QR10R or on a stable dose and brand for 30 days
7. Absence of exclusion criteria
Exclusion Criteria:
1. History or evidence of malabsorption syndromes
2. Exposure to any experimental agent within 30 days of onset of this protocol
3. Women who are pregnant or planning to become pregnant
4. Women of childbearing potential not practicing contraception
5. Women who are breastfeeding
6. Enrollment in another research study within 30 days of or during this trial
7. Alcoholism
8. Patients taking phenytoin (Dilantin) or other therapy affecting folate levels
9. Dementia (MMSE <22)
10. Seizure disorder
11. Folate deficiency
12. Megaloblastic anemia
13. Cardiovascular disorder/arrhythmia
14. Impaired kidney function, defined as creatinine levels of 2.5 x ULN
15. Impaired liver function, defined as AST or ALT of 3 X ULN
16. Advanced ALS patients, defined as those with any of the following: forced vital capacity <60% (use of BIPAP is allowed); tracheostomy; or mechanical ventilation
17. Use of any of the following medications: cytosine, arabinoside, methotrexate, daunorubicin, sulfonamides, zidovudine, lorazepam, coumadin, sulfamethoxazole, and trimethoprim
18. Patients taking Lithium within 30 days of or during this trial
19. Incapable of providing informed consent and complying with trial procedures
Weill Cornell Medical Center/New York Presbyterian Hospital
New York, New York
10021
United States
Methodist Neurological Institute
Houston, Texas
77030
United States
Universitäts- und Rehabilitationskliniken Ulm
Ulm
Germany
Milano Neurological Institute
Milan
Italy
Umea University
Umea
Sweden