Neurofibromatosis 1Phase 2NF1NACNCT04481035
Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1
A Phase 2 study testing N-acetylcysteine (NAC) in people with Neurofibromatosis 1, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.
Trial summary
Children with neurofibromatosis type 1 (NF1) commonly suffer from the effects of cognitive, behavioral, and motor impairments. At present there is no specific treatment for this NF1 complication. Read more about this study
- Who is it for?
- Ages 8 to 16 yearsHealthy volunteers can take part
- Conditions the study is for
- Neurofibromatosis 1
- What is being tested?
- N-acetylcysteine (NAC)
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 5 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Jan 2019to 16 Dec 2021
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 8 to 16 years
- All sexes
- Healthy volunteers accepted
- Child
Who may be able to join
- Males and females aged 8 - 16 years at time of enrollment whom meet NIH diagnostic criteria for NF1.
- Participants must have a full-scale intelligence quotient (IQ) of 70 or above, as determined by neurocognitive testing within the last 3 years or during the enrollment process.
- Participants on stimulant or any other psychotropic medication should stay on a stable dose for at least 30 days before entering the study.
Who cannot join
- Participants should not be receiving chemotherapy currently, or have received chemotherapy in the 6 months prior to entering the study.
- No active intracranial lesions (stable low grade glioma are acceptable) or epilepsy diagnosis.
- Major Depression, Bipolar Disorder, Conduct Disorder, Adjustment Disorder, other major Anxiety Disorders, or other developmental psychiatric diagnoses, based on the child's history or on parent and child responses from the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS). Note that while this is an exclusion for participation in the study if there is a prior evaluation available, this becomes a criterion, after inclusion, for the investigator to withdraw the child from the study prior to completion if identified on the first study day.
- For females, pregnancy.
- Current use of antidepressants, non-stimulant ADHD medications, dopamine blocking agents, mood stabilizers.
- Implanted brain stimulator, vagal nerve stimulator, ventriculoperitoneal (VP) shunt, cardiac pacemaker, or implanted medication port.
- Asthma (bronchospasm has been reported as occurring infrequently and unpredictable when acetylcysteine is used as a mucolytica agent).
- High risk of upper gastrointestinal (GI) hemorrhage. Examples: presence of esophageal varices or peptic ulcers
Trial locations and contacts
1 site in 1 country.
United States1 site
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
About this study
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.
Read the detailed description
The aims of this application are to gain information in children with NF1 about possible clinical benefit of anti-oxidant treatment and to develop and evaluate quantitative brain-based and blood biomarkers relating to presence of NF1, symptom severity, and response to antioxidant therapy. Clinically, 50% of children with NF1 are underperforming or failing at school [1]. This frequently leads to decreased educational attainment and fewer opportunities as adults. An important first step was preliminary work using the PANESS scale and Transcranial Magnetic Stimulation (TMS)-evoked Short Interval Cortical Inhibition (rSICI) in children with NF1. The investigators propose to develop and extend our understanding of NF1-related motor and learning behavior in response to antioxidant therapy with NAC. The purpose of the present study is to 1) evaluate tolerability, safety, and clinical benefit of NAC in this double-blind placebo controlled study; 2) to evaluate motor function (PANESS) and physiology (TMS) biomarkers at baseline and after treatment; and 3) to quantify metabolomics profiles at baseline and after treatment. The investigators propose to study 20 children with NF1, ages 8-16 years, at baseline and after completion of 8 weeks of treatment with NAC.
NAC therapy, if successful, is expected improve these parameters. The trial endpoints are: Does behavior improve? Does motor function improve? Are there TMS biomarkers that reflect the presence of NF1 and the response to NAC treatment? Are there metabolomics measures that reflect the presence of NF1 and the response to treatment? The investigators hypothesize that predictive measures exist and can be used as a foundation for an application for funding for a larger, more definitive, placebo-controlled trial involving biomarkers and clinical outcomes. The investigators believe this work has the potential to lay groundwork for future use of relevant biomarkers for treatment and outcomes research for NF1 as well as other biologically similar conditions, collectively designated the "RASopathies" (due to involvement of the RAS family of proteins) and ultimately to guide development of more effective treatments based on disease pathophysiology.
SPECIFIC AIMS
This study involves the following aims:
Specific Aim 1: Primary Outcome of Study In children and adolescents with NF1, to characterize the behavioral and motor effects of 8 weeks of N-acetylcysteine (NAC) treatment in a cohort of 20 children and adolescents with NF1. The investigators will evaluate tolerability, safety, and clinical benefit of NAC in this double-blind crossover placebo controlled study. Aim 1.1: Characterize effects of NAC treatment on motor function in kids with NF1 using the Physical and Neurological Examination for Subtle Signs (PANESS). This is a validated scale that consistently demonstrates significant impairments in children with ADHD, and which preliminary data suggest may demonstrate more extreme problems in children with NF1 than age-matched healthy controls (unpublished data from CCHMC). The investigators hypothesize that motor function scores rated with the PANESS scale will improve after treatment with NAC. Aim 1.2: Characterize effects of NAC treatment on ADHD symptoms in children with NF1. The investigators hypothesize that ADHD attention and hyperactive/impulsive symptoms, rated with the DuPaul Diagnostic and Statistical Manual Diploma in Social Medicine (DSM-5) based clinical rating scales, will improve after treatment with NAC.
Specific Aim 2: Experimental aim # 1 In the same cohort, the investigators will identify potential novel biomarkers of neurodevelopmental burden in NF1. Aim 2.1: Describe the function and physiology of the motor system using Transcranial Magnetic Stimulation (TMS) as a possible disease biomarker of NF1. Preliminary measures in our NF1 population also show abnormalities similar to established findings in ADHD. The investigators hypothesize that children with NF1 will have significantly less motor cortex inhibition using TMS measurements, and these measures will improve ("normalize") upon NAC treatment. The investigators will compare to age-matched healthy controls at Cincinnati Children's. Aim 2.2: The investigators propose to evaluate autotaxin as a candidate biomarker of oligodendrocyte dysfunction in NF1 participants. Preliminary data from biomarker discovery analysis of serum samples from healthy controls and NF1 patients showed lysophosphatidylcholine (LPC) depletion compared to healthy age/sex matched controls. In gene expression analysis autotaxin was elevated 4 times in neurofibroma Schwann cells compared to normal nerve Schwann cells. The investigators will collect serum and plasma from participants to assess autotaxin/LPC axis prior and post-NAC therapy. The investigators hypothesize that autotaxin axis abnormalities will be a biomarker of response to antioxidant therapy in our NF1 population.
Specific Aim 3: Experimental aim # 2 In the same cohort, to evaluate metabolomics profiles as a possible disease biomarker that is affected by NF1 and by treatment with NAC as per Aim 1. Hypothesis 4: The investigators hypothesize that specific profiles will predict clinical response to antioxidant therapy compared to age-matched healthy control (unpublished data from CCHMC).
- Conditions
- Neurofibromatosis 1
- Being tested
- N-acetylcysteine (NAC), Placebo
- Medical subject headings
- Neurofibromatosis 1
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
N-acetylcysteine (NAC)Drug
Also called Chemical Name: Cysteine, N-acetyl-, L, Commercial Name(s): Acetein; Acetadote, Acetylcysteine; Airbron; Broncholysin; Fluimucetin; Fluimucil; Inspir; Mucofilin; Mucomyst; Mucosolvin; NAC; Paravolex; Respaire, Synonym:L-alpha-acetamido-beta-mercaptopropionic acid; Mercapturic acid; N-Acetyl-3-mercaptoalanine; N-Acetylcysteine
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.
PlaceboOther
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.
| Study group | Role | What they receive |
|---|---|---|
| N-Acetylcysteine | Experimental | 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. Receives: Drug: N-acetylcysteine (NAC) |
| Placebo | Placebo comparator | 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. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change From Baseline in Motor Function Measured by Physical and Neurological Examination for Subtle Signs (PANESS)
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).
Measured: 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).
