<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04481035</url>
  </required_header>
  <id_info>
    <org_study_id>2018-0344</org_study_id>
    <nct_id>NCT04481035</nct_id>
  </id_info>
  <brief_title>Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1</brief_title>
  <acronym>NF1NAC</acronym>
  <official_title>Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Hospital Medical Center, Cincinnati</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Children's Hospital Medical Center, Cincinnati</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Children with neurofibromatosis type 1 (NF1) commonly suffer from the effects of cognitive,&#xD;
      behavioral, and motor impairments. At present there is no specific treatment for this NF1&#xD;
      complication. However, data from rodent models of NF1 along with uncontrolled clinical&#xD;
      observations in children with NF1 suggest that the anti-oxidant, glutamate modulating&#xD;
      compound N-Acetyl Cysteine (NAC) may reduce these impairments. Of particular interest is a&#xD;
      murine study analyzing the central nervous system manifestations of NF1 at our institution.&#xD;
      That study revealed a role for myelin-forming oligodendrocytes in the control of nitric oxide&#xD;
      synthases (NOS) and their product, nitric oxide, in maintenance of brain structure and&#xD;
      function, including regulation of behavior and motor control. Treating these mice with NAC&#xD;
      corrected cellular and behavioral abnormalities. N-Acetyl Cysteine is available over the&#xD;
      counter and has been used by thousands of individuals; moreover, it has shown some promise in&#xD;
      clinical trials for psychiatric disorders.&#xD;
&#xD;
      In order to better understand treatment mechanisms, and possibly predict long-term outcomes,&#xD;
      the investigators propose concurrently to explore Specific Aim 1 (1.1, 1.2, and 1.3)&#xD;
      exploratory potential disease biomarkers as outlined below. The primary outcome of this study&#xD;
      is motor function rated with the Physical and Neurological Examination for Subtle Signs&#xD;
      (PANESS), a validated scale that consistently demonstrates significant impairments in&#xD;
      children with Attention Deficit Hyperactivity Disorder (ADHD), and which our preliminary data&#xD;
      suggest may demonstrate more extreme problems in children with NF1. The first exploratory&#xD;
      biomarker is motor system inhibitory physiology, measured using Transcranial Magnetic&#xD;
      Stimulation (TMS). Preliminary measures in our NF1 population also show abnormalities similar&#xD;
      to established findings in ADHD. The second exploratory biomarker is metabolomics profiling&#xD;
      for the biomarker of oligodendrocyte dysfunction in NF1 participants: autotaxin. Preliminary&#xD;
      data in our NF1 population showed specific signal abnormalities in the NF1 population&#xD;
      compared to healthy controls. Therefore, the investigators propose to perform a double-blind&#xD;
      placebo controlled, prospective, Phase IIa study to explore safety, tolerability, and&#xD;
      efficacy of NAC on learning and motor behavior in children with NF1 aged 8 through 16 years&#xD;
      old.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The aims of this application are to gain information in children with NF1 about possible&#xD;
      clinical benefit of anti-oxidant treatment and to develop and evaluate quantitative&#xD;
      brain-based and blood biomarkers relating to presence of NF1, symptom severity, and response&#xD;
      to antioxidant therapy. Clinically, 50% of children with NF1 are underperforming or failing&#xD;
      at school [1]. This frequently leads to decreased educational attainment and fewer&#xD;
      opportunities as adults. An important first step was preliminary work using the PANESS scale&#xD;
      and Transcranial Magnetic Stimulation (TMS)-evoked Short Interval Cortical Inhibition (rSICI)&#xD;
      in children with NF1. The investigators propose to develop and extend our understanding of&#xD;
      NF1-related motor and learning behavior in response to antioxidant therapy with NAC. The&#xD;
      purpose of the present study is to 1) evaluate tolerability, safety, and clinical benefit of&#xD;
      NAC in this double-blind placebo controlled study; 2) to evaluate motor function (PANESS) and&#xD;
      physiology (TMS) biomarkers at baseline and after treatment; and 3) to quantify metabolomics&#xD;
      profiles at baseline and after treatment. The investigators propose to study 20 children with&#xD;
      NF1, ages 8-16 years, at baseline and after completion of 8 weeks of treatment with NAC.&#xD;
&#xD;
      NAC therapy, if successful, is expected improve these parameters. The trial endpoints are:&#xD;
      Does behavior improve? Does motor function improve? Are there TMS biomarkers that reflect the&#xD;
      presence of NF1 and the response to NAC treatment? Are there metabolomics measures that&#xD;
      reflect the presence of NF1 and the response to treatment? The investigators hypothesize that&#xD;
      predictive measures exist and can be used as a foundation for an application for funding for&#xD;
      a larger, more definitive, placebo-controlled trial involving biomarkers and clinical&#xD;
      outcomes. The investigators believe this work has the potential to lay groundwork for future&#xD;
      use of relevant biomarkers for treatment and outcomes research for NF1 as well as other&#xD;
      biologically similar conditions, collectively designated the &quot;RASopathies&quot; (due to&#xD;
      involvement of the RAS family of proteins) and ultimately to guide development of more&#xD;
      effective treatments based on disease pathophysiology.&#xD;
&#xD;
