N-acetylcysteine for Lupus

(NAC Trial)

Recruiting at 7 trial locations

Overseen By Kyriakos Kirou, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: State University of New York - Upstate Medical University

Must be taking: Immunosuppressants, Antimalarials, Corticosteroids

Must not be taking: Cyclophosphamide, mTOR inhibitors, Antioxidants

Disqualifiers: Acute SLE flare, Pregnancy, Serious comorbidities, Active infections, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

290 Participants Needed

Trial Summary

What is the purpose of this trial?

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease which often has debilitating and potentially life-threatening consequences. The cause of SLE is unknown and current therapies lack specificity and carry significant side-effects. We previously discovered the depletion of glutathione in lymphocytes of patients with SLE and associated this metabolic change with the elevation of the mitochondrial transmembrane potential. This study will titrate to tolerance during an initial 3 month open label period and then subjects will be randomized to one of 2 arms. It was determined by statistical analysis that each group must have 105 subjects. All subjects will be enrolled and evaluated for tolerance of NAC between dosages of 2.4 g/day and 4.8 g/day for 3 months. After A 3-month open-label dose-titration phase, SLE subjects will be randomized into 2 groups of 105 subjects either to continue the tolerated dosage of NAC or switched to equal number of placebo capsules. There will be up to seven study visits per SLE subject, including the screening and wash out visits. Visits 2-6 will be scheduled three months apart. The study will last 13 months with the wash-out visit. Each subject will donate approximately 100 ml of blood for biomarker studies at each visit. Healthy control subjects will donate blood at the same time. They will be matched to the SLE subjects by gender, age within 10 years, and ethnicity. Their blood will be used as reference for biomarker assays. There is a consent form required to participate in the phase II study.

Will I have to stop taking my current medications?

The trial does not require you to stop taking your current medications if they are stable immunosuppressants, antimalarials, or oral corticosteroids, as long as they meet specific dosage limits. However, you must stop taking NAC or other antioxidants at least one month before screening, and avoid certain vitamins and medications like high doses of vitamin C, vitamin E, and acetaminophen.

What evidence supports the effectiveness of the drug N-acetylcysteine for lupus?

Research suggests that N-acetylcysteine (NAC), an antioxidant, may help improve symptoms in lupus patients by reducing oxidative stress, which is an imbalance between free radicals and antioxidants in the body. Studies have shown improvements in kidney function and disease activity in lupus patients taking NAC, but more controlled trials are needed to confirm these benefits. ^{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 as an antioxidant in various conditions, including lupus. Some studies have shown improvements in health markers without significant safety concerns, but more research is needed to confirm its safety in high doses. ^{1 2 3 4 5}

How is the drug N-acetylcysteine unique for treating lupus?

N-acetylcysteine (NAC) is unique for treating lupus because it acts as a strong antioxidant, helping to balance oxidative stress, which is often present in lupus patients. This antioxidant property may improve symptoms and outcomes when added to standard lupus treatments, although more research is needed to confirm its effectiveness. ^{1 2 3 4 5}

Research Team

Andras Perl, M.D., Ph.D.

Principal Investigator

State University of New York - Upstate Medical University

Eligibility Criteria

Adults over 18 with active Systemic Lupus Erythematosus (SLE) can join this trial. They should have a certain level of disease activity but not in the kidneys or central nervous system, and be on stable medication doses for SLE. People who are pregnant, breastfeeding, recently in other trials, or have serious health issues like heart failure cannot participate.

Inclusion Criteria

I have been diagnosed with lupus and meet at least 4 of the criteria set by the American College of Rheumatology.

I've been on stable doses of certain medications for my condition and my disease activity meets specific criteria.

I am older than 18 years.

Exclusion Criteria

I am currently taking mTOR inhibitors for my condition.

I am taking no more than 1g of acetaminophen daily or participated in the pilot RCT.

Active chronic infections (e.g., HIV, hepatitis B virus, hepatitis C virus, mycobacteria); patient with oral steroid-dependent asthma; Infections requiring intravenous antibiotics within a month or oral antibiotics within two weeks of screening; Patients taking (unwilling or unable to stop) NAC or other antioxidants within 1 month of screening

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Open-label Titration

Participants receive NAC in a dose range of 2.4 g/day to 4.8 g/day, titrated to tolerance

3 months

1 visit (in-person)

Randomized Treatment

Participants are randomized to continue NAC or switch to placebo, with dosage maintained

9 months

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 month

1 visit (in-person)

Treatment Details

Interventions

• N-acetylcysteine
• Placebo

Trial Overview The study tests N-acetylcysteine (NAC), an antioxidant thought to help with SLE symptoms by adjusting glutathione levels. Participants will first find a tolerable dose over three months before being randomly assigned to continue NAC or switch to placebo for another ten months.

Participant Groups

Group I: NAC Active Control 1 Intervention

2.4 g - 4.8 g of NAC daily starting after 3 month open label titration period.

