A Phase 3 interventional study of Leflunomide and Methotrexate-Sulfasalazine-Hydroxychloroquine in Rheumatoid Arthritis, sponsored by University of Nebraska. Completed at 1 site in United States. Open to participants aged 19 Years to 80 Years. Per ClinicalTrials.gov, last updated 2023-10-02.
Sponsored by University of Nebraska · Phase 3, Interventional, and Treatment
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.
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.
3,554 studies on the registry are indexed under Arthritis; 317 are open to participants now.
This study's enrollment of 69 is below the median of 90 across 2,377 interventional studies indexed under Arthritis.
Browse Arthritis studies →University of Nebraska is the lead sponsor of 473 studies on the registry; 66 are open to participants now.
Of its 75 completed or terminated interventional studies of FDA-regulated products, 46 (61%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Group A: Leflunomide alone
Drug: Leflunomide
Methotrexate, Sulfasalazine, Hydroxychloroquine.
Drug: Methotrexate-Sulfasalazine-Hydroxychloroquine
Leflunomide-Sulfasalazine-Hydroxychloroquine
Drug: Leflunomide-Sulfasalazine-Hydroxychloroquine
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
Also known as: Arava®
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).
Also known as: Trexall, Rheumatrex, Azulfidine®, Plaquenil®
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).
Also known as: Arava®, Azulfidine®, Plaquenil®
Measuring the Safety and Efficacy of a New DMARD, Leflunomide Alone or in Combination With Traditional DMARD's. Participants Reaching ACR 20 Response. at 48 Weeks
The combination of Methotrexate-Sulfasalazine-Hydroxychloroquine has been shown to be more effective than Methotrexate alone or the double combination of Methotrexate-Hydroxychloroquine. Primary outcome is ACR 20 response at 48 weeks. An ACR 20 Response is a measure of at least 20% improvement in the number of tender and swollen joints. and a 20% improvement in at least 3 of the following: the patient's global assessment of disease status; the patient's assessment of pain; the patient's assessment of function; the physician's global assessment of disease status; serum C-reactive protein levels.
Time frame: 48 weeks
| Milestone | 1- Leflunomide Alone - vs Combination Therapy | Methotrexate-Sulfasalazine-Hydroxychloroquine | Leflunomide-Sulfasalazine-Hydroxychloroquine |
|---|---|---|---|
| Started | 22 | 23 | 24 |
| Completed | 15 | 20 | 14 |
| Not completed | 7 | 3 | 10 |
The combination of Methotrexate-Sulfasalazine-Hydroxychloroquine has been shown to be more effective than Methotrexate alone or the double combination of Methotrexate-Hydroxychloroquine. Primary outcome is ACR 20 response at 48 weeks. An ACR 20 Response is a measure of at least 20% improvement in the number of tender and swollen joints. and a 20% improvement in at least 3 of the following: the patient's global assessment of disease status; the patient's assessment of pain; the patient's assessment of function; the physician's global assessment of disease status; serum C-reactive protein levels.
| Participants | 1 Leflunomide Alone vs Combination Therapy | Methotrexate-Sulfasalazine-Hydroxychloroquine | Leflunomide-Sulfasalazine-Hydroxychloroquine |
|---|---|---|---|
| Measuring the Safety and Efficacy of a New DMARD, Leflunomide Alone or in Combination With Traditional DMARD's. Participants Reaching ACR 20 Response. at 48 Weeks | 8 | 20 | 12 |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| 1 Leflunomide Alone vs Combination Therapy | — | 1/22 (4.5%) | 1/22 (4.5%) |
| Methotrexate-Sulfasalazine-Hydroxychloroquine | — | 0/23 (0%) | 2/23 (8.7%) |
| Leflunomide-Sulfasalazine-Hydroxychloroquine | — | 0/24 (0%) | 6/24 (25%) |
| Event | 1 Leflunomide Alone vs Combination Therapy | Methotrexate-Sulfasalazine-Hydroxychloroquine | Leflunomide-Sulfasalazine-Hydroxychloroquine |
|---|---|---|---|
| lung carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/22 | 0/23 | 0/24 |
| Event | 1 Leflunomide Alone vs Combination Therapy | Methotrexate-Sulfasalazine-Hydroxychloroquine | Leflunomide-Sulfasalazine-Hydroxychloroquine |
|---|---|---|---|
| GI distressGastrointestinal disorders | 1/22 | 1/23 | 3/24 |
| KeratitisSkin and subcutaneous tissue disorders | 0/22 | 1/23 | 0/24 |
| AlopeciaSkin and subcutaneous tissue disorders | 0/22 | 0/23 | 1/24 |
| DepressionPsychiatric disorders | 0/22 | 0/23 | 1/24 |
| Elevated liver enzymesHepatobiliary disorders | 0/22 | 0/23 | 1/24 |
| Age, Categorical(Participants) | 1- Leflunomide Alone - vs Combination Therapy | Methotrexate-Sulfasalazine-Hydroxychloroquine | Leflunomide-Sulfasalazine-Hydroxychloroquine | Total |
|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 18 | 20 | 19 | 57 |
| >=65 years | 4 | 3 | 5 | 12 |
| Age, Continuous(years) | 1- Leflunomide Alone - vs Combination Therapy | Methotrexate-Sulfasalazine-Hydroxychloroquine | Leflunomide-Sulfasalazine-Hydroxychloroquine | Total |
|---|---|---|---|---|
| Mean | 50 ± 5 | 54 ± 6 | 51 ± 4 | 52 ± 4 |
| Sex: Female, Male(Participants) | 1- Leflunomide Alone - vs Combination Therapy | Methotrexate-Sulfasalazine-Hydroxychloroquine | Leflunomide-Sulfasalazine-Hydroxychloroquine | Total |
|---|---|---|---|---|
| Female | 17 | 12 | 16 | 45 |
| Male | 5 | 11 | 8 | 24 |
| Region of Enrollment(participants) | 1- Leflunomide Alone - vs Combination Therapy | Methotrexate-Sulfasalazine-Hydroxychloroquine | Leflunomide-Sulfasalazine-Hydroxychloroquine | Total |
|---|---|---|---|---|
| United States | 22 | 23 | 24 | 69 |
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