NCT04481035: NF1NAC

Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1

Completed Phase 2 Results posted Last updated 31 July 2025

What this trial tests

Phase 2 trial testing N-acetylcysteine (NAC) in Neurofibromatosis 1 in 5 participants. Completed in 16 December 2021.

Timeline

15 January 2019

Primary endpoint
14 June 2020

16 December 2021

Quick facts

Lead sponsor	Children's Hospital Medical Center, Cincinnati
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	crossover
Masking	quadruple
Primary purpose	treatment
Enrollment	5
Start date	15 January 2019
Primary completion	14 June 2020
Estimated completion	16 December 2021
Sites	1 location across United States

Drugs / interventions tested

• N-acetylcysteine (NAC)
• Placebo

Conditions studied

• Neurofibromatosis 1 — all drugs for Neurofibromatosis 1 →

Sponsor

Children's Hospital Medical Center, Cincinnati

Who can join

Adults 8 to 16, any sex, with Neurofibromatosis 1. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline in Motor Function Measured by Physical and Neurological Examination for Subtle Signs (PANESS) Primary · 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preliminary data suggest may demonstrate more extreme problems in children with NF1 than age-matched healthy controls (unpublished data from CCHMC).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 sy

Group	Value	95% CI
N-Acetylcysteine	0	-8 – 2
Placebo	3	-4 – 25

Change From Baseline in ADHD Symptoms as Reported Via Parent/Teacher Surveys Primary · 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).

Group	Value	95% CI
N-Acetylcysteine	-12.5	± 13.1
Placebo	-3.75	± 12.0

Transcranial Magnetic Stimulation (TMS) - Cortical Silent Period Secondary · 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).

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.

Group	Value	95% CI
N-Acetylcysteine	6	± 19
Placebo	-4	± 18

Sponsor's own description

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.

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

1. The Contribution of Oxidative Stress to <i>NF1</i>-Altered Tumors.
   Kuhn E, Natacci F, Corbo M, Pisani L, et al · · 2023 · cited 4× · PMID 37627552 · DOI 10.3390/antiox12081557
2. Reactive oxygen species (ROS) in cancer: from mechanism to therapeutic implications.
   Akter S, Madhuvilakku R, Kar AK, Nila IS, et al · · 2026 · PMID 41881983 · DOI 10.1038/s41392-026-02583-x