      SPECIFIC AIMS&#xD;
&#xD;
      This study involves the following aims:&#xD;
&#xD;
      Specific Aim 1: Primary Outcome of Study In children and adolescents with NF1, to&#xD;
      characterize the behavioral and motor effects of 8 weeks of N-acetylcysteine (NAC) treatment&#xD;
      in a cohort of 20 children and adolescents with NF1. The investigators will evaluate&#xD;
      tolerability, safety, and clinical benefit of NAC in this double-blind crossover placebo&#xD;
      controlled study. Aim 1.1: Characterize effects of NAC treatment on motor function in kids&#xD;
      with NF1 using the Physical and Neurological Examination for Subtle Signs (PANESS). This is a&#xD;
      validated scale that consistently demonstrates significant impairments in children with ADHD,&#xD;
      and which preliminary data suggest may demonstrate more extreme problems in children with NF1&#xD;
      than age-matched healthy controls (unpublished data from CCHMC). The investigators&#xD;
      hypothesize that motor function scores rated with the PANESS scale will improve after&#xD;
      treatment with NAC. Aim 1.2: Characterize effects of NAC treatment on ADHD symptoms in&#xD;
      children with NF1. The investigators hypothesize that ADHD attention and&#xD;
      hyperactive/impulsive symptoms, rated with the DuPaul Diagnostic and Statistical Manual&#xD;
      Diploma in Social Medicine (DSM-5) based clinical rating scales, will improve after treatment&#xD;
      with NAC.&#xD;
&#xD;
      Specific Aim 2: Experimental aim # 1 In the same cohort, the investigators will identify&#xD;
      potential novel biomarkers of neurodevelopmental burden in NF1. Aim 2.1: Describe the&#xD;
      function and physiology of the motor system using Transcranial Magnetic Stimulation (TMS) as&#xD;
      a possible disease biomarker of NF1. Preliminary measures in our NF1 population also show&#xD;
      abnormalities similar to established findings in ADHD. The investigators hypothesize that&#xD;
      children with NF1 will have significantly less motor cortex inhibition using TMS&#xD;
      measurements, and these measures will improve (&quot;normalize&quot;) upon NAC treatment. The&#xD;
      investigators will compare to age-matched healthy controls at Cincinnati Children's. Aim 2.2:&#xD;
      The investigators propose to evaluate autotaxin as a candidate biomarker of oligodendrocyte&#xD;
      dysfunction in NF1 participants. Preliminary data from biomarker discovery analysis of serum&#xD;
      samples from healthy controls and NF1 patients showed lysophosphatidylcholine (LPC) depletion&#xD;
      compared to healthy age/sex matched controls. In gene expression analysis autotaxin was&#xD;
      elevated 4 times in neurofibroma Schwann cells compared to normal nerve Schwann cells. The&#xD;
      investigators will collect serum and plasma from participants to assess autotaxin/LPC axis&#xD;
      prior and post-NAC therapy. The investigators hypothesize that autotaxin axis abnormalities&#xD;
      will be a biomarker of response to antioxidant therapy in our NF1 population.&#xD;
&#xD;
      Specific Aim 3: Experimental aim # 2 In the same cohort, to evaluate metabolomics profiles as&#xD;
      a possible disease biomarker that is affected by NF1 and by treatment with NAC as per Aim 1.&#xD;
      Hypothesis 4: The investigators hypothesize that specific profiles will predict clinical&#xD;
      response to antioxidant therapy compared to age-matched healthy control (unpublished data&#xD;
      from CCHMC).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 15, 2019</start_date>
  <completion_date type="Anticipated">January 1, 2024</completion_date>
  <primary_completion_date type="Actual">June 14, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <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.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <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.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change From Baseline in Motor Function Measured by Physical and Neurological Examination for Subtle Signs (PANESS)</measure>
    <time_frame>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).</time_frame>
    <description>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).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change From Baseline in ADHD Symptoms as Reported Via Parent/Teacher Surveys</measure>
    <time_frame>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).</time_frame>
    <description>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).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Transcranial Magnetic Stimulation (TMS) - Cortical Silent Period</measure>
    <time_frame>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).</time_frame>
    <description>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 &quot;GABA B&quot; 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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metabolic Testing Biomarkers</measure>
    <time_frame>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).</time_frame>
    <description>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.&#xD;
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.&#xD;
Data is not yet available as the samples in storage for follow up study.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Evaluation of Change From Baseline in Metabolomics Profiles as a Possible Disease Biomarker Metabolic Testing Biomarkers - Samples in Storage for Follow up Study</measure>
    <time_frame>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).</time_frame>
    <description>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).</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Neurofibromatosis 1</condition>
  <arm_group>
