Trial Outcomes & Findings for Antioxidant Therapy With N-acetylcysteine for Children With Neurofibromatosis Type 1 (NCT NCT04481048)

Last Updated: 2026-06-05

Results Overview

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preliminary data suggest may demonstrate more extreme problems in children with NF1 than age-matched healthy controls (unpublished data from CCHMC).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).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

25 participants

Primary outcome timeframe

Baseline vs. end of treatment, 8 weeks

Results posted on

2026-06-05

Participant Flow

Recruitment occurred through clinic and IRB-approved study registry review. Determination of enrollment eligibility was a multi-step process. The study team screened and reviewed medical histories of 481 children and adolescents with NF1, of whom 203 (42%) were deemed eligible. From this eligible group, 25 (12%) agreed to participate. The first patient was enrolled and randomized February 23, 2021 and the last completed a final treatment visit November 13, 2023.

After screening and baseline assessments, participants were randomized 1:1 to receive N-acetylcysteine (NAC) or matching placebo using permuted block randomization stratified by age, sex, and ADHD status. The study was double-blind; only the investigational pharmacy was unblinded. NAC was administered orally for 8 weeks at \~70 mg/kg/day divided BID with weight-based dosing. Placebo was identical in appearance and schedule.

Participant milestones

Participant milestones
Measure	N-Acetylcysteine (NAC) 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) N-Acetyl cysteine: Eight (8) weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC).	Placebo Each subject will be dosed with placebo for 8 weeks. Placebo: Eight (8) weeks of treatment with placebo.
Overall Study STARTED	12	13
Overall Study COMPLETED	7	13
Overall Study NOT COMPLETED	5	0

Reasons for withdrawal

Reasons for withdrawal
Measure	N-Acetylcysteine (NAC) 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) N-Acetyl cysteine: Eight (8) weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC).	Placebo Each subject will be dosed with placebo for 8 weeks. Placebo: Eight (8) weeks of treatment with placebo.
Overall Study Lost to Follow-up	1	0
Overall Study Physician Decision	2	0
Overall Study Adverse Event	2	0

Baseline Characteristics

Antioxidant Therapy With N-acetylcysteine for Children With Neurofibromatosis Type 1

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	N-Acetylcysteine (NAC) n=12 Participants 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) N-Acetyl cysteine: Eight (8) weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC).	Placebo n=13 Participants Each subject will be dosed with placebo for 8 weeks. Placebo: Eight (8) weeks of treatment with placebo.	Total n=25 Participants Total of all reporting groups
Age, Categorical <=18 years	12 Participants n=20 Participants	13 Participants n=20 Participants	25 Participants n=40 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants
Age, Categorical >=65 years	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants
Age, Continuous	12.8 years STANDARD_DEVIATION 2.7 • n=20 Participants	12.1 years STANDARD_DEVIATION 3.3 • n=20 Participants	12.4 years STANDARD_DEVIATION 3.0 • n=40 Participants
Sex: Female, Male Female	5 Participants n=20 Participants	7 Participants n=20 Participants	12 Participants n=40 Participants
Sex: Female, Male Male	7 Participants n=20 Participants	6 Participants n=20 Participants	13 Participants n=40 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants
Race (NIH/OMB) Asian	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants
Race (NIH/OMB) Black or African American	0 Participants n=20 Participants	2 Participants n=20 Participants	2 Participants n=40 Participants
Race (NIH/OMB) White	12 Participants n=20 Participants	11 Participants n=20 Participants	23 Participants n=40 Participants
Race (NIH/OMB) More than one race	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	12 Participants n=20 Participants	13 Participants n=20 Participants	25 Participants n=40 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants
Region of Enrollment United States	12 Participants n=20 Participants	13 Participants n=20 Participants	25 Participants n=40 Participants

PRIMARY outcome

Timeframe: Baseline vs. end of treatment, 8 weeks

Population: 25 were enrolled and randomized (12 active NAC; 13 placebo). 2 (NAC group) were withdrawn after randomization, before receiving drug and were not analyzed. 2 (NAC group) withdrew during treatment, prior to primary outcome assessment at week 8. Therefore, completer analysis was done with 8 NAC, 13 placebo, at week 8. We also did intention to treat with 10 NAC, 13 placebo, using last observation carried forward. For the 12-week washout analysis, one NAC was lost to follow up.

