N-Acetylcysteine for Mitochondrial Disease

Overseen By Kris Engelstad, MS, CGC

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Michio Hirano, MD

Disqualifiers: Normal glutathione, Pregnant, Medically unstable, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

18 Participants Needed

Trial Summary

What is the purpose of this trial?

N-Acetylcysteine (NAC), an anti-oxidant, will be studied to investigate the effects on brain glutathione levels, cognitive skills, motor skills, and quality of life. A group of 18 participants will take either 1800, 3600 or 5400 mg per day of N-acetylcysteine (NAC) for 3 months in this dose escalation study. The investigators want to determine first if the 3600 mg dose per day is safe and might provide some efficacy. If the 3600 mg dose is safe, then additional participants will be treated with 5400 mg per day of NAC, for up to a total of 18 participants. If the 3600 mg per day dose is unsafe, then participants will be treated with the 1800 mg per day dose. Data from this pilot study will be used to determine the most safe and effective dose of NAC for a future clinical trial.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. Please consult with the study team for guidance.

What evidence supports the effectiveness of the drug N-Acetylcysteine for mitochondrial disease?

N-Acetylcysteine (NAC) is known for its antioxidant properties, which help protect cells from damage. It has shown benefits in conditions related to oxidative stress, such as multiple sclerosis and some types of cancer, suggesting it might also help in mitochondrial diseases where oxidative stress is a factor. ^{1 2 3 4 5}

Is N-Acetylcysteine (NAC) safe for humans?

N-Acetylcysteine (NAC) is generally considered safe for humans and has been used for various conditions, including as an antioxidant and mucolytic (helps break down mucus). However, it can cause some adverse reactions, which may limit its use in certain individuals. ^{1 6 7 8 9}

How is the drug N-Acetylcysteine unique for treating mitochondrial disease?

N-Acetylcysteine (NAC) is unique for treating mitochondrial disease because it acts as an antioxidant that helps replenish glutathione, a key molecule in protecting cells from damage. Unlike other treatments, NAC has a long history of use in various conditions due to its ability to target multiple pathways, although its specific use in mitochondrial disease is still being explored. ^{1 5 7 10 11}

Research Team

Michio Hirano, MD

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for adults aged 18-80 with low brain glutathione levels and the m.3243A>G mitochondrial mutation. Participants must be able to follow the study protocol and not be pregnant, lactating, allergic to NAC or sulfur drugs, or medically unstable.

Inclusion Criteria

I carry or might carry the m.3243A>G mitochondrial mutation.

I am between 18 and 80 years old.

You have low levels of brain glutathione detected by magnetic resonance imaging.

Exclusion Criteria

Pregnant or lactating individuals

I am allergic to NAC or sulfur drugs.

Inability to adhere to study protocol

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive N-acetylcysteine (NAC) at doses of 1800, 3600, or 5400 mg per day for 3 months in a dose escalation study

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of functional exercise capacity, performance scale, and brain glutathione levels

4 months

Treatment Details

Interventions

• N-Acetylcysteine

Trial Overview The study tests different doses of N-Acetylcysteine (NAC) on brain health and quality of life in people with a specific mitochondrial disease. It starts at 3600 mg/day to check safety and effectiveness before possibly increasing to 5400 mg/day or decreasing to 1800 mg/day based on results.

Participant Groups

Group I: Active drug (NAC) Experimental Treatment 1 Intervention

Participants will receive NAC for 3 months.

N-Acetylcysteine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Mucomyst for:

• Mucolytic agent
• Acetaminophen overdose

Approved in European Union as Fluimucil for:

• Mucolytic agent
• Respiratory tract disorders

Approved in Canada as N-Acetylcysteine for:

• Mucolytic agent
• Acetaminophen overdose

Who Is Running the Clinical Trial?

Michio Hirano, MD

Lead Sponsor

Trials

2

Recruited

20+

Darryl C. De Vivo, MD

Lead Sponsor

Trials

1

Recruited

20+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

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]

The innovative master protocol and primary outcome assessment for N-acetyl-L-leucine (IB1001) are designed to address the unique challenges of treating ultra-rare neurodegenerative disorders, involving three multinational phase II trials for Niemann-Pick disease type C, GM2 gangliosidoses, and ataxia telangiectasia.

