Ignite Creation Date:
2025-12-24 @ 10:22 PM
Ignite Modification Date:
2025-12-28 @ 5:39 AM
Study NCT ID:
NCT04481035
Status:
COMPLETED
Last Update Posted:
2025-07-31
First Post:
2020-04-14
Is Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1
Sponsor:
Organization:
Raw JSON
{'hasResults': True, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24', 'submissionTracking': {'firstMcpInfo': {'postDateStruct': {'date': '2021-07-08', 'type': 'ACTUAL'}}}}, 'conditionBrowseModule': {'meshes': [{'id': 'D009456', 'term': 'Neurofibromatosis 1'}], 'ancestors': [{'id': 'D017253', 'term': 'Neurofibromatoses'}, {'id': 'D009455', 'term': 'Neurofibroma'}, {'id': 'D018317', 'term': 'Nerve Sheath Neoplasms'}, {'id': 'D009380', 'term': 'Neoplasms, Nerve Tissue'}, {'id': 'D009370', 'term': 'Neoplasms by Histologic Type'}, {'id': 'D009369', 'term': 'Neoplasms'}, {'id': 'D009386', 'term': 'Neoplastic Syndromes, Hereditary'}, {'id': 'D020752', 'term': 'Neurocutaneous Syndromes'}, {'id': 'D009422', 'term': 'Nervous System Diseases'}, {'id': 'D020271', 'term': 'Heredodegenerative Disorders, Nervous System'}, {'id': 'D019636', 'term': 'Neurodegenerative Diseases'}, {'id': 'D010523', 'term': 'Peripheral Nervous System Diseases'}, {'id': 'D009468', 'term': 'Neuromuscular Diseases'}, {'id': 'D030342', 'term': 'Genetic Diseases, Inborn'}, {'id': 'D009358', 'term': 'Congenital, Hereditary, and Neonatal Diseases and Abnormalities'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'D000111', 'term': 'Acetylcysteine'}, {'id': 'D001239', 'term': 'Inhalation'}], 'ancestors': [{'id': 'D003545', 'term': 'Cysteine'}, {'id': 'D000603', 'term': 'Amino Acids, Sulfur'}, {'id': 'D013457', 'term': 'Sulfur Compounds'}, {'id': 'D009930', 'term': 'Organic Chemicals'}, {'id': 'D000596', 'term': 'Amino Acids'}, {'id': 'D000602', 'term': 'Amino Acids, Peptides, and Proteins'}, {'id': 'D015656', 'term': 'Respiratory Mechanics'}, {'id': 'D012119', 'term': 'Respiration'}, {'id': 'D012143', 'term': 'Respiratory Physiological Phenomena'}, {'id': 'D002943', 'term': 'Circulatory and Respiratory Physiological Phenomena'}]}}, 'resultsSection': {'moreInfoModule': {'pointOfContact': {'email': 'donald.gilbert@cchmc.org', 'phone': '513-636-4222', 'title': 'Donald L. Gilbert MD', 'organization': "Cincinnati Children's Hospital Medical Center"}, 'certainAgreement': {'piSponsorEmployee': False, 'restrictiveAgreement': False}}, 'adverseEventsModule': {'timeFrame': '18 weeks', 'eventGroups': [{'id': 'EG000', 'title': 'N-Acetylcysteine Treatment', 'description': 'Participants will be dosed with 70 mg/kg/dose (max dose 900 mg) three times per day of N-Acetylcysteine (NAC) for eight (8) weeks.', 'otherNumAtRisk': 5, 'deathsNumAtRisk': 5, 'otherNumAffected': 0, 'seriousNumAtRisk': 5, 'deathsNumAffected': 0, 'seriousNumAffected': 0}, {'id': 'EG001', 'title': 'Placebo', 'description': 'Participants will be dosed three times per day with a placebo for eight (8) weeks.', 'otherNumAtRisk': 5, 'deathsNumAtRisk': 5, 'otherNumAffected': 0, 'seriousNumAtRisk': 5, 'deathsNumAffected': 0, 'seriousNumAffected': 0}], 'frequencyThreshold': '5'}, 'outcomeMeasuresModule': {'outcomeMeasures': [{'type': 'PRIMARY', 'title': 'Change From Baseline in Motor Function Measured by Physical and Neurological Examination for Subtle Signs (PANESS)', 'denoms': [{'units': 'Participants', 'counts': [{'value': '5', 'groupId': 'OG000'}, {'value': '5', 'groupId': 'OG001'}]}], 'groups': [{'id': 'OG000', 'title': 'N-Acetylcysteine', 'description': 'Participants will be dosed with 70 mg/kg/dose (max dose 900 mg) three times per day of N-Acetylcysteine (NAC) for eight (8) weeks. This is a double-blind study, neither study participant nor study team members will know whether the participant is given study drug or placebo until after all data is collected.\n\nN-acetylcysteine (NAC): The study design is essentially a cross-sectional survey and then longitudinal evaluation of cognition and behavior, motor function, cortical function, and metabolomics profiles in NF1 before and after 8 weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC) or placebo. This is a cross-over double-blind placebo controlled study. Participants in the experimental phase/arm will receive 70 mg/kg/dose (max dose 900 mg) three times per day of NAC for eight (8) weeks.'}, {'id': 'OG001', 'title': 'Placebo', 'description': 'Participants will be dosed three times per day with a placebo for eight (8) weeks. This is a double-blind study, neither study participant nor study team members will know whether the participant is given study drug or placebo until after all data is collected.\n\nPlacebo: The study design is essentially a cross-sectional survey and then longitudinal evaluation of cognition and behavior, motor function, cortical function, and metabolomics profiles in NF1 before and after 8 weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC) or placebo. This is a cross-over double-blind placebo controlled study. Participants in the placebo phase/arm will receive placebo (non-drug) three times per day for eight (8) weeks.'}], 'classes': [{'categories': [{'measurements': [{'value': '0', 'groupId': 'OG000', 'lowerLimit': '-8', 'upperLimit': '2'}, {'value': '3', 'groupId': 'OG001', 'lowerLimit': '-4', 'upperLimit': '25'}]}]}], 'paramType': 'MEDIAN', 'timeFrame': 'At baseline and end of 8 weeks treatment with either NAC or placebo (weeks 0 and 8 for treatment phase one of this cross-over double blind study and at weeks 10 and 18 for treatment phase two).', 'description': 'Characterize effects of NAC treatment on motor function in kids with NF1 using the Physical and Neurological Examination for Subtle Signs (PANESS). This is a validated scale that consistently demonstrates significant impairments in children with ADHD, and which preliminary data suggest may demonstrate more extreme problems in children with NF1 than age-matched healthy controls (unpublished data from CCHMC). The investigators hypothesize that motor function scores rated with the PANESS scale will improve after treatment with NAC. The range of this scale is 0-119, higher scores correlate with symptom severity (worse outcome).', 'unitOfMeasure': 'score on a scale', 'dispersionType': 'Full Range', 'reportingStatus': 'POSTED', 'populationDescription': 'Descriptive only'}, {'type': 'PRIMARY', 'title': 'Change From Baseline in ADHD Symptoms as Reported Via Parent/Teacher Surveys', 'denoms': [{'units': 'Participants', 'counts': [{'value': '5', 'groupId': 'OG000'}, {'value': '5', 'groupId': 'OG001'}]}], 'groups': [{'id': 'OG000', 'title': 'N-Acetylcysteine', 'description': 'Participants will be dosed with 70 mg/kg/dose (max dose 900 mg) three times per day of N-Acetylcysteine (NAC) for eight (8) weeks. This is a double-blind study, neither study participant nor study team members will know whether the participant is given study drug or placebo until after all data is collected.\n\nN-acetylcysteine (NAC): The study design is essentially a cross-sectional survey and then longitudinal evaluation of cognition and behavior, motor function, cortical function, and metabolomics profiles in NF1 before and after 8 weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC) or placebo. This is a cross-over double-blind placebo controlled study. Participants in the experimental phase/arm will receive 70 mg/kg/dose (max dose 900 mg) three times per day of NAC for eight (8) weeks.'}, {'id': 'OG001', 'title': 'Placebo', 'description': 'Participants will be dosed three times per day with a placebo for eight (8) weeks. This is a double-blind study, neither study participant nor study team members will know whether the participant is given study drug or placebo until after all data is collected.\n\nPlacebo: The study design is essentially a cross-sectional survey and then longitudinal evaluation of cognition and behavior, motor function, cortical function, and metabolomics profiles in NF1 before and after 8 weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC) or placebo. This is a cross-over double-blind placebo controlled study. Participants in the placebo phase/arm will receive placebo (non-drug) three times per day for eight (8) weeks.'}], 'classes': [{'categories': [{'measurements': [{'value': '-12.5', 'spread': '13.1', 'groupId': 'OG000'}, {'value': '-3.75', 'spread': '12.0', 'groupId': 'OG001'}]}]}], 'paramType': 'MEAN', 'timeFrame': 'At baseline and end of 8 weeks treatment with either NAC or placebo (weeks 0 and 8 for treatment phase one of this cross-over double blind study and at weeks 10 and 18 for treatment phase two).', 'description': 'Characterize effects of NAC treatment on ADHD symptoms in children with NF1. The investigators hypothesize that ADHD attention and hyperactive/impulsive symptoms, rated with the DuPaul DSM-5 based clinical rating scales, will improve after treatment with NAC. The range of this scale is 0-56, higher scores correlate with symptom severity (worse outcome).', 'unitOfMeasure': 'units on a scale', 'dispersionType': 'Standard Deviation', 'reportingStatus': 'POSTED', 'populationDescription': 'Modified ITT - all participants who received at least one dose of study drug'}, {'type': 'SECONDARY', 'title': 'Transcranial Magnetic Stimulation (TMS) - Cortical Silent Period', 'denoms': [{'units': 'Participants', 'counts': [{'value': '5', 'groupId': 'OG000'}, {'value': '5', 'groupId': 'OG001'}]}], 'groups': [{'id': 'OG000', 'title': 'N-Acetylcysteine', 'description': 'Participants will be dosed with 70 mg/kg/dose (max dose 900 mg) three times per day of N-Acetylcysteine (NAC) for eight (8) weeks. This is a double-blind study, neither study participant nor study team members will know whether the participant is given study drug or placebo until after all data is collected.\n\nN-acetylcysteine (NAC): The study design is essentially a cross-sectional survey and then longitudinal evaluation of cognition and behavior, motor function, cortical function, and metabolomics profiles in NF1 before and after 8 weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC) or placebo. This is a cross-over double-blind placebo controlled study. Participants in the experimental phase/arm will receive 70 mg/kg/dose (max dose 900 mg) three times per day of NAC for eight (8) weeks.'}, {'id': 'OG001', 'title': 'Placebo', 'description': 'Participants will be dosed three times per day with a placebo for eight (8) weeks. This is a double-blind study, neither study participant nor study team members will know whether the participant is given study drug or placebo until after all data is collected.\n\nPlacebo: The study design is essentially a cross-sectional survey and then longitudinal evaluation of cognition and behavior, motor function, cortical function, and metabolomics profiles in NF1 before and after 8 weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC) or placebo. This is a cross-over double-blind placebo controlled study. Participants in the placebo phase/arm will receive placebo (non-drug) three times per day for eight (8) weeks.'}], 'classes': [{'categories': [{'measurements': [{'value': '6', 'spread': '19', 'groupId': 'OG000'}, {'value': '-4', 'spread': '18', 'groupId': 'OG001'}]}]}], 'paramType': 'MEAN', 'timeFrame': 'At baseline and end of 8 weeks treatment with either NAC or placebo (weeks 0 and 8 for treatment phase one of this cross-over double blind study and at weeks 10 and 18 for treatment phase two).', 'description': 'Transcranial Magnetic Stimulation (TMS) - Cortical Silent Period (CSP). This measure describes the function and physiology of the motor system using Transcranial Magnetic Stimulation (TMS) over the brain to evoke a muscle twitch in the hand. These evoked potentials provide information about the instantaneous balance of excitation and inhibition in the brain, which in turn relate in part to neurotransmitter levels that can be altered by diseases and by treatments. This measure reflects an inhibitory neurotransmitter called GABA-B and its action at a particular receptor - the "GABA B" receptor. A lengthening of the duration of CSP indicates more inhibition, which is good (within a healthy range of approximately 50 to 150 ms, because outside of that range is abnormal). Here we report the average difference before and after treatment.', 'unitOfMeasure': 'ms', 'dispersionType': 'Standard Deviation', 'reportingStatus': 'POSTED', 'populationDescription': 'modified ITT - at least one dose given'}, {'type': 'SECONDARY', 'title': 'Metabolic Testing Biomarkers', 'timeFrame': 'At baseline and end of 8 weeks treatment with either NAC or placebo (weeks 0 and 8 for treatment phase one of this cross-over double blind study and at weeks 10 and 18 for treatment phase two).', 'description': 'The investigators propose to evaluate the autotaxin/LPC axis. High autotaxin levels correlate with a worse outcome. Low lysophosphatidylcholine (LPC) levels correlate to a worse outcome. The investigators will collect serum and plasma from participants to assess autotaxin/LPC axis prior and post-NAC therapy.\n\nWe will perform serum targeted analysis for LPC, autotaxin activity and LPA measurements pre and post-treatment. We will perform a highly specific mass spectrometry target analysis of LPC species from serum for clinical correlation. We will use authentic standards to accurately measure low and high levels of these biomarkers. We will quantify autotaxin enzyme activity using a fluorometric assay to correlate with LPC measurements. We will quantify LPA using serum ELISA kit.\n\nData is not yet available as the samples in storage for follow up study.', 'reportingStatus': 'NOT_POSTED', 'denomUnitsSelected': 'Participants', 'anticipatedPostingDate': '2025-12'}, {'type': 'OTHER_PRE_SPECIFIED', 'title': 'Evaluation of Change From Baseline in Metabolomics Profiles as a Possible Disease Biomarker Metabolic Testing Biomarkers - Samples in Storage for Follow up Study', 'timeFrame': 'At baseline and end of 8 weeks treatment with either NAC or placebo (weeks 0 and 8 for treatment phase one of this cross-over double blind study and at weeks 10 and 18 for treatment phase two).', 'description': 'In the same cohort, to evaluate metabolomics profiles as a possible disease biomarker that is affected by NF1 and by treatment with NAC as per Aim 1. Hypothesis 4: The investigators hypothesize that specific profiles will predict clinical response to antioxidant therapy compared to age-matched healthy control (unpublished data from CCHMC).', 'reportingStatus': 'NOT_POSTED', 'denomUnitsSelected': 'Participants', 'anticipatedPostingDate': '2025-12'}]}, 'participantFlowModule': {'groups': [{'id': 'FG000', 'title': 'N-Acetylcysteine Followed by Placebo', 'description': 'Participants will be dosed with 70 mg/kg/dose (max dose 900 mg) three times per day of N-Acetylcysteine (NAC) for eight (8) weeks, followed by placebo three times per day for 8 weeks.'}, {'id': 'FG001', 'title': 'Placebo Followed by N-Acetylcysteine', 'description': 'Participants will be dosed three times per day with a placebo for eight (8) weeks followed by 70 mg/kg/dose (max dose 900 mg) three times per day of N-Acetylcysteine for 8 weeks.'}], 'periods': [{'title': 'Period 1', 'milestones': [{'type': 'STARTED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '3'}, {'groupId': 'FG001', 'numSubjects': '2'}]}, {'type': 'COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '3'}, {'groupId': 'FG001', 'numSubjects': '2'}]}, {'type': 'NOT COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '0'}, {'groupId': 'FG001', 'numSubjects': '0'}]}]}, {'title': 'Period 2', 'milestones': [{'type': 'STARTED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '3'}, {'groupId': 'FG001', 'numSubjects': '2'}]}, {'type': 'COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '3'}, {'groupId': 'FG001', 'numSubjects': '2'}]}, {'type': 'NOT COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '0'}, {'groupId': 'FG001', 'numSubjects': '0'}]}]}]}, 'baselineCharacteristicsModule': {'denoms': [{'units': 'Participants', 'counts': [{'value': '3', 'groupId': 'BG000'}, {'value': '2', 'groupId': 'BG001'}, {'value': '5', 'groupId': 'BG002'}]}], 'groups': [{'id': 'BG000', 'title': 'N-Acetylcysteine Followed by Placebo', 'description': 'Participants will be dosed with 70 mg/kg/dose (max dose 900 mg) three times per day of N-Acetylcysteine (NAC) for eight (8) weeks, followed by placebo three times per day for 8 weeks.'}, {'id': 'BG001', 'title': 'Placebo Followed by N-Acetylcysteine', 'description': 'Participants will be dosed three times per day with a placebo for eight (8) weeks followed by 70 mg/kg/dose (max dose 900 mg) three times per day of N-Acetylcysteine for 8 weeks.'}, {'id': 'BG002', 'title': 'Total', 'description': 'Total of all reporting groups'}], 'measures': [{'title': 'Age, Continuous', 'classes': [{'categories': [{'measurements': [{'value': '13', 'groupId': 'BG000', 'lowerLimit': '12', 'upperLimit': '15'}, {'value': '14.5', 'groupId': 'BG001', 'lowerLimit': '12', 'upperLimit': '17'}, {'value': '13', 'groupId': 'BG002', 'lowerLimit': '12', 'upperLimit': '17'}]}]}], 'paramType': 'MEDIAN', 'unitOfMeasure': 'years', 'dispersionType': 'FULL_RANGE'}, {'title': 'Sex: Female, Male', 'classes': [{'categories': [{'title': 'Female', 'measurements': [{'value': '0', 'groupId': 'BG000'}, {'value': '0', 'groupId': 'BG001'}, {'value': '0', 'groupId': 'BG002'}]}, {'title': 'Male', 'measurements': [{'value': '3', 'groupId': 'BG000'}, {'value': '2', 'groupId': 'BG001'}, {'value': '5', 'groupId': 'BG002'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'unitOfMeasure': 'Participants'}, {'title': 'Ethnicity (NIH/OMB)', 'classes': [{'categories': [{'title': 'Hispanic or Latino', 'measurements': [{'value': '0', 'groupId': 'BG000'}, {'value': '0', 'groupId': 'BG001'}, {'value': '0', 'groupId': 'BG002'}]}, {'title': 'Not Hispanic or Latino', 'measurements': [{'value': '3', 'groupId': 'BG000'}, {'value': '2', 'groupId': 'BG001'}, {'value': '5', 'groupId': 'BG002'}]}, {'title': 'Unknown or Not Reported', 'measurements': [{'value': '0', 'groupId': 'BG000'}, {'value': '0', 'groupId': 'BG001'}, {'value': '0', 'groupId': 'BG002'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'unitOfMeasure': 'Participants'}, {'title': 'Race (NIH/OMB)', 'classes': [{'categories': [{'title': 'American Indian or Alaska Native', 'measurements': [{'value': '0', 'groupId': 'BG000'}, {'value': '0', 'groupId': 'BG001'}, {'value': '0', 'groupId': 'BG002'}]}, {'title': 'Asian', 'measurements': [{'value': '0', 'groupId': 'BG000'}, {'value': '0', 'groupId': 'BG001'}, {'value': '0', 'groupId': 'BG002'}]}, {'title': 'Native Hawaiian or Other Pacific Islander', 'measurements': [{'value': '0', 'groupId': 'BG000'}, {'value': '0', 'groupId': 'BG001'}, {'value': '0', 'groupId': 'BG002'}]}, {'title': 'Black or African American', 'measurements': [{'value': '0', 'groupId': 'BG000'}, {'value': '0', 'groupId': 'BG001'}, {'value': '0', 'groupId': 'BG002'}]}, {'title': 'White', 'measurements': [{'value': '3', 'groupId': 'BG000'}, {'value': '2', 'groupId': 'BG001'}, {'value': '5', 'groupId': 'BG002'}]}, {'title': 'More than one race', 'measurements': [{'value': '0', 'groupId': 'BG000'}, {'value': '0', 'groupId': 'BG001'}, {'value': '0', 'groupId': 'BG002'}]}, {'title': 'Unknown or Not Reported', 'measurements': [{'value': '0', 'groupId': 'BG000'}, {'value': '0', 'groupId': 'BG001'}, {'value': '0', 'groupId': 'BG002'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'unitOfMeasure': 'Participants'}, {'title': 'Physical and Neurological Examination for Subtle Signs (PANESS) Total', 'classes': [{'categories': [{'measurements': [{'value': '45', 'spread': '11', 'groupId': 'BG000'}, {'value': '38', 'spread': '4.2', 'groupId': 'BG001'}, {'value': '42', 'spread': '8.7', 'groupId': 'BG002'}]}]}], 'paramType': 'MEAN', 'description': 'Physical and Neurological Examination for Subtle Signs (PANESS) measure of motor function. The PANESS test measures timed movements, lateral preference, motor overflow, dysrhythmia, coordination, gait, balance, and motor persistence. The range of this scale is 0-119, higher scores correlate with symptom severity (worse outcome).', 'unitOfMeasure': 'units on a scale', 'dispersionType': 'STANDARD_DEVIATION'}, {'title': 'Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS), DuPaul DSM-5 based scale', 'classes': [{'categories': [{'measurements': [{'value': '35', 'spread': '5.4', 'groupId': 'BG000'}, {'value': '51', 'spread': '0', 'groupId': 'BG001'}, {'value': '39', 'spread': '8.3', 'groupId': 'BG002'}]}]}], 'paramType': 'MEAN', 'description': 'Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS), DuPaul DSM-5 based clinical rating scale. The range of this scale is 0-56, higher scores correlate with symptom severity (worse outcome).', 'unitOfMeasure': 'units on a scale', 'dispersionType': 'STANDARD_DEVIATION'}]}}, 'documentSection': {'largeDocumentModule': {'largeDocs': [{'date': '2020-03-09', 'size': 880645, 'label': 'Study Protocol and Statistical Analysis Plan', 'hasIcf': False, 'hasSap': True, 'filename': 'Prot_SAP_000.pdf', 'typeAbbrev': 'Prot_SAP', 'uploadDate': '2021-06-15T10:00', 'hasProtocol': True}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE2'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'RANDOMIZED', 'maskingInfo': {'masking': 'QUADRUPLE', 'whoMasked': ['PARTICIPANT', 'CARE_PROVIDER', 'INVESTIGATOR', 'OUTCOMES_ASSESSOR'], 'maskingDescription': "Participants will be randomly assigned to treatment I or II (double blind: NAC study drug or placebo) for 8 weeks then cross over to the other treatment option. Drug/placebo is formulated by the investigational pharmacy at Cincinnati Children's hospital. Encapsulated drug/placebo appear identical. If drug/placebo is administered as a powder, a flavor masking agent is applied to both to enforce the participant treatment blinding. Unmasking of the treatment blind will only occur after data is collected and analyzed."}, 'primaryPurpose': 'TREATMENT', 'interventionModel': 'CROSSOVER', 'interventionModelDescription': 'This is a double-blind placebo controlled, prospective, Phase IIa study to explore safety, tolerability, and efficacy of NAC on learning and motor behavior in children with NF1 aged 8 through 16 years old.'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 5}}, 'statusModule': {'overallStatus': 'COMPLETED', 'startDateStruct': {'date': '2019-01-15', 'type': 'ACTUAL'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2024-02', 'completionDateStruct': {'date': '2021-12-16', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2025-07-15', 'studyFirstSubmitDate': '2020-04-14', 'resultsFirstSubmitDate': '2021-06-16', 'studyFirstSubmitQcDate': '2020-07-17', 'lastUpdatePostDateStruct': {'date': '2025-07-31', 'type': 'ACTUAL'}, 'resultsFirstSubmitQcDate': '2022-02-16', 'studyFirstPostDateStruct': {'date': '2020-07-22', 'type': 'ACTUAL'}, 'resultsFirstPostDateStruct': {'date': '2022-03-15', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2020-06-14', 'type': 'ACTUAL'}}, 'outcomesModule': {'otherOutcomes': [{'measure': 'Evaluation of Change From Baseline in Metabolomics Profiles as a Possible Disease Biomarker Metabolic Testing Biomarkers - Samples in Storage for Follow up Study', 'timeFrame': 'At baseline and end of 8 weeks treatment with either NAC or placebo (weeks 0 and 8 for treatment phase one of this cross-over double blind study and at weeks 10 and 18 for treatment phase two).', 'description': 'In the same cohort, to evaluate metabolomics profiles as a possible disease biomarker that is affected by NF1 and by treatment with NAC as per Aim 1. Hypothesis 4: The investigators hypothesize that specific profiles will predict clinical response to antioxidant therapy compared to age-matched healthy control (unpublished data from CCHMC).'}], 'primaryOutcomes': [{'measure': 'Change From Baseline in Motor Function Measured by Physical and Neurological Examination for Subtle Signs (PANESS)', 'timeFrame': 'At baseline and end of 8 weeks treatment with either NAC or placebo (weeks 0 and 8 for treatment phase one of this cross-over double blind study and at weeks 10 and 18 for treatment phase two).', 'description': 'Characterize effects of NAC treatment on motor function in kids with NF1 using the Physical and Neurological Examination for Subtle Signs (PANESS). This is a validated scale that consistently demonstrates significant impairments in children with ADHD, and which preliminary data suggest may demonstrate more extreme problems in children with NF1 than age-matched healthy controls (unpublished data from CCHMC). The investigators hypothesize that motor function scores rated with the PANESS scale will improve after treatment with NAC. The range of this scale is 0-119, higher scores correlate with symptom severity (worse outcome).'}, {'measure': 'Change From Baseline in ADHD Symptoms as Reported Via Parent/Teacher Surveys', 'timeFrame': 'At baseline and end of 8 weeks treatment with either NAC or placebo (weeks 0 and 8 for treatment phase one of this cross-over double blind study and at weeks 10 and 18 for treatment phase two).', 'description': 'Characterize effects of NAC treatment on ADHD symptoms in children with NF1. The investigators hypothesize that ADHD attention and hyperactive/impulsive symptoms, rated with the DuPaul DSM-5 based clinical rating scales, will improve after treatment with NAC. The range of this scale is 0-56, higher scores correlate with symptom severity (worse outcome).'}], 'secondaryOutcomes': [{'measure': 'Transcranial Magnetic Stimulation (TMS) - Cortical Silent Period', 'timeFrame': 'At baseline and end of 8 weeks treatment with either NAC or placebo (weeks 0 and 8 for treatment phase one of this cross-over double blind study and at weeks 10 and 18 for treatment phase two).', 'description': 'Transcranial Magnetic Stimulation (TMS) - Cortical Silent Period (CSP). This measure describes the function and physiology of the motor system using Transcranial Magnetic Stimulation (TMS) over the brain to evoke a muscle twitch in the hand. These evoked potentials provide information about the instantaneous balance of excitation and inhibition in the brain, which in turn relate in part to neurotransmitter levels that can be altered by diseases and by treatments. This measure reflects an inhibitory neurotransmitter called GABA-B and its action at a particular receptor - the "GABA B" receptor. A lengthening of the duration of CSP indicates more inhibition, which is good (within a healthy range of approximately 50 to 150 ms, because outside of that range is abnormal). Here we report the average difference before and after treatment.'}, {'measure': 'Metabolic Testing Biomarkers', 'timeFrame': 'At baseline and end of 8 weeks treatment with either NAC or placebo (weeks 0 and 8 for treatment phase one of this cross-over double blind study and at weeks 10 and 18 for treatment phase two).', 'description': 'The investigators propose to evaluate the autotaxin/LPC axis. High autotaxin levels correlate with a worse outcome. Low lysophosphatidylcholine (LPC) levels correlate to a worse outcome. The investigators will collect serum and plasma from participants to assess autotaxin/LPC axis prior and post-NAC therapy.\n\nWe will perform serum targeted analysis for LPC, autotaxin activity and LPA measurements pre and post-treatment. We will perform a highly specific mass spectrometry target analysis of LPC species from serum for clinical correlation. We will use authentic standards to accurately measure low and high levels of these biomarkers. We will quantify autotaxin enzyme activity using a fluorometric assay to correlate with LPC measurements. We will quantify LPA using serum ELISA kit.\n\nData is not yet available as the samples in storage for follow up study.'}]}, 'oversightModule': {'oversightHasDmc': False, 'isFdaRegulatedDrug': True, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'conditions': ['Neurofibromatosis 1']}, 'referencesModule': {'references': [{'pmid': '16522267', 'type': 'BACKGROUND', 'citation': 'Acosta MT, Gioia GA, Silva AJ. Neurofibromatosis type 1: new insights into neurocognitive issues. Curr Neurol Neurosci Rep. 2006 Mar;6(2):136-43. doi: 10.1007/s11910-996-0036-5.'}, {'pmid': '2121371', 'type': 'BACKGROUND', 'citation': 'Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, Collins F. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell. 1990 Nov 16;63(4):851-9. doi: 10.1016/0092-8674(90)90151-4.'}, {'pmid': '12583841', 'type': 'BACKGROUND', 'citation': 'Rosser TL, Packer RJ. Neurocognitive dysfunction in children with neurofibromatosis type 1. Curr Neurol Neurosci Rep. 2003 Mar;3(2):129-36. doi: 10.1007/s11910-003-0064-3.'}, {'pmid': '25284746', 'type': 'BACKGROUND', 'citation': 'Casnar CL, Janke KM, van der Fluit F, Brei NG, Klein-Tasman BP. Relations between fine motor skill and parental report of attention in young children with neurofibromatosis type 1. J Clin Exp Neuropsychol. 2014;36(9):930-43. doi: 10.1080/13803395.2014.957166. 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Epub 2012 Oct 19.'}, {'pmid': '21321335', 'type': 'BACKGROUND', 'citation': 'Gilbert DL, Isaacs KM, Augusta M, Macneil LK, Mostofsky SH. Motor cortex inhibition: a marker of ADHD behavior and motor development in children. Neurology. 2011 Feb 15;76(7):615-21. doi: 10.1212/WNL.0b013e31820c2ebd.'}, {'pmid': '24413361', 'type': 'BACKGROUND', 'citation': 'Chen TH, Wu SW, Welge JA, Dixon SG, Shahana N, Huddleston DA, Sarvis AR, Sallee FR, Gilbert DL. Reduced short interval cortical inhibition correlates with atomoxetine response in children with attention-deficit hyperactivity disorder (ADHD). J Child Neurol. 2014 Dec;29(12):1672-9. doi: 10.1177/0883073813513333. Epub 2014 Jan 10.'}, {'pmid': '18164210', 'type': 'BACKGROUND', 'citation': "Dennis J, White MA, Forrest AD, Yuelling LM, Nogaroli L, Afshari FS, Fox MA, Fuss B. Phosphodiesterase-Ialpha/autotaxin's MORFO domain regulates oligodendroglial process network formation and focal adhesion organization. Mol Cell Neurosci. 2008 Feb;37(2):412-24. doi: 10.1016/j.mcn.2007.10.018. Epub 2007 Nov 12."}, {'pmid': '12176993', 'type': 'BACKGROUND', 'citation': 'Tokumura A, Majima E, Kariya Y, Tominaga K, Kogure K, Yasuda K, Fukuzawa K. Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biol Chem. 2002 Oct 18;277(42):39436-42. doi: 10.1074/jbc.M205623200. Epub 2002 Aug 9.'}, {'pmid': '12837632', 'type': 'BACKGROUND', 'citation': 'Fox MA, Colello RJ, Macklin WB, Fuss B. Phosphodiesterase-Ialpha/autotaxin: a counteradhesive protein expressed by oligodendrocytes during onset of myelination. Mol Cell Neurosci. 2003 Jul;23(3):507-19. doi: 10.1016/s1044-7431(03)00073-3.'}, {'pmid': '24987341', 'type': 'BACKGROUND', 'citation': 'Chen YW, Lin HC, Ng MC, Hsiao YH, Wang CC, Gean PW, Chen PS. 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Muscle Nerve. 1997 May;20(5):570-6. doi: 10.1002/(sici)1097-4598(199705)20:53.0.co;2-6.'}, {'pmid': '10590943', 'type': 'BACKGROUND', 'citation': 'Ziemann U. Intracortical inhibition and facilitation in the conventional paired TMS paradigm. Electroencephalogr Clin Neurophysiol Suppl. 1999;51:127-36. No abstract available.'}, {'pmid': '26537928', 'type': 'BACKGROUND', 'citation': 'Erkan E, Zhao X, Setchell K, Devarajan P. Distinct urinary lipid profile in children with focal segmental glomerulosclerosis. Pediatr Nephrol. 2016 Apr;31(4):581-8. doi: 10.1007/s00467-015-3239-7. Epub 2015 Nov 4.'}, {'pmid': '9474057', 'type': 'BACKGROUND', 'citation': 'Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol. 1998 Jan;108(1):1-16. doi: 10.1016/s0168-5597(97)00096-8.'}]}, 'descriptionModule': {'briefSummary': 'Children with neurofibromatosis type 1 (NF1) commonly suffer from the effects of cognitive, behavioral, and motor impairments. At present there is no specific treatment for this NF1 complication. However, data from rodent models of NF1 along with uncontrolled clinical observations in children with NF1 suggest that the anti-oxidant, glutamate modulating compound N-Acetyl Cysteine (NAC) may reduce these impairments. Of particular interest is a murine study analyzing the central nervous system manifestations of NF1 at our institution. That study revealed a role for myelin-forming oligodendrocytes in the control of nitric oxide synthases (NOS) and their product, nitric oxide, in maintenance of brain structure and function, including regulation of behavior and motor control. Treating these mice with NAC corrected cellular and behavioral abnormalities. N-Acetyl Cysteine is available over the counter and has been used by thousands of individuals; moreover, it has shown some promise in clinical trials for psychiatric disorders.\n\nIn order to better understand treatment mechanisms, and possibly predict long-term outcomes, the investigators propose concurrently to explore Specific Aim 1 (1.1, 1.2, and 1.3) exploratory potential disease biomarkers as outlined below. The primary outcome of this study is motor function rated with the Physical and Neurological Examination for Subtle Signs (PANESS), a validated scale that consistently demonstrates significant impairments in children with Attention Deficit Hyperactivity Disorder (ADHD), and which our preliminary data suggest may demonstrate more extreme problems in children with NF1. The first exploratory biomarker is motor system inhibitory physiology, measured using Transcranial Magnetic Stimulation (TMS). Preliminary measures in our NF1 population also show abnormalities similar to established findings in ADHD. The second exploratory biomarker