Treatment of Systemic Lupus Erythematosus (SLE) With N-acetylcysteine

Systemic Lupus Erythematosus Clinical Trial

— NAC  

Official title:

Treatment of Systemic Lupus Erythematosus (SLE) With N-acetylcysteine (NAC) (SNAC)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00775476
• Other study ID #: IRBnet # 1566736
• Secondary ID: NIH Award #1U01A
• Status: Recruiting
• Phase: Phase 2
• Start date: March 31, 2022
• Est. completion date: December 2027

Study information

• Verified date: October 2023
• Source: State University of New York - Upstate Medical University
• Contact: Andras Perl, M.D., Ph.D.
• Phone: (315) 464-4194
• Email: perla[@]upstate.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

Subjects will take NAC in a dose range of 2.4 g/day to 4.8 g/day which will be titrated to tolerance during an initial 3-month open label period. After the 3-month open label period, patients in each arm will continue taking equal numbers of capsules representing a dosage that has been titrated to tolerance. As an example, the patients tolerating 2.4 g/day, or 4 capsules containing 600 mg of NAC, after 3 months will be randomized to take 4 NAC or 4 placebo (2.4 g/day dextrose) capsules twice daily for the 9 subsequent months.

The primary outcome variable will be the response (yes/no) in the SLE Respinder Index or SRI at Month 12 (reduction ≥ 4 points in SELENA-SLEDAI score and therefore also called SRI-4; no new BILAG A organ domain score and no more than 1 new BILAG B organ domain score; and no worsening in Physician's Global Assessment (PGA) score) by ≥ 0.3 points versus baseline). A positive response will also require no treatment failure, defined as the need for non-protocol treatment, i.e., new or increased immunosuppressives or antimalarials; increased or parenteral corticosteroids; or premature discontinuation from study treatment. Corticosteroids can be tapered off at the investigator's discretion, based on disease activity. Four weeks after randomization, once tapered, corticosteroids can only be increased again to the dosage preceding the last taper step; any larger increase will be deemed a treatment failure. In addition, any increase in corticosteroid dosage during the last 3 months of the trial will result in declaration of treatment failure.

We will monitor tolerance and safety, and assess SLEDAI, BILAG, FAS, PROMIS, ASRS, prednisone use, liver and bone marrow function as secondary outcomes.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 290
• Est. completion date: December 2027
• Est. primary completion date: October 31, 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Age > 18 years old.

SLE with = 4 of eleven diagnostic criteria approved by the American College of Rheumatology

Stable immunosuppressants (MMF = 3 g/day, azathioprine = 100 mg/day; methotrexate = 15 mg/day) and/or antimalarials (hydroxychloroquine = 400 mg/day) for 30 days prior to screening; stable oral corticosteroids for 2 weeks prior to screening; = 20 mg/day prednisone or equivalent; stable belimumab for 90 days prior to screening;

BILAG 2004 index level A disease activity in = 1 organ/system except renal or central nervous system or (ii) BILAG 2004 index level B disease activity in = 2 organs/systems if no level A disease activity is present and (iii) SLEDAI = 6;

Exclusion Criteria:

Acute flare of SLE threatening vital organs and requiring intravenous

Pregnant or lactating

Moderately serious or serious comorbidities (e.g., diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, chronic renal insufficiency)

Patients receiving cyclophosphamide within 3 months

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

Patients who participated in the pilot RCT or are taking daily acetaminophen (</= 1 g/day PRN is allowed if documented)

Patients receiving rituximab within 12 months or other biologic therapy within five half-lives

Patients receiving mTOR inhibitors (rapamycin/sirolimus, everolimus)

Patients enrolled in other interventional trials

Healthy subjects serve as controls for in vitro immunological studies

Related Conditions & MeSH terms

• Lupus Erythematosus, Systemic
• Systemic Lupus Erythematosus

Intervention

Drug:
• N-acetylcysteine
Capsules of NAC, each containing 600 mg of NAC between dosages of 2.4 g to 4.8 g daily
• Placebo
placebo (sugar) twice daily, daily dosage will match that of NAC that was tolerated between daily dosages of 2.4 g and 4.8 g during the open-label titration phase.

Locations

Country	Name	City	State
United States	Penn State MS Hershey Medical Center	Hershey	Pennsylvania
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Yale Center for Clinical Investigation	New Haven	Connecticut
United States	Hospital for Special Surgery	New York	New York
United States	SUNY Upstate Medical University	Syracuse	New York

Sponsors (6)

Lead Sponsor	Collaborator
State University of New York - Upstate Medical University	Cedars-Sinai Medical Center, Hospital for Special Surgery, New York, Penn State University, University of Rochester, Yale University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Therapeutic benefit	Positive response on the SLE Responder Index (SRI) in the NAC arm vs placebo	12 months
Primary	Improvement of disease activity	Improvement of disease activity as measurable by the reduction of SLEDAI or BILAG disease activity scores and the reduction of prednisone usage	12 months
Primary	Tolerance and safety	Monitor adverse events and tolerance of the study drug	12 months
Secondary	Immunobiological outcomes measurable improved lymphocyte function	Immunobiological outcomes measurable by improved markers of glutathioen depletion, mitochondrial function and activation of T and B lymphocytes	12 months