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

NCT04481048 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 2020-0412
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Neurofibromatosis 1

Keywords

Neurofibromatosis 1; ADHD; Transcranial Magnetic Stimulation; Magnetic Resonance Imaging; N-acetylcysteine

Outcome Measures

Primary Outcomes (1)

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preliminary data suggest may demonstrate more extreme problems in children with NF1 than age-matched healthy controls (unpublished data from CCHMC).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

  Baseline vs. end of treatment, 8 weeks

Secondary Outcomes (4)

• Change From Baseline in ADHD Symptoms as Reported Via Parent/Teacher Surveys

  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

  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

  baseline vs. end of treatment, 8 weeks

• Change From Baseline in Microstructural Properties of Brain Tissue Visualized by Magnetic Resonance Imaging (MRI)

  baseline vs. end of treatment, 8 weeks

Study Arms (2)

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)

Drug: N-Acetyl cysteine

Placebo

PLACEBO COMPARATOR

Each subject will be dosed with placebo for 8 weeks.

Other: Placebo

Interventions

N-Acetyl cysteine DRUG

Eight (8) weeks of treatment with an FDA approved medication, N-acetylcysteine (NAC).

Also known as: •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

N-Acetylcysteine (NAC)

Placebo OTHER

Eight (8) weeks of treatment with placebo.

Placebo

Eligibility Criteria

• Age: 8 Years - 16 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• United States Department of Defense: collaborator
• Children's Hospital Medical Center, Cincinnati: lead

Study Sites (1)

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Related Publications (28)

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  PMID: 36996759 RESULT

MeSH Terms

Conditions

Neurofibromatosis 1; Attention Deficit Disorder with Hyperactivity

Interventions

Acetylcysteine; Inhalation; N-monoacetylcystine

Condition Hierarchy (Ancestors)

Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Respiratory Mechanics; Respiration; Respiratory Physiological Phenomena; Circulatory and Respiratory Physiological Phenomena

Results Point of Contact

• Title: Donald L. Gilbert MD
• Organization: Cincinnati Children's Hospital Medical Center

donald.gilbert@cchmc.org

513-636-4222

Study Officials

• Donald Gilbert, MD MS

  Children's Hospital Medical Center, Cincinnati

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: In order to preserve the double-masking of the trial, only the investigation pharmacy will be unmasked. Both treatments (NAC and placebo) will be distributed from the investigational pharmacy. Except for the pharmacist, all staff will be blinded to the treatment sequence.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a phase II, double blind, placebo-controlled clinical trial with the goal to explore safety, tolerability, and efficacy of N-acetylcysteine (NAC).

Study Record Dates

• First Submitted: May 15, 2020
• First Posted: July 22, 2020
• Study Start: February 23, 2021
• Primary Completion: June 25, 2024
• Study Completion: June 25, 2024
• Last Updated: June 5, 2026
• Results First Posted: June 5, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months after publication with no end date
• Access Criteria: Access is through the Mendeley website. No proposal or data sharing agreement needed.

Locations

US (1)