Trial Outcomes & Findings for Triple III Comparison of Leflunomide Alone Versus Two DMARD Combinations in the Treatment of Rheumatoid Arthritis (NCT NCT00579878)

Last Updated: 2023-10-02

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

69 participants

Primary outcome timeframe

48 weeks

Results posted on

2023-10-02

Participant Flow

No events occurred prior to assignment of study arm treatments.

Participant milestones

Participant milestones
Measure	1- Leflunomide Alone - vs Combination Therapy Group A: Leflunomide alone Leflunomide: 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 Leflunomide: 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-Hydroxychloroquine Methotrexate: Dose will start at 10mg/week. If total remission (according to ACR criteria) has not been achieved and labs are acceptable at the 8-week evaluation, the dosage will be increased to a dose of 15 mg/week Accordingly, if total remission has not been achieved and labs remain acceptable at the 16-week evaluation, the dosage will be increased to the top dose of 20 mg/week 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, the dosage will be increased to the top dose of 1000 mg bid (2000 mg/day) Hydroxychloroquine: Dosing will be started and maintained throughout the study at a dose of 200 mg bid (400 mg/day). Intervention will remain as listed above. Methotrexate-Sulfasalazine-Hydroxychloroquine: Methotrexate: dosing starts at 10mg/week (4 tabs/wk	Leflunomide-Sulfasalazine-Hydroxychloroquine Leflunomide-Sulfasalazine-Hydroxychloroquine: 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).
Overall Study STARTED	22	23	24
Overall Study COMPLETED	15	20	14
Overall Study NOT COMPLETED	7	3	10

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Triple III Comparison of Leflunomide Alone Versus Two DMARD Combinations in the Treatment of Rheumatoid Arthritis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	1- Leflunomide Alone - vs Combination Therapy n=22 Participants Group A: Leflunomide alone Leflunomide: 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 Leflunomide: 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-Hydroxychloroquine n=23 Participants Methotrexate: Dose will start at 10mg/week. If total remission (according to ACR criteria) has not been achieved and labs are acceptable at the 8-week evaluation, the dosage will be increased to a dose of 15 mg/week Accordingly, if total remission has not been achieved and labs remain acceptable at the 16-week evaluation, the dosage will be increased to the top dose of 20 mg/week 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, the dosage will be increased to the top dose of 1000 mg bid (2000 mg/day) Hydroxychloroquine: Dosing will be started and maintained throughout the study at a dose of 200 mg bid (400 mg/day). Intervention will remain as listed above. Methotrexate-Sulfasalazine-Hydroxychloroquine: Methotrexate: dosing starts at 10mg/week (4 tabs/wk	Leflunomide-Sulfasalazine-Hydroxychloroquine n=24 Participants Leflunomide-Sulfasalazine-Hydroxychloroquine: 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).	Total n=69 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	18 Participants n=5 Participants	20 Participants n=7 Participants	19 Participants n=5 Participants	57 Participants n=4 Participants
Age, Categorical >=65 years	4 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants	12 Participants n=4 Participants
Age, Continuous	50 years STANDARD_DEVIATION 5 • n=5 Participants	54 years STANDARD_DEVIATION 6 • n=7 Participants	51 years STANDARD_DEVIATION 4 • n=5 Participants	52 years STANDARD_DEVIATION 4 • n=4 Participants
Sex: Female, Male Female	17 Participants n=5 Participants	12 Participants n=7 Participants	16 Participants n=5 Participants	45 Participants n=4 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	11 Participants n=7 Participants	8 Participants n=5 Participants	24 Participants n=4 Participants
Region of Enrollment United States	22 participants n=5 Participants	23 participants n=7 Participants	24 participants n=5 Participants	69 participants n=4 Participants

PRIMARY outcome

Timeframe: 48 weeks

Population: This will result in a study power of 80%. This power has been calculated assuming an 80% efficacy of the methotrexate-sulfasalazine-hydroxychloroquine combination, an 80% efficacy of the leflunomide-sulfasalazine-hydroxychloroquine combination, and a 40% efficacy of leflunomide alone.

Outcome measures

Outcome measures
Measure	1 Leflunomide Alone vs Combination Therapy n=22 Participants Group A: Leflunomide alone Leflunomide: 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 Leflunomide: 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-Hydroxychloroquine n=23 Participants Methotrexate: start 10mg/wk. If total remission (ACR criteria) not achieved, labs acceptable at 8-wks, dose will increase to 15 mg/wk. If total remission not achieved, labs acceptable at16-wks, dose will increase to 20 mg/wk.Dose will remain stable to end of study. Sulfasalazine: Start at 500mg bid. Dose remain steady to 24-wks. If total remission not achieved and labs acceptable, dose to increase to 1000 mg bid. Hydroxychloroquine: Started and maintain throughout study at 200mg bid Intervention will as listed above. Methotrexate-Sulfasalazine-Hydroxychloroquine: 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 5	Leflunomide-Sulfasalazine-Hydroxychloroquine n=24 Participants Leflunomide-Sulfasalazine-Hydroxychloroquine: 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).
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 Participants	20 Participants	12 Participants

Adverse Events

1 Leflunomide Alone vs Combination Therapy

Serious events: 1 serious events

Other events: 1 other events

Deaths: 0 deaths

Methotrexate-Sulfasalazine-Hydroxychloroquine

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Leflunomide-Sulfasalazine-Hydroxychloroquine

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	1 Leflunomide Alone vs Combination Therapy n=22 participants at risk Group A: Leflunomide alone Leflunomide: 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 Leflunomide: 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-Hydroxychloroquine n=23 participants at risk Methotrexate: start 10mg/wk. If remission (ACR criteria) not achieved, labs acceptable at 8-wks, dose will to 15 mg/wk. If remission not achieved, labs acceptable at16-wk, increase to 20 mg/wk.Dose stable to end of study. Sulfasalazine: Start at 500mg bid. Dose steady to 24-wks. If total remission not achieved/labs acceptable, dose to 1000mg bid. Hydroxychloroquine: Start/maintain throughout study at 200mg bid Intervention will as listed above. Methotrexate-Sulfasalazine-Hydroxychloroquine: Methotrexate: starts 10mg/wk. If total remission (according to ACR criteria) not achieved labs are acceptable at 8-wks, dose increase to 15mg/wk; at 16-wks, dose increase to 20mg/wk. Dose stable until the end of study. Sulfasalazine: start at 500mg bid. Dose steady to 24-wks. If total remission not achieved by this time and labs acceptable, dose will increase to 1000mg bid Hydroxychloroquine; started and maintained throughout the study at 200 mg bid	Leflunomide-Sulfasalazine-Hydroxychloroquine n=24 participants at risk Leflunomide-Sulfasalazine-Hydroxychloroquine: 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).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) lung carcinoma	4.5% 1/22 • Number of events 1	0.00% 0/23	0.00% 0/24

Other adverse events

Other adverse events
Measure	1 Leflunomide Alone vs Combination Therapy n=22 participants at risk Group A: Leflunomide alone Leflunomide: 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 Leflunomide: 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-Hydroxychloroquine n=23 participants at risk Methotrexate: start 10mg/wk. If remission (ACR criteria) not achieved, labs acceptable at 8-wks, dose will to 15 mg/wk. If remission not achieved, labs acceptable at16-wk, increase to 20 mg/wk.Dose stable to end of study. Sulfasalazine: Start at 500mg bid. Dose steady to 24-wks. If total remission not achieved/labs acceptable, dose to 1000mg bid. Hydroxychloroquine: Start/maintain throughout study at 200mg bid Intervention will as listed above. Methotrexate-Sulfasalazine-Hydroxychloroquine: Methotrexate: starts 10mg/wk. If total remission (according to ACR criteria) not achieved labs are acceptable at 8-wks, dose increase to 15mg/wk; at 16-wks, dose increase to 20mg/wk. Dose stable until the end of study. Sulfasalazine: start at 500mg bid. Dose steady to 24-wks. If total remission not achieved by this time and labs acceptable, dose will increase to 1000mg bid Hydroxychloroquine; started and maintained throughout the study at 200 mg bid	Leflunomide-Sulfasalazine-Hydroxychloroquine n=24 participants at risk Leflunomide-Sulfasalazine-Hydroxychloroquine: 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).
Gastrointestinal disorders GI distress	4.5% 1/22 • Number of events 1	4.3% 1/23 • Number of events 1	12.5% 3/24 • Number of events 3
Skin and subcutaneous tissue disorders Alopecia	0.00% 0/22	0.00% 0/23	4.2% 1/24 • Number of events 1
Psychiatric disorders Depression	0.00% 0/22	0.00% 0/23	4.2% 1/24 • Number of events 1
Hepatobiliary disorders Elevated liver enzymes	0.00% 0/22	0.00% 0/23	4.2% 1/24 • Number of events 1
Skin and subcutaneous tissue disorders Keratitis	0.00% 0/22	4.3% 1/23 • Number of events 1	0.00% 0/24

Additional Information

James O'Dell

University of Nebraska Medical Center

Phone: 402 559-7288

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place