Change From Baseline in ADHD Symptoms as Reported Via Parent/Teacher Surveys
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).
Measured: 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).
Secondary outcomes (1)
Transcranial Magnetic Stimulation (TMS) - Cortical Silent Period
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.
Measured: 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).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jul 2020
- Study start15 Jan 2019
- Primary completion14 Jun 2020
- Study completion16 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (27)Papers the sponsor has linked to this study.
- Other trials for Neurofibromatosis 1Studies of the same condition, open and under way.
- More trials run by Children's Hospital Medical Center, CincinnatiThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- This is a double-blind placebo controlled, prospective, Phase IIa study to explore safety, tolerability, and efficacy of NAC on learning and motor behavior in children with NF1 aged 8 through 16 years old.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 5 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Hospital Medical Center, Cincinnati
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Donald L Gilbert, MD, MS, Principal investigator, Children's Hospital Medical Center, Cincinnati
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04481035
- Sponsor's protocol ID
- 2018-0344
- Acronym
- NF1NAC
- Status last verified
- Mar 2026
- First submitted
- 14 Apr 2020
- Last updated
- 21 Apr 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: Identifiable individual participant data will not be available to other researchers.
Publications
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.
PubMed 16522267Ballester 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.
PubMed 2121371Rosser 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.
PubMed 12583841Casnar 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.
PubMed 25284746Walsh 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.
PubMed 27527646Acosta 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.
PubMed 22821737Pride 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.
PubMed 20142468Wang 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.
PubMed 22901811Karlsgodt 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.
PubMed 23094098Gilbert 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.
PubMed 21321335Chen 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.
PubMed 24413361Dennis 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.
PubMed 18164210Tokumura 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.
PubMed 12176993Fox 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.
PubMed 12837632Chen 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.
PubMed 24987341
Study at a glance
From the registry record, last updated by the sponsor on 21 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1
- ClinicalTrials.gov ID
- NCT04481035
- Acronym / sponsor ID
- NF1NAC / 2018-0344
- Conditions
- Neurofibromatosis 1
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 5 participants (actual)
- Lead sponsor
- Children's Hospital Medical Center, CincinnatiUniversity, hospital or other
- Study start
- 15 Jan 2019 (actual)
- Primary completion
- 14 Jun 2020 (actual)
- Study completion
- 16 Dec 2021 (actual)
- First posted
- 22 Jul 2020 (actual)
- Results
- Posted 15 Mar 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Children with neurofibromatosis type 1 (NF1) commonly suffer from the effects of cognitive, behavioral, and motor impairments. At present there is no specific treatment for this NF1 complication. However, data from rodent models of NF1 along with uncontrolled clinical observations in children with NF1 suggest that the anti-oxidant, glutamate modulating compound N-Acetyl Cysteine (NAC) may reduce these impairments. Of particular interest is a murine study analyzing the central nervous system manifestations of NF1 at our institution. That study revealed a role for myelin-forming oligodendrocytes in the control of nitric oxide synthases (NOS) and their product, nitric oxide, in maintenance of brain structure and function, including regulation of behavior and motor control. Treating these mice with NAC corrected cellular and behavioral abnormalities. N-Acetyl Cysteine is available over the counter and has been used by thousands of individuals; moreover, it has shown some promise in clinical trials for psychiatric disorders.
In order to better understand treatment mechanisms, and possibly predict long-term outcomes, the investigators propose concurrently to explore Specific Aim 1 (1.1, 1.2, and 1.3) exploratory potential disease biomarkers as outlined below. The primary outcome of this study is motor function rated with the Physical and Neurological Examination for Subtle Signs (PANESS), a validated scale that consistently demonstrates significant impairments in children with Attention Deficit Hyperactivity Disorder (ADHD), and which our preliminary data suggest may demonstrate more extreme problems in children with NF1. The first exploratory biomarker is motor system inhibitory physiology, measured using Transcranial Magnetic Stimulation (TMS). Preliminary measures in our NF1 population also show abnormalities similar to established findings in ADHD. The second exploratory biomarker is metabolomics profiling for the biomarker of oligodendrocyte dysfunction in NF1 participants: autotaxin. Preliminary data in our NF1 population showed specific signal abnormalities in the NF1 population compared to healthy controls. Therefore, the investigators propose to perform a double-blind placebo controlled, prospective, Phase IIa study to explore safety, tolerability, and efficacy of NAC on learning and motor behavior in children with NF1 aged 8 through 16 years old.
