Treatment of Systemic Lupus Erythematosus (SLE) With N-acetylcysteine (NAC)

This study has suspended participant recruitment.
(Funds from original NIH grant, AT4332, have been exhausted. While new funding is thought with revised study design, no new patients will be recruited.)
Sponsor:
Information provided by (Responsible Party):
State University of New York - Upstate Medical University
ClinicalTrials.gov Identifier:
NCT00775476
First received: October 17, 2008
Last updated: December 12, 2013
Last verified: December 2013
  Purpose

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 (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:

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.


Condition Intervention Phase
Systemic Lupus Erythematosus
Drug: N-acetylcysteine
Drug: Placebo
Phase 1
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by State University of New York - Upstate Medical University:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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


Estimated Enrollment: 478
Study Start Date: March 2009
Estimated Study Completion Date: June 2019
Estimated Primary Completion Date: October 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: NAC Group 1
1.2 g of NAC two times daily
Drug: N-acetylcysteine
Capsules of NAC, 1.2 g twice daily
Active Comparator: NAC Group 2
2.4 g of NAC two times daily
Drug: N-acetylcysteine
Capsules of NAC, 2.4 g twice daily
Placebo Comparator: Placebo
2.4 g of placebo 2 times per day
Drug: Placebo
2.4 g of placebo (sugar) twice daily

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Age > 18 years old.

SLE with ≥ 4 of eleven diagnostic criteria approved by the American College of Rheumatology

Be on stable medications: prednisone (only ≤ 10 mg /day), anti-malarials (≤ 400 mg/day hydroxychlroquine), and commonly used immunosuppressants such as azathioprine (≤ 200 mg/day), methotrexate (≤ 25 mg/week), mycophenolate mofetil (≤ 3,000 mg/day), or mycophenolic acid (≤ 1,440 mg/day) are allowed, unless excluded as noted below.

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)

History of chronic infections (e.g., HIV, hepatitis B virus, hepatitis C virus, mycobacteria, bronchiectasis)

Infections in the past month history of severe or recurrent infections

Smokers

Over-the-counter antioxidants that can enhance the effect of NAC

Acetaminophen (Tylenol) which is metabolized by hepatic cytochrome P450 enzymes, primarily CYP2E1, to a toxic intermediate compound (N-acetyl-para benzoquine imide), requiring detoxification by hepatic GSH

One daily dose of multivitamin, containing ≤ 500 mg of vitamin C and ≤ 30 IU of vitamin E will be allowed for each patient

Patients receiving biologicals (rituximab, abatacept)

Patients enrolled in other clinical trials

Healthy subjects serve as controls for in vitro immunological studies

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00775476

Locations
United States, New York
SUNY Upstate Medical University
Syracuse, New York, United States, 13210
Sponsors and Collaborators
State University of New York - Upstate Medical University
Investigators
Principal Investigator: Andras Perl, M.D., Ph.D. State University of New York - Upstate Medical University
  More Information

No publications provided by State University of New York - Upstate Medical University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: State University of New York - Upstate Medical University
ClinicalTrials.gov Identifier: NCT00775476     History of Changes
Other Study ID Numbers: IRBnet # 247162, NIH Award # 1R01AT004332-01A1
Study First Received: October 17, 2008
Last Updated: December 12, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by State University of New York - Upstate Medical University:
Systemic lupus erythematosus (SLE), an autoimmune disease

Additional relevant MeSH terms:
Lupus Erythematosus, Systemic
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases
Acetylcysteine
N-monoacetylcystine
Anti-Infective Agents
Antidotes
Antioxidants
Antiviral Agents
Expectorants
Free Radical Scavengers
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Respiratory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014