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Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1 (NF1NAC)

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ClinicalTrials.gov Identifier: NCT04481035
Recruitment Status : Active, not recruiting
First Posted : July 22, 2020
Last Update Posted : July 22, 2020
Sponsor:
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati

Brief Summary:

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.

In 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.


Condition or disease Intervention/treatment Phase
Neurofibromatosis 1 Drug: N-acetylcysteine (NAC) Other: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: 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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: 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.
Primary Purpose: Treatment
Official Title: Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1
Actual Study Start Date : January 15, 2019
Actual Primary Completion Date : June 25, 2020
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
Experimental: N-Acetylcysteine
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.
Drug: N-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.
Other Names:
  • 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; Mercpaturic acid; N-Acetyl-3-mercaptoalanine; N-Acetylcysteine

Placebo Comparator: Placebo
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.
Other: Placebo
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.




Primary Outcome Measures :
  1. Change from Baseline in Motor Function Measured by Physical and Neurological Examination for Subtle Signs (PANESS) [ Time Frame: through 18 weeks (at weeks 0, 8, 10, and 18) ]
    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).

  2. Change from Baseline in ADHD Symptoms as Reported via Parent/Teacher Surveys [ Time Frame: through 18 weeks (at weeks 0, 4, 8, 10, 14, and 18) ]
    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).


Secondary Outcome Measures :
  1. Change from Baseline in Motor Function and Physiology Measured by Transcranial Magnetic Stimulation (TMS) [ Time Frame: through 18 weeks (at weeks 0, 8, 10, and 18) ]
    Describe the function and physiology of the motor system using Transcranial Magnetic Stimulation (TMS) as a possible disease biomarker of NF1. Preliminary measures in an 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 our internal age-matched healthy controls at Cincinnati Children's.

  2. Change in Autotaxin Levels [ Time Frame: through 18 weeks (at weeks 0, 8, 10, and 18) ]
    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.


Other Outcome Measures:
  1. Evaluation of Change from Baseline in Metabolomics Profiles as a Possible Disease Biomarker [ Time Frame: through 18 weeks (at weeks 0, 8, 10, and 18) ]
    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).



Information from the National Library of Medicine

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Ages Eligible for Study:   8 Years to 16 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Males and females aged 8 - 16 years at time of enrollment whom meet NIH diagnostic criteria for NF1.
  2. 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.
  3. Participants on stimulant or any other psychotropic medication should stay on a stable dose for at least 30 days before entering the study.

Exclusion Criteria:

  1. Participants should not be receiving chemotherapy currently, or have received chemotherapy in the 6 months prior to entering the study.
  2. No active intracranial lesions (stable low grade glioma are acceptable) or epilepsy diagnosis.
  3. 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.
  4. For females, pregnancy.
  5. Current use of antidepressants, non-stimulant ADHD medications, dopamine blocking agents, mood stabilizers.
  6. Implanted brain stimulator, vagal nerve stimulator, ventriculoperitoneal (VP) shunt, cardiac pacemaker, or implanted medication port.
  7. Asthma (bronchospasm has been reported as occurring infrequently and unpredictable when acetylcysteine is used as a mucolytica agent).
  8. High risk of upper gastrointestinal (GI) hemorrhage. Examples: presence of esophageal varices or peptic ulcers

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 ClinicalTrials.gov identifier (NCT number): NCT04481035


Locations
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United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati
Investigators
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Principal Investigator: Carlos E Prada, MD Children's Hospital Medical Center, Cincinnati
Principal Investigator: Donald L Gilbert, MD, MS Children's Hospital Medical Center, Cincinnati
Publications of Results:

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Responsible Party: Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier: NCT04481035    
Other Study ID Numbers: 2018-0344
First Posted: July 22, 2020    Key Record Dates
Last Update Posted: July 22, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Identifiable individual participant data will not be available to other researchers.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neurofibromatoses
Neurofibromatosis 1
Neurofibroma
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes