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SOD1 Inhibition by Pyrimethamine in Familial Amyotrophic Lateral Sclerosis (ALS)

This study has been completed.
Muscular Dystrophy Association
Information provided by (Responsible Party):
Dr. Dale J. Lange, Weill Medical College of Cornell University Identifier:
First received: December 17, 2009
Last updated: August 14, 2016
Last verified: August 2016

December 17, 2009
August 14, 2016
November 2009
December 2014   (Final data collection date for primary outcome measure)
Protein in the cerebrospinal fluid [ Time Frame: baseline, week 12, end of study ]
Same as current
Complete list of historical versions of study NCT01083667 on Archive Site
Adverse Events [ Time Frame: Week 3, 6, 9, 12, 15, 18, 24, 30, & 36 visits ]
Same as current
Not Provided
Not Provided
SOD1 Inhibition by Pyrimethamine in Familial Amyotrophic Lateral Sclerosis (ALS)
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.

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. We will also assess the feasibility of proceeding to phase II/III studies using pyrimethamine. Using futility methodology in which patients treated with pyrimethamine will be compared to historical controls, 40 patients with mild to moderate FALS and SOD1 mutations will receive up to 75 mg of pyrimethamine for 36 weeks. A change of 15% in the slope of decline will be deemed significant with a power of 80.7 percent. Change in ALS-FRS 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.

Phase 1
Phase 2
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Familial Amyotrophic Lateral Sclerosis
Drug: Pyrimethamine
Open Label, dose escalating,
Other Name: Daraprim
Experimental: Pyrimethamine
Open label. Only one arm will receive the intervention.
Intervention: Drug: Pyrimethamine
Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
May 2016
December 2014   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
Contact information is only displayed when the study is recruiting subjects
United States,   Germany,   Italy,   Sweden
Not Provided
Not Provided
Not Provided
Dr. Dale J. Lange, Weill Medical College of Cornell University
Weill Medical College of Cornell University
Muscular Dystrophy Association
Principal Investigator: Dale J. Lange, M.D. Hospital for Special Surgery/Weill Cornell Medical Center
Weill Medical College of Cornell University
August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP