<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/NCT04481048</url>
  </required_header>
  <id_info>
    <org_study_id>2020-0412</org_study_id>
    <nct_id>NCT04481048</nct_id>
  </id_info>
  <brief_title>Antioxidant Therapy With N-acetylcysteine for Children With Neurofibromatosis Type 1</brief_title>
  <acronym>DoDNAC</acronym>
  <official_title>Antioxidant Therapy With N-acetylcysteine for Motor Behavior and/or Learning 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>
    <collaborator>
      <agency>United States Department of Defense</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </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. In this project, the investigators will assess the safety and clinical benefit&#xD;
      of N-acetylcysteine (NAC) as a pharmacological intervention in children with NF1. This drug&#xD;
      choice is based on the recent findings from mouse models to study the central nervous system&#xD;
      manifestations of NF1 at Cincinnati Children's Hospital Medical Center (CCHMC). These&#xD;
      findings revealed a role for myelin-forming oligodendrocytes in the control of nitric oxide&#xD;
      synthases (NOS) and their product, nitric oxide (NO), 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. This data from animal models of NF1 along&#xD;
      with uncontrolled clinical observations in children with NF1 suggest that the antioxidant&#xD;
      compound, NAC, may reduce these impairments. Therefore, the investigators propose performing&#xD;
      a single center double-blind placebo controlled, prospective, Phase II study to explore&#xD;
      safety, tolerability, and efficacy of NAC on motor behavior and/or learning in children with&#xD;
      NF1 aged 8 through 16 years old. Participants will be carefully monitored for side effects.&#xD;
      Primary and secondary outcome measures will be administered at baseline, follow-up, and&#xD;
      post-treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a phase II clinical trial with the goal to explore safety, tolerability, and efficacy&#xD;
      of NAC on motor behavior in children with NF1 aged 8 through 16 years old. The investigators&#xD;
      hypothesize that NAC therapy will improve motor function evaluated by the PANESS scale. This&#xD;
      is based on studies demonstrating that NAC significantly improved impairments in the animal&#xD;
      model of NF1. The investigators will also analyze NAC effects on attention deficit and&#xD;
      impulsivity in children with NF1.&#xD;
&#xD;
      This study will also help develop novel predictive biomarkers of response to neurocognitive&#xD;
      therapies in patients with NF1 which are needed to evaluate treatment outcomes.&#xD;
&#xD;
      The investigators will gain information in children with NF1 about possible clinical benefit&#xD;
      of anti-oxidant treatment and to develop and evaluate quantitative brain-based and blood&#xD;
      biomarkers relating to presence of NF1, symptom severity, and response to antioxidant&#xD;
      therapy. Clinically, 50 percent of children with NF1 are underperforming or failing at&#xD;
      school. This frequently leads to decreased educational attainment and fewer opportunities as&#xD;
      adults. An important first step was preliminary work using the PANESS scale and Transcranial&#xD;
      Magnetic Stimulation (TMS)-evoked Short Interval Cortical Inhibition (rSICI) in children with&#xD;
      NF1. The investigators propose to develop and extend understanding of NF1-related motor and&#xD;
      learning behavior in response to antioxidant therapy with NAC. The purpose of the present&#xD;
      study is to 1) evaluate tolerability, safety, and clinical benefit of NAC in this&#xD;
      double-blind placebo controlled study using the motor function scale (PANESS); 2) to evaluate&#xD;
      the effects of NAC on measures of NF1 neurocognitive symptomatology (ADHD/impulsive symptoms,&#xD;
      executive function, working memory); and 3) to determine if TMS measurement (SICI) in&#xD;
      children with NF1 will correlate with clinical effects of NAC treatment and evaluate utility&#xD;
      of advanced brain imaging and spectroscopy measurements in children with NF1, and effects of&#xD;
      NAC therapy.&#xD;
&#xD;
      The investigators propose to study 58 children with NF1, ages 8-16 years, at baseline and&#xD;
      after completion of 8 weeks of treatment with NAC, followed by a washout period of 4 weeks.&#xD;
&#xD;
      The investigators believe this work has the potential to lay groundwork for future use of&#xD;
      relevant biomarkers for treatment and outcomes research for NF1 as well as other biologically&#xD;
      similar conditions, collectively designated the &quot;RASopathies&quot; (due to involvement of the RAS&#xD;
      family of proteins) and ultimately to guide development of more effective treatments based on&#xD;
      disease pathophysiology.&#xD;
&#xD;
      STUDY OBJECTIVE:&#xD;
&#xD;
      NAC Trial at Cincinnati Children's Hospital Medical Center (CCHMC) The investigators propose&#xD;
      performing a single center randomized double-blind placebo controlled, prospective, Phase II&#xD;
      study to explore safety, tolerability, and efficacy of NAC on motor behavior in children with&#xD;
      NF1 aged 8 through 16 years old.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      The investigators hypothesize that NAC therapy will improve motor function evaluated by the&#xD;
