Clinical trial NCT00775476: Treatment of Systemic Lupus Erythematosus (SLE) With N-acetylcysteine
Official title: Treatment of Systemic Lupus Erythematosus (SLE) With N-acetylcysteine (NAC) (SNAC)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus
Keywords: Systemic lupus erythematosus (SLE), an autoimmune disease
Lead sponsor: State University of New York - Upstate Medical University
Sponsor class: OTHER
Collaborators: name: Cedars-Sinai Medical Center
name: University of Rochester
name: Yale University
name: Penn State University
name: Hospital for Special Surgery, New York
name: Ohio State University
name: Oklahoma City VA Health Care System
name: St. Luke's Hospital and Health Network, Pennsylvania
First posted: 2008-10-20
Enrollment: 290
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18;
* Male or female;
* ≥ 4 ACR SLE classification criteria (104,105);
* Positive ANA at a titer of ≥ 1/80;
* Stable immunosuppressants (MMF ≤ 3 g/day, azathioprine ≤ 150 mg/day; methotrexate ≤ 25 mg/week; leflunomide ≤ 20 mg/week; cyclosporin 100 mg/day; voclosporin 47.4 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 or anifrolumab for 90 days prior to screening;
* BILAG 2004 index (48) level A disease activity in ≥ 1 organ/system except renal or central nervous system or BILAG 2004 index level B disease activity in ≥ 1 organs/systems if no level A disease activity is present and SLEDAI ≥ 6 (106);
* Enrollment is approved by adjudication committee within 10 days, which may include retesting and communication with study sites, as necessary.
* Patients may be considered for enrollment 12 months after rituximab treatment, or 6 months after rituximab treatment if their B cell counts have normalized.

Participant Exclusion Criteria

* Acute SLE flare threatening vital organs;
* Pregnant or lactating;
* Moderately serious or serious comorbidities (e.g., diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, chronic renal insufficiency) that in investigator's opinion confers high risk for adverse events;
* Patients receiving cyclophosphamide within 3 months;
* Active chronic infections (e.g., HIV, hepatitis B virus, hepatitis C virus, mycobacteria); patients 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 (which is considered sufficient time to revert GSH to pre-treatment levels (29);
* Patients who participated in the pilot RCT or are taking daily acetaminophen (≤ 1 g/day prn is allowed if documented);
* Patients receiving mTOR inhibitors (rapamycin/sirolimus, everolimus);
* Patients enrolled in other interventional trials.
* Patients should not take medications containing acetaminophen (Tylenol) as it may reduce the effectiveness of NAC. 1 g/day of acetaminophen is allowed if documented.
* Patients should avoid taking more than 500 mg of vitamin C and more than 30 IU of vitamin E daily as both vitamin C and E can confound the study results.

Primary outcomes:
measure: Therapeutic benefit
timeFrame: 12 months
measure: Improvement of disease activity
timeFrame: 12 months
measure: Tolerance and safety
timeFrame: 12 months
Secondary outcomes:
measure: Immunobiological outcomes measurable improved lymphocyte function
timeFrame: 12 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: New Haven
country: United States
facility: Yale Center for Clinical Investigation
state: Connecticut
city: New York
country: United States
facility: Hospital for Special Surgery
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: VA Medical Center
state: Oklahoma
city: Allentown
country: United States
facility: St. Luke's University Health Network
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State MS Hershey Medical Center
state: Pennsylvania
Study officials:
affiliation: State University of New York - Upstate Medical University
name: Andras Perl, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hannon CW, McCourt C, Lima HC, Chen S, Bennett C. Interventions for cutaneous disease in systemic lupus erythematosus. Cochrane Database Syst Rev. 2021 Mar 9;3(3):CD007478. doi: 10.1002/14651858.CD007478.pub2.
citation: Lai ZW, Hanczko R, Bonilla E, Caza TN, Clair B, Bartos A, Miklossy G, Jimah J, Doherty E, Tily H, Francis L, Garcia R, Dawood M, Yu J, Ramos I, Coman I, Faraone SV, Phillips PE, Perl A. N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2012 Sep;64(9):2937-46. doi: 10.1002/art.34502.