Neurofibromatosis 1Phase 2DoDNACNCT04481048
Antioxidant Therapy With N-acetylcysteine for Children With Neurofibromatosis Type 1
A Phase 2 study testing N-Acetyl cysteine 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-Acetyl cysteine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 25 participants
- Where
- 1 siteUnited States
- Study dates
- 23 Feb 2021to 25 Jun 2024
- Phase
- Phase 2
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
- You can be in this study if you have any of the following:
- Males and females older than 8 years and younger than 16 years old
- Has a diagnosis of NF1 (neurofibromatosis type 1)
- Has an abnormal PANESS score
- Has an intelligence quotient (IQ) at or above 70
- Participants on stimulant or any other psychotropic medication should stay on a stable dose (no change in dose) for at least 30 days before entering the study and maintain that dose while in the study
Who cannot join
- You cannot be in this study if you have any of the following:
- Younger than 8 years or older than 16 years ѱ
- Do not have a diagnosis of NF1 ѱ
- IQ below 70 ѱ
- Had a dose change of any stimulant or psychotropic medication in the last month (30 days) ѱ
- Are being treated with chemotherapy or had chemotherapy in the last 6 months
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- Have epilepsy ѱ
- High risk of upper gastrointestinal (GI, the stomach and the small and large intestine) hemorrhage (bleeding). Examples: presence of esophageal varices or peptic ulcers
- Active intracranial lesions (abnormality found on brain imaging such as an MRI) (stable low-grade glioma is acceptable) or epilepsy diagnosis ѱ
- Have Major Depression, Bipolar Disorder, Conduct Disorder, Adjustment Disorder, other major Anxiety Disorders, or other developmental psychiatric diagnoses, based on history. ADHD is allowed.
- For females, pregnancy
- Is currently using antidepressants, dopamine blocking agents, or mood stabilizers
- Have any of the following medical devices: implanted brain stimulator, vagal nerve stimulator, ventriculoperitoneal (VP) shunt, cardiac pacemaker, or implanted medication port ѱ
- Asthma (bronchospasm has been reported as occurring infrequently and unpredictably when NAC is used as a mucolytic agent)
- Current use of MEKINIST (MEK-inhibitor) or use within 30 days
- ѱ Indicates Inclusion/Exclusion Criteria for the treatment- and non-treatment cohorts (no mark indicates exclusion requirements for the 12-week treatment-cohort only).
Trial locations and contacts
1 site in 1 country.
United States1 site
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
About this study
Official title: Antioxidant Therapy With N-acetylcysteine for Motor Behavior and/or Learning in Children With Neurofibromatosis Type 1
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.
Read the detailed description
This is a phase II clinical trial with the goal to explore safety, tolerability, and efficacy of NAC on motor behavior in children with NF1 aged 8 through 16 years old. The investigators hypothesize that NAC therapy will improve motor function evaluated by the Physical and Neurological Examination for Soft Signs (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 (SICI) 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 a protein first discovered in rat sarcomas (RAS), but not technically an acronym). RAS is family of proteins. This work may ultimately 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:
- 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 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).
- To determine if TMS measurement (SICI) in children with NF1 will correlate with clinical effects of NAC treatment.
- 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.
- To evaluate safety and tolerability of NAC in children with NF1.
- Conditions
- Neurofibromatosis 1
- Being tested
- N-Acetyl cysteine, Placebo
- Keywords
- Neurofibromatosis 1, ADHD, Transcranial Magnetic Stimulation, Magnetic Resonance Imaging, N-acetylcysteine
- Medical subject headings
- Neurofibromatosis 1, Attention Deficit Disorder with Hyperactivity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
N-Acetyl cysteineDrug
Also called •Chemical Name: Cysteine, N-acetyl-, L, •Commercial Name(s): Acetin; Acetadote, Acetylcysteine; Airbron; Broncholysin; Fluimucetin; Fluimucil; Inspir; Mucomyst; Mucosolvin; NAC; Parvolex; Respaire, •Synonym:L-alpha-acetamido-beta-mercaptopropionic acid; Mercapturic acid; N-Acetyl-3-mercaptoalanine; N-Acetylcysteine
Eight (8) weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC).
PlaceboOther
Eight (8) weeks of treatment with placebo.
| Study group | Role | What they receive |
|---|---|---|
| N-Acetylcysteine (NAC) | Experimental | 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) Receives: Drug: N-Acetyl cysteine |
| Placebo | Placebo comparator | Each subject will be dosed with placebo for 8 weeks. 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 Soft Signs (PANESS)
Characterize effects of NAC treatment on motor function in kids with NF1 using the Physical and Neurological Examination for Soft 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: Baseline vs. end of treatment, 8 weeks
Secondary outcomes (4)
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 Diagnostic and Statistical Manual (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: baseline vs. end of treatment, 8 weeks
Change From Baseline in Motor Cortex Inhibition/Excitation Measures, Expressed as Ratios of Single to Paired Pulse Transcranial Magnetic Stimulation (TMS) Motor Evoked Potential Amplitudes
Describe the function and physiology of the motor system using Transcranial Magnetic Stimulation (TMS) as a possible disease biomarker of NF1. Output is quantified from surface EMG tracings after motor cortex stimulation with TMS. SICI, ICF, and LICI are standard paired pulse (condition/test-pulse) measures where the outcome is expressed as a ratio of motor evoked potential amplitudes. Ratios < 1.0 represent inhibition, ratios > 1.0 represent facilitation. CSP is a silent period in EMG activity, measure in milliseconds (ms).
Measured: baseline vs. end of treatment, 8 weeks
Change From Baseline in Motor Cortex Inhibition/Excitation Measures, Expressed as Milliseconds of Single to Paired Pulse Transcranial Magnetic Stimulation (TMS) Motor Evoked Potential Amplitudes
Describe the function and physiology of the motor system using Transcranial Magnetic Stimulation (TMS) as a possible disease biomarker of NF1. Output is quantified from surface EMG tracings after motor cortex stimulation with TMS. CSP is a silent period in EMG activity, measure in milliseconds (ms).
Measured: baseline vs. end of treatment, 8 weeks
Change From Baseline in Microstructural Properties of Brain Tissue Visualized by Magnetic Resonance Imaging (MRI)
To quantify microstructural properties of brain tissue based on water diffusion, glutathione (GSH) concentration, glutamate/glutamine (GLX) concentration, 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.
Measured: baseline vs. end of treatment, 8 weeks
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 start23 Feb 2021
- Primary completion25 Jun 2024
- Study completion25 Jun 2024
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 (28)Papers the sponsor has linked to this study.
- Other trials for Neurofibromatosis 1Studies of the same condition, open and under way.
- 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
- Parallel groups
- 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).
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 25 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Hospital Medical Center, Cincinnati
- Sponsor type
- University, hospital or other
- Collaborators
- United States Department of Defense
- Responsible party
- Sponsor
- Investigators
- Donald Gilbert, MD MS, Principal investigator, Children's Hospital Medical Center, Cincinnati
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04481048
- Sponsor's protocol ID
- 2020-0412
- Acronym
- DoDNAC
- Status last verified
- May 2026
- First submitted
- 15 May 2020
- Last updated
- 5 Jun 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data tables, with de-identified individual participant data, will be stored at Mendeley Data
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