      PANESS scale. This is based on studies demonstrating that NAC significantly improved&#xD;
      impairments in the animal model of NF1. The investigators will also analyze NAC effects on&#xD;
      attention deficit and impulsivity in children with NF1.&#xD;
&#xD;
      Specific Aim:&#xD;
&#xD;
      The primary outcome of this study is to characterize the effects of NAC treatment on motor&#xD;
      function in children and adolescents with NF1 using the PANESS. The investigators hypothesize&#xD;
      that motor function scores rated with the PANESS scale will improve after treatment with NAC.&#xD;
&#xD;
      Secondary Aims:&#xD;
&#xD;
        1. To evaluate the effects of NAC on measures of NF1 neurocognitive symptomatology&#xD;
           (ADHD/impulsive symptoms, executive function, working memory), the investigators will&#xD;
           use Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) committee&#xD;
           recommended assessments tools DuPaul ADHD rating scale (ADHD-RS), Behavioral Rating&#xD;
           Inventory of Executive Function second edition (BRIEF-2), Wechsler Intelligence Scale&#xD;
           for Children, Fifth Edition (WISC-V) subtests, and Test of Variables of Attention&#xD;
           (TOVA).&#xD;
&#xD;
        2. To determine if TMS measurement (SICI) in children with NF1 will correlate with clinical&#xD;
           effects of NAC treatment.&#xD;
&#xD;
        3. To quantify microstructural properties of brain tissue based on water diffusion,&#xD;
           glutathione GSH concentrations, and gamma-aminobutyric acid (GABA) concentration using&#xD;
           brain magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in&#xD;
           children with NF1. This will allow for regional correlation between imaging,&#xD;
           spectroscopy and neuropsychometric outcomes. The investigators will also determine if&#xD;
           these magnetic resonance based outcomes correlate with clinical effects of NAC&#xD;
           treatment.&#xD;
&#xD;
        4. To evaluate safety and tolerability of NAC in children with NF1.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 15, 2020</start_date>
  <completion_date type="Anticipated">December 2024</completion_date>
  <primary_completion_date type="Anticipated">June 2024</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>Parallel Assignment</intervention_model>
    <intervention_model_description>This is a phase II, double blind, placebo-controlled clinical trial with the goal to explore safety, tolerability, and efficacy of N-acetylcysteine (NAC).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>In order to preserve the double-masking of the trial, only the investigation pharmacy will be unmasked. Both treatments (NAC and placebo) will be distributed from the investigational pharmacy. Except for the pharmacist, all staff will be blinded to the treatment sequence.</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>through 12 weeks (at weeks 0, 8, and 12)</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>
  <secondary_outcome>
    <measure>Change from Baseline in ADHD Symptoms as Reported via Parent/Teacher Surveys</measure>
    <time_frame>through 12 weeks (at weeks 0, 8, and 12)</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 Diagnostic and Statistical Manual Diploma in Social Medicine (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>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Motor Function and Physiology Measured by Transcranial Magnetic Stimulation (TMS)</measure>
    <time_frame>through 12 weeks (at weeks 0, 8, and 12)</time_frame>
    <description>Describe the function and physiology of the motor system using Transcranial Magnetic Stimulation (TMS) as a possible disease biomarker of NF1. Preliminary measures in an 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 (&quot;normalize&quot;) upon NAC treatment. The investigators will compare to our internal age-matched healthy controls at Cincinnati Children's.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Microstructural Properties of Brain Tissue Visualized by Magnetic Resonance Imaging (MRI)</measure>
    <time_frame>through 12 weeks (at weeks 0, 8, and 12)</time_frame>
    <description>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. We will also determine if these magnetic resonance based outcomes correlate with clinical effects of NAC treatment.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">58</enrollment>
  <condition>Neurofibromatosis 1</condition>
  <arm_group>
    <arm_group_label>N-Acetylcysteine (NAC)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <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.&#xD;
Table 3: NAC Dosing Participant's weight (kg) Dose (BID) &lt; 20 700 mg 21-39 1050 mg &gt; 40 1350 mg&#xD;
*Max dose not to exceed 2700mg/day (1350mg BID)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Each subject will be dosed with placebo for 8 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Single Visit/Non-Treatment Arm</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Based on preliminary data, an additional &quot;Single visit, non-treatment&quot; cohort will include 40 individuals with NF1 for a single &quot;biomarker&quot; study visit. These individuals will undergo motor function (PANESS) and brain-based measures (TMS, MRI-MRS, DTI) as biomarkers of impaired executive function (ADHD-RS; BRIEF-2; TOVA) but will not be assigned to receive NAC/Placebo.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>N-Acetyl cysteine</intervention_name>
