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

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Brief Title

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

Official Title

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

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.
    

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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

Change from Baseline in Motor Function Measured by Physical and Neurological Examination for Subtle Signs (PANESS)

Secondary Outcome

 Change from Baseline in Motor Function and Physiology Measured by Transcranial Magnetic Stimulation (TMS)

Condition

Neurofibromatosis 1

Intervention

N-acetylcysteine (NAC)

Study Arms / Comparison Groups

 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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

5

Start Date

January 15, 2019

Completion Date

December 2020

Primary Completion Date

June 25, 2020

Eligibility 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
      

Gender

All

Ages

8 Years - 16 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Carlos E Prada, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04481035

Organization ID

2018-0344


Responsible Party

Sponsor

Study Sponsor

Children's Hospital Medical Center, Cincinnati


Study Sponsor

Carlos E Prada, MD, Principal Investigator, Children's Hospital Medical Center, Cincinnati


Verification Date

April 2020