Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis, CNTO 148, Methotrexate, Joint pain, Arthritis
Brief summary
Multicenter, randomized, double-blind, placebo-controlled, 5-arm, dose-ranging study to assess the efficacy of subcutaneous injections of Golimumab (CNTO 148), 50 or 100 mg, at either 2- or 4- week intervals in subjects with active RA despite MTX therapy.
Detailed description
This is an experimental medical research study. The purpose of this study is to determine if Golimumab is safe and effective in the treatment of rheumatoid arthritis. Subjects will receive subcutaneous injections of either 50 or 100 mg Golimumab or placebo every two or four weeks or an infusion of infliximab at week 20, 22, 28, 36, 44 for 48 weeks
Interventions
DRUGGolimumab
Type=exact, unit=mg/ml, number= 50 to 100 , form=powder for solution for infusion, route=sub cutaneous.
DRUGMTX
Type=exact, unit=mg/ml, number= 10, form=powder for solution for infusion, route=sub cutaneous
DRUGPlacebo
Type=exact, unit=mg/ml, form=powder for solution for infusion, route=sub cutaneous
DRUGInfliximab
Type=exact, unit=mg/ml number= 10, form=powder for solution for infusion, route=sub cutaneous
Sponsors
Centocor BV
Centocor, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of RA according to the American College of Rheumatology criteria for at least 3 months prior to screening * Have active Rheumatoid Arthritis at the time of screening and at baseline, as defined by 6 or more swollen joints and 6 or more tender joints and additional laboratory criteria
Exclusion criteria
* Have other inflammatory diseases, including but not limited to ankylosing spondylitis, systemic lupus erythematosus, Lyme disease * Received disease-modifying antirheumatic drugs (\[DMARDs\] eg, D penicillamine, hydroxychloroquine, chloroquine, oral or parenteral gold, interleukin \[IL\]-1 receptor antagonist \[anakinra\], azathioprine, sulphasalazine, agents other than MTX) within 4 weeks prior to the first study dose
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Meeting the American College of Rheumatology 20 (ACR 20) Response at Week 16 | Week 16 | ACR 20 response is a decrease of at least 20 per cent in both tender and swollen joint count and in 3 to 5 assessments (participant's assessment of pain visual analog scale \[VAS\] with 0, no pain to 10, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity \[0, very well to 10, very poor and 0, no arthritis activity to 10, extremely active, respectively\]; Health Assessment Questionnaire \[HAQ\]: 20-questions on life activities \[0, no difficulty to 3, inability to perform a task\]; C-reactive protein\[CRP\]). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of ACR-N, Index of Improvement at Week 16 | Week 16 | The ACR-N index of improvement is the minimum of the following: 1) the percent decrease from baseline in tender joint counts; 2) the percent decrease from baseline in swollen joint counts; 3) the median percent decrease from baseline for the following: a. Patient's assessment of pain as measured on a 10 cm visual assessment scale (0-10, 10 worst pain) Patient's global assessment of disease activity (VAS 0-10); c. Physician's global assessment of disease activity (VAS 0-10) d. Physical function as measured by the Health Assessment Questionnaire; e. C-Reactive Protein measurement. |
Participant flow
Recruitment details
A total of 172 participants were randomly assigned to treatments at 33 sites: 16 in North America (13 in the US and 3 in Canada), 12 in Europe (3 in Belgium, 4 in the UK, 5 in Germany), and 5 in Australia. The study period extended from 01 Dec 2003 to 21 Feb 2006.