Outcome measures

Outcome measures
Measure	Placebo n=13 Participants Each subject will be dosed with placebo for 8 weeks. Placebo: Eight (8) weeks of treatment with placebo.	N-Acetylcysteine (NAC) n=8 Participants 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) N-Acetyl cysteine: Eight (8) weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC).
Change From Baseline in Motor Function Measured by Physical and Neurological Examination for Soft Signs (PANESS)	-3.1 units on a scale Standard Deviation 12.7	-3.3 units on a scale Standard Deviation 9.3

SECONDARY outcome

Timeframe: baseline vs. end of treatment, 8 weeks

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).

Outcome measures

Outcome measures
Measure	Placebo n=13 Participants Each subject will be dosed with placebo for 8 weeks. Placebo: Eight (8) weeks of treatment with placebo.	N-Acetylcysteine (NAC) n=7 Participants 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) N-Acetyl cysteine: Eight (8) weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC).
Change From Baseline in ADHD Symptoms as Reported Via Parent/Teacher Surveys	-4.5 score on a scale Standard Deviation 6.8	-1.9 score on a scale Standard Deviation 1.1

SECONDARY outcome

Timeframe: baseline vs. end of treatment, 8 weeks

Population: TMS data not available on all participants - one participant refused; several had high resting motor thresholds precluding obtaining data for some measures

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).

Outcome measures

Outcome measures
Measure	Placebo n=13 Participants Each subject will be dosed with placebo for 8 weeks. Placebo: Eight (8) weeks of treatment with placebo.	N-Acetylcysteine (NAC) n=7 Participants 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) N-Acetyl cysteine: Eight (8) weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC).
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 Short Interval Cortical Inhibition (SICI)	0.05 ratios of paired to single pulse MEPs Standard Deviation 0.4	-0.19 ratios of paired to single pulse MEPs Standard Deviation 0.12
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 Intracortical Facilitation (ICF)	-0.03 ratios of paired to single pulse MEPs Standard Deviation 0.24	-0.08 ratios of paired to single pulse MEPs Standard Deviation 0.13
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 Long interval cortical inhibition (LICI)	0.23 ratios of paired to single pulse MEPs Standard Deviation 0.50	-0.10 ratios of paired to single pulse MEPs Standard Deviation 0.20

SECONDARY outcome

Timeframe: baseline vs. end of treatment, 8 weeks

Population: TMS data not available on all participants - one participant refused; several had high resting motor thresholds precluding obtaining data for some measures

Outcome measures

Outcome measures
Measure	Placebo n=8 Participants Each subject will be dosed with placebo for 8 weeks. Placebo: Eight (8) weeks of treatment with placebo.	N-Acetylcysteine (NAC) n=5 Participants 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) N-Acetyl cysteine: Eight (8) weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC).
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	6.3 milliseconds (ms) Standard Deviation 34.5	-6.8 milliseconds (ms) Standard Deviation 36.0

SECONDARY outcome

Timeframe: baseline vs. end of treatment, 8 weeks

Population: Data quality review led to removal of participant data for some outcomes. Adequate MR Spectroscopy data for NAC group ranged from 5 to 8 participants, for Placebo group from 9 to 11 participants.

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.

Outcome measures

Outcome measures
Measure	Placebo n=13 Participants Each subject will be dosed with placebo for 8 weeks. Placebo: Eight (8) weeks of treatment with placebo.	N-Acetylcysteine (NAC) n=8 Participants 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) N-Acetyl cysteine: Eight (8) weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC).
Change From Baseline in Microstructural Properties of Brain Tissue Visualized by Magnetic Resonance Imaging (MRI) GSH	-0.11 mM Standard Deviation 0.22	0.13 mM Standard Deviation 0.46
Change From Baseline in Microstructural Properties of Brain Tissue Visualized by Magnetic Resonance Imaging (MRI) GABA	-0.06 mM Standard Deviation 0.61	-0.44 mM Standard Deviation 0.75
Change From Baseline in Microstructural Properties of Brain Tissue Visualized by Magnetic Resonance Imaging (MRI) GLX	-0.18 mM Standard Deviation 1.0	0.11 mM Standard Deviation 0.30
Change From Baseline in Microstructural Properties of Brain Tissue Visualized by Magnetic Resonance Imaging (MRI) GLU	-0.70 mM Standard Deviation 1.2	-0.62 mM Standard Deviation 2.2
Change From Baseline in Microstructural Properties of Brain Tissue Visualized by Magnetic Resonance Imaging (MRI) Cr	0.05 mM Standard Deviation 0.6	-0.49 mM Standard Deviation 1.9
Change From Baseline in Microstructural Properties of Brain Tissue Visualized by Magnetic Resonance Imaging (MRI) Cho	0.0 mM Standard Deviation 0.20	-0.05 mM Standard Deviation 0.20
Change From Baseline in Microstructural Properties of Brain Tissue Visualized by Magnetic Resonance Imaging (MRI) NAA	0.25 mM Standard Deviation 0.90	-0.06 mM Standard Deviation 1.2

