Treatment of Systemic Lupus Erythematosus (SLE) With N-acetylcysteine (NAC)
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.
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 (matched by age and sex) were studied.
The 36 SLE subjects were divided into 3 groups of 12. Each group received a different dose of NAC (N-acetylcysteine)or placebo as follows:
Group 1: 9 received 600mg of NAC two times a Day, 3 received placebo; Group 2: 9 received 1200mg of NAC two times a Day, 3 received placebo; Group 3: 9 received 2400mg of NAC two times a Day, 3 received placebo;
To account for attrition 12 subjects were randomized in each group (9 active, 3 placebo).
At each subject visit, blood from a healthy donor was drawn and used as control. The control blood was used for flow cytometry measurements of GSH and in vitro immunological studies. In addition to GSH measurements and immunologic studies, routine labs., ASRS self-reporting assessment questionnaire, and SLEDAI/BILAG/Fatigue scores were obtained for the SLE subjects. The healthy control subjects also answered the ASRS self-reporting questionnaire. The ASRS questionnaire was incorporated into the study procedures in October, 2009. It is designed to assess a patient's ability to concentrate which could be affected by the involvement of the Central Nervous System (CNS) in lupus. There were up to 5 study visits per SLE subjects in a period of four months.
At each visit up to 100 ml of blood were drawn from each subject. 20 ml are needed for routine labs. and up to 80 ml are needed for the GSH and immunological tests.
Dose comparisons were based on continuous monitoring of adverse events and drug tolerance.
Aim 2 will determine the tolerance and impact of two NAC doses on disease activity and prednisone use in 165 subjects with SLE in a double-blind placebo-controlled 12-month study. It is designed to detect clinically meaningful differences in disease activity in the patient population.
It was determined by statistical analysis that each group must have 55 subjects. SLE subjects will be randomized into 3 groups of 55 subjects to receive 1.2 g of NAC twice a day, 2.4 g of NAC twice a day, or placebo. There will be up to seven study visits per SLE subject, including the screening and wash out visits. Visits 1-5 will be scheduled three months apart. The study will last 13 months with the wash out visit. Each subject will donate approximately 80 ml of blood for research 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 research assays.
The inclusion and exclusion criteria will be the same as in Aim 1 and the same subjects may continue to participate. There is a new consent form required to participate in the second phase.
Systemic Lupus Erythematosus
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Treatment of Systemic Lupus Erythematosus (SLE) With N-acetylcysteine|
- Tolerance and safety [ Time Frame: 4 months ] [ Designated as safety issue: Yes ]Tolerance and safety were primary clinical outcome measures of Aim 1
- Reversing or moderating the depletion of glutathione [ Time Frame: 4 months ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: Yes ]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 ] [ Designated as safety issue: No ]Reversal or moderation of glutathione depletion over a period of 12 months in patients with SLE under Aim 2
- Immunobiological outcomes measurable improved lymphocyte function [ Time Frame: 3 months under Aim 1 and 12 months under Aim 2 ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: Yes ]Liver and bone marrow function under Aim 2
|Study Start Date:||March 2009|
|Estimated Study Completion Date:||June 2014|
|Estimated Primary Completion Date:||March 2014 (Final data collection date for primary outcome measure)|
Active Comparator: NAC Group 1
1.2 g of NAC two times daily
Capsules of NAC, 1.2 g twice daily
Active Comparator: NAC Group 2
2.4 g of NAC two times daily
Capsules of NAC, 2.4 g twice daily
Placebo Comparator: Placebo
2.4 g of placebo 2 times per day
2.4 g of placebo (sugar) twice daily
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.
|Contact: Andras Perl, M.D., Ph.D.||(315) firstname.lastname@example.org|
|Contact: Irene M. Ramos, M.S.||(315) email@example.com|
|United States, New York|
|SUNY Upstate Medical University||Recruiting|
|Syracuse, New York, United States, 13210|
|Contact: Andras Perl, M.D., Ph.D. 315-464-4194 firstname.lastname@example.org|
|Contact: Irene M Ramos, M.S. (315) 464-5247 email@example.com|
|Principal Investigator: Andras Perl, M.D., Ph.D.|
|Sub-Investigator: Home Neupane, M.D.|
|Sub-Investigator: Fatme Allam, M.D.|
|Sub-Investigator: Zhiwei Lai, M.D.|
|Sub-Investigator: Robert Hanczko, Ph.D.|
|Sub-Investigator: Tiffany N. Telarico, B.S.|
|Sub-Investigator: Adam Bartos, Ph.D.|
|Sub-Investigator: Gabriella Miklossy, Ph.D.|
|Sub-Investigator: Jianghong Yu, M.D.|
|Sub-Investigator: Gergely Talaber, MD, PhD|
|Sub-Investigator: Ashwini Shadakshari, MD|
|Sub-Investigator: Mark Woodford, BS|
|Sub-Investigator: Rebecca Borsuk, BS|
|Sub-Investigator: Edward Doherty, BS|
|Sub-Investigator: Hiroshi Kato, MD|
|Sub-Investigator: Zachary Oaks, BS|
|Sub-Investigator: Kaiser Alam, PhD|
|SUNY Upstate Medical University||Recruiting|
|Syracuse, New York, United States, 13210|
|Contact: Irene Ramos, M.S. 315-464-5247 firstname.lastname@example.org|
|Principal Investigator:||Andras Perl, M.D., Ph.D.||State University of New York - Upstate Medical University|