    <arm_group_label>N-Acetylcysteine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>N-acetylcysteine (NAC)</intervention_name>
    <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.</description>
    <arm_group_label>N-Acetylcysteine</arm_group_label>
    <other_name>Chemical Name: Cysteine, N-acetyl-, L</other_name>
    <other_name>Commercial Name(s): Acetein; Acetadote, Acetylcysteine; Airbron; Broncholysin; Fluimucetin; Fluimucil; Inspir; Mucofilin; Mucomyst; Mucosolvin; NAC; Paravolex; Respaire</other_name>
    <other_name>Synonym:L-alpha-acetamido-beta-mercaptopropionic acid; Mercapturic acid; N-Acetyl-3-mercaptoalanine; N-Acetylcysteine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <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 placebo phase/arm will receive placebo (non-drug) three times per day for eight (8) weeks.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Males and females aged 8 - 16 years at time of enrollment whom meet NIH diagnostic&#xD;
             criteria for NF1.&#xD;
&#xD;
          2. Participants must have a full-scale intelligence quotient (IQ) of 70 or above, as&#xD;
             determined by neurocognitive testing within the last 3 years or during the enrollment&#xD;
             process.&#xD;
&#xD;
          3. Participants on stimulant or any other psychotropic medication should stay on a stable&#xD;
             dose for at least 30 days before entering the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Participants should not be receiving chemotherapy currently, or have received&#xD;
             chemotherapy in the 6 months prior to entering the study.&#xD;
&#xD;
          2. No active intracranial lesions (stable low grade glioma are acceptable) or epilepsy&#xD;
             diagnosis.&#xD;
&#xD;
          3. Major Depression, Bipolar Disorder, Conduct Disorder, Adjustment Disorder, other major&#xD;
             Anxiety Disorders, or other developmental psychiatric diagnoses, based on the child's&#xD;
             history or on parent and child responses from the Kiddie Schedule for Affective&#xD;
             Disorders and Schizophrenia (KSADS). Note that while this is an exclusion for&#xD;
             participation in the study if there is a prior evaluation available, this becomes a&#xD;
             criterion, after inclusion, for the investigator to withdraw the child from the study&#xD;
             prior to completion if identified on the first study day.&#xD;
&#xD;
          4. For females, pregnancy.&#xD;
&#xD;
          5. Current use of antidepressants, non-stimulant ADHD medications, dopamine blocking&#xD;
             agents, mood stabilizers.&#xD;
&#xD;
          6. Implanted brain stimulator, vagal nerve stimulator, ventriculoperitoneal (VP) shunt,&#xD;
             cardiac pacemaker, or implanted medication port.&#xD;
&#xD;
          7. Asthma (bronchospasm has been reported as occurring infrequently and unpredictable&#xD;
             when acetylcysteine is used as a mucolytica agent).&#xD;
&#xD;
          8. High risk of upper gastrointestinal (GI) hemorrhage. Examples: presence of esophageal&#xD;
             varices or peptic ulcers&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>8 Years</minimum_age>
    <maximum_age>16 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Donald L Gilbert, MD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Hospital Medical Center, Cincinnati</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Acosta MT, Gioia GA, Silva AJ. Neurofibromatosis type 1: new insights into neurocognitive issues. Curr Neurol Neurosci Rep. 2006 Mar;6(2):136-43. doi: 10.1007/s11910-996-0036-5.</citation>
    <PMID>16522267</PMID>
  </reference>
  <reference>
    <citation>Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, Collins F. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell. 1990 Nov 16;63(4):851-9. doi: 10.1016/0092-8674(90)90151-4.</citation>
    <PMID>2121371</PMID>
  </reference>
  <reference>
    <citation>Rosser TL, Packer RJ. Neurocognitive dysfunction in children with neurofibromatosis type 1. Curr Neurol Neurosci Rep. 2003 Mar;3(2):129-36. doi: 10.1007/s11910-003-0064-3.</citation>
    <PMID>12583841</PMID>
  </reference>
  <reference>
    <citation>Casnar CL, Janke KM, van der Fluit F, Brei NG, Klein-Tasman BP. Relations between fine motor skill and parental report of attention in young children with neurofibromatosis type 1. J Clin Exp Neuropsychol. 2014;36(9):930-43. doi: 10.1080/13803395.2014.957166. Epub 2014 Oct 6.</citation>
    <PMID>25284746</PMID>
  </reference>
  <reference>
    <citation>Walsh KS, Janusz J, Wolters PL, Martin S, Klein-Tasman BP, Toledo-Tamula MA, Thompson HL, Payne JM, Hardy KK, de Blank P, Semerjian C, Gray LS, Solomon SE, Ullrich N; REiNS International Collaboration. Neurocognitive outcomes in neurofibromatosis clinical trials: Recommendations for the domain of attention. Neurology. 2016 Aug 16;87(7 Suppl 1):S21-30. doi: 10.1212/WNL.0000000000002928.</citation>
    <PMID>27527646</PMID>
  </reference>
  <reference>
    <citation>Acosta MT, Bearden CE, Castellanos FX, Cutting L, Elgersma Y, Gioia G, Gutmann DH, Lee YS, Legius E, Muenke M, North K, Parada LF, Ratner N, Hunter-Schaedle K, Silva AJ. The Learning Disabilities Network (LeaDNet): using neurofibromatosis type 1 (NF1) as a paradigm for translational research. Am J Med Genet A. 2012 Sep;158A(9):2225-32. doi: 10.1002/ajmg.a.35535. Epub 2012 Jul 20. Erratum In: Am J Med Genet A. 2013 Jan;161A(1):236. Castellanos, Xavier F [corrected to Castellanos, F Xavier].</citation>
    <PMID>22821737</PMID>
  </reference>
  <reference>
    <citation>Pride N, Payne JM, Webster R, Shores EA, Rae C, North KN. Corpus callosum morphology and its relationship to cognitive function in neurofibromatosis type 1. J Child Neurol. 2010 Jul;25(7):834-41. doi: 10.1177/0883073809350723. Epub 2010 Feb 8.</citation>
