Triple III Comparison of Leflunomide Alone Versus Two DMARD Combinations in the Treatment of Rheumatoid Arthritis
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Leflunomide; Methotrexate-Sulfasalazine-Hydroxychloroquine; Leflunomide-Sulfasalazine-Hydroxychloroquine
Intervention type(s): Drug; Drug; Drug
Intervention description(s): A loading dose of 100 mg (or placebo) for three (3) days will be given. Following that three-day period, a dose of 20 mg/day will be maintained throughout the remainder of the study. This dose may be decreased to 10 mg/day at the discretion of the treating physician if minor toxicities occur (e.g., diarrhea, liver enzyme elevations; Methotrexate:
dosing starts at 10mg/week (4 tabs/wk). If total remission (according to ACR criteria found in Appendix II) has not been achieved and the labs are acceptable at the 8-week evaluation, the dose increased to 15 mg/week (6 tabs/wk);at the 16-week evaluation, the dose increased to 20 mg/week (8 tabs/wk). This dose will remain stable until the end of the study.
Sulfasalazine: dosing will start at 500 mg bid (1000 mg/day). This dose will remain steady until the 24-week evaluation. If total remission has not been achieved by this time and the labs remain acceptable,dose will be increased to 1000 mg bid (2000 mg/day) Hydroxychloroquine: dosing will be started and maintained throughout the study at 200 mg bid (400 mg/day).; Leflunomide: dose of 100 mg (or placebo) for three (3) days. Followed by a dose of 20 mg/day will be maintained throughout the remainder of the study. dose may be decreased to 10 mg/day at the discretion of the treating physician if minor toxicities occur Sulfasalazine: dosing will start at 500 mg bid (1000 mg/day). This dose will remain steady until the 24-week evaluation. If total remission has not been achieved by this time and the labs remain acceptable, dose will be increased to 1000 mg bid (2000 mg/day) Hydroxychloroquine: dosing will be started and maintained throughout the study at 200 mg bid (400 mg/day).
Other intervention name(s): Arava®; Trexall, Rheumatrex; Azulfidine®; Plaquenil®; Arava®; Azulfidine®; Plaquenil®
Intervention MeSH terms: Hydroxychloroquine; Sulfasalazine; Methotrexate; Leflunomide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment