Ignite Creation Date:
2025-12-25 @ 12:37 AM
Ignite Modification Date:
2025-12-27 @ 5:39 AM
Study NCT ID:
NCT01083667
Status:
COMPLETED
Last Update Posted:
2017-06-19
First Post:
2009-12-17
Is NOT Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
SOD1 Inhibition by Pyrimethamine in Familial Amyotrophic Lateral Sclerosis (ALS)
Sponsor:
Organization:
Raw JSON
{'hasResults': True, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'D000690', 'term': 'Amyotrophic Lateral Sclerosis'}], 'ancestors': [{'id': 'D013118', 'term': 'Spinal Cord Diseases'}, {'id': 'D002493', 'term': 'Central Nervous System Diseases'}, {'id': 'D009422', 'term': 'Nervous System Diseases'}, {'id': 'D016472', 'term': 'Motor Neuron Disease'}, {'id': 'D019636', 'term': 'Neurodegenerative Diseases'}, {'id': 'D057177', 'term': 'TDP-43 Proteinopathies'}, {'id': 'D009468', 'term': 'Neuromuscular Diseases'}, {'id': 'D057165', 'term': 'Proteostasis Deficiencies'}, {'id': 'D008659', 'term': 'Metabolic Diseases'}, {'id': 'D009750', 'term': 'Nutritional and Metabolic Diseases'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'D011739', 'term': 'Pyrimethamine'}], 'ancestors': [{'id': 'D011743', 'term': 'Pyrimidines'}, {'id': 'D006573', 'term': 'Heterocyclic Compounds, 1-Ring'}, {'id': 'D006571', 'term': 'Heterocyclic Compounds'}]}}, 'resultsSection': {'moreInfoModule': {'pointOfContact': {'email': 'langed@hss.edu', 'phone': '6467978917', 'title': 'Dale Lange', 'organization': 'HSS/WCMC'}, 'certainAgreement': {'piSponsorEmployee': False, 'restrictiveAgreement': False}}, 'adverseEventsModule': {'timeFrame': "AE's were collected over the course of the study and up to 30 days following the last dose taken.", '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.\n\nSAE reporting per criteria od clinicaltrials.gov", 'eventGroups': [{'id': 'EG000', 'title': 'Pyrimethamine', 'description': 'Open label. Only one arm will receive the intervention.\n\nPyrimethamine: Open Label, dose escalating,', 'otherNumAtRisk': 32, 'deathsNumAtRisk': 32, 'otherNumAffected': 14, 'seriousNumAtRisk': 32, 'deathsNumAffected': 0, 'seriousNumAffected': 1}], 'otherEvents': [{'term': 'Headache', 'notes': 'headache following spinal tap', 'stats': [{'groupId': 'EG000', 'numAtRisk': 32, 'numEvents': 13, 'numAffected': 13}], 'organSystem': 'Nervous system disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'CTCAE (4.0)'}, {'term': 'Nausea', 'notes': 'GI nausea', 'stats': [{'groupId': 'EG000', 'numAtRisk': 32, 'numEvents': 14, 'numAffected': 14}], 'organSystem': 'Metabolism and nutrition disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'CTCAE (4.0)'}, {'term': 'Diarrhea', 'stats': [{'groupId': 'EG000', 'numAtRisk': 32, 'numEvents': 6, 'numAffected': 6}], 'organSystem': 'Metabolism and nutrition disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'CTCAE (4.0)'}, {'term': 'Pain', 'notes': 'Pain following Spinal Tap', 'stats': [{'groupId': 'EG000', 'numAtRisk': 32, 'numEvents': 5, 'numAffected': 5}], 'organSystem': 'Musculoskeletal and connective tissue disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'CTCAE (4.0)'}, {'term': 'weight loss', 'notes': 'greater than 5% was recorded', 'stats': [{'groupId': 'EG000', 'numAtRisk': 32, 'numEvents': 3, 'numAffected': 3}], 'organSystem': 'Metabolism and nutrition disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'CTCAE (4.0)'}, {'term': 'Upper respiratory infection', 'notes': 'URI infection and Pneumonia', 'stats': [{'groupId': 'EG000', 'numAtRisk': 32, 'numEvents': 4, 'numAffected': 4}], 'organSystem': 'Infections and infestations', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'CTCAE (4.0)'}, {'term': 'decreased appetite', 'stats': [{'groupId': 'EG000', 'numAtRisk': 32, 'numEvents': 2, 'numAffected': 2}], 'organSystem': 'Metabolism and nutrition disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'CTCAE (4.0)'}], 'seriousEvents': [{'term': 'Pneumonia', 'notes': 'Patient admitted to the hospital with pneumonia while on study, course complicated by discovery of a congenital esophageal fistula which was repaired, patient discharged home and continued on the study. The event was not related to study medication.', 'stats': [{'groupId': 'EG000', 'numAtRisk': 32, 'numEvents': 1, 'numAffected': 1}], 'organSystem': 'Infections and infestations', 'assessmentType': 'SYSTEMATIC_ASSESSMENT', 'sourceVocabulary': 'CTCAE (4.0)'}], 'frequencyThreshold': '0'}, 'outcomeMeasuresModule': {'outcomeMeasures': [{'type': 'PRIMARY', 'title': 'Mean Change in SOD1 CSF', 'denoms': [{'units': 'Participants', 'counts': [{'value': '22', 'groupId': 'OG000'}]}], 'groups': [{'id': 'OG000', 'title': 'Pyrimethamine', 'description': 'Open label. Only one arm will receive the intervention.\n\nPyrimethamine: Open Label, dose escalating,'}], 'classes': [{'categories': [{'measurements': [{'value': '6.8', 'groupId': 'OG000', 'lowerLimit': '3.4', 'upperLimit': '10.3'}]}]}], 'paramType': 'MEAN', 'timeFrame': 'baseline, Visit 6 week 18, end of study', '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', 'unitOfMeasure': 'ng/ml', 'dispersionType': '95% Confidence Interval', 'reportingStatus': 'POSTED', 'populationDescription': '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.'}, {'type': 'SECONDARY', 'title': 'Appel ALS Score', 'denoms': [{'units': 'Participants', 'counts': [{'value': '22', 'groupId': 'OG000'}]}], 'groups': [{'id': 'OG000', 'title': 'Pyrimethamine', 'description': 'Open label. Only one arm will receive the intervention.\n\nPyrimethamine: Open Label, dose escalating,'}], 'classes': [{'categories': [{'measurements': [{'value': '18', 'groupId': 'OG000', 'lowerLimit': '12', 'upperLimit': '24'}]}]}], 'paramType': 'NUMBER', 'timeFrame': 'Week 0, 6, 18, and end of study', '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.', 'unitOfMeasure': 'units on a scale', 'dispersionType': '95% Confidence Interval', 'reportingStatus': 'POSTED', 'populationDescription': '22 subjects completed to visit 9 and had a final score for Appel Score. Reported is the mean change from Baseline to week 36'}]}, 'participantFlowModule': {'groups': [{'id': 'FG000', 'title': 'Pyrimethamine', 'description': 'Open label. Only one arm will receive the intervention.\n\nPyrimethamine: Open Label, dose escalating,'}], 'periods': [{'title': 'Overall Study', 'milestones': [{'type': 'STARTED', 'achievements': [{'comment': 'enrolled', 'groupId': 'FG000', 'numSubjects': '32'}]}, {'type': 'COMPLETED', 'achievements': [{'comment': '22 completed to visit 9, the last visit on study.', 'groupId': 'FG000', 'numSubjects': '22'}]}, {'type': 'NOT COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '10'}]}]}], 'recruitmentDetails': 'Patient were recruited from all sites and referrals received from other physicians. Subjects also contacted sites from ClinicalTrials.gov posting'}, 'baselineCharacteristicsModule': {'denoms': [{'units': 'Participants', 'counts': [{'value': '32', 'groupId': 'BG000'}]}], 'groups': [{'id': 'BG000', 'title': 'Pyrimethamine', 'description': 'Open label. Only one arm will receive the intervention.