Adverse Events

N-Acetylcysteine (NAC)

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	N-Acetylcysteine (NAC) n=12 participants at risk 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) N-Acetyl cysteine: Eight (8) weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC).	Placebo n=13 participants at risk Each subject will be dosed with placebo for 8 weeks. Placebo: Eight (8) weeks of treatment with placebo.
Gastrointestinal disorders Constipation	8.3% 1/12 • Number of events 1 • 12 weeks Participants and/or their parents received scheduled assessments as outlined in the study protocol. These included prompts such as 'Have there been any changes in your health since the last visit?' and 'Is there anything you would like to share with the study team?' Responses were reviewed and monitored by study personnel.	0.00% 0/13 • 12 weeks Participants and/or their parents received scheduled assessments as outlined in the study protocol. These included prompts such as 'Have there been any changes in your health since the last visit?' and 'Is there anything you would like to share with the study team?' Responses were reviewed and monitored by study personnel.
Gastrointestinal disorders Abdominal pain	0.00% 0/12 • 12 weeks Participants and/or their parents received scheduled assessments as outlined in the study protocol. These included prompts such as 'Have there been any changes in your health since the last visit?' and 'Is there anything you would like to share with the study team?' Responses were reviewed and monitored by study personnel.	7.7% 1/13 • Number of events 1 • 12 weeks Participants and/or their parents received scheduled assessments as outlined in the study protocol. These included prompts such as 'Have there been any changes in your health since the last visit?' and 'Is there anything you would like to share with the study team?' Responses were reviewed and monitored by study personnel.
Infections and infestations Infection	0.00% 0/12 • 12 weeks Participants and/or their parents received scheduled assessments as outlined in the study protocol. These included prompts such as 'Have there been any changes in your health since the last visit?' and 'Is there anything you would like to share with the study team?' Responses were reviewed and monitored by study personnel.	15.4% 2/13 • Number of events 2 • 12 weeks Participants and/or their parents received scheduled assessments as outlined in the study protocol. These included prompts such as 'Have there been any changes in your health since the last visit?' and 'Is there anything you would like to share with the study team?' Responses were reviewed and monitored by study personnel.
Psychiatric disorders Irritability	16.7% 2/12 • Number of events 2 • 12 weeks Participants and/or their parents received scheduled assessments as outlined in the study protocol. These included prompts such as 'Have there been any changes in your health since the last visit?' and 'Is there anything you would like to share with the study team?' Responses were reviewed and monitored by study personnel.	0.00% 0/13 • 12 weeks Participants and/or their parents received scheduled assessments as outlined in the study protocol. These included prompts such as 'Have there been any changes in your health since the last visit?' and 'Is there anything you would like to share with the study team?' Responses were reviewed and monitored by study personnel.
Psychiatric disorders Anxiety	0.00% 0/12 • 12 weeks Participants and/or their parents received scheduled assessments as outlined in the study protocol. These included prompts such as 'Have there been any changes in your health since the last visit?' and 'Is there anything you would like to share with the study team?' Responses were reviewed and monitored by study personnel.	15.4% 2/13 • Number of events 2 • 12 weeks Participants and/or their parents received scheduled assessments as outlined in the study protocol. These included prompts such as 'Have there been any changes in your health since the last visit?' and 'Is there anything you would like to share with the study team?' Responses were reviewed and monitored by study personnel.
General disorders Fatigue	8.3% 1/12 • Number of events 1 • 12 weeks Participants and/or their parents received scheduled assessments as outlined in the study protocol. These included prompts such as 'Have there been any changes in your health since the last visit?' and 'Is there anything you would like to share with the study team?' Responses were reviewed and monitored by study personnel.	0.00% 0/13 • 12 weeks Participants and/or their parents received scheduled assessments as outlined in the study protocol. These included prompts such as 'Have there been any changes in your health since the last visit?' and 'Is there anything you would like to share with the study team?' Responses were reviewed and monitored by study personnel.

Additional Information

Donald L. Gilbert MD

Cincinnati Children's Hospital Medical Center

Phone: 513-636-4222

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place