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

February 27, 2024 updated by: State University of New York - Upstate Medical University

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Estimated)

290

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Andras Perl, M.D., Ph.D.
  • Phone Number: (315) 464-4194
  • Email: perla@upstate.edu

Study Contact Backup

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90048
        • Recruiting
        • Cedars-Sinai Medical Center
        • Contact:
        • Contact:
        • Principal Investigator:
          • Daniel Wallace, MD
    • Connecticut
      • New Haven, Connecticut, United States, 06519
        • Recruiting
        • Yale Center for Clinical Investigation
        • Contact:
        • Principal Investigator:
          • Fotios Koumpouras, M.D.
    • New York
      • New York, New York, United States, 10021
        • Recruiting
        • Hospital for Special Surgery
        • Contact:
          • Emily Wu
          • Phone Number: 212-774-2967
          • Email: wue@hss.edu
        • Contact:
          • Kyriakos Kirou, M.D.
          • Phone Number: 212 606 1728
          • Email: KirouK@HSS.EDU
        • Principal Investigator:
          • Kyriakos Kirou, M.D.
        • Sub-Investigator:
          • David Fernandez, M.D.
      • Syracuse, New York, United States, 13210
        • Recruiting
        • SUNY Upstate Medical University
        • Contact:
        • Principal Investigator:
          • Andras Perl, M.D., Ph.D.
        • Sub-Investigator:
          • Jihad Ben Gabr, M.D.
        • Sub-Investigator:
          • Sheetal Rayancha, M.D.
        • Contact:
    • Pennsylvania
      • Hershey, Pennsylvania, United States, 17033

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: NAC
2.4 g - 4.8 g of NAC daily starting after 3 month open label titration period.
Drug: N-acetylcysteine
Capsules of NAC, each containing 600 mg of NAC between dosages of 2.4 g to 4.8 g daily
Placebo Comparator: Placebo
2.4 g - 4.8 g of placebo per day after 3 month open label titration period.
Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Therapeutic benefit
Time Frame: 12 months
Positive response on the SLE Responder Index (SRI) in the NAC arm vs placebo
12 months
Improvement of disease activity
Time Frame: 12 months
Improvement of disease activity as measurable by the reduction of SLEDAI or BILAG disease activity scores and the reduction of prednisone usage
12 months
Tolerance and safety
Time Frame: 12 months
Monitor adverse events and tolerance of the study drug
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Immunobiological outcomes measurable improved lymphocyte function
Time Frame: 12 months
Immunobiological outcomes measurable by improved markers of glutathioen depletion, mitochondrial function and activation of T and B lymphocytes
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

State University of New York - Upstate Medical University

Collaborators

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

Investigators

  • Principal Investigator: Andras Perl, M.D., Ph.D., State University of New York - Upstate Medical University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 31, 2022

Primary Completion (Estimated)

October 31, 2026

Study Completion (Estimated)

December 1, 2027

Study Registration Dates

First Submitted

October 17, 2008

First Submitted That Met QC Criteria

October 17, 2008

First Posted (Estimated)

October 20, 2008

Study Record Updates

Last Update Posted (Estimated)

February 29, 2024

Last Update Submitted That Met QC Criteria

February 27, 2024

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRBnet # 1566736
  • NIH Award #1U01AR076092 - 01A1

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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