| Conditions: |
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Systemic Lupus Erythematosus |
| Purpose: |
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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.
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| Study Summary: |
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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.
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| Criteria: |
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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
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| NCT ID: |
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NCT00775476 |
| Primary Contact: |
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Principal Investigator
Andras Perl, M.D., Ph.D.
State University of New York - Upstate Medical University
Andras Perl, M.D., Ph.D.
Phone: (315) 464-4194
Email: perla@upstate.edu
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| Backup Contact: |
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Email: ramosi@upstate.edu
Irene M. Ramos, M.S.
Phone: (315) 464-5247
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| Location Contact: |
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Syracuse, New York 13210
United States
Irene Ramos, M.S.
Phone: 315-464-5247
Email: ramosi@upstate.edu
Site Status: Recruiting |