The novel Clinical Impression of Change in Severity (CI-CS) assessment allows for a personalized evaluation of treatment effects, capturing meaningful clinical changes in patients' functional performance, which is crucial for understanding the efficacy of N-acetyl-L-leucine in these rare diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia. Fields, T., Patterson, M., Bremova-Ertl, T., et al.[2021]

N-acetylcysteine (NAC) has shown potential benefits in various conditions linked to oxidative stress, but clinical trials have produced inconsistent results, particularly in diseases like HIV and chronic obstructive pulmonary disease (COPD).

While NAC is routinely used for treating paracetamol overdose, its efficacy in other areas, such as cancer recurrence and preventing kidney damage from radiocontrast, remains uncertain, with recent studies yielding mixed outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-acetylcysteine -- passe-partout or much ado about nothing? Aitio, ML.[2018]

A study involving 7 patients with relapsing-remitting multiple sclerosis found that the combination of glatiramer acetate (GA) and N-acetylcysteine (NAC) was safe and well tolerated over a 36-week treatment period.

Given the favorable safety profile observed, further studies to evaluate the efficacy of this combination treatment in MS patients are warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and Safety of Combined Glatiramer Acetate and N-Acetylcysteine in Relapsing-Remitting Multiple Sclerosis. Schipper, HM., Arnold, D., GrandʼMaison, F., et al.[2019]

Mito10-NAC, a new mitochondria-targeted version of N-acetylcysteine (NAC), is nearly 2000-fold more effective than NAC in inhibiting the growth of various cancer cells, including pancreatic cancer cells.

The antiproliferative effects of Mito10-NAC and NAC appear to be independent of their antioxidant properties, suggesting a different mechanism of action that involves inhibiting mitochondrial respiration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiproliferative effects of mitochondria-targeted N-acetylcysteine and analogs in cancer cells. Cheng, G., Hardy, M., Kalyanaraman, B.[2023]

In a study involving 33 participants with ryanodine receptor 1-related myopathies, N-acetylcysteine (NAC) was found to be safe and well-tolerated, but it did not significantly reduce oxidative stress levels or improve physical endurance as measured by the 6-minute walk test over a 6-month period.

Despite participants showing elevated oxidative stress and decreased endurance at baseline, NAC treatment did not lead to any meaningful changes in these measures, indicating that it may not be an effective intervention for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies. Todd, JJ., Lawal, TA., Witherspoon, JW., et al.[2020]

N-acetylcysteine (NAC) effectively increases plasma cysteine and glutathione levels, particularly at a dose of 70 mg/kg, which also correlates with improved handgrip exercise performance.

Higher doses of NAC (140 mg/kg) can lead to significant gastrointestinal adverse reactions, suggesting that lower doses may be safer and still effective for enhancing thiol levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-acetylcysteine in handgrip exercise: plasma thiols and adverse reactions. Ferreira, LF., Campbell, KS., Reid, MB.[2021]

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]

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 a versatile compound that serves as a precursor to important antioxidants and has been used historically for treating respiratory issues and acetaminophen overdose.

Recent studies suggest that NAC may have therapeutic potential in a variety of conditions, including cancer, heart disease, and HIV, due to its strong antioxidant properties that combat free radical damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-acetylcysteine. [2013]

N-acetylcysteine (NAC) has a wide range of clinical applications, including treatment for paracetamol overdose and various disorders, due to its antioxidative properties and ability to restore impaired cellular components.

NAC's unique effectiveness is likely due to its ability to reduce disulfide bonds in proteins, which alters their structure and function, although more research is needed to fully understand its mechanisms and how it interacts with cell signaling pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The chemistry and biological activities of N-acetylcysteine. Samuni, Y., Goldstein, S., Dean, OM., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

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

2. England pubmed.ncbi.nlm.nih.gov

A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia. [2021]

3. England pubmed.ncbi.nlm.nih.gov

N-acetylcysteine -- passe-partout or much ado about nothing? [2018]

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

Tolerability and Safety of Combined Glatiramer Acetate and N-Acetylcysteine in Relapsing-Remitting Multiple Sclerosis. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Antiproliferative effects of mitochondria-targeted N-acetylcysteine and analogs in cancer cells. [2023]

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

Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies. [2020]

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

N-acetylcysteine in handgrip exercise: plasma thiols and adverse reactions. [2021]

8. 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]

9. Germany pubmed.ncbi.nlm.nih.gov

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

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

N-acetylcysteine. [2013]

11. Netherlands pubmed.ncbi.nlm.nih.gov

The chemistry and biological activities of N-acetylcysteine. [2022]