\n\nPyrimethamine: Open Label, dose escalating,'}], 'measures': [{'title': 'Age, Categorical', 'classes': [{'categories': [{'title': '<=18 years', 'measurements': [{'value': '0', 'groupId': 'BG000'}]}, {'title': 'Between 18 and 65 years', 'measurements': [{'value': '31', 'groupId': 'BG000'}]}, {'title': '>=65 years', 'measurements': [{'value': '1', 'groupId': 'BG000'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'description': 'age of subjects enrolled', 'unitOfMeasure': 'Participants'}, {'title': 'Age, Continuous', 'classes': [{'categories': [{'measurements': [{'value': '48', 'groupId': 'BG000', 'lowerLimit': '19', 'upperLimit': '72'}]}]}], 'paramType': 'MEAN', 'unitOfMeasure': 'years', 'dispersionType': 'FULL_RANGE'}, {'title': 'Sex: Female, Male', 'classes': [{'categories': [{'title': 'Female', 'measurements': [{'value': '16', 'groupId': 'BG000'}]}, {'title': 'Male', 'measurements': [{'value': '16', 'groupId': 'BG000'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'description': 'gender of subjects enrolled', 'unitOfMeasure': 'Participants'}, {'title': 'Region of Enrollment', 'classes': [{'title': 'United States', 'categories': [{'measurements': [{'value': '20', 'groupId': 'BG000'}]}]}, {'title': 'Italy', 'categories': [{'measurements': [{'value': '8', 'groupId': 'BG000'}]}]}, {'title': 'Germany', 'categories': [{'measurements': [{'value': '4', 'groupId': 'BG000'}]}]}], 'paramType': 'NUMBER', 'description': 'enrollment of subjects in US and Europe', 'unitOfMeasure': 'participants'}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE1', 'PHASE2'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'NA', 'maskingInfo': {'masking': 'NONE'}, 'primaryPurpose': 'TREATMENT', 'interventionModel': 'SINGLE_GROUP'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 32}}, 'statusModule': {'overallStatus': 'COMPLETED', 'startDateStruct': {'date': '2009-11'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2017-05', 'completionDateStruct': {'date': '2016-05', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2017-05-19', 'studyFirstSubmitDate': '2009-12-17', 'resultsFirstSubmitDate': '2017-02-17', 'studyFirstSubmitQcDate': '2010-03-08', 'lastUpdatePostDateStruct': {'date': '2017-06-19', 'type': 'ACTUAL'}, 'resultsFirstSubmitQcDate': '2017-05-19', 'studyFirstPostDateStruct': {'date': '2010-03-10', 'type': 'ESTIMATED'}, 'resultsFirstPostDateStruct': {'date': '2017-06-19', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2014-12', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Mean Change in SOD1 CSF', 'timeFrame': 'baseline, Visit 6 week 18, end of study', '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'}], 'secondaryOutcomes': [{'measure': 'Appel ALS Score', 'timeFrame': 'Week 0, 6, 18, and end of study', '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.'}]}, 'oversightModule': {'oversightHasDmc': True}, 'conditionsModule': {'keywords': ['ALS', 'Familial ALS', 'SOD1 Gene Mutation'], 'conditions': ['Familial Amyotrophic Lateral Sclerosis']}, 'descriptionModule': {'briefSummary': '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.', 'detailedDescription': "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.\n\nInhibiting 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."}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT', 'OLDER_ADULT'], 'minimumAge': '18 Years', 'healthyVolunteers': False, 'eligibilityCriteria': 'Inclusion Criteria:\n\n* Subjects with definite, probable, or laboratory supported probable ALS will be eligible.