Group II: Placebo Placebo Group 1 Intervention

2.4 g - 4.8 g of placebo per day after 3 month open label titration period.

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

Approved in United States as N-acetylcysteine for:

• Acetaminophen overdose
• Chronic bronchitis
• Cystic fibrosis
• Mucolytic agent

Approved in European Union as N-acetylcysteine for:

• Paracetamol overdose
• Chronic bronchitis
• Cystic fibrosis
• Mucolytic agent

Who Is Running the Clinical Trial?

State University of New York - Upstate Medical University

Lead Sponsor

Trials

176

Recruited

27,600+

Ohio State University

Collaborator

Trials

891

Recruited

2,659,000+

St. Luke's Hospital and Health Network, Pennsylvania

Collaborator

Trials

17

Recruited

2,004,000+

Oklahoma City VA Health Care System

Collaborator

Trials

1

Recruited

290+

Cedars-Sinai Medical Center

Collaborator

Trials

523

Recruited

165,000+

Yale University

Collaborator

Trials

1,963

Recruited

3,046,000+

University of Rochester

Collaborator

Trials

883

Recruited

555,000+

Hospital for Special Surgery, New York

Collaborator

Trials

257

Recruited

61,800+

Penn State University

Collaborator

Trials

380

Recruited

131,000+

Findings from Research

In two cases of early-stage lupus nephritis, treatment with 1,200 mg of N-acetylcysteine (NAC) alongside standard therapy led to significant improvements in oxidative stress markers, including increased glutathione levels and decreased lipid peroxidation.

The addition of NAC also resulted in notable improvements in routine blood counts, urine protein levels, and overall disease activity, suggesting its potential as a beneficial adjunct treatment for lupus nephritis, although further research is needed to understand the mechanisms involved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early-stage lupus nephritis treated with N-acetylcysteine: A report of two cases. Li, M., Gao, W., Ma, J., et al.[2020]

In a study of 32 patients with systemic lupus erythematosus (SLE), both N-acetylcysteine (NAC) and atorvastatin significantly improved endothelial dysfunction, as indicated by reductions in stiffness index and reflection index after treatment.

NAC treatment also led to a notable decrease in inflammatory markers (C-reactive protein and malondialdehyde), suggesting it not only improves endothelial function but also reduces oxidative stress in SLE patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improvement in endothelial dysfunction in patients with systemic lupus erythematosus with N-acetylcysteine and atorvastatin. Kudaravalli, J.[2022]

In a study using female B/W mice as a model for systemic lupus erythematosus (SLE), the antioxidants N-acetylcysteine (NAC) and cysteamine (CYST) significantly improved survival rates, with CYST-treated mice living an average of 48 weeks compared to 33 weeks for controls.

NAC was effective in suppressing anti-DNA antibody levels and prolonging survival, while CYST, despite increasing anti-DNA levels and causing some kidney inflammation, prevented renal insufficiency and also improved survival, suggesting that antioxidants may help manage SLE by reducing oxidative damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antioxidants suppress mortality in the female NZB x NZW F1 mouse model of systemic lupus erythematosus (SLE). Suwannaroj, S., Lagoo, A., Keisler, D., et al.[2017]

A 46-year-old patient with lupus nephritis showed improved health markers after taking 1800 mg of N-acetylcysteine (NAC), including increased glutathione levels and normalized malondialdehyde levels, indicating reduced oxidative stress.

The patient's urinary protein levels and overall health also improved, suggesting that NAC may enhance standard lupus treatment, but further well-controlled trials are necessary to confirm its effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of high dose of N-acetylcysteine in lupus nephritis: a case report and literature review. Tewthanom, K., Janwitayanujit, S., Totemchockcyakarn, K., et al.[2013]

In a randomized, double-blind trial involving 80 patients with systemic lupus erythematosus (SLE), N-acetylcysteine (NAC) at 1800 mg/day for 3 months significantly reduced disease activity, as shown by lower scores on the British Isles Lupus Assessment Group (BILAG) and SLE Disease Activity Index (SLEDAI).

The NAC treatment led to improvements across various organ systems affected by SLE, with no reported adverse events, suggesting it is a safe and effective adjunct therapy for managing SLE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of N-acetylcysteine on systemic lupus erythematosus disease activity and its associated complications: a randomized double-blind clinical trial study. Abbasifard, M., Khorramdelazad, H., Rostamian, A., et al.[2023]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Early-stage lupus nephritis treated with N-acetylcysteine: A report of two cases. [2020]

2. India pubmed.ncbi.nlm.nih.gov

Improvement in endothelial dysfunction in patients with systemic lupus erythematosus with N-acetylcysteine and atorvastatin. [2022]

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

Antioxidants suppress mortality in the female NZB x NZW F1 mouse model of systemic lupus erythematosus (SLE). [2017]

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

The effect of high dose of N-acetylcysteine in lupus nephritis: a case report and literature review. [2013]

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

Effects of N-acetylcysteine on systemic lupus erythematosus disease activity and its associated complications: a randomized double-blind clinical trial study. [2023]