    <PMID>20142468</PMID>
  </reference>
  <reference>
    <citation>Wang Y, Kim E, Wang X, Novitch BG, Yoshikawa K, Chang LS, Zhu Y. ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities. Cell. 2012 Aug 17;150(4):816-30. doi: 10.1016/j.cell.2012.06.034.</citation>
    <PMID>22901811</PMID>
  </reference>
  <reference>
    <citation>Karlsgodt KH, Rosser T, Lutkenhoff ES, Cannon TD, Silva A, Bearden CE. Alterations in white matter microstructure in neurofibromatosis-1. PLoS One. 2012;7(10):e47854. doi: 10.1371/journal.pone.0047854. Epub 2012 Oct 19.</citation>
    <PMID>23094098</PMID>
  </reference>
  <reference>
    <citation>Gilbert DL, Isaacs KM, Augusta M, Macneil LK, Mostofsky SH. Motor cortex inhibition: a marker of ADHD behavior and motor development in children. Neurology. 2011 Feb 15;76(7):615-21. doi: 10.1212/WNL.0b013e31820c2ebd.</citation>
    <PMID>21321335</PMID>
  </reference>
  <reference>
    <citation>Chen TH, Wu SW, Welge JA, Dixon SG, Shahana N, Huddleston DA, Sarvis AR, Sallee FR, Gilbert DL. Reduced short interval cortical inhibition correlates with atomoxetine response in children with attention-deficit hyperactivity disorder (ADHD). J Child Neurol. 2014 Dec;29(12):1672-9. doi: 10.1177/0883073813513333. Epub 2014 Jan 10.</citation>
    <PMID>24413361</PMID>
  </reference>
  <reference>
    <citation>Dennis J, White MA, Forrest AD, Yuelling LM, Nogaroli L, Afshari FS, Fox MA, Fuss B. Phosphodiesterase-Ialpha/autotaxin's MORFO domain regulates oligodendroglial process network formation and focal adhesion organization. Mol Cell Neurosci. 2008 Feb;37(2):412-24. doi: 10.1016/j.mcn.2007.10.018. Epub 2007 Nov 12.</citation>
    <PMID>18164210</PMID>
  </reference>
  <reference>
    <citation>Tokumura A, Majima E, Kariya Y, Tominaga K, Kogure K, Yasuda K, Fukuzawa K. Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biol Chem. 2002 Oct 18;277(42):39436-42. doi: 10.1074/jbc.M205623200. Epub 2002 Aug 9.</citation>
    <PMID>12176993</PMID>
  </reference>
  <reference>
    <citation>Fox MA, Colello RJ, Macklin WB, Fuss B. Phosphodiesterase-Ialpha/autotaxin: a counteradhesive protein expressed by oligodendrocytes during onset of myelination. Mol Cell Neurosci. 2003 Jul;23(3):507-19. doi: 10.1016/s1044-7431(03)00073-3.</citation>
    <PMID>12837632</PMID>
  </reference>
  <reference>
    <citation>Chen YW, Lin HC, Ng MC, Hsiao YH, Wang CC, Gean PW, Chen PS. Activation of mGluR2/3 underlies the effects of N-acetylcystein on amygdala-associated autism-like phenotypes in a valproate-induced rat model of autism. Front Behav Neurosci. 2014 Jun 17;8:219. doi: 10.3389/fnbeh.2014.00219. eCollection 2014.</citation>
    <PMID>24987341</PMID>
  </reference>
  <reference>
    <citation>Mayes DA, Rizvi TA, Titus-Mitchell H, Oberst R, Ciraolo GM, Vorhees CV, Robinson AP, Miller SD, Cancelas JA, Stemmer-Rachamimov AO, Ratner N. Nf1 loss and Ras hyperactivation in oligodendrocytes induce NOS-driven defects in myelin and vasculature. Cell Rep. 2013 Sep 26;4(6):1197-212. doi: 10.1016/j.celrep.2013.08.011. Epub 2013 Sep 12.</citation>
    <PMID>24035394</PMID>
  </reference>
  <reference>
    <citation>Garcia RJ, Francis L, Dawood M, Lai ZW, Faraone SV, Perl A. Attention deficit and hyperactivity disorder scores are elevated and respond to N-acetylcysteine treatment in patients with systemic lupus erythematosus. Arthritis Rheum. 2013 May;65(5):1313-8. doi: 10.1002/art.37893.</citation>
    <PMID>23400548</PMID>
  </reference>
  <reference>
    <citation>Fernandes BS, Dean OM, Dodd S, Malhi GS, Berk M. N-Acetylcysteine in depressive symptoms and functionality: a systematic review and meta-analysis. J Clin Psychiatry. 2016 Apr;77(4):e457-66. doi: 10.4088/JCP.15r09984.</citation>
    <PMID>27137430</PMID>
  </reference>
  <reference>
    <citation>Hardan AY, Fung LK, Libove RA, Obukhanych TV, Nair S, Herzenberg LA, Frazier TW, Tirouvanziam R. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry. 2012 Jun 1;71(11):956-61. doi: 10.1016/j.biopsych.2012.01.014. Epub 2012 Feb 18.</citation>
    <PMID>22342106</PMID>
  </reference>
  <reference>
    <citation>Berk M, Dean O, Cotton SM, Gama CS, Kapczinski F, Fernandes BS, Kohlmann K, Jeavons S, Hewitt K, Allwang C, Cobb H, Bush AI, Schapkaitz I, Dodd S, Malhi GS. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. J Affect Disord. 2011 Dec;135(1-3):389-94. doi: 10.1016/j.jad.2011.06.005. Epub 2011 Jun 29.</citation>
    <PMID>21719110</PMID>
  </reference>
  <reference>
    <citation>Fluvoxamine for the treatment of anxiety disorders in children and adolescents. The Research Unit on Pediatric Psychopharmacology Anxiety Study Group. N Engl J Med. 2001 Apr 26;344(17):1279-85. doi: 10.1056/NEJM200104263441703.</citation>
    <PMID>11323729</PMID>
  </reference>
  <reference>
    <citation>Axelrod BN. Validity of the Wechsler abbreviated scale of intelligence and other very short forms of estimating intellectual functioning. Assessment. 2002 Mar;9(1):17-23. doi: 10.1177/1073191102009001003.</citation>
    <PMID>11911230</PMID>
  </reference>
  <reference>
    <citation>Zhu J, Tulsky DS, Price L, Chen HY. WAIS-III reliability data for clinical groups. J Int Neuropsychol Soc. 2001 Nov;7(7):862-6.</citation>
    <PMID>11771629</PMID>
  </reference>
  <reference>
    <citation>Mills KR, Nithi KA. Corticomotor threshold to magnetic stimulation: normal values and repeatability. Muscle Nerve. 1997 May;20(5):570-6. doi: 10.1002/(sici)1097-4598(199705)20:53.0.co;2-6.</citation>
    <PMID>9140363</PMID>
  </reference>
  <reference>
    <citation>Ziemann U. Intracortical inhibition and facilitation in the conventional paired TMS paradigm. Electroencephalogr Clin Neurophysiol Suppl. 1999;51:127-36. No abstract available.</citation>
