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

Primary Purpose

Systemic Lupus Erythematosus

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
N-acetylcysteine
Placebo
Sponsored by
State University of New York - Upstate Medical University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Systemic Lupus Erythematosus focused on measuring Systemic lupus erythematosus (SLE), an autoimmune disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Age > 18 years old.

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

Stable immunosuppressants (MMF ≤ 3 g/day, azathioprine ≤ 100 mg/day; methotrexate ≤ 15 mg/day) and/or antimalarials (hydroxychloroquine ≤ 400 mg/day) for 30 days prior to screening; stable oral corticosteroids for 2 weeks prior to screening; ≤ 20 mg/day prednisone or equivalent; stable belimumab for 90 days prior to screening;

BILAG 2004 index level A disease activity in ≥ 1 organ/system except renal or central nervous system or (ii) BILAG 2004 index level B disease activity in ≥ 2 organs/systems if no level A disease activity is present and (iii) SLEDAI ≥ 6;

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)

Patients receiving cyclophosphamide within 3 months

Active chronic infections (e.g., HIV, hepatitis B virus, hepatitis C virus, mycobacteria); patient with oral steroid-dependent asthma;

Infections requiring intravenous antibiotics within a month or oral antibiotics within two weeks of screening; Patients taking (unwilling or unable to stop) NAC or other antioxidants within 1 month of screening

Patients who participated in the pilot RCT or are taking daily acetaminophen (</= 1 g/day PRN is allowed if documented)

Patients receiving rituximab within 12 months or other biologic therapy within five half-lives

Patients receiving mTOR inhibitors (rapamycin/sirolimus, everolimus)

Patients enrolled in other interventional trials

Healthy subjects serve as controls for in vitro immunological studies

Sites / Locations

  • SUNY Upstate Medical UniversityRecruiting
  • SUNY Upstate Medical UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

NAC

Placebo

Arm Description

2.4 g - 4.8 g of NAC daily starting after 3 month open label titration period.

2.4 g - 4.8 g of placebo per day after 3 month open label titration period.

Outcomes

Primary Outcome Measures

Therapeutic benefit
Positive response on the SLE Responder Index (SRI) in the NAC arm vs placebo
Improvement of disease activity
Improvement of disease activity as measurable by the reduction of SLEDAI or BILAG disease activity scores and the reduction of prednisone usage
Tolerance and safety
Monitor adverse events and tolerance of the study drug

Secondary Outcome Measures

Immunobiological outcomes measurable improved lymphocyte function
Immunobiological outcomes measurable by improved markers of glutathioen depletion, mitochondrial function and activation of T and B lymphocytes

Full Information

First Posted
October 17, 2008
Last Updated
October 17, 2023
Sponsor
State University of New York - Upstate Medical University
Collaborators
Cedars-Sinai Medical Center, University of Rochester, Yale University, Penn State University, Hospital for Special Surgery, New York
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1. Study Identification

Unique Protocol Identification Number
NCT00775476
Brief Title
Treatment of Systemic Lupus Erythematosus (SLE) With N-acetylcysteine
Acronym
NAC
Official Title
Treatment of Systemic Lupus Erythematosus (SLE) With N-acetylcysteine (NAC) (SNAC)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 31, 2022 (Actual)
Primary Completion Date
October 31, 2026 (Anticipated)
Study Completion Date
December 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
State University of New York - Upstate Medical University
Collaborators
Cedars-Sinai Medical Center, University of Rochester, Yale University, Penn State University, Hospital for Special Surgery, New York