Detailed description
The aims of this application are to gain information in children with NF1 about possible clinical benefit of anti-oxidant treatment and to develop and evaluate quantitative brain-based and blood biomarkers relating to presence of NF1, symptom severity, and response to antioxidant therapy. Clinically, 50% of children with NF1 are underperforming or failing at school [1]. This frequently leads to decreased educational attainment and fewer opportunities as adults. An important first step was preliminary work using the PANESS scale and Transcranial Magnetic Stimulation (TMS)-evoked Short Interval Cortical Inhibition (rSICI) in children with NF1. The investigators propose to develop and extend our understanding of NF1-related motor and learning behavior in response to antioxidant therapy with NAC. The purpose of the present study is to 1) evaluate tolerability, safety, and clinical benefit of NAC in this double-blind placebo controlled study; 2) to evaluate motor function (PANESS) and physiology (TMS) biomarkers at baseline and after treatment; and 3) to quantify metabolomics profiles at baseline and after treatment. The investigators propose to study 20 children with NF1, ages 8-16 years, at baseline and after completion of 8 weeks of treatment with NAC.
NAC therapy, if successful, is expected improve these parameters. The trial endpoints are: Does behavior improve? Does motor function improve? Are there TMS biomarkers that reflect the presence of NF1 and the response to NAC treatment? Are there metabolomics measures that reflect the presence of NF1 and the response to treatment? The investigators hypothesize that predictive measures exist and can be used as a foundation for an application for funding for a larger, more definitive, placebo-controlled trial involving biomarkers and clinical outcomes. The investigators believe this work has the potential to lay groundwork for future use of relevant biomarkers for treatment and outcomes research for NF1 as well as other biologically similar conditions, collectively designated the "RASopathies" (due to involvement of the RAS family of proteins) and ultimately to guide development of more effective treatments based on disease pathophysiology.
SPECIFIC AIMS
This study involves the following aims:
Specific Aim 1: Primary Outcome of Study In children and adolescents with NF1, to characterize the behavioral and motor effects of 8 weeks of N-acetylcysteine (NAC) treatment in a cohort of 20 children and adolescents with NF1. The investigators will evaluate tolerability, safety, and clinical benefit of NAC in this double-blind crossover placebo controlled study. Aim 1.1: Characterize effects of NAC treatment on motor function in kids with NF1 using the Physical and Neurological Examination for Subtle Signs (PANESS). This is a validated scale that consistently demonstrates significant impairments in children with ADHD, and which preliminary data suggest may demonstrate more extreme problems in children with NF1 than age-matched healthy controls (unpublished data from CCHMC). The investigators hypothesize that motor function scores rated with the PANESS scale will improve after treatment with NAC. Aim 1.2: Characterize effects of NAC treatment on ADHD symptoms in children with NF1. The investigators hypothesize that ADHD attention and hyperactive/impulsive symptoms, rated with the DuPaul Diagnostic and Statistical Manual Diploma in Social Medicine (DSM-5) based clinical rating scales, will improve after treatment with NAC.