is metabolomics profiling for the biomarker of oligodendrocyte dysfunction in NF1 participants: autotaxin. Preliminary data in our NF1 population showed specific signal abnormalities in the NF1 population compared to healthy controls. Therefore, the investigators propose to perform a double-blind placebo controlled, prospective, Phase IIa study to explore safety, tolerability, and efficacy of NAC on learning and motor behavior in children with NF1 aged 8 through 16 years old.', 'detailedDescription': 'The aims of this application are to gain information in children with NF1 about possible clinical benefit of anti-oxidant treatment and to develop and evaluate quantitative brain-based and blood biomarkers relating to presence of NF1, symptom severity, and response to antioxidant therapy. Clinically, 50% of children with NF1 are underperforming or failing at school \\[1\\]. This frequently leads to decreased educational attainment and fewer opportunities as adults. An important first step was preliminary work using the PANESS scale and Transcranial Magnetic Stimulation (TMS)-evoked Short Interval Cortical Inhibition (rSICI) in children with NF1. The investigators propose to develop and extend our understanding of NF1-related motor and learning behavior in response to antioxidant therapy with NAC. The purpose of the present study is to 1) evaluate tolerability, safety, and clinical benefit of NAC in this double-blind placebo controlled study; 2) to evaluate motor function (PANESS) and physiology (TMS) biomarkers at baseline and after treatment; and 3) to quantify metabolomics profiles at baseline and after treatment. The investigators propose to study 20 children with NF1, ages 8-16 years, at baseline and after completion of 8 weeks of treatment with NAC.\n\nNAC therapy, if successful, is expected improve these parameters. The trial endpoints are: Does behavior improve? Does motor function improve? Are there TMS biomarkers that reflect the presence of NF1 and the response to NAC treatment? Are there metabolomics measures that reflect the presence of NF1 and the response to treatment? The investigators hypothesize that predictive measures exist and can be used as a foundation for an application for funding for a larger, more definitive, placebo-controlled trial involving biomarkers and clinical outcomes. The investigators believe this work has the potential to lay groundwork for future use of relevant biomarkers for treatment and outcomes research for NF1 as well as other biologically similar conditions, collectively designated the "RASopathies" (due to involvement of the RAS family of proteins) and ultimately to guide development of more effective treatments based on disease pathophysiology.\n\nSPECIFIC AIMS\n\nThis study involves the following aims:\n\nSpecific Aim 1: Primary Outcome of Study In children and adolescents with NF1, to characterize the behavioral and motor effects of 8 weeks of N-acetylcysteine (NAC) treatment in a cohort of 20 children and adolescents with NF1. The investigators will evaluate tolerability, safety, and clinical benefit of NAC in this double-blind crossover placebo controlled study. Aim 1.1: Characterize effects of NAC treatment on motor function in kids with NF1 using the Physical and Neurological Examination for Subtle Signs (PANESS). This is a validated scale that consistently demonstrates significant impairments in children with ADHD, and which preliminary data suggest may demonstrate more extreme problems in children with NF1 than age-matched healthy controls (unpublished data from CCHMC). The investigators hypothesize that motor function scores rated with the PANESS scale will improve after treatment with NAC. Aim 1.2: Characterize effects of NAC treatment on ADHD symptoms in children with NF1. The investigators hypothesize that ADHD attention and hyperactive/impulsive symptoms, rated with the DuPaul Diagnostic and Statistical Manual Diploma in Social Medicine (DSM-5) based clinical rating scales, will improve after treatment with NAC.\n\nSpecific Aim 2: Experimental aim # 1 In the same cohort, the investigators will identify potential novel biomarkers of neurodevelopmental burden in NF1. Aim 2.1: Describe the function and physiology of the motor system using Transcranial Magnetic Stimulation (TMS) as a possible disease biomarker of NF1. Preliminary measures in our NF1 population also show abnormalities similar to established findings in ADHD. The investigators hypothesize that children with NF1 will have significantly less motor cortex inhibition using TMS measurements, and these measures will improve ("normalize") upon NAC treatment. The investigators will compare to age-matched healthy controls at Cincinnati Children\'s. Aim 2.2: The investigators propose to evaluate autotaxin as a candidate biomarker of oligodendrocyte dysfunction in NF1 participants. Preliminary data from biomarker discovery analysis of serum samples from healthy controls and NF1 patients showed lysophosphatidylcholine (LPC) depletion compared to healthy age/sex matched controls. In gene expression analysis autotaxin was elevated 4 times in neurofibroma Schwann cells compared to normal nerve Schwann cells. The investigators will collect serum and plasma from participants to assess autotaxin/LPC axis prior and post-NAC therapy. The investigators hypothesize that autotaxin axis abnormalities will be a biomarker of response to antioxidant therapy in our NF1 population.