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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01083667
Recruitment Status : Completed
First Posted : March 10, 2010
Results First Posted : June 19, 2017
Last Update Posted : June 19, 2017
Muscular Dystrophy Association
Information provided by (Responsible Party):
Dr. Dale J. Lange, Weill Medical College of Cornell University

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
Familial Amyotrophic Lateral Sclerosis Drug: Pyrimethamine 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of SOD1 Inhibition by Pyrimethamine in Familial ALS
Study Start Date : November 2009
Actual Primary Completion Date : December 2014
Actual Study Completion Date : May 2016

Arm Intervention/treatment
Experimental: Pyrimethamine
Open label. Only one arm will receive the intervention.
Drug: Pyrimethamine
Open Label, dose escalating,
Other Name: Daraprim

Primary Outcome Measures :
  1. 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

Secondary Outcome Measures :
  1. Appel ALS Score [ Time Frame: 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.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01083667

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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
Ulm, Germany
Milano Neurological Institute
Milan, Italy
Umea University
Umea, Sweden
Sponsors and Collaborators
Weill Medical College of Cornell University
Muscular Dystrophy Association
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Principal Investigator: Dale J. Lange, M.D. Hospital for Special Surgery/Weill Cornell Medical Center
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Responsible Party: Dr. Dale J. Lange, Neurologist in Chief, Weill Medical College of Cornell University Identifier: NCT01083667    
Other Study ID Numbers: 0903010259
First Posted: March 10, 2010    Key Record Dates
Results First Posted: June 19, 2017
Last Update Posted: June 19, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Dr. Dale J. Lange, Weill Medical College of Cornell University:
Familial ALS
SOD1 Gene Mutation
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Folic Acid Antagonists
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action