Specific Aim 2: Experimental aim # 1 In the same cohort, the investigators will identify potential novel biomarkers of neurodevelopmental burden in NF1. Aim 2.1: Describe the function and physiology of the motor system using Transcranial Magnetic Stimulation (TMS) as a possible disease biomarker of NF1. Preliminary measures in our NF1 population also show abnormalities similar to established findings in ADHD. The investigators hypothesize that children with NF1 will have significantly less motor cortex inhibition using TMS measurements, and these measures will improve ("normalize") upon NAC treatment. The investigators will compare to age-matched healthy controls at Cincinnati Children's. Aim 2.2: The investigators propose to evaluate autotaxin as a candidate biomarker of oligodendrocyte dysfunction in NF1 participants. Preliminary data from biomarker discovery analysis of serum samples from healthy controls and NF1 patients showed lysophosphatidylcholine (LPC) depletion compared to healthy age/sex matched controls. In gene expression analysis autotaxin was elevated 4 times in neurofibroma Schwann cells compared to normal nerve Schwann cells. The investigators will collect serum and plasma from participants to assess autotaxin/LPC axis prior and post-NAC therapy. The investigators hypothesize that autotaxin axis abnormalities will be a biomarker of response to antioxidant therapy in our NF1 population.
Specific Aim 3: Experimental aim # 2 In the same cohort, to evaluate metabolomics profiles as a possible disease biomarker that is affected by NF1 and by treatment with NAC as per Aim 1. Hypothesis 4: The investigators hypothesize that specific profiles will predict clinical response to antioxidant therapy compared to age-matched healthy control (unpublished data from CCHMC).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| N-Acetylcysteine | Experimental | Drug: N-acetylcysteine (NAC)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. |
| Placebo | Placebo comparator | Other: PlaceboParticipants 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. |
Who may qualify
- Ages
- 8 to 16 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- Males and females aged 8 - 16 years at time of enrollment whom meet NIH diagnostic criteria for NF1.
- Participants must have a full-scale intelligence quotient (IQ) of 70 or above, as determined by neurocognitive testing within the last 3 years or during the enrollment process.
- Participants on stimulant or any other psychotropic medication should stay on a stable dose for at least 30 days before entering the study.
Key exclusion criteria (8 listed)
- Participants should not be receiving chemotherapy currently, or have received chemotherapy in the 6 months prior to entering the study.
- No active intracranial lesions (stable low grade glioma are acceptable) or epilepsy diagnosis.
- Major Depression, Bipolar Disorder, Conduct Disorder, Adjustment Disorder, other major Anxiety Disorders, or other developmental psychiatric diagnoses, based on the child's history or on parent and child responses from the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS). Note that while this is an exclusion for participation in the study if there is a prior evaluation available, this becomes a criterion, after inclusion, for the investigator to withdraw the child from the study prior to completion if identified on the first study day.
- For females, pregnancy.
- Current use of antidepressants, non-stimulant ADHD medications, dopamine blocking agents, mood stabilizers.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| N-acetylcysteine (NAC)Also: Chemical Name: Cysteine, N-acetyl-, L, Commercial Name(s): Acetein; Acetadote, Acetylcysteine; Airbron; Broncholysin; Fluimucetin; Fluimucil; Inspir; Mucofilin; Mucomyst; Mucosolvin; NAC; Paravolex; Respaire, Synonym:L-alpha-acetamido-beta-mercaptopropionic acid; Mercapturic acid; N-Acetyl-3-mercaptoalanine; N-AcetylcysteineThe 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. | Drug | N-Acetylcysteine |
| PlaceboThe 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. | Other | Placebo |
Primary outcome
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).
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).
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).
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).
1 secondary outcome
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).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Apr 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 16522267Acosta 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.
- Background: PubMed 2121371Ballester 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.
- Background: PubMed 12583841Rosser 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.
- Background: PubMed 25284746Casnar 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.
- Background: PubMed 27527646Walsh 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.
- Background: PubMed 22821737Acosta 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.
- Background: PubMed 20142468Pride 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.
- Background: PubMed 22901811Wang 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.
- Background: PubMed 23094098Karlsgodt 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.
- Background: PubMed 21321335Gilbert 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.
- Background: PubMed 24413361Chen 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.
- Background: PubMed 18164210Dennis 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.
- Individual participant dataSharing planned: No. Identifiable individual participant data will not be available to other researchers.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Donald L Gilbert, MD, MS principal investigator
Children's Hospital Medical Center, Cincinnati
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing N-acetylcysteine (NAC) in people with Neurofibromatosis 1, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Mar 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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).). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04481035, which also lists 27 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Apr 2026.