Clinical trial NCT00447265: Etanercept for the Treatment of Lupus Nephritis
Official title: A Randomized, Double-Blind, Placebo-Controlled, Phase II, Multi-Center Study for Treatment of Lupus Nephritis by Inhibition of Tumor Necrosis Factor-alpha Using Etanercept
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Lupus Nephritis
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2007-03-14
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune disease in which the body's immune system attacks its own normal tissues. This abnormal autoimmune response can result in damage to many parts of the body, including the skin, joints, lungs, heart, brain, intestines, and kidneys. Kidney problems occur in 60-75 % of lupus patients. The development of lupus-related kidney disease (called lupus nephritis) is associated with an overall worse prognosis.

SLE is usually treated with drugs that try to block inflammation caused by the immune system. These treatments can create their own problems and they do not cure lupus. The drugs that are often used to treat lupus nephritis include prednisone (steroids), cyclophosphamide (Cytoxan), azathioprine (AZA or Imuran), and mycophenolate mofetil (MMF or Cellcept). The main purpose of this study is to evaluate the safety and tolerability of etanercept compared to placebo in combination with standard of care to treat individuals with active lupus nephritis.

Detailed description: Kidney problems associated with lupus nephritis range from asymptomatic protein in the urine to rapidly progressive glomerulonephritis, leading to end-stage renal disease. The goal of therapies is to control kidney manifestations in order to avoid kidney failure, the occurrence of other medical problems and death.

The treatment of lupus nephritis remains problematic. Despite the use of currently available therapies, patients experience disease relapse. Over time, patients develop significant morbidity from the disease as well as from medications used for treatment.

Etanercept, a TNF inhibitor, is proposed as a potential treatment for lupus nephritis. TNF increases the number of reactive B and T cells. TNF levels can be elevated in lupus. Etanercept is believed to work by blocking inflammation, and it is hoped that it will lessen the signs and symptoms of lupus-related kidney disease.

The purpose of this study is to evaluate the safety and tolerability of etanercept compared to placebo in combination with standard therapy to treat individuals with mild or moderately active lupus nephritis.

This study will last 1 year. Participants will be randomly assigned to receive either etanercept or placebo in addition to their regular medications. Participants will self-administer 50 mg etanercept or placebo injections once a week. They will continue receiving their usual treatment with corticosteroids and either MMF, Mycophenolic Acid, or AZA. Treatment with study medication will occur for 24 weeks.

There will be a screening visit followed by a randomization visit, where subjects will receive and learn how to administer the study drug. Subjects will come to the clinic for 9 study visits. A physical exam and blood and urine collection will occur at most study visits. Participants will also be asked to complete a questionnaire on their health at most study visits. Subjects will be contacted by phone 5 times during the 24-week period to assess for adverse events and worsening disease status.

Eligibility criteria: Inclusion Criteria:

* Meets at least 4 of the 11 American College of Rheumatology (ACR) 1982 Revised Criteria for the Classification of SLE
* Active lupus nephritis
* Currently has antibodies to double-stranded DNA (dsDNA)
* Currently receiving treatment consisting of at least 1.5 g/day of MMF OR at least 720 mg/day orally of Mycophenolic Acid OR at least 1.5 mg/kg once per day of AZA for lupus nephritis, for at least 28 days prior to study entry
* Stable medication regimen for at least 4 weeks prior to study entry
* Able and willing to self-administer study drug OR has a designated caregiver at home to administer study drug injections
* Willing to use acceptable forms of contraception for the duration of the study

Exclusion Criteria:

* Moderately severe anemia
* Neutropenia
* Thrombocytopenia
* Blood creatinine levels greater than 3.0 mg/dl
* Positive PPD without ongoing treatment for at least 30 days prior to study entry
* Pulmonary fibrotic changes
* Active infections (e.g., HIV, hepatitis B virus \[HBV\], hepatitis C virus \[HCV\]) and/or serologic evidence of prior exposure to hepatitis B
* Received a live vaccine within 3 months prior to study entry
* Doubled serum creatinine levels within the 3 months prior to study entry OR end-stage kidney disease
* Dialysis-dependent end-stage kidney disease or membranous nephritis
* History of cancer. Individuals with a history of cervical carcinoma in situ and resected basal and squamous cell carcinomas of the skin are not excluded.
* Receiving prednisone greater than 20 mg/day or equivalent corticosteroid treatment
* Pulse intravenous methylprednisolone within 30 days prior to study entry
* Receiving immunosuppressive agents other than prednisone, MMF, Mycophenolic Acid, AZA, or hydroxychloroquine
* Oral or intravenous cyclosporine, leflunomide IVIG, or plasmapheresis within 3 months prior to study entry
* Current or previous cyclophosphamide treatment
* Use of other experimental agent within 90 days prior to study entry
* Severe, progressive, or uncontrolled kidney, liver, blood, stomach, lung, heart, or brain disease. Individuals with any of these conditions that are related to active SLE are not excluded.
* Previous use of rituximab within 12 months prior to study entry
* Previous or current exposure to any of the following: etanercept (Enbrel), adalimumab (Humira), infliximab (Remicade), or anakinra (Kineret)
* Meets New York Heart Association classification of congestive heart failure (CHF) Class III or greater
* History of myocardial infarction or ischemia
* Current or history of substance abuse
* Known hypersensitivity to any component of the study drug
* Poorly controlled or advanced diabetes mellitus
* History of multiple sclerosis, transverse myelitis, optic neuritis, or epilepsy
* History of noncompliance with other therapies
* Pregnancy or breastfeeding

Primary outcomes:
measure: Number of Adverse Events (AEs)Grade 3 or Higher Experienced by Participant During Treatment Phase of Study
timeFrame: 24 Weeks
Secondary outcomes:
measure: Number of Participant Adverse Events (AEs) From Baseline to Early Study Withdrawal Visit
timeFrame: 39 Weeks
measure: Percent of Participants Who Achieved a Renal Response at Week 24
timeFrame: Week 24
measure: Time to Participant's Renal Response
timeFrame: First 24 Weeks of Study Period
measure: Participant Systematic Lupus Erythematosus Disease Activity Index (SLEDAI) Score at Baseline and at Early Study Withdrawal Visit
timeFrame: Baseline, Week 39 (Early Study Withdrawal Visit)
measure: Number of Participants With a C to B Score Change From Baseline to Week 24 in the British Isles Lupus Assessment Group (BILAG) Mucocutaneous Score
timeFrame: Baseline, Week 24
measure: Number of Participants With a B to D Change From Baseline to Week 24 in the British Isles Lupus Assessment Group (BILAG) Musculoskeletal Score
timeFrame: Baseline, Week 24
measure: Number of Participants With an A to B Score Change From Baseline to Week 24 in the British Isles Lupus Assessment Group (BILAG) Renal Score
timeFrame: Baseline, Week 24
measure: Participant Medical Outcome Study Short-Form 36 (SF-36) Physical Component Score at Baseline and Week 24
timeFrame: Baseline, Week 24
measure: Participant Medical Outcome Study Short Form 36 (SF-36) Mental Component Score at Baseline and Week 24
timeFrame: Baseline, Week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado Health Sciences Center
state: Colorado
city: Manhasset
country: United States
facility: Feinstein Institute for Medical Research NS-L1J Health System
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Division of Rheumatology, University of California, San Francisco
name: Maria Dall'Era, MD
role: STUDY_CHAIR
affiliation: Department of Medicine, University of California, San Francisco
name: David Wofsy, MD
role: STUDY_CHAIR
References:
citation: Aringer M, Graninger WB, Steiner G, Smolen JS. Safety and efficacy of tumor necrosis factor alpha blockade in systemic lupus erythematosus: an open-label study. Arthritis Rheum. 2004 Oct;50(10):3161-9. doi: 10.1002/art.20576.
citation: De Rycke L, Baeten D, Kruithof E, Van den Bosch F, Veys EM, De Keyser F. The effect of TNFalpha blockade on the antinuclear antibody profile in patients with chronic arthritis: biological and clinical implications. Lupus. 2005;14(12):931-7. doi: 10.1191/0961203305lu2240rr.
citation: Mor A, Bingham CO 3rd, Barisoni L, Lydon E, Belmont HM. Proliferative lupus nephritis and leukocytoclastic vasculitis during treatment with etanercept. J Rheumatol. 2005 Apr;32(4):740-3.
citation: Scheinfeld N. A comprehensive review and evaluation of the side effects of the tumor necrosis factor alpha blockers etanercept, infliximab and adalimumab. J Dermatolog Treat. 2004 Sep;15(5):280-94. doi: 10.1080/09546630410017275.