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

5 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests N-Acetyl Cysteine (NAC), a common supplement, to see if it can help children with neurofibromatosis type 1 (NF1) who have cognitive, behavioral, and motor issues. NAC works by reducing harmful substances in the brain, potentially improving behavior and motor skills. NAC is a precursor to glutathione (GSH) and has been studied for its neuroprotective and cognitive benefits in various conditions.

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.

What evidence supports the effectiveness of the drug N-acetylcysteine (NAC) for treating Neurofibromatosis Type 1?

N-acetylcysteine (NAC) has shown effectiveness as an antioxidant in other conditions, such as cystic fibrosis, where it improved lung function and helped manage airway infections. Its antioxidant properties may offer potential benefits for Neurofibromatosis Type 1 by reducing oxidative stress, although direct evidence for this specific condition is not available. ^{1 2 3 4 5}

Is N-acetylcysteine (NAC) generally safe for human use?

N-acetylcysteine (NAC) is generally considered safe for human use and is well-tolerated. It has been used as an antioxidant and mucolytic (helps clear mucus) in various conditions like chronic obstructive pulmonary disease (COPD) and cystic fibrosis, and as an antidote for paracetamol overdose. ^{1 2 4 6 7}

How is the drug N-acetylcysteine (NAC) unique for treating Neurofibromatosis Type 1?

N-acetylcysteine (NAC) is unique because it acts as a powerful antioxidant, which may help manage oxidative stress, a factor in many diseases, including Neurofibromatosis Type 1. Unlike other treatments, NAC is known for its ability to replenish glutathione (a key antioxidant in the body) and has been used in various conditions to reduce inflammation and oxidative damage. ^{1 4 5 8 9}

Research Team

Donald L Gilbert, MD, MS

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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) 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]

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 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]

References

1. Italy pubmed.ncbi.nlm.nih.gov

N-acetylcysteine inhibits TNF-alpha, sTNFR, and TGF-beta1 release by alveolar macrophages in idiopathic pulmonary fibrosis in vitro. [2016]

2. England 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. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Use of oral N-acetylcysteine for protection of melanocytic nevi against UV-induced oxidative stress: towards a novel paradigm for melanoma chemoprevention. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

N-acetylcysteine (NAC) and Its Role in Clinical Practice Management of Cystic Fibrosis (CF): A Review. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

N-acetylcysteine Pharmacology and Applications in Rare Diseases-Repurposing an Old Antioxidant. [2023]

6. England 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. [2020]

7. England 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. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of N-acetylcysteine following repeated intravenous infusion in haemodialysed patients. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Clinical applications of N-acetylcysteine. [2013]