    <description>Eight (8) weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC).</description>
    <arm_group_label>N-Acetylcysteine (NAC)</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; Mercpaturic acid; N-Acetyl-3-mercaptoalanine; N-Acetylcysteine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Eight (8) weeks of treatment with placebo.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria ѱ:&#xD;
&#xD;
        You can be in this study if you have any of the following:&#xD;
&#xD;
          1. Males and females older than 8 years and younger than 16 years old&#xD;
&#xD;
          2. Has a diagnosis of NF1 (neurofibromatosis type 1)&#xD;
&#xD;
          3. Has an abnormal PANESS score&#xD;
&#xD;
          4. Has an IQ (intelligence quotient) at or above 70&#xD;
&#xD;
          5. Participants on stimulant or any other psychotropic medication should stay on a stable&#xD;
             dose (no change in dose) for at least 30 days before entering the study and maintain&#xD;
             that dose while in the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        You cannot be in this study if you have any of the following:&#xD;
&#xD;
          1. Younger than 8 years or older than 16 years ѱ&#xD;
&#xD;
          2. Do not have a diagnosis of NF1 ѱ&#xD;
&#xD;
          3. IQ below 70 ѱ&#xD;
&#xD;
          4. Had a dose change of any stimulant or psychotropic medication in the last month (30&#xD;
             days) ѱ&#xD;
&#xD;
          5. Are being treated with chemotherapy or had chemotherapy in the last 6 months&#xD;
&#xD;
          6. Have epilepsy ѱ&#xD;
&#xD;
          7. High risk of upper gastrointestinal (GI, the stomach and the small and large&#xD;
             intestine) hemorrhage (bleeding). Examples: presence of esophageal varices or peptic&#xD;
             ulcers&#xD;
&#xD;
          8. Active intracranial lesions (abnormality found on brain imaging such as an MRI)&#xD;
             (stable low-grade glioma is acceptable) or epilepsy diagnosis ѱ&#xD;
&#xD;
          9. Have Major Depression, Bipolar Disorder, Conduct Disorder, Adjustment Disorder, other&#xD;
             major Anxiety Disorders, or other developmental psychiatric diagnoses, based on&#xD;
             history. ADHD is OK&#xD;
&#xD;
         10. For females, pregnancy&#xD;
&#xD;
         11. Is currently using antidepressants, dopamine blocking agents, or mood stabilizers&#xD;
&#xD;
         12. Have any of the following medical devices: implanted brain stimulator, vagal nerve&#xD;
             stimulator, VP (ventriculoperitoneal) shunt, cardiac pacemaker, or implanted&#xD;
             medication port ѱ&#xD;
&#xD;
         13. Asthma (bronchospasm has been reported as occurring infrequently and unpredictably&#xD;
             when NAC is used as a mucolytic agent)&#xD;
&#xD;
         14. Current use of MEKINIST (MEK-inhibitor) or use within 30 days&#xD;
&#xD;
        ѱ Indicates Inclusion/Exclusion Criteria for the treatment- and non-treatment cohorts (no&#xD;
        mark indicates exclusion requirements for the 12-week treatment-cohort only).&#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 Gilbert, MD MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Hospital Medical Center, Cincinnati</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Lindsey Aschbacher-Smith, MS</last_name>
    <phone>513-803-0077</phone>
    <email>Lindsey.Aschbacher-Smith@cchmc.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Laurie Bailey, MS</last_name>
    <phone>513-636-4507</phone>
    <email>Laurie.Bailey@cchmc.org</email>
  </overall_contact_backup>
  <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>
    <status>Recruiting</status>
    <contact>
      <last_name>Lindsey Aschbacher-Smith, MS</last_name>
      <phone>513-803-0077</phone>
      <email>Lindsey.Aschbacher-Smith@cchmc.org</email>
    </contact>
    <investigator>
      <last_name>Carlos E Prada, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Donald L Gilbert, MD, MS</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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  </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>
  <results_reference>
    <citation>Doherty AC, Huddleston DA, Horn PS, Ratner N, Simpson BN, Schorry EK, Aschbacher-Smith L, Prada CE, Gilbert DL. Motor Function and Physiology in Youth With Neurofibromatosis Type 1. Pediatr Neurol. 2023 Jun;143:34-43. doi: 10.1016/j.pediatrneurol.2023.02.014. Epub 2023 Mar 3.</citation>
    <PMID>36996759</PMID>
  </results_reference>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>May 15, 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>
  <last_update_submitted>July 10, 2023</last_update_submitted>
  <last_update_submitted_qc>July 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 12, 2023</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>
  </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>May 17, 2023</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/48/NCT04481048/Prot_SAP_002.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>May 17, 2023</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/48/NCT04481048/ICF_003.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT04481048
org study id: 2020-0412
nct id: NCT04481048
lead sponsor: 
collaborator: 
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. 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.
