Official Title: “Triple III Comparison of Leflunomide Alone Versus Two DMARD Combinations (Leflunomide-Hydroxychloroquine-Sulfasalazine or Methotrexate-Hydroxychloroquine-Sulfasalazine) in the Treatment of Rheumatoid Arthritis”

The study has been designed as a 48-week, double-blind, randomized, controlled study comparing the use of leflunomide alone to combinations of leflunomide-sulfasalazine-HCQ, and methotrexate-sulfasalazine-HCQ.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Active Control, Parallel Assignment, Safety/Efficacy Study

Objectives: The combination of methotrexate-sulfasalazine-hydroxychloroquine has been shown to be more effective than methotrexate alone or the double combination of methotrexate-sulfasalazine or methotrexate-hydroxychloroquine. The objective of this study is to look at the safety and efficacy of a new DMARD, leflunomide, alone or in combination with traditional DMARDs (sulfasalazine and hydroxychloroquine).

Research Design: This protocol has been designed as a 48 week, double blind, randomized, prospective and controlled. A total of 180 subjects will be enrolled, and randomly assigned to one of three study arms (60 subjects in each arm): 1) leflunomide alone; 2) leflunomide-sulfasalazine-hydroxychloroquine; 3) methotrexate-sulfasalazine-hydroxychloroquine. All subjects will receive an identical number of medications in a combination of active drug and placebo. Patients are further stratified into two groups: methotrexate-naïve (no history of methotrexate); and methotrexate-failure (failed to achieve clinical response at top dose of 20 mg/week for at least 8 weeks).

Methotrexate-naïve patients will start the study at 10 mg/week methotrexate with possible increases at next evaluations dependent on remission criteria. Methotrexate-failure patients will start the study at the top study dose of 20 mg/week and remain at that dose for the entire study.

Methodology: All patients will be recruited from outpatient academic, private practice, and VA rheumatology clinics. Subjects will be between the ages of 19 and 80 years. No pediatric subjects will be enrolled. No enrollment restrictions are based on race, ethnic origin or gender. Inclusion criteria includes: formal diagnosis of rheumatoid arthritis per ACR criteria; disease duration of >6 months; at least 6 swollen and 6 tender joints on examination; and negative urine pregnancy test for premenopausal females. Specific exclusion criteria includes: previous treatment with leflunomide or combination DMARDs; abnormal lab values; history of allergy to sulfa, aspirin or tartrazine; any significant comorbid diseases; and unwillingness to avoid alcohol. Study subjects will return for evaluations every 8 weeks. All patients will be monitored for efficacy and signs of drug toxicity throughout the study by laboratory examination (CBC with platelets, AST or ALT, albumin, creatinine, and erythrocyte sedimentation rate), hand x-rays, retinal examination, and chest x-rays (if indicated). Every six months subjects will be asked to complete the ClinHAQ and SF36 questionnaires, designed to evaluate the effect of RA on daily live (ADLs). Subjects will be withdrawn from the study: due to pregnancy; serious adverse event not alleviated by symptomatic treatment; recurrent toxicity that reappears after treatment or drug suspension; lack of efficacy (20% improvement by week 32); non-compliance with the protocol; or withdrawal of consent. The primary study outcome measures were planned before data collection began.

Clinical Relationship: Rheumatoid arthritis is a chronic disease affecting a large proportion of the population. It produces significant morbidity and may result in premature mortality. The majority of patients with RA remain on disease-modifying agents for less than two years because of toxicity or lack of efficacy. Because of the failure of standard therapies to consistently halt and slow the progression of disease and the incidence of side effects, new approaches are clearly needed.

Primary:

• Measuring the safety and efficacy of a new DMARD, Leflunomide,alone or in combination with traditional DMARD's. 48 weeks Yes

Inclusion Criteria:

• Age greater or 19 years and less than or 80 years old
• Duration of disease greater or equal to 6 months
• Diagnosis of RA with criteria
• Negative urine pregnancy test
• Be capable of understanding and giving written, voluntary informed consent
• Must present with at least six swollen and six tender joints at the screening evaluation

Exclusion Criteria:

• Patients treated previously with leflunomide
• Patients that have been treated with methotrexate in combination with any of the study drugs
• Patients with a history of allergy to, or any history of significant clinical or laboratory adverse experience associated with any of the study drugs
• Doses of oral steroids that are either unstable or greater than 10mg/day
• Stage IV disease or other significant disease including chest x-rays that show evidence of rheumatoid lung disease. Stage IV disease is defined as x-ray evidence of cartilage/bone destruction with fibrous or bony ankylosis; creatinine greater than 2.0mg/dL, AST or ALT greater normal
• Any significant liver, renal , hematologic, pulmonary, cardiovascular disease (including uncontrolled hypertension), any active peptic ulcer disease, or visual problems including a recent decrease in acuity, retinal disease, or macular degeneration
• Patients who are not willing to abstain from alcohol consumption
• Women of childbearing potential who are not practicing a successful method of contraception, or wish to become pregnant
• Patients that are unable to understand the study procedures and/or give written informed consent.

Lead Sponsor: University of Nebraska

University of Nebraska Medical Center

Omaha Nebraska 69198-3025 United States

Overall Clinical Trial Officials and Contacts

James R O'Dell, MD Principal Investigator University of Nebraska  

Information obtained from ClinicalTrials.gov on July 18, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00579878

Study ID Number: IRB # 012-01

ClinicalTrials.gov Identifier: NCT00579878

Health Authority: United States: Food and Drug Administration