Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease. Although current therapies afford clinical improvement, they are not curative and are associated with significant side-effects. We previously discovered that a natural antioxidant, glutathione (GSH), is depleted in lymphocytes of SLE patients. We also found that the activation of mechanistic target of rapamycin (mTOR), a sensor of oxidative stress, contributes to abnormal T-cell lineage specification and dysfunction in SLE. In lupus-prone mice, N-acetylcysteine (NAC), which acts a precursor of GSH and an antioxidant by itself, abrogated the disease. While intravenous NAC has been safely used in humans for other indications, it is unavailable as an oral medication by prescription. Therefore, we initiated a randomized, double-blind, placebo-controlled pilot study to evaluate the safety, tolerance, as well as immunological and therapeutic impact of NAC in 36 SLE patients. In this study, NAC was found to be safe, and it improved disease activity, reversed GSH depletion and blocked pro-inflammatory mTOR activation over 3 months. These results clearly warrant confirmation in a trial with longer treatment duration. To address this critical gap in knowledge, we propose a U34 planning grant for a multi-center, randomized, double-blind, placebo-controlled phase II clinical trial of the safety and efficacy of NAC in SLE patients.
The aims for this U34 application include: 1) Bringing together lupus clinical trial experts in a multi-center study with a coherent management structure and a clear communication strategy; 2) Refining the Clinical Protocol for determining the safety and efficacy of NAC; the trial conception has been, in response to reviews and NIAMS input, re-designed to ensure a clinically meaningful premise and efficient and affordable trial size using a novel approach and the recently validated SLE Responder Index (SRI) to evaluate primary clinical efficacy outcome; 3) Standardizing clinical assessment techniques to ensure reliability of the primary and secondary outcome measures across the collaborating centers; 4) Designing and implementing a 21 CRF part 11 compliant electronic data capture system (eDC), which will be based on the existing case report forms (CRFs); 5) Establishing centralized monitoring procedures for data collection and management; 6) Finalizing the Data and Safety Monitoring Plan, Standard Operating Procedures, Manual of Operating Procedures, and Investigators Brochure to meet FDA, OHRP and NIAMS requirements for a U01 (multi-site) Clinical Trial Implementation Cooperative Agreement. The preliminary specific aims for the future clinical trial will be to: 1) Confirm safety and determine efficacy of NAC relative to placebo in 210 SLE patients, (105 patients per arm, with up to 20 additional subjects proposed to enroll for titration of NAC to tolerance within a dosage range of 2.4 g/day to 4.8 g/day through an initial 3-month open label period) during a 12-month intervention followed by a 1-month washout; 2) Determine whether the reversal of GSH depletion and blockade of mTOR are sustained over 12 months and predict responsiveness to NAC. This study will establish the role of NAC as a novel, safe, effective, and biomarker-driven approach in the treatment of SLE.
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology that affects 1.5 million people in the United States. The disease has debilitating and potentially life-threatening consequences with mortality still approaching 10% over 5 years. There is unmet medical need, as current treatments are only partially effective and have significant side effects. As originally uncovered in our laboratory and overwhelmingly confirmed by others, a natural antioxidant, glutathione, is depleted in lymphocytes of patients with SLE; this may be a key factor that causes immune system dysfunction and contributes to self-destructive autoimmunity. Administration of N-acetylcysteine (NAC), which serves as a precursor of glutathione, improves the clinical outcome of murine lupus. NAC limits the toxicity of pro-oxidant, immunosuppressant medications that are commonly used in patients with SLE. Moreover, NAC improves fatigue, the most disabling symptom reported by patients with SLE. Although NAC is inexpensive and widely distributed in health food stores, and large doses can be safely administered to humans intravenously, it is currently unavailable as an oral medication by prescription. Therefore, we initiated a randomized, double-blind, placebo-controlled phase I/II study of NAC in 36 SLE patients to evaluate its safety, tolerance, and metabolic, immunological, and therapeutic effects. The results of this pilot study show that 2.4 g/day NAC and 4.8 g/day NAC are safe and they improve disease activity and fatigue through inhibiting the autoimmune inflammatory process over 3 months. This U34 planning grant has been initiated to bring together experienced lupus investigators with a coherent management structure and clear communication strategy to evaluate the safety and clinical efficacy of NAC over 12 months in a phase II multi- center, randomized, double-blind, placebo-controlled clinical trial, designated as SLE treatment with NAC (SNAC), that meets FDA, OHRP and NIAMS regulations and policy requirements. The preliminary specific aims for the future clinical trial will: 1) Determine the tolerance, safety, and therapeutic efficacy of NAC, within a dosage range of 2.4 g/day to 4.8 g/day to be titrated to tolerance during an initial 3-month open label period, in comparison to placebo in SLE patients during a 12-month intervention followed by a 1-month washout. 2) Determine whether the reversal of glutathione depletion is sustained over 12 months and predicts response to NAC.
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