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is a phase II, double blind, placebo-controlled clinical trial with the goal to explore safety, tolerability, and efficacy of N-acetylcysteine (NAC).
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: In order to preserve the double-masking of the trial, only the investigation pharmacy will be unmasked. Both treatments (NAC and placebo) will be distributed from the investigational pharmacy. Except for the pharmacist, all staff will be blinded to the treatment sequence.
measure: Change from Baseline in Motor Function Measured by Physical and Neurological Examination for Subtle Signs (PANESS)
time frame: through 12 weeks (at weeks 0, 8, and 12)
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: through 12 weeks (at weeks 0, 8, and 12)
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 Diagnostic and Statistical Manual Diploma in Social Medicine (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: Change from Baseline in Motor Function and Physiology Measured by Transcranial Magnetic Stimulation (TMS)
time frame: through 12 weeks (at weeks 0, 8, and 12)
description: Describe the function and physiology of the motor system using Transcranial Magnetic Stimulation (TMS) as a possible disease biomarker of NF1. Preliminary measures in an 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 our internal age-matched healthy controls at Cincinnati Children's.
measure: Change from Baseline in Microstructural Properties of Brain Tissue Visualized by Magnetic Resonance Imaging (MRI)
time frame: through 12 weeks (at weeks 0, 8, and 12)
description: 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. We will also determine if these magnetic resonance based outcomes correlate with clinical effects of NAC treatment.
arm group label: N-Acetylcysteine (NAC)
arm group type: Experimental
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)
arm group label: Placebo
arm group type: Placebo Comparator
description: Each subject will be dosed with placebo for 8 weeks.
arm group label: Single Visit/Non-Treatment Arm
arm group type: No Intervention
description: Based on preliminary data, an additional "Single visit, non-treatment" cohort will include 40 individuals with NF1 for a single "biomarker" study visit. These individuals will undergo motor function (PANESS) and brain-based measures (TMS, MRI-MRS, DTI) as biomarkers of impaired executive function (ADHD-RS; BRIEF-2; TOVA) but will not be assigned to receive NAC/Placebo.
intervention type: Drug
intervention name: N-Acetyl cysteine
description: Eight (8) weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC).
arm group label: N-Acetylcysteine (NAC)
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; Mercpaturic acid; N-Acetyl-3-mercaptoalanine; N-Acetylcysteine
intervention type: Other
intervention name: Placebo
description: Eight (8) weeks of treatment with placebo.
arm group label: Placebo
criteria: 
gender: All
minimum age: 8 Years
maximum age: 16 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Donald Gilbert, MD MS
role: Principal Investigator
affiliation: Children's Hospital Medical Center, Cincinnati
last name: Lindsey Aschbacher-Smith, MS
phone: 513-803-0077
email: Lindsey.Aschbacher-Smith@cchmc.org
last name: Laurie Bailey, MS
phone: 513-636-4507
email: Laurie.Bailey@cchmc.org
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: United States
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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
citation: Doherty AC, Huddleston DA, Horn PS, Ratner N, Simpson BN, Schorry EK, Aschbacher-Smith L, Prada CE, Gilbert DL. Motor Function and Physiology in Youth With Neurofibromatosis Type 1. Pediatr Neurol. 2023 Jun;143:34-43. doi: 10.1016/j.pediatrneurol.2023.02.014. Epub 2023 Mar 3.
PMID: 36996759
responsible party type: Sponsor
mesh term: Neurofibromatoses
mesh term: Neurofibromatosis 1
mesh term: Neurofibroma
mesh term: Acetylcysteine
mesh term: N-monoacetylcystine
sharing ipd: No
provided document: 
provided document: 