Antioxidant Therapy with N-acetylcysteine for Neurofibromatosis Type 1

(NF1NAC Trial)

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Hospital Medical Center, Cincinnati

Must not be taking: Antidepressants, Non-stimulant ADHD, Mood stabilizers, others

Disqualifiers: Chemotherapy, Epilepsy, Major depression, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests N-acetylcysteine (NAC), an antioxidant, to determine its effectiveness for learning and motor issues in children with neurofibromatosis type 1 (NF1). NF1 can lead to problems with thinking, behavior, and movement, and currently, no specific treatment exists for these issues. The trial aims to assess whether NAC can improve these symptoms safely and effectively. Suitable candidates for this trial are children aged 8-16 with NF1, who have no major mental health conditions or recent chemotherapy treatment. As a Phase 2 trial, this research measures how well NAC works in an initial, smaller group of children with NF1.

Will I have to stop taking my current medications?

If you are taking stimulant or psychotropic medications, you need to stay on a stable dose for at least 30 days before joining the study. However, if you are currently using antidepressants, non-stimulant ADHD medications, dopamine blocking agents, or mood stabilizers, you cannot participate in the trial.

Is there any evidence suggesting that N-acetylcysteine (NAC) is likely to be safe for humans?

Past studies have shown that N-acetylcysteine (NAC) is safe for both animals and humans. Research indicates that many people have used NAC, available over the counter, without safety issues. Studies have found that NAC is generally as safe as other common treatments. People have used it for various health issues without major safety concerns. This evidence suggests that NAC is likely safe for use in clinical trials with children who have neurofibromatosis type 1 (NF1). ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for neurofibromatosis type 1?

Unlike the standard treatments for Neurofibromatosis Type 1, which often focus on managing symptoms with medications like antihypertensives or surgery for tumor removal, N-acetylcysteine (NAC) takes a different approach. NAC is an antioxidant that targets oxidative stress in the body, which is thought to contribute to the development of symptoms in this condition. Researchers are excited because NAC could potentially slow down or alter the progression of the disease by addressing this underlying mechanism, offering a new avenue for treatment beyond symptom management.

What evidence suggests that N-acetylcysteine might be an effective treatment for neurofibromatosis type 1?

Research has shown that N-acetylcysteine (NAC) might help improve thinking, behavior, and movement problems in children with neurofibromatosis type 1 (NF1). Animal studies found that NAC corrected issues in brain cells and behavior. These studies suggest that NAC works by balancing antioxidants and affecting glutamate, which is important for brain health. Observations in children with NF1 have also shown some improvements with NAC use. In this trial, participants will receive either NAC or a placebo to further evaluate its potential benefits for NF1. Although NAC is commonly available and used for other conditions, its benefits for NF1 remain under investigation. ^{1 2 4 5 6}

Who Is on the Research Team?

Donald L Gilbert, MD, MS

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Are You a Good Fit for This Trial?

This trial is for children aged 8-16 with Neurofibromatosis type 1 (NF1) and an IQ of 70 or above. They must not be on chemotherapy, have active brain lesions, epilepsy, or use certain medications like antidepressants. Children with asthma or at high risk for GI bleeding are excluded.

Inclusion Criteria

Boys and girls between 8 and 16 years old who have been diagnosed with NF1 according to specific criteria from the National Institutes of Health.

Participants must have a full-scale intelligence quotient (IQ) of 70 or above, as determined by neurocognitive testing within the last 3 years or during the enrollment process

Participants on stimulant or any other psychotropic medication should stay on a stable dose for at least 30 days before entering the study

Exclusion Criteria

Participants should not be receiving chemotherapy currently, or have received chemotherapy in the 6 months prior to entering the study

For females, pregnancy

You do not have any active brain lesions or epilepsy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive N-Acetylcysteine (NAC) or placebo for 8 weeks in a double-blind crossover study

8 weeks

Regular visits for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• N-acetylcysteine (NAC)

Trial Overview

The study tests if the antioxidant N-acetylcysteine (NAC) can improve learning and motor behavior in kids with NF1 compared to a placebo. It's a double-blind study, meaning neither participants nor researchers know who gets NAC or placebo.

How Is the Trial Designed?

Group I: N-Acetylcysteine Experimental Treatment 1 Intervention

Participants will be dosed with 70 mg/kg/dose (max dose 900 mg) three times per day of N-Acetylcysteine (NAC) for eight (8) weeks. This is a double-blind study, neither study participant nor study team members will know whether the participant is given study drug or placebo until after all data is collected.

Group II: Placebo Placebo Group 1 Intervention

Participants will be dosed three times per day with a placebo for eight (8) weeks. This is a double-blind study, neither study participant nor study team members will know whether the participant is given study drug or placebo until after all data is collected.

N-acetylcysteine (NAC) is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Acetadote for:

• Acetaminophen overdose
• Chronic bronchitis
• Cystic fibrosis
• Pneumonia
• Chronic obstructive pulmonary disease (COPD)
• Mucolytic agent

Approved in European Union as Fluimucil for:

• Symptomatic treatment of respiratory tract disorders associated with productive cough
• Chronic bronchitis
• Cystic fibrosis
• Pneumonia
• Chronic obstructive pulmonary disease (COPD)
• Mucolytic agent

Approved in Canada as Mucomyst for:

• Symptomatic treatment of respiratory tract disorders associated with productive cough
• Chronic bronchitis
• Cystic fibrosis
• Pneumonia
• Chronic obstructive pulmonary disease (COPD)
• Mucolytic agent

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Published Research Related to This Trial

N-acetylcysteine (NAC) can significantly reduce the production of inflammatory markers like TNF-alpha and TGF-beta1 in alveolar macrophages from patients with idiopathic pulmonary fibrosis (IPF), suggesting its potential as an anti-inflammatory treatment.