\n\n 1. ALS diagnosed as probable, laboratory supported probable or definite according to the World Federation of Neurology El Escorial criteria \\[Brooks et al. 2000\\]\n 2. Age 18 or older\n 3. Capable of providing informed consent and complying with trial procedures\n 4. SOD1 mutation confirmation by study team\n 5. Not taking Riluzole (Rilutek) or on a stable dose for 30 days\n 6. Not taking Coenzyme QR10R or on a stable dose and brand for 30 days\n 7. Absence of exclusion criteria\n\nExclusion Criteria:\n\n1. History or evidence of malabsorption syndromes\n2. Exposure to any experimental agent within 30 days of onset of this protocol\n3. Women who are pregnant or planning to become pregnant\n4. Women of childbearing potential not practicing contraception\n5. Women who are breastfeeding\n6. Enrollment in another research study within 30 days of or during this trial\n7. Alcoholism\n8. Patients taking phenytoin (Dilantin) or other therapy affecting folate levels\n9. Dementia (MMSE \\<22)\n10. Seizure disorder\n11. Folate deficiency\n12. Megaloblastic anemia\n13. Cardiovascular disorder/arrhythmia\n14. Impaired kidney function, defined as creatinine levels of 2.5 x ULN\n15. Impaired liver function, defined as AST or ALT of 3 X ULN\n16. Advanced ALS patients, defined as those with any of the following: forced vital capacity \\<60% (use of BIPAP is allowed); tracheostomy; or mechanical ventilation\n17. Use of any of the following medications: cytosine, arabinoside, methotrexate, daunorubicin, sulfonamides, zidovudine, lorazepam, coumadin, sulfamethoxazole, and trimethoprim\n18. Patients taking Lithium within 30 days of or during this trial\n19. Incapable of providing informed consent and complying with trial procedures'}, 'identificationModule': {'nctId': 'NCT01083667', 'briefTitle': 'SOD1 Inhibition by Pyrimethamine in Familial Amyotrophic Lateral Sclerosis (ALS)', 'organization': {'class': 'OTHER', 'fullName': 'Weill Medical College of Cornell University'}, 'officialTitle': 'Phase I/II Study of SOD1 Inhibition by Pyrimethamine in Familial ALS', 'orgStudyIdInfo': {'id': '0903010259'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'EXPERIMENTAL', 'label': 'Pyrimethamine', 'description': 'Open label. Only one arm will receive the intervention.', 'interventionNames': ['Drug: Pyrimethamine']}], 'interventions': [{'name': 'Pyrimethamine', 'type': 'DRUG', 'otherNames': ['Daraprim'], 'description': 'Open Label, dose escalating,', 'armGroupLabels': ['Pyrimethamine']}]}, 'contactsLocationsModule': {'locations': [{'zip': '10021', 'city': 'New York', 'state': 'New York', 'country': 'United States', 'facility': 'Weill Cornell Medical Center/New York Presbyterian Hospital', 'geoPoint': {'lat': 40.71427, 'lon': -74.00597}}, {'zip': '77030', 'city': 'Houston', 'state': 'Texas', 'country': 'United States', 'facility': 'Methodist Neurological Institute', 'geoPoint': {'lat': 29.76328, 'lon': -95.36327}}, {'city': 'Ulm', 'country': 'Germany', 'facility': 'Universitäts- und Rehabilitationskliniken Ulm', 'geoPoint': {'lat': 48.39841, 'lon': 9.99155}}, {'city': 'Milan', 'country': 'Italy', 'facility': 'Milano Neurological Institute', 'geoPoint': {'lat': 45.46427, 'lon': 9.18951}}, {'city': 'Umeå', 'country': 'Sweden', 'facility': 'Umea University', 'geoPoint': {'lat': 63.82842, 'lon': 20.25972}}], 'overallOfficials': [{'name': 'Dale J. Lange, M.D.', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'Hospital for Special Surgery/Weill Cornell Medical Center'}]}, 'ipdSharingStatementModule': {'ipdSharing': 'UNDECIDED'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Weill Medical College of Cornell University', 'class': 'OTHER'}, 'collaborators': [{'name': 'Muscular Dystrophy Association', 'class': 'OTHER'}], 'responsibleParty': {'type': 'PRINCIPAL_INVESTIGATOR', 'investigatorTitle': 'Neurologist in Chief', 'investigatorFullName': 'Dr. Dale J. Lange', 'investigatorAffiliation': 'Weill Medical College of Cornell University'}}}}