SOD1 Inhibition by Pyrimethamine in Familial Amyotrophic Lateral Sclerosis (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.
Familial Amyotrophic Lateral Sclerosis
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I/II Study of SOD1 Inhibition by Pyrimethamine in Familial ALS|
- Protein in the cerebrospinal fluid [ Time Frame: baseline, week 12, end of study ] [ Designated as safety issue: No ]
- Adverse Events [ Time Frame: Week 3, 6, 9, 12, 15, 18, 24, 30, & 36 visits ] [ Designated as safety issue: No ]
|Study Start Date:||November 2009|
|Estimated Study Completion Date:||December 2015|
|Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
Open label. Only one arm will receive the intervention.
Open Label, dose escalating,
Other Name: Daraprim
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01083667
|United States, New York|
|Weill Cornell Medical Center/New York Presbyterian Hospital|
|New York, New York, United States, 10021|
|United States, Texas|
|Methodist Neurological Institute|
|Houston, Texas, United States, 77030|
|Universitäts- und Rehabilitationskliniken Ulm|
|Milano Neurological Institute|
|Principal Investigator:||Dale J. Lange, M.D.||Hospital for Special Surgery/Weill Cornell Medical Center|