N-Acetylcysteine for Chronic Fatigue Syndrome

(NAC ME/CFS Trial)

Overseen By Dikoma C. Shungu, Ph.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Weill Medical College of Cornell University

Disqualifiers: Mood disorders, Anxiety, Neurological illness, others

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

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

Compensation: Varies

Number of Visits: 3

Duration: 4 weeks

95 Participants Needed

Trial Summary

What is the purpose of this trial?

Chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS) is an unexplained multisymptom/multisystem disorder for which there are currently no validated treatments. The present exploratory clinical trial aims to advance our understand of the mechanisms of in situ GSH synthesis control through assessment of the response of brain GSH and plasma markers of oxidative stress to different doses of NAC in comparison to placebo, as a potential treatment for ME/CFS that would provide neuroprotection against oxidative stress by restoring cortical GSH reserves. If successful, this exploratory clinical trial would address a significant public health concern by shedding new light onto the mechanisms of action of NAC in brain GSH restoration, which could open a new avenue for the development of potentially effective treatments for a disorder, ME/CFS, that currently has none.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What evidence supports the effectiveness of the drug N-Acetylcysteine for Chronic Fatigue Syndrome?

N-Acetylcysteine (NAC) has shown some benefits in reducing fatigue in conditions like multiple sclerosis and improving symptoms in chronic bronchitis, suggesting it might help with fatigue-related symptoms in Chronic Fatigue Syndrome as well. ^{1 2 3 4 5}

Is N-Acetylcysteine (NAC) safe for human use?

N-Acetylcysteine (NAC) has been used safely for over 30 years as a treatment for various conditions, including respiratory diseases. Studies show it is well-tolerated, with few side effects reported, even when used long-term. ^{2 6 7 8 9}

How does the drug N-Acetylcysteine differ from other treatments for Chronic Fatigue Syndrome?

N-Acetylcysteine (NAC) is unique because it acts as an antioxidant and mucolytic (helps break down mucus), which may help reduce oxidative stress and inflammation, potentially benefiting conditions like Chronic Fatigue Syndrome. Unlike other treatments, NAC has been used to improve immunity and reduce symptoms in respiratory and viral conditions, suggesting it might offer a novel approach for managing Chronic Fatigue Syndrome. ^{6 7 9 10 11}

Research Team

Dikoma C. Shungu, Ph.D.

Principal Investigator

Weill Medical College of Cornell University

Eligibility Criteria

This trial is for adults aged 21-60 with a primary diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and low baseline GSH levels. Participants must be able to consent. Excluded are those with significant mental disorders, neurological illnesses, unstable medical conditions, history of alcohol abuse, positive drug or pregnancy tests, or contraindications for MRI.

Inclusion Criteria

I am willing and able to give my consent for treatment.

I am between 21 and 60 years old.

I am between 21 and 60 years old.

Exclusion Criteria

You have a history of alcohol abuse.

You have drugs or other substances in your urine when you are tested.

I have significant mental health issues, including mood or anxiety disorders.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive different doses of NAC (0 mg/day, 900 mg/day, 3600 mg/day) or placebo for 4 weeks

4 weeks

1 baseline visit (in-person), self-administration

Follow-up

Participants are monitored for changes in GSH levels and oxidative stress markers after treatment

4 weeks

1 follow-up visit (in-person)

Treatment Details

Interventions

• N-Acetylcysteine

Trial Overview The trial is testing the effects of N-Acetylcysteine (NAC) at different doses (900mg/day and 3600mg/day) versus a placebo on brain GSH and plasma markers in ME/CFS patients. The goal is to see if NAC can protect against oxidative stress by restoring cortical GSH reserves.

Participant Groups

Group I: NAC 3600mg/day Active Control 1 Intervention

Subjects who pass screening may be randomly assigned to this arm where they will self administer NAC 3600mg/day caplets for a four week period

Group II: NAC 900mg/day Active Control 1 Intervention

Subjects who pass screening may be randomly assigned to this arm where they will self administer NAC 900mg/day caplets for a four week period

Group III: NAC 0mg/day (Placebo) Placebo Group 1 Intervention

Subjects who pass screening may be randomly assigned to this arm where they will self administer NAC 0mg/day (placebo) caplets for a four week period

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?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

Findings from Research

In a study involving 70 cystic fibrosis (CF) patients over 24 weeks, those taking oral N-acetylcysteine (NAC) maintained or slightly improved their lung function, while those on placebo experienced a decline, indicating NAC's potential to stabilize lung health in CF.

