Rheumatoid ArthritisPhase 3NCT00579878
Triple III Comparison of Leflunomide Alone Versus Two DMARD Combinations in the Treatment of Rheumatoid Arthritis
A Phase 3 study testing Leflunomide, Methotrexate-Sulfasalazine-Hydroxychloroquine and Leflunomide-Sulfasalazine-Hydroxychloroquine in people with Rheumatoid Arthritis, run by University of Nebraska at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 19 to 80 years
- Conditions the study is for
- Rheumatoid Arthritis
- What is being tested?
- Leflunomide, Methotrexate-Sulfasalazine-Hydroxychloroquine and Leflunomide-Sulfasalazine-Hydroxychloroquine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 69 participants
- Where
- 1 siteUnited States
- Study dates
- 27 Mar 2001to 11 Mar 2010
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 19 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Nebraska Medical Center
Omaha, Nebraska, 69198-3025
About this study
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.
Read the 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.
- Conditions
- Rheumatoid Arthritis
- Being tested
- Leflunomide, Methotrexate-Sulfasalazine-Hydroxychloroquine, Leflunomide-Sulfasalazine-Hydroxychloroquine
- Medical subject headings
- Arthritis, Rheumatoid
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LeflunomideDrug
Also called Arava®
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-Sulfasalazine-HydroxychloroquineDrug
Also called Trexall, Rheumatrex, Azulfidine®, Plaquenil®
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-Sulfasalazine-HydroxychloroquineDrug
Also called Arava®, 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).
| Study group | Role | What they receive |
|---|---|---|
| Leflunomide alone vs combination therapy | Active comparator | Group A: Leflunomide alone Receives: Drug: Leflunomide |
| Methotrexate-Sulfasalazine-Hydroxychloroquine | Active comparator | Methotrexate, Sulfasalazine, Hydroxychloroquine. Receives: Drug: Methotrexate-Sulfasalazine-Hydroxychloroquine |
| Leflunomide-Sulfasalazine-Hydroxychloroquine | Active comparator | Leflunomide-Sulfasalazine-Hydroxychloroquine Receives: Drug: Leflunomide-Sulfasalazine-Hydroxychloroquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 48 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Dec 2007 (estimated)
- Study start27 Mar 2001
- Primary completion11 Mar 2010
- Study completion11 Mar 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Rheumatoid ArthritisStudies of the same condition, open and under way.
- More trials run by University of NebraskaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 69 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Nebraska
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- James R O'Dell, MD, Principal investigator, University of Nebraska
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00579878
- Sponsor's protocol ID
- 0012-01-FB
- Status last verified
- Sep 2023
- First submitted
- 17 Dec 2007
- Last updated
- 2 Oct 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 2 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00579878
- Acronym / sponsor ID
- 0012-01-FB
- Conditions
- Rheumatoid Arthritis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 69 participants (actual)
- Lead sponsor
- University of NebraskaUniversity, hospital or other
- Study start
- 27 Mar 2001 (actual)
- Primary completion
- 11 Mar 2010 (actual)
- Study completion
- 11 Mar 2010 (actual)
- First posted
- 24 Dec 2007 (estimated)
- Results
- Posted 14 May 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Leflunomide alone vs combination therapy | Active comparator | Drug: LeflunomideGroup A: Leflunomide alone |
| Methotrexate-Sulfasalazine-Hydroxychloroquine | Active comparator | Drug: Methotrexate-Sulfasalazine-HydroxychloroquineMethotrexate, Sulfasalazine, Hydroxychloroquine. |
| Leflunomide-Sulfasalazine-Hydroxychloroquine | Active comparator | Drug: Leflunomide-Sulfasalazine-HydroxychloroquineLeflunomide-Sulfasalazine-Hydroxychloroquine |
Who may qualify
- Ages
- 19 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LeflunomideAlso: Arava®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 | Drug | Leflunomide alone vs combination therapy |
| Methotrexate-Sulfasalazine-HydroxychloroquineAlso: Trexall, Rheumatrex, Azulfidine®, Plaquenil®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). | Drug | Methotrexate-Sulfasalazine-Hydroxychloroquine |
| Leflunomide-Sulfasalazine-HydroxychloroquineAlso: Arava®, 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). | Drug | Leflunomide-Sulfasalazine-Hydroxychloroquine |
Primary outcome
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
Time frame: 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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Oct 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
James R O'Dell, MD principal investigator
University of Nebraska
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Leflunomide, Methotrexate-Sulfasalazine-Hydroxychloroquine and Leflunomide-Sulfasalazine-Hydroxychloroquine in people with Rheumatoid Arthritis, run by University of Nebraska at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 May 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 (time frame: 48 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Oct 2023.