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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. We previously discovered the depletion of glutathione in lymphocytes of patients with SLE and associated this metabolic change with the elevation of the mitochondrial transmembrane potential. This study will titrate to tolerance during an initial 3 month open label period and then subjects will be randomized to one of 2 arms. It was determined by statistical analysis that each group must have 105 subjects. All subjects will be enrolled and evaluated for tolerance of NAC between dosages of 2.4 g/day and 4.8 g/day for 3 months. After A 3-month open-label dose-titration phase, SLE subjects will be randomized into 2 groups of 105 subjects either to continue the tolerated dosage of NAC or switched to equal number of placebo capsules. There will be up to seven study visits per SLE subject, including the screening and wash out visits. Visits 2-6 will be scheduled three months apart. The study will last 13 months with the wash-out visit. Each subject will donate approximately 100 ml of blood for biomarker studies 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 biomarker assays. There is a consent form required to participate in the phase II study.
Detailed Description
Subjects will take NAC in a dose range of 2.4 g/day to 4.8 g/day which will be titrated to tolerance during an initial 3-month open label period. After the 3-month open label period, patients in each arm will continue taking equal numbers of capsules representing a dosage that has been titrated to tolerance. As an example, the patients tolerating 2.4 g/day, or 4 capsules containing 600 mg of NAC, after 3 months will be randomized to take 4 NAC or 4 placebo (2.4 g/day dextrose) capsules twice daily for the 9 subsequent months. The primary outcome variable will be the response (yes/no) in the SLE Respinder Index or SRI at Month 12 (reduction ≥ 4 points in SELENA-SLEDAI score and therefore also called SRI-4; no new BILAG A organ domain score and no more than 1 new BILAG B organ domain score; and no worsening in Physician's Global Assessment (PGA) score) by ≥ 0.3 points versus baseline). A positive response will also require no treatment failure, defined as the need for non-protocol treatment, i.e., new or increased immunosuppressives or antimalarials; increased or parenteral corticosteroids; or premature discontinuation from study treatment. Corticosteroids can be tapered off at the investigator's discretion, based on disease activity. Four weeks after randomization, once tapered, corticosteroids can only be increased again to the dosage preceding the last taper step; any larger increase will be deemed a treatment failure. In addition, any increase in corticosteroid dosage during the last 3 months of the trial will result in declaration of treatment failure. We will monitor tolerance and safety, and assess SLEDAI, BILAG, FAS, PROMIS, ASRS, prednisone use, liver and bone marrow function as secondary outcomes.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Systemic Lupus Erythematosus
Keywords
Systemic lupus erythematosus (SLE), an autoimmune disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
This study will titrate to tolerance during an initial 3 month open label period and then subjects will be randomized to one of 2 arms.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
290 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
NAC
Arm Type
Active Comparator
Arm Description
2.4 g - 4.8 g of NAC daily starting after 3 month open label titration period.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
2.4 g - 4.8 g of placebo per day after 3 month open label titration period.
Intervention Type
Drug
Intervention Name(s)
N-acetylcysteine
Intervention Description
Capsules of NAC, each containing 600 mg of NAC between dosages of 2.4 g to 4.8 g daily
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
placebo (sugar) twice daily, daily dosage will match that of NAC that was tolerated between daily dosages of 2.4 g and 4.8 g during the open-label titration phase.
Primary Outcome Measure Information:
Title
Therapeutic benefit
Description
Positive response on the SLE Responder Index (SRI) in the NAC arm vs placebo
Time Frame
12 months
Title
Improvement of disease activity
Description
Improvement of disease activity as measurable by the reduction of SLEDAI or BILAG disease activity scores and the reduction of prednisone usage
Time Frame
12 months
Title
Tolerance and safety
Description
Monitor adverse events and tolerance of the study drug
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Immunobiological outcomes measurable improved lymphocyte function
Description
Immunobiological outcomes measurable by improved markers of glutathioen depletion, mitochondrial function and activation of T and B lymphocytes
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Age > 18 years old. SLE with ≥ 4 of eleven diagnostic criteria approved by the American College of Rheumatology Stable immunosuppressants (MMF ≤ 3 g/day, azathioprine ≤ 100 mg/day; methotrexate ≤ 15 mg/day) and/or antimalarials (hydroxychloroquine ≤ 400 mg/day) for 30 days prior to screening; stable oral corticosteroids for 2 weeks prior to screening; ≤ 20 mg/day prednisone or equivalent; stable belimumab for 90 days prior to screening; BILAG 2004 index level A disease activity in ≥ 1 organ/system except renal or central nervous system or (ii) BILAG 2004 index level B disease activity in ≥ 2 organs/systems if no level A disease activity is present and (iii) SLEDAI ≥ 6; 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) Patients receiving cyclophosphamide within 3 months Active chronic infections (e.g., HIV, hepatitis B virus, hepatitis C virus, mycobacteria); patient with oral steroid-dependent asthma; Infections requiring intravenous antibiotics within a month or oral antibiotics within two weeks of screening; Patients taking (unwilling or unable to stop) NAC or other antioxidants within 1 month of screening Patients who participated in the pilot RCT or are taking daily acetaminophen (</= 1 g/day PRN is allowed if documented) Patients receiving rituximab within 12 months or other biologic therapy within five half-lives Patients receiving mTOR inhibitors (rapamycin/sirolimus, everolimus) Patients enrolled in other interventional trials Healthy subjects serve as controls for in vitro immunological studies
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Andras Perl, M.D., Ph.D.
Phone
(315) 464-4194
Email
perla@upstate.edu
First Name & Middle Initial & Last Name or Official Title & Degree
FNU Ruchi, M.D.
Phone
(315) 464-1779
Email
ruchif@upstate.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andras Perl, M.D., Ph.D.
Organizational Affiliation
State University of New York - Upstate Medical University
Official's Role
Principal Investigator
Facility Information:
Facility Name
SUNY Upstate Medical University
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Andras Perl, M.D., Ph.D.
Phone
315-464-4194
Email
perla@upstate.edu
First Name & Middle Initial & Last Name & Degree
Bryan Blaker, B.S.
Phone
(315) 464-6481
Email
blakerb@upstate.edu
First Name & Middle Initial & Last Name & Degree
Andras Perl, M.D., Ph.D.
First Name & Middle Initial & Last Name & Degree
Jihad Ben Gabr, M.D.
First Name & Middle Initial & Last Name & Degree
Sheetal Rayancha, M.D.
Facility Name
SUNY Upstate Medical University
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bryan Blaker, B.S.
Phone
315-464-6418
Email
blakerb@upstate.edu

12. IPD Sharing Statement

Citations:
PubMed Identifier
33687069
Citation
Hannon CW, McCourt C, Lima HC, Chen S, Bennett C. Interventions for cutaneous disease in systemic lupus erythematosus. Cochrane Database Syst Rev. 2021 Mar 9;3(3):CD007478. doi: 10.1002/14651858.CD007478.pub2.
Results Reference
derived
PubMed Identifier
22549432
Citation
Lai ZW, Hanczko R, Bonilla E, Caza TN, Clair B, Bartos A, Miklossy G, Jimah J, Doherty E, Tily H, Francis L, Garcia R, Dawood M, Yu J, Ramos I, Coman I, Faraone SV, Phillips PE, Perl A. N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2012 Sep;64(9):2937-46. doi: 10.1002/art.34502.
Results Reference
derived

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

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