    <PMID>10590943</PMID>
  </reference>
  <reference>
    <citation>Erkan E, Zhao X, Setchell K, Devarajan P. Distinct urinary lipid profile in children with focal segmental glomerulosclerosis. Pediatr Nephrol. 2016 Apr;31(4):581-8. doi: 10.1007/s00467-015-3239-7. Epub 2015 Nov 4.</citation>
    <PMID>26537928</PMID>
  </reference>
  <reference>
    <citation>Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol. 1998 Jan;108(1):1-16. doi: 10.1016/s0168-5597(97)00096-8.</citation>
    <PMID>9474057</PMID>
  </reference>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>April 14, 2020</study_first_submitted>
  <study_first_submitted_qc>July 17, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 22, 2020</study_first_posted>
  <results_first_submitted>June 16, 2021</results_first_submitted>
  <results_first_submitted_qc>February 16, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">March 15, 2022</results_first_posted>
  <last_update_submitted>July 18, 2022</last_update_submitted>
  <last_update_submitted_qc>July 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 25, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neurofibromatoses</mesh_term>
    <mesh_term>Neurofibromatosis 1</mesh_term>
    <mesh_term>Neurofibroma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetylcysteine</mesh_term>
    <mesh_term>N-monoacetylcystine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Identifiable individual participant data will not be available to other researchers.</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 9, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/35/NCT04481035/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>N-Acetylcysteine Followed by Placebo</title>
          <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, followed by placebo three times per day for 8 weeks.</description>
        </group>
        <group group_id="P2">
          <title>Placebo Followed by N-Acetylcysteine</title>
          <description>Participants will be dosed three times per day with a placebo for eight (8) weeks followed by 70 mg/kg/dose (max dose 900 mg) three times per day of N-Acetylcysteine for 8 weeks.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Period 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Period 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>N-Acetylcysteine Followed by Placebo</title>
          <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, followed by placebo three times per day for 8 weeks.</description>
        </group>
        <group group_id="B2">
          <title>Placebo Followed by N-Acetylcysteine</title>
          <description>Participants will be dosed three times per day with a placebo for eight (8) weeks followed by 70 mg/kg/dose (max dose 900 mg) three times per day of N-Acetylcysteine for 8 weeks.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="3"/>
            <count group_id="B2" value="2"/>
            <count group_id="B3" value="5"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13" lower_limit="12" upper_limit="15"/>
                    <measurement group_id="B2" value="14.5" lower_limit="12" upper_limit="17"/>
                    <measurement group_id="B3" value="13" lower_limit="12" upper_limit="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Physical and Neurological Examination for Subtle Signs (PANESS) Total</title>
          <description>Physical and Neurological Examination for Subtle Signs (PANESS) measure of motor function. The PANESS test measures timed movements, lateral preference, motor overflow, dysrhythmia, coordination, gait, balance, and motor persistence. The range of this scale is 0-119, higher scores correlate with symptom severity (worse outcome).</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="45" spread="11"/>
                    <measurement group_id="B2" value="38" spread="4.2"/>
                    <measurement group_id="B3" value="42" spread="8.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS), DuPaul DSM-5 based scale</title>
          <description>Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS), DuPaul DSM-5 based clinical rating scale. The range of this scale is 0-56, higher scores correlate with symptom severity (worse outcome).</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="35" spread="5.4"/>
                    <measurement group_id="B2" value="51" spread="0"/>
                    <measurement group_id="B3" value="39" spread="8.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in Motor Function Measured by Physical and Neurological Examination for Subtle Signs (PANESS)</title>
        <description>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).</description>
        <time_frame>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).</time_frame>
        <population>Descriptive only</population>
        <group_list>
          <group group_id="O1">
            <title>N-Acetylcysteine</title>
            <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.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>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.&#xD;
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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Motor Function Measured by Physical and Neurological Examination for Subtle Signs (PANESS)</title>
          <description>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).</description>
          <population>Descriptive only</population>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" lower_limit="-8" upper_limit="2"/>
                    <measurement group_id="O2" value="3" lower_limit="-4" upper_limit="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in ADHD Symptoms as Reported Via Parent/Teacher Surveys</title>
