What is the mechanism of action of this treatment?

N-acetylcysteine (NAC) is an antioxidant that modulates nitric oxide synthases (NOS) and nitric oxide (NO) levels, which are crucial in maintaining brain structure and function. In Neurofibromatosis type 1 (NF1), dysregulated NO can contribute to cognitive, behavioral, and motor impairments. By reducing oxidative stress and normalizing NO levels, NAC helps alleviate these symptoms, offering a targeted approach to managing the neurological complications of NF1. This mechanism is significant for NF1 patients as it addresses the underlying cellular abnormalities contributing to their condition.

What side effects are associated with this type of intervention?

N-acetylcysteine (NAC) is being studied for its potential benefits in treating cognitive, behavioral, and motor impairments in children with Neurofibromatosis type 1 (NF1). Common side effects of NAC include gastrointestinal issues such as nausea, vomiting, and diarrhea. Other potential side effects may include rash, fever, and headache. As with any treatment, it is important to monitor for adverse reactions and consult with a healthcare provider to manage any side effects effectively.

What prior FDA approvals exist?

Currently, there are no specific FDA-approved treatments for the cognitive, behavioral, and motor impairments associated with Neurofibromatosis type 1 (NF1). The trial involving N-acetylcysteine (NAC) is exploring its potential benefits based on its antioxidant properties and ability to modulate nitric oxide synthases (NOS) and nitric oxide (NO) levels. This approach is novel, and while NAC has shown promise in preclinical models, it is still under investigation for its efficacy and safety in children with NF1.

What other types of research exist?

Promising alternatives to N-acetylcysteine (NAC) for Neurofibromatosis type 1 (NF1) patients could include eNOS modulators such as tetrahydrobiopterin and folic acid, which are known to affect nitric oxide synthases (NOS) and nitric oxide (NO) levels.

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Antioxidant

Antioxidant Therapy for Neurofibromatosis Type 1 (DoDNAC Trial)

Phase 2

Waitlist Available

Led By Carlos E Prada, MD

Research Sponsored by Children's Hospital Medical Center, Cincinnati

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Has a diagnosis of NF1 (neurofibromatosis type 1)

Has an IQ (intelligence quotient) at or above 70

Must not have

Have epilepsy

Active intracranial lesions (abnormality found on brain imaging such as an MRI) (stable low-grade glioma is acceptable) or epilepsy diagnosis

Timeline

Screening 3 weeks

Treatment Varies

Follow Up through 12 weeks (at weeks 0, 8, and 12)

Summary

This trial is testing a medication called NAC in children aged 8-16 with a condition called NF1. These children often have problems with movement and behavior, and there is no current treatment for these issues. NAC works by reducing harmful molecules in the brain, which may help improve these symptoms.

Who is the study for?

This trial is for children aged 8-16 with neurofibromatosis type 1 (NF1) and an IQ of 70 or above. They must have a specific abnormal score on a motor skills test and be on stable doses of any psychotropic medication. It excludes those without NF1, under chemotherapy, with epilepsy, certain medical devices, using specific drugs like MEKINIST within the last month, or with severe psychiatric disorders.

What is being tested?

The study tests N-acetylcysteine (NAC), an antioxidant therapy against a placebo in children with NF1 to see if it improves cognitive and motor functions. This Phase II trial is double-blind and controlled; participants won't know which treatment they're getting to ensure unbiased results.

What are the potential side effects?

While closely monitoring for side effects during the trial, potential risks may include allergic reactions due to NAC's mucolytic properties causing bronchospasm (tightening of airways), gastrointestinal bleeding in high-risk individuals, and other unspecified drug-related adverse events.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have been diagnosed with neurofibromatosis type 1.

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My IQ is 70 or higher.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have epilepsy.

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I have a stable low-grade brain tumor or epilepsy.

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I do not have Neurofibromatosis type 1.

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I am at high risk for serious stomach or intestine bleeding.

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I am currently taking medication for depression, mood, or dopamine regulation.

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I am currently on chemotherapy or had it within the last 6 months.

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My IQ is below 70.

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I am either younger than 8 or older than 16 years old.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ through 12 weeks (at weeks 0, 8, and 12)

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~through 12 weeks (at weeks 0, 8, and 12)

This trial's timeline: 3 weeks for screening, Varies for treatment, and through 12 weeks (at weeks 0, 8, and 12) for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Change from Baseline in Motor Function Measured by Physical and Neurological Examination for Subtle Signs (PANESS)

Secondary study objectives

Change from Baseline in ADHD Symptoms as Reported via Parent/Teacher Surveys

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

Change from Baseline in Motor Function and Physiology Measured by Transcranial Magnetic Stimulation (TMS)

Side effects data

From 2024 Phase 2 trial • 13 Patients • NCT03499249

62%

GGT 400 IU/L >pre-KP value

46%

AST 400 IU/L >pre-KP value

31%

Loss of an IV

23%

Emesis with feeds

15%

Febrile illness

15%

Conjugated bilirubin 3 mg/dL >pre-KP value

Tachycardia

ALT 700 IU/L >pre-KP value

INR >2.0

Total bilirubin 5 mg/dL >pre-KP value

100%

80%

60%

40%

20%

Study treatment Arm

N-Acetylcysteine Treatment

Trial Design

3Treatment groups

Experimental Treatment

Active Control

Placebo Group

Group I: N-Acetylcysteine (NAC)Experimental Treatment1 Intervention

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)

Group II: Single Visit/Non-Treatment ArmActive Control1 Intervention

Based on preliminary data, an additional "Single visit, non-treatment" cohort will include 40 individuals with NF1 for a single "biomarker" study visit. These individuals will undergo motor function (PANESS) and brain-based measures (TMS, MRI-MRS, DTI) as biomarkers of impaired executive function (ADHD-RS; BRIEF-2; TOVA) but will not be assigned to receive NAC/Placebo.

Group III: PlaceboPlacebo Group1 Intervention

Each subject will be dosed with placebo for 8 weeks.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

N-Acetyl cysteine

2022

Completed Phase 4

~190

0 / 10Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

N-acetylcysteine (NAC) is an antioxidant that modulates nitric oxide synthases (NOS) and nitric oxide (NO) levels, which are crucial in maintaining brain structure and function. In Neurofibromatosis type 1 (NF1), dysregulated NO can contribute to cognitive, behavioral, and motor impairments. By reducing oxidative stress and normalizing NO levels, NAC helps alleviate these symptoms, offering a targeted approach to managing the neurological complications of NF1. This mechanism is significant for NF1 patients as it addresses the underlying cellular abnormalities contributing to their condition.

Nitric oxide, peroxynitrite and nitroso-compounds formation by ultraviolet A (UVA) irradiated human squamous cell carcinoma: potential role of nitric oxide in cancer prognosis.Nitric Oxide as a Potential Adjuvant Therapeutic for Neuroblastoma: Effects of NO on Murine N2a Cells.Nf1 loss and Ras hyperactivation in oligodendrocytes induce NOS-driven defects in myelin and vasculature.