Antioxidant Therapy With N-acetylcysteine for Children With Neurofibromatosis Type 1

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Brief Title

Antioxidant Therapy With N-acetylcysteine for Children With Neurofibromatosis Type 1

Official Title

Antioxidant Therapy With N-acetylcysteine for Motor Behavior and/or Learning 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. In this project, the investigators will assess the safety and clinical benefit
      of N-acetylcysteine (NAC) as a pharmacological intervention in children with NF1. This drug
      choice is based on the recent findings from mouse models to study the central nervous system
      manifestations of NF1 at Cincinnati Children's Hospital Medical Center (CCHMC). These
      findings revealed a role for myelin-forming oligodendrocytes in the control of nitric oxide
      synthases (NOS) and their product, nitric oxide (NO), in maintenance of brain structure and
      function, including regulation of behavior and motor control. Treating these mice with NAC
      corrected cellular and behavioral abnormalities. This data from animal models of NF1 along
      with uncontrolled clinical observations in children with NF1 suggest that the antioxidant
      compound, NAC, may reduce these impairments. Therefore, the investigators propose performing
      a single center double-blind placebo controlled, prospective, Phase II study to explore
      safety, tolerability, and efficacy of NAC on motor behavior and/or learning in children with
      NF1 aged 8 through 16 years old. Participants will be carefully monitored for side effects.
      Primary and secondary outcome measures will be administered at baseline, follow-up, and
      post-treatment.
    

Detailed Description

      This is a phase II clinical trial with the goal to explore safety, tolerability, and efficacy
      of NAC on motor behavior in children with NF1 aged 8 through 16 years old. The investigators
      hypothesize that NAC therapy will improve motor function evaluated by the PANESS scale. This
      is based on studies demonstrating that NAC significantly improved impairments in the animal
      model of NF1. The investigators will also analyze NAC effects on attention deficit and
      impulsivity in children with NF1.

      This study will also help develop novel predictive biomarkers of response to neurocognitive
      therapies in patients with NF1 which are needed to evaluate treatment outcomes.

      The investigators will 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 percent of children with NF1 are underperforming or failing at
      school. 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 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 using the motor function scale (PANESS); 2) to evaluate
      the effects of NAC on measures of NF1 neurocognitive symptomatology (ADHD/impulsive symptoms,
      executive function, working memory); and 3) to determine if TMS measurement (SICI) in
      children with NF1 will correlate with clinical effects of NAC treatment and evaluate utility
      of advanced brain imaging and spectroscopy measurements in children with NF1, and effects of
      NAC therapy.

      The investigators propose to study 58 children with NF1, ages 8-16 years, at baseline and
      after completion of 8 weeks of treatment with NAC, followed by a washout period of 4 weeks.

      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.

      STUDY OBJECTIVE:

      NAC Trial at Cincinnati Children's Hospital Medical Center (CCHMC) The investigators propose
      performing a single center randomized double-blind placebo controlled, prospective, Phase II
      study to explore safety, tolerability, and efficacy of NAC on motor behavior in children with
      NF1 aged 8 through 16 years old.

      Hypothesis:

      The investigators hypothesize that NAC therapy will improve motor function evaluated by the
      PANESS scale. This is based on studies demonstrating that NAC significantly improved
      impairments in the animal model of NF1. The investigators will also analyze NAC effects on
      attention deficit and impulsivity in children with NF1.

      Specific Aim:

      The primary outcome of this study is to characterize the effects of NAC treatment on motor
      function in children and adolescents with NF1 using the PANESS. The investigators hypothesize
      that motor function scores rated with the PANESS scale will improve after treatment with NAC.

      Secondary Aims:

        1. To evaluate the effects of NAC on measures of NF1 neurocognitive symptomatology
           (ADHD/impulsive symptoms, executive function, working memory), the investigators will
           use Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) committee
           recommended assessments tools DuPaul ADHD rating scale (ADHD-RS), Behavioral Rating
           Inventory of Executive Function second edition (BRIEF-2), Wechsler Intelligence Scale
           for Children, Fifth Edition (WISC-V) subtests, and Test of Variables of Attention
           (TOVA).

        2. To determine if TMS measurement (SICI) in children with NF1 will correlate with clinical
           effects of NAC treatment.

        3. To quantify microstructural properties of brain tissue based on water diffusion,
           glutathione GSH concentrations, and gamma-aminobutyric acid (GABA) concentration using
           brain magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in
           children with NF1. This will allow for regional correlation between imaging,
           spectroscopy and neuropsychometric outcomes. The investigators will also determine if
           these magnetic resonance based outcomes correlate with clinical effects of NAC
           treatment.

        4. To evaluate safety and tolerability of NAC in children with NF1.
    

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 ADHD Symptoms as Reported via Parent/Teacher Surveys

Condition

Neurofibromatosis 1

Intervention

N-Acetyl cysteine

Study Arms / Comparison Groups

 N-Acetylcysteine (NAC)
Description:  Each subject will be dosed with approximately 70 mg/kg/day of NAC for 8 weeks. To facilitate drug compounding, three tiers of drug dose will be administered based on body weight as described in Table 3.
Table 3: NAC Dosing Participant's weight (kg) Dose (BID) < 20 700 mg 21-39 1050 mg > 40 1350 mg
*Max dose not to exceed 2700mg/day (1350mg BID)

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

58

Start Date

December 15, 2020

Completion Date

December 2024

Primary Completion Date

June 2024

Eligibility Criteria

        Inclusion Criteria:

          -  Male and females aged 8 - 16 years (up to 16 years and 6 months) at time of enrollment

          -  Meets NIH diagnostic criteria for NF1

          -  Abnormal PANESS study (score at or above the age/sex-based mean)

          -  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

          -  Participants on stimulant or any other psychotropic medication should stay on a stable
             dose (no change in dose) for at least 30 days before entering the study. A stable dose
             should be maintained throughout the study until completion of all study visits.

        Exclusion Criteria:

          -  Participants should not be receiving chemotherapy currently, or have received
             chemotherapy in the 6 months prior to entering the study

          -  Active intracranial lesions (stable low grade glioma is acceptable)

          -  History of seizure disorder or epilepsy. History of a single seizure that occurred
             more than 12 months prior to enrollment is acceptable. History of febrile seizures if
             the last febrile seizure occurred more than 12 months prior to enrollment is
             acceptable. Recurrent, unprovoked seizures (epilepsy) is sufficient for exclusion.

          -  Major Depression, Bipolar Disorder, Conduct Disorder, Adjustment Disorder, other major
             Anxiety Disorders, or other developmental psychiatric diagnoses, based on history

          -  For females, pregnancy

          -  Implanted brain stimulator, vagal nerve stimulator, ventriculoperitoneal shunt,
             cardiac pacemaker, or implanted medication port

          -  Asthma (bronchospasm has been reported as occurring infrequently and unpredictably
             when NAC is used as a mucolytic agent)

          -  High risk of upper gastrointestinal hemorrhage. Examples: presence of esophageal
             varices or peptic ulcers

          -  Current use of MEKINIST (MEK-inhibitor) or use within 30 days
      

Gender

All

Ages

8 Years - 16 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Carlos E Prada, MD, 513-803-0077, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04481048

Organization ID

2020-0412


Responsible Party

Sponsor

Study Sponsor

Children's Hospital Medical Center, Cincinnati

Collaborators

 United States Department of Defense

Study Sponsor

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


Verification Date

January 2021