        <description>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).</description>
        <time_frame>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).</time_frame>
        <population>Modified ITT - all participants who received at least one dose of study drug</population>
        <group_list>
          <group group_id="O1">
            <title>N-Acetylcysteine</title>
            <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.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>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.&#xD;
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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in ADHD Symptoms as Reported Via Parent/Teacher Surveys</title>
          <description>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).</description>
          <population>Modified ITT - all participants who received at least one dose of study drug</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-12.5" spread="13.1"/>
                    <measurement group_id="O2" value="-3.75" spread="12.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Transcranial Magnetic Stimulation (TMS) - Cortical Silent Period</title>
        <description>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 &quot;GABA B&quot; 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.</description>
        <time_frame>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).</time_frame>
        <population>modified ITT - at least one dose given</population>
        <group_list>
          <group group_id="O1">
            <title>N-Acetylcysteine</title>
            <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.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>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.&#xD;
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.</description>
          </group>
        </group_list>
        <measure>
          <title>Transcranial Magnetic Stimulation (TMS) - Cortical Silent Period</title>
          <description>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 &quot;GABA B&quot; 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.</description>
          <population>modified ITT - at least one dose given</population>
          <units>ms</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6" spread="19"/>
                    <measurement group_id="O2" value="-4" spread="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Metabolic Testing Biomarkers</title>
        <description>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.&#xD;
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.&#xD;
Data is not yet available as the samples in storage for follow up study.</description>
        <time_frame>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).</time_frame>
        <posting_date>01/2024</posting_date>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Evaluation of Change From Baseline in Metabolomics Profiles as a Possible Disease Biomarker Metabolic Testing Biomarkers - Samples in Storage for Follow up Study</title>
        <description>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).</description>
        <time_frame>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).</time_frame>
        <posting_date>01/2024</posting_date>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>18 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>N-Acetylcysteine Treatment</title>
          <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.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Participants will be dosed three times per day with a placebo for eight (8) weeks.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Donald L. Gilbert MD</name_or_title>
      <organization>Cincinnati Children's Hospital Medical Center</organization>
      <phone>513-636-4222</phone>
      <email>donald.gilbert@cchmc.org</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04481035
org study id: 2018-0344
nct id: NCT04481035
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
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.
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).
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.
primary purpose: Treatment
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.
measure: Change From Baseline in Motor Function Measured by Physical and Neurological Examination for Subtle Signs (PANESS)
time frame: 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).
description: 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).
measure: Change From Baseline in ADHD Symptoms as Reported Via Parent/Teacher Surveys
time frame: 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).
description: 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).
measure: Transcranial Magnetic Stimulation (TMS) - Cortical Silent Period
time frame: 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).
description: 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.
measure: Metabolic Testing Biomarkers
time frame: 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).
description: 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.
measure: Evaluation of Change From Baseline in Metabolomics Profiles as a Possible Disease Biomarker Metabolic Testing Biomarkers - Samples in Storage for Follow up Study
time frame: 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).
description: 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).
arm group label: N-Acetylcysteine
arm group type: Experimental
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.
arm group label: Placebo
arm group type: Placebo Comparator
description: 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.
intervention type: Drug
intervention name: N-acetylcysteine (NAC)
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.