\n\nSpecific Aim 3: Experimental aim # 2 In the same cohort, to evaluate metabolomics profiles as a possible disease biomarker that is affected by NF1 and by treatment with NAC as per Aim 1. Hypothesis 4: The investigators hypothesize that specific profiles will predict clinical response to antioxidant therapy compared to age-matched healthy control (unpublished data from CCHMC).'}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['CHILD'], 'maximumAge': '16 Years', 'minimumAge': '8 Years', 'healthyVolunteers': True, 'eligibilityCriteria': "Inclusion Criteria:\n\n1. Males and females aged 8 - 16 years at time of enrollment whom meet NIH diagnostic criteria for NF1.\n2. Participants must have a full-scale intelligence quotient (IQ) of 70 or above, as determined by neurocognitive testing within the last 3 years or during the enrollment process.\n3. Participants on stimulant or any other psychotropic medication should stay on a stable dose for at least 30 days before entering the study.\n\nExclusion Criteria:\n\n1. Participants should not be receiving chemotherapy currently, or have received chemotherapy in the 6 months prior to entering the study.\n2. No active intracranial lesions (stable low grade glioma are acceptable) or epilepsy diagnosis.\n3. Major Depression, Bipolar Disorder, Conduct Disorder, Adjustment Disorder, other major Anxiety Disorders, or other developmental psychiatric diagnoses, based on the child's history or on parent and child responses from the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS). Note that while this is an exclusion for participation in the study if there is a prior evaluation available, this becomes a criterion, after inclusion, for the investigator to withdraw the child from the study prior to completion if identified on the first study day.\n4. For females, pregnancy.\n5. Current use of antidepressants, non-stimulant ADHD medications, dopamine blocking agents, mood stabilizers.\n6. Implanted brain stimulator, vagal nerve stimulator, ventriculoperitoneal (VP) shunt, cardiac pacemaker, or implanted medication port.\n7. Asthma (bronchospasm has been reported as occurring infrequently and unpredictable when acetylcysteine is used as a mucolytica agent).\n8. High risk of upper gastrointestinal (GI) hemorrhage. Examples: presence of esophageal varices or peptic ulcers"}, 'identificationModule': {'nctId': 'NCT04481035', 'acronym': 'NF1NAC', 'briefTitle': 'Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1', 'organization': {'class': 'OTHER', 'fullName': "Children's Hospital Medical Center, Cincinnati"}, 'officialTitle': 'Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1', 'orgStudyIdInfo': {'id': '2018-0344'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'EXPERIMENTAL', 'label': 'N-Acetylcysteine', 'description': 'Participants will be dosed with 70 mg/kg/dose (max dose 900 mg) three times per day of N-Acetylcysteine (NAC) for eight (8) weeks. This is a double-blind study, neither study participant nor study team members will know whether the participant is given study drug or placebo until after all data is collected.', 'interventionNames': ['Drug: N-acetylcysteine (NAC)']}, {'type': 'PLACEBO_COMPARATOR', 'label': 'Placebo', 'description': 'Participants will be dosed three times per day with a placebo for eight (8) weeks. This is a double-blind study, neither study participant nor study team members will know whether the participant is given study drug or placebo until after all data is collected.', 'interventionNames': ['Other: Placebo']}], 'interventions': [{'name': 'N-acetylcysteine (NAC)', 'type': 'DRUG', 'otherNames': ['Chemical Name: Cysteine, N-acetyl-, L', 'Commercial Name(s): Acetein; Acetadote, Acetylcysteine; Airbron; Broncholysin; Fluimucetin; Fluimucil; Inspir; Mucofilin; Mucomyst; Mucosolvin; NAC; Paravolex; Respaire', 'Synonym:L-alpha-acetamido-beta-mercaptopropionic acid; Mercapturic acid; N-Acetyl-3-mercaptoalanine; N-Acetylcysteine'], 'description': 'The study design is essentially a cross-sectional survey and then longitudinal evaluation of cognition and behavior, motor function, cortical function, and metabolomics profiles in NF1 before and after 8 weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC) or placebo. This is a cross-over double-blind placebo controlled study. Participants in the experimental phase/arm will receive 70 mg/kg/dose (max dose 900 mg) three times per day of NAC for eight (8) weeks.', 'armGroupLabels': ['N-Acetylcysteine']}, {'name': 'Placebo', 'type': 'OTHER', 'description': 'The study design is essentially a cross-sectional survey and then longitudinal evaluation of cognition and behavior, motor function, cortical function, and metabolomics profiles in NF1 before and after 8 weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC) or placebo. This is a cross-over double-blind placebo controlled study. Participants in the placebo phase/arm will receive placebo (non-drug) three times per day for eight (8) weeks.', 'armGroupLabels': ['Placebo']}]}, 'contactsLocationsModule': {'locations': [{'zip': '45229', 'city': 'Cincinnati', 'state': 'Ohio', 'country': 'United States', 'facility': "Cincinnati Children's Hospital Medical Center", 'geoPoint': {'lat': 39.12711, 'lon': -84.51439}}], 'overallOfficials': [{'name': 'Donald L Gilbert, MD, MS', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': "Children's Hospital Medical Center, Cincinnati"}]}, 'ipdSharingStatementModule': {'ipdSharing': 'NO', 'description': 'Identifiable individual participant data will not be available to other researchers.'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': "Children's Hospital Medical Center, Cincinnati", 'class': 'OTHER'}, 'responsibleParty': {'type': 'SPONSOR'}}}}