Despite the positive effects on lung function, NAC did not significantly reduce levels of human neutrophil elastase (HNE), a marker of inflammation, suggesting that while NAC may help with lung function, its mechanism of action regarding inflammation needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial. Conrad, C., Lymp, J., Thompson, V., et al.[2015]

N-acetyl cysteine (NAC) was found to be well-tolerated in individuals with progressive multiple sclerosis (MS), with a high adherence rate of 94%, and a similar incidence of adverse events compared to placebo (60% vs. 80%).

While NAC did not significantly reduce fatigue compared to placebo (mean improvement of 11 points on NAC vs. 18 points on placebo), it did not show a meaningful impact on oxidative biomarkers, suggesting that the dosing or administration method may need to be reconsidered.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study of oxidative pathways in MS fatigue: randomized trial of N-acetyl cysteine. Krysko, KM., Bischof, A., Nourbakhsh, B., et al.[2022]

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]

In a 3-month study involving patients with chronic bronchitis, oral N-acetylcysteine (Fabrol) significantly improved symptoms like difficulty in expectoration and cough severity compared to a placebo.

The treatment was well tolerated, with fewer side effects reported in the N-acetylcysteine group than in the placebo group, suggesting it is a safe option for managing chronic bronchitis symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of oral acetylcysteine (Fabrol) in chronic bronchitis: a double-blind placebo controlled study. Jackson, IM., Barnes, J., Cooksey, P.[2017]

Oral N-acetylcysteine (NAC) significantly reduces the risk of exacerbations in chronic bronchitis patients, with a relative benefit of 1.56 and a number-needed-to-treat of 5.8 based on a systematic review of 11 trials involving 2,011 patients.

NAC also improves symptoms in 61.4% of patients compared to 34.6% in the placebo group, with a relative benefit of 1.78 and a number-needed-to-treat of 3.7, while showing no increase in gastrointestinal adverse effects compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. Stey, C., Steurer, J., Bachmann, S., et al.[2019]

In a 12-month study involving 161 bronchiectasis patients, those treated with N-acetylcysteine experienced significantly fewer exacerbations (1.31 vs. 1.98 per patient-year) compared to the control group, indicating its efficacy in reducing flare-ups.

The N-acetylcysteine group also showed a notable improvement in quality of life and a significant reduction in sputum volume, with no severe adverse events reported, suggesting it is a safe long-term treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of N-acetylcysteine on exacerbations of bronchiectasis (BENE): a randomized controlled trial. Qi, Q., Ailiyaer, Y., Liu, R., et al.[2020]

In a study involving 262 participants, long-term treatment with N-acetylcysteine (NAC) significantly reduced the frequency, severity, and duration of influenza-like episodes, particularly in elderly individuals.

While NAC did not prevent influenza virus infection, it notably decreased the number of symptomatic cases, with only 25% of NAC-treated individuals developing symptoms compared to 79% in the placebo group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. De Flora, S., Grassi, C., Carati, L.[2019]

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]

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 systematic review of 3 randomized controlled trials and 5 observational studies involving a total of 21,141 patients evaluated the effects of N-acetylcysteine (NAC) on COVID-19 pneumonia, but the evidence for its efficacy was very low due to serious imprecision and indirectness.

While NAC showed no significant impact on in-hospital mortality or the need for ICU admission in RCTs, some observational studies suggested potential benefits, indicating that further research is needed to confirm its safety and effectiveness in treating COVID-19 pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-acetylcysteine efficacy in patients hospitalized with COVID-19 pneumonia: a systematic review and meta-analysis. Paraskevas, T., Kantanis, A., Karalis, I., et al.[2023]

A study involving 46 healthy participants demonstrated that a new 2% oral N-acetylcysteine formulation is bioequivalent to an existing reference product, meaning they have similar pharmacokinetic profiles.

The new formulation was found to be safe and well tolerated, with most side effects being mild or moderate and not linked to the study drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, open-label, crossover study evaluating bioequivalence of two N-acetylcysteine 2% oral solution formulations in healthy subjects . Donath, F., Armogida, M., Shneyer, L.[2019]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial. [2015]

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

A pilot study of oxidative pathways in MS fatigue: randomized trial of N-acetyl cysteine. [2022]

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

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

4. England pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of oral acetylcysteine (Fabrol) in chronic bronchitis: a double-blind placebo controlled study. [2017]

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

The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Effect of N-acetylcysteine on exacerbations of bronchiectasis (BENE): a randomized controlled trial. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. [2019]

8. 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]

9. 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]

10. Germany pubmed.ncbi.nlm.nih.gov

N-acetylcysteine efficacy in patients hospitalized with COVID-19 pneumonia: a systematic review and meta-analysis. [2023]

11. Germany pubmed.ncbi.nlm.nih.gov

A randomized, open-label, crossover study evaluating bioequivalence of two N-acetylcysteine 2% oral solution formulations in healthy subjects . [2019]