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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Neurofibromatosis 1
• Intervention / Treatment: Drug: N-acetylcysteine (NAC); Other: Placebo

Detailed Description

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.

NAC 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.

SPECIFIC AIMS

This study involves the following aims:

Specific 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.

Specific 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.

Specific 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).

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 16 years (Child)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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; Mercapturic 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Motor Function Measured by Physical and Neurological Examination for Subtle Signs (PANESS)	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).	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).
Change From Baseline in ADHD Symptoms as Reported Via Parent/Teacher Surveys	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).	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).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transcranial Magnetic Stimulation (TMS) - Cortical Silent Period	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.	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).
Metabolic Testing Biomarkers	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. We 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. Data is not yet available as the samples in storage for follow up study.	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).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of Change From Baseline in Metabolomics Profiles as a Possible Disease Biomarker Metabolic Testing Biomarkers - Samples in Storage for Follow up Study	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).	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).

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Donald L Gilbert, MD, MS, Children's Hospital Medical Center, Cincinnati

Publications and helpful links

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Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2019
• Primary Completion (Actual): June 14, 2020
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: April 14, 2020
• First Submitted That Met QC Criteria: July 17, 2020
• First Posted (Actual): July 22, 2020

Study Record Updates

• Last Update Posted (Actual): March 19, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Neoplasms, Nerve Tissue; Peripheral Nervous System Diseases; Nervous System Neoplasms; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Nerve Sheath Neoplasms; Neurocutaneous Syndromes; Peripheral Nervous System Neoplasms; Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: 2018-0344 (M D Anderson Cancer Center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Identifiable individual participant data will not be available to other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No