In a study involving 16 IPF patients, NAC demonstrated a dose-dependent effect, with the highest concentration (10 mM) leading to substantial suppression of both spontaneous and LPS-stimulated inflammatory responses, indicating its possible role in slowing disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-acetylcysteine inhibits TNF-alpha, sTNFR, and TGF-beta1 release by alveolar macrophages in idiopathic pulmonary fibrosis in vitro. Cu, A., Ye, Q., Sarria, R., et al.[2016]

N-acetylcysteine (NAC) is effective in promoting the synthesis of glutathione (GSH), which helps detoxify the body and combat oxidative stress, making it beneficial for conditions like HIV, cancer, and heart disease.

NAC is the primary treatment for acetaminophen-induced liver damage and also serves as a chelating agent for acute heavy metal poisoning, protecting organs and aiding in metal elimination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical applications of N-acetylcysteine. Kelly, GS.[2013]

In a double-blind, placebo-controlled trial involving 41 cystic fibrosis (CF) patients and 13 primary ciliary dyskinesia (PCD) patients, N-acetylcysteine (NAC) showed improved lung function in CF patients during periods of lower airway infections.

No beneficial effects of NAC were observed in PCD patients, indicating that the treatment may be more effective for those with cystic fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The clinical effect and the effect on the ciliary motility of oral N-acetylcysteine in patients with cystic fibrosis and primary ciliary dyskinesia. Stafanger, G., Garne, S., Howitz, P., et al.[2022]

N-acetylcysteine (NAC) significantly reduced the rate of healthcare resource utilization (HCU) events related to COPD exacerbations by 20% compared to placebo, with an even greater reduction of 23% in current and ex-smokers.

In patients using long-acting bronchodilators without inhaled corticosteroids (ICS), NAC led to a remarkable 60% reduction in exacerbation rates compared to those receiving placebo, suggesting NAC could be a beneficial alternative to ICS in certain COPD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of smoking status and concomitant medications on the effect of high-dose N-acetylcysteine on chronic obstructive pulmonary disease exacerbations: A post-hoc analysis of the PANTHEON study. Papi, A., Zheng, J., Criner, GJ., et al.[2020]

A clinical trial called NINCFB is investigating the long-term effects of N-acetylcysteine (NAC) on quality of life and exacerbation rates in 119 patients with non-cystic fibrosis bronchiectasis over 52 weeks.

The study aims to provide evidence on NAC's impact on airway bacterial colonization, chronic inflammation, and oxidative stress, which could inform future treatment guidelines for NCFB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of N-acetylcysteine in patients with non-cystic fibrosis bronchiectasis (NINCFB): study protocol for a multicentre, double-blind, randomised, placebo-controlled trial. Liao, Y., Wu, Y., Zi, K., et al.[2022]

In a study involving 12 hemodialysis patients, intravenous administration of 2 g of N-acetylcysteine (NAC) over 3 hours was found to be safe, with no observed side effects during the six dialysis sessions.

NAC reached a steady state concentration after the fourth infusion, indicating effective pharmacokinetics in dialysis patients, with a significant dialytic clearance of 5.52 l/h.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of N-acetylcysteine following repeated intravenous infusion in haemodialysed patients. Soldini, D., Zwahlen, H., Gabutti, L., et al.[2018]

N-acetylcysteine (NAC) is an antioxidant that helps replenish glutathione and has various mechanisms of action, making it useful in both prescription and over-the-counter applications.

Despite its long history and potential benefits in treating rare diseases related to mitochondrial dysfunction, there is a lack of comprehensive clinical studies on NAC's pharmacokinetics and pharmacodynamics, highlighting the need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-acetylcysteine Pharmacology and Applications in Rare Diseases-Repurposing an Old Antioxidant. Sahasrabudhe, SA., Terluk, MR., Kartha, RV.[2023]

Citations

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This data from animal models of NF1 along with uncontrolled clinical observations in children with NF1 suggest that the antioxidant compound, NAC, may reduce ...

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Antioxidant Therapy With N-acetylcysteine for Learning ...

The primary outcome of this study is motor function rated with the Physical and Neurological Examination for Subtle Signs (PANESS), a validated scale that ...

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Children with neurofibromatosis type 1 (NF1) commonly suffer from the effects of cognitive, behavioral, and motor impairments.

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N-Acetylcysteine: A Review of Clinical Usefulness (an Old ...

NAC acts synergistically to improve the efficacy of the drug by decreasing tumor viability, increasing apoptosis, and decreasing expression of ...

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Children with neurofibromatosis type 1 (NF1) commonly suffer from the effects of cognitive, behavioral, and motor impairments.

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N-Acetylcysteine (NAC): Impacts on Human Health - PMC

In general, studies with inhaled NAC demonstrated a safety profile similar to other formulations, demonstrating good tolerance to this type of formulation [25, ...