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

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 if it can enhance brain function, motor skills, and overall quality of life in individuals with mitochondrial disease. Researchers will administer varying doses to identify a safe and potentially effective amount. Participants must have low levels of the brain chemical glutathione and a specific genetic mutation associated with mitochondrial issues. As a Phase 1 trial, this research aims to understand how the treatment works in people, providing participants the chance to be among the first to receive this potentially groundbreaking therapy.

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.

Is there any evidence suggesting that N-Acetylcysteine is likely to be safe for humans?

Research has shown that N-acetylcysteine (NAC) is generally safe. Problems rarely occur and usually arise only with very high doses or specific administration methods. NAC is often used safely for various brain-related conditions. Some studies have mentioned it might not always prevent certain cell damage, but it remains a good treatment option due to its safety.

This trial is in an early stage, so researchers are still determining the safest dose. Treatments in early trials undergo close monitoring to ensure safety. So far, participants have tolerated NAC well. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for mitochondrial disease?

N-Acetylcysteine (NAC) is unique for treating mitochondrial disease because it acts as an antioxidant, directly targeting oxidative stress, which is a major contributor to mitochondrial dysfunction. While most current treatments focus on managing symptoms, NAC aims to address one of the root causes by replenishing the body's levels of glutathione, a crucial antioxidant. Researchers are excited about NAC because it offers a potential new approach that could improve cellular energy production and overall function in patients with mitochondrial disorders.

What evidence suggests that N-Acetylcysteine might be an effective treatment for mitochondrial disease?

Research has shown that N-acetylcysteine (NAC), the treatment under study in this trial, can enhance cellular energy production. One study found that NAC restored crucial levels of glutathione in cells, reducing damage. This restoration might aid in repairing brain cells affected by certain diseases. NAC has also demonstrated protective effects in conditions like temporal lobe epilepsy by potentially reducing harmful proteins. Although not all studies report positive outcomes, these findings suggest that NAC might address cellular issues by reducing harmful chemicals and supporting cell repair. ^{2 3 5 6 7}

Who Is on the Research Team?

Michio Hirano, MD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

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.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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) 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]

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) 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8698433/

N-Acetylcysteine Reverses the Mitochondrial Dysfunction ... In this study, we found that NAC could act at the mitochondrial level, replenishing mtGSH, reducing superoxide levels within mitochondria, and ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10376274/

N-acetylcysteine Pharmacology and Applications in Rare ... In this review, we attempt to summarize the existing literature focused on NAC explorations in rare diseases targeting mitochondrial dysfunction.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05241262

NCT05241262 | Study of N-acetylcysteine in the Treatment ... These low levels can reduce the repair processes in the brain to fix toxic chemicals that result from a mitochondrial disorder. The investigators are aware of a ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0143417922000695

Protective effect of N-acetyl cysteine on the mitochondrial ... These findings indicate that NAC plays a neuroprotective role in temporal lobe epilepsy, probably through decreasing the mTOR protein level.

5. nature.com nature.com/articles/s41387-021-00177-w

N-acetylcysteine supplementation did not reverse ... Our results indicate that NAC supplementation provides little protection against free radicals, apoptosis, and inflammation in the salivary gland mitochondria ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8234027/

N-Acetylcysteine (NAC): Impacts on Human Health - PMC It has a well-established safety profile, and its toxicity is uncommon and dependent on the route of administration and high dosages. Its remarkable antioxidant ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0028390825002333

The neuroprotective effects of N-acetylcysteine in ... NAC remains among the strongest candidates with a high safety profile for managing several types of neurological disorders. Graphical abstract. Image 1.