arm group label: N-Acetylcysteine
other name: Chemical Name: Cysteine, N-acetyl-, L
other name: Commercial Name(s): Acetein; Acetadote, Acetylcysteine; Airbron; Broncholysin; Fluimucetin; Fluimucil; Inspir; Mucofilin; Mucomyst; Mucosolvin; NAC; Paravolex; Respaire
other name: Synonym:L-alpha-acetamido-beta-mercaptopropionic acid; Mercapturic acid; N-Acetyl-3-mercaptoalanine; N-Acetylcysteine
intervention type: Other
intervention name: Placebo
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 placebo phase/arm will receive placebo (non-drug) three times per day for eight (8) weeks.
arm group label: Placebo
criteria: 
gender: All
minimum age: 8 Years
maximum age: 16 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Donald L Gilbert, MD, MS
role: Principal Investigator
affiliation: Children's Hospital Medical Center, Cincinnati
facility: 
country: United States
citation: Acosta MT, Gioia GA, Silva AJ. Neurofibromatosis type 1: new insights into neurocognitive issues. Curr Neurol Neurosci Rep. 2006 Mar;6(2):136-43. doi: 10.1007/s11910-996-0036-5.
PMID: 16522267
citation: Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, Collins F. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell. 1990 Nov 16;63(4):851-9. doi: 10.1016/0092-8674(90)90151-4.
PMID: 2121371
citation: Rosser TL, Packer RJ. Neurocognitive dysfunction in children with neurofibromatosis type 1. Curr Neurol Neurosci Rep. 2003 Mar;3(2):129-36. doi: 10.1007/s11910-003-0064-3.
PMID: 12583841
citation: Casnar CL, Janke KM, van der Fluit F, Brei NG, Klein-Tasman BP. Relations between fine motor skill and parental report of attention in young children with neurofibromatosis type 1. J Clin Exp Neuropsychol. 2014;36(9):930-43. doi: 10.1080/13803395.2014.957166. Epub 2014 Oct 6.
PMID: 25284746
citation: Walsh KS, Janusz J, Wolters PL, Martin S, Klein-Tasman BP, Toledo-Tamula MA, Thompson HL, Payne JM, Hardy KK, de Blank P, Semerjian C, Gray LS, Solomon SE, Ullrich N; REiNS International Collaboration. Neurocognitive outcomes in neurofibromatosis clinical trials: Recommendations for the domain of attention. Neurology. 2016 Aug 16;87(7 Suppl 1):S21-30. doi: 10.1212/WNL.0000000000002928.
PMID: 27527646
citation: Acosta MT, Bearden CE, Castellanos FX, Cutting L, Elgersma Y, Gioia G, Gutmann DH, Lee YS, Legius E, Muenke M, North K, Parada LF, Ratner N, Hunter-Schaedle K, Silva AJ. The Learning Disabilities Network (LeaDNet): using neurofibromatosis type 1 (NF1) as a paradigm for translational research. Am J Med Genet A. 2012 Sep;158A(9):2225-32. doi: 10.1002/ajmg.a.35535. Epub 2012 Jul 20. Erratum In: Am J Med Genet A. 2013 Jan;161A(1):236. Castellanos, Xavier F [corrected to Castellanos, F Xavier].
PMID: 22821737
citation: Pride N, Payne JM, Webster R, Shores EA, Rae C, North KN. Corpus callosum morphology and its relationship to cognitive function in neurofibromatosis type 1. J Child Neurol. 2010 Jul;25(7):834-41. doi: 10.1177/0883073809350723. Epub 2010 Feb 8.
PMID: 20142468
citation: Wang Y, Kim E, Wang X, Novitch BG, Yoshikawa K, Chang LS, Zhu Y. ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities. Cell. 2012 Aug 17;150(4):816-30. doi: 10.1016/j.cell.2012.06.034.
PMID: 22901811
citation: Karlsgodt KH, Rosser T, Lutkenhoff ES, Cannon TD, Silva A, Bearden CE. Alterations in white matter microstructure in neurofibromatosis-1. PLoS One. 2012;7(10):e47854. doi: 10.1371/journal.pone.0047854. Epub 2012 Oct 19.
PMID: 23094098
citation: Gilbert DL, Isaacs KM, Augusta M, Macneil LK, Mostofsky SH. Motor cortex inhibition: a marker of ADHD behavior and motor development in children. Neurology. 2011 Feb 15;76(7):615-21. doi: 10.1212/WNL.0b013e31820c2ebd.
PMID: 21321335
citation: Chen TH, Wu SW, Welge JA, Dixon SG, Shahana N, Huddleston DA, Sarvis AR, Sallee FR, Gilbert DL. Reduced short interval cortical inhibition correlates with atomoxetine response in children with attention-deficit hyperactivity disorder (ADHD). J Child Neurol. 2014 Dec;29(12):1672-9. doi: 10.1177/0883073813513333. Epub 2014 Jan 10.
PMID: 24413361
citation: Dennis J, White MA, Forrest AD, Yuelling LM, Nogaroli L, Afshari FS, Fox MA, Fuss B. Phosphodiesterase-Ialpha/autotaxin's MORFO domain regulates oligodendroglial process network formation and focal adhesion organization. Mol Cell Neurosci. 2008 Feb;37(2):412-24. doi: 10.1016/j.mcn.2007.10.018. Epub 2007 Nov 12.
PMID: 18164210
citation: Tokumura A, Majima E, Kariya Y, Tominaga K, Kogure K, Yasuda K, Fukuzawa K. Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biol Chem. 2002 Oct 18;277(42):39436-42. doi: 10.1074/jbc.M205623200. Epub 2002 Aug 9.
PMID: 12176993
citation: Fox MA, Colello RJ, Macklin WB, Fuss B. Phosphodiesterase-Ialpha/autotaxin: a counteradhesive protein expressed by oligodendrocytes during onset of myelination. Mol Cell Neurosci. 2003 Jul;23(3):507-19. doi: 10.1016/s1044-7431(03)00073-3.
PMID: 12837632
citation: Chen YW, Lin HC, Ng MC, Hsiao YH, Wang CC, Gean PW, Chen PS. Activation of mGluR2/3 underlies the effects of N-acetylcystein on amygdala-associated autism-like phenotypes in a valproate-induced rat model of autism. Front Behav Neurosci. 2014 Jun 17;8:219. doi: 10.3389/fnbeh.2014.00219. eCollection 2014.
PMID: 24987341
citation: Mayes DA, Rizvi TA, Titus-Mitchell H, Oberst R, Ciraolo GM, Vorhees CV, Robinson AP, Miller SD, Cancelas JA, Stemmer-Rachamimov AO, Ratner N. Nf1 loss and Ras hyperactivation in oligodendrocytes induce NOS-driven defects in myelin and vasculature. Cell Rep. 2013 Sep 26;4(6):1197-212. doi: 10.1016/j.celrep.2013.08.011. Epub 2013 Sep 12.
PMID: 24035394
citation: Garcia RJ, Francis L, Dawood M, Lai ZW, Faraone SV, Perl A. Attention deficit and hyperactivity disorder scores are elevated and respond to N-acetylcysteine treatment in patients with systemic lupus erythematosus. Arthritis Rheum. 2013 May;65(5):1313-8. doi: 10.1002/art.37893.
PMID: 23400548
citation: Fernandes BS, Dean OM, Dodd S, Malhi GS, Berk M. N-Acetylcysteine in depressive symptoms and functionality: a systematic review and meta-analysis. J Clin Psychiatry. 2016 Apr;77(4):e457-66. doi: 10.4088/JCP.15r09984.
PMID: 27137430
citation: Hardan AY, Fung LK, Libove RA, Obukhanych TV, Nair S, Herzenberg LA, Frazier TW, Tirouvanziam R. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry. 2012 Jun 1;71(11):956-61. doi: 10.1016/j.biopsych.2012.01.014. Epub 2012 Feb 18.
PMID: 22342106
citation: Berk M, Dean O, Cotton SM, Gama CS, Kapczinski F, Fernandes BS, Kohlmann K, Jeavons S, Hewitt K, Allwang C, Cobb H, Bush AI, Schapkaitz I, Dodd S, Malhi GS. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. J Affect Disord. 2011 Dec;135(1-3):389-94. doi: 10.1016/j.jad.2011.06.005. Epub 2011 Jun 29.
PMID: 21719110
citation: Fluvoxamine for the treatment of anxiety disorders in children and adolescents. The Research Unit on Pediatric Psychopharmacology Anxiety Study Group. N Engl J Med. 2001 Apr 26;344(17):1279-85. doi: 10.1056/NEJM200104263441703.
PMID: 11323729
citation: Axelrod BN. Validity of the Wechsler abbreviated scale of intelligence and other very short forms of estimating intellectual functioning. Assessment. 2002 Mar;9(1):17-23. doi: 10.1177/1073191102009001003.
PMID: 11911230
citation: Zhu J, Tulsky DS, Price L, Chen HY. WAIS-III reliability data for clinical groups. J Int Neuropsychol Soc. 2001 Nov;7(7):862-6.
PMID: 11771629
citation: Mills KR, Nithi KA. Corticomotor threshold to magnetic stimulation: normal values and repeatability. Muscle Nerve. 1997 May;20(5):570-6. doi: 10.1002/(sici)1097-4598(199705)20:53.0.co;2-6.
PMID: 9140363
citation: Ziemann U. Intracortical inhibition and facilitation in the conventional paired TMS paradigm. Electroencephalogr Clin Neurophysiol Suppl. 1999;51:127-36. No abstract available.
PMID: 10590943
citation: Erkan E, Zhao X, Setchell K, Devarajan P. Distinct urinary lipid profile in children with focal segmental glomerulosclerosis. Pediatr Nephrol. 2016 Apr;31(4):581-8. doi: 10.1007/s00467-015-3239-7. Epub 2015 Nov 4.
PMID: 26537928
citation: Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol. 1998 Jan;108(1):1-16. doi: 10.1016/s0168-5597(97)00096-8.
PMID: 9474057
responsible party type: Sponsor
mesh term: Neurofibromatoses
mesh term: Neurofibromatosis 1
mesh term: Neurofibroma
mesh term: Acetylcysteine
mesh term: N-monoacetylcystine
sharing ipd: No
ipd description: Identifiable individual participant data will not be available to other researchers.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 