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

Study Status: Suspended
Recruit Status: Suspended
Study Type: Interventional

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

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. Existing data in the literature provide evidence that a natural antioxidant, glutathione, is depleted in T cells of patients with SLE. This may be a key factor underlying abnormal activation and predisposition of T lymphocytes to pro-inflammatory cell death via necrosis. Administration of N-acetylcysteine (NAC), that serves as a precursor of glutathione (GSH), improves the clinical outcome of murine lupus, and limits the toxicity of pro-oxidant/immunosuppressant medications commonly used in patients with SLE. NAC is widely available in health food stores and large doses (up to 8 g/day) can be safely administered to humans. In a one-year study of patients with inflammatory lung disease treated with prednisone and azathioprine, addition of NAC (1.8 g/day) diminished disease severity and reduced drug toxicity in comparison to placebo. Moreover, oral NAC has been found to improve muscle fatigue which is reported to be the most disabling symptom in 53% of patients with SLE. Thus, establishing a dose ranging between 1.2-7.2 g/day that is well tolerated and capable of raising intracellular GSH in lupus patients and determining its immunological and therapeutic impact in SLE appears to be well justified.

The study will consist of two parts, Aim 1 and Aim 2.

AIM 1:

The purpose of Aim 1 was to establish the optimal daily oral dose of NAC that can be well tolerated without side effects and can normalize or moderate the depletion of GSH in lupus T cells.

36 SLE subjects and 42 healthy controls

Detailed Summary:

Based on the analysis of the data obtained during Aim 1 the Safety Monitoring Board concluded during their meeting on April, 2011 that Aim 2 should proceed using two NAC dosing arms instead of one. Although a fourth dosing group was originally proposed for Aim 1, the board decided not to proceed with this last dosing group of 4800 mg of NAC two times a day. Per protocol, 75% of the active subjects in each dose needed to tolerate the dose in order to proceed to the next higher dosing group. Although 100% of the subjects tolerated the first and second doses, 3 out of 9 subjects experienced transient nausea with the third dose. The board concluded that NAC dose 1 of 0.6 g twice a day was ineffective while both doses 2 (1.2 g twice a day) and 3 (2.4 g twice a day) provided benefits. All doses were safe. The onset of action and efficacy of dose 3 appears superior to that of dose 2.

Lupus disease activity during Aim 2 will be assessed by SLEDAI and BILAG scores, liver and bone marrow function, and overall fatigue. Sustained improvement of T cell dysfunction, B cell subsets, mitochondrial function and production of nitric oxide will be investigated as immunological outcomes. Both SLE and Healthy control subjects will continue to answer the ASRS self-reporting questionnaire.


Sponsor: State University of New York - Upstate Medical University

Current Primary Outcome:

  • Tolerance and safety [ Time Frame: 4 months ]
    Tolerance and safety were primary clinical outcome measures of Aim 1
  • Reversing or moderating the depletion of glutathione [ Time Frame: 4 months ]
    Reversing or moderating the depletion of glutathione in peripheral blood lymphocytes of patients with SLE was a primary biological outcome measure of Aim 1
  • 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 under Aim 2
  • Reversal or moderation of glutathione depletion [ Time Frame: 12 months ]
    Reversal or moderation of glutathione depletion over a period of 12 months in patients with SLE under Aim 2


Original Primary Outcome:

  • Lupus disease activity: SLEDAI, BILAG [ Time Frame: 4 months ]
  • SLEDAI/BILAG [ Time Frame: 4 months ]


Current Secondary Outcome:

  • Immunobiological outcomes measurable improved lymphocyte function [ Time Frame: 3 months under Aim 1 and 12 months under Aim 2 ]
    Immunobiological outcomes measurable by improved markers of mitochondrial function and activation of T and B lymphocytes
  • Liver and bone marrow function [ Time Frame: 12 months ]
    Liver and bone marrow function under Aim 2


Original Secondary Outcome: Immunobiological outcomes- measurable increase or normalization of GSH [ Time Frame: 12 months ]

Information By: State University of New York - Upstate Medical University

Dates:
Date Received: October 17, 2008
Date Started: March 2009
Date Completion: June 2019
Last Updated: December 12, 2013
Last Verified: December 2013