Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1
Condition: Neurofibromatosis 1
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma
Intervention: N-acetylcysteine (NAC); Placebo
Intervention 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.; 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.
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
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.
Enrollment: 5.0
Sex: All
Minimum age: 8 Years
Maximum age: 16 Years
Healthy volunteers: Accepts Healthy Volunteers

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.
    

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