Overview
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.
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