Participants by arm
| Arm | Count |
|---|---|
| Group I: Placebo Crossover to Infliximab Placebo subcutaneous (SC) injections every 2 weeks (Wks) from Week (Wk) 0 thru Wk 18 plus Methotrexate (MTX) (Wks 0, 2, 4, 6, 8, 10, 12, 14, 16, and 18); after all study evaluations at Wk 20, open-label infliximab intravenous (IV) infusions: 3 milligrams per kilogram (mg/kg) at Wks 20, 22, 28 and then every 8 Wks thru Wk 44. Continue stable dose of MTX throughout the study. | 35 |
| Group II: Golimumab 50 mg Every 4 Weeks Golimumab (CNTO148) 50 milligram (mg) SC injections every 4 Wks from Wk 0 thru Wk 18 plus MTX (Wks 0, 4, 8, 12, and 16); Placebo SC injections were to be administered at interim visits (Wks 2, 6, 10, 14, and 18) plus MTX. Participants continued at 50 mg of golimumab at Wk 20, and then every 4 Wks thru Wk 48. Continue stable dose of MTX throughout the study. Participants remained blinded thru the end of study. Also referred to as Group II: golimumab 50 mg plus placebo every 4 Wks. | 35 |
| Group III: Golimumab 50 mg Every 2 or 4 Weeks Golimumab 50 mg SC injections every 2 Wks from Wk 0 thru Wk 18 plus MTX (Wks 0, 2, 4, 6, 8, 10, 12, 14, 16, and 18); Participants continued at 50 mg of golimumab at Wk 20, and then every 4 Wks through Wk 48. Continue stable dose of MTX throughout the study. Participants remained blinded thru the end of study. Also referred to as GroupIII: Golimumab 50 mg every 2 or 4 Wks. | 34 |
| Group IV: Golibumab 100 mg Every 4 Weeks Golimumab 100 mg SC injections every 4 Wks thru Wk 18 plus MTX (Wks 0, 4, 8, 12, and 16); Placebo SC injections were to be administered at interim visits (Wks 2, 6, 10, 14, and 18) plus MTX. Participants continued at 100 mg of golimumab at Wk 20, and then every 4 Wks through Wk 48. Continue stable dose of MTX throughout the study. Participants remained blinded through the end of study. Also referred to as Group IV: golimumab 100 mg plus placebo every 4 Wks. | 34 |
| Group V: Golimumab 100 mg Every 2 or 4 Weeks Golimumab 100 mg SC injections every 2 Wks from Wk 0 thru Wk 18 plus MTX (Wks 0, 2, 4, 6, 8, 10, 12, 14, 16, and 18); Participants continued at 100 mg of golimumab at Wk 20, and then every 4 Wks through Wk 48. Continue stable dose of MTX throughout the study. Participants remained blinded thru the end of study. Also referred to as Group V: Golimumab 100 mg every 2 or 4 Wks. | 34 |
| Total | 172 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 2 | 4 | 3 | 1 |
| Overall Study | Other | 3 | 2 | 5 | 1 | 0 |
| Overall Study | Unsatisfactory therapeutic effect | 5 | 3 | 1 | 4 | 4 |
Baseline characteristics
| Characteristic | Group I: Placebo Crossover to Infliximab | Group II: Golimumab 50 mg Every 4 Weeks | Group III: Golimumab 50 mg Every 2 or 4 Weeks | Group IV: Golibumab 100 mg Every 4 Weeks | Group V: Golimumab 100 mg Every 2 or 4 Weeks | Total |
|---|---|---|---|---|---|---|
| Age Continuous | 53.8 Years STANDARD_DEVIATION 12.9 | 56.1 Years STANDARD_DEVIATION 10.5 | 50.4 Years STANDARD_DEVIATION 13.1 | 56.3 Years STANDARD_DEVIATION 12.1 | 54.1 Years STANDARD_DEVIATION 14.1 | 54.2 Years STANDARD_DEVIATION 12.6 |
| Sex: Female, Male Female | 26 Participants | 30 Participants | 23 Participants | 26 Participants | 27 Participants | 132 Participants |
| Sex: Female, Male Male | 9 Participants | 5 Participants | 11 Participants | 8 Participants | 7 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 34 | 34 / 37 | 29 / 32 | 29 / 33 | 33 / 35 |
| serious Total, serious adverse events | 2 / 34 | 7 / 37 | 5 / 32 | 5 / 33 | 5 / 35 |
Outcome results
Primary
Number of Participants Meeting the American College of Rheumatology 20 (ACR 20) Response at Week 16
ACR 20 response is a decrease of at least 20 per cent in both tender and swollen joint count and in 3 to 5 assessments (participant's assessment of pain visual analog scale \[VAS\] with 0, no pain to 10, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity \[0, very well to 10, very poor and 0, no arthritis activity to 10, extremely active, respectively\]; Health Assessment Questionnaire \[HAQ\]: 20-questions on life activities \[0, no difficulty to 3, inability to perform a task\]; C-reactive protein\[CRP\]).
Time frame: Week 16
Population: Intent to treat (ITT). Participants considered non-responder if used any pre-specified prohibited medications or discontinued subcutaneous (SC) study agent due to lack of efficacy. Missing ACR components were imputed by Last Observation Carried Forward (LOCF) unless all ACR components are missing in which case considered non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo Crossover to Infliximab | Number of Participants Meeting the American College of Rheumatology 20 (ACR 20) Response at Week 16 | 13 Participants |
| Group II: Golimumab 50 mg Every 4 Weeks | Number of Participants Meeting the American College of Rheumatology 20 (ACR 20) Response at Week 16 | 21 Participants |
| Group III: Golimumab 50 mg Every 2 or 4 Weeks | Number of Participants Meeting the American College of Rheumatology 20 (ACR 20) Response at Week 16 | 17 Participants |
| Group IV: Golibumab 100 mg Every 4 Weeks | Number of Participants Meeting the American College of Rheumatology 20 (ACR 20) Response at Week 16 | 19 Participants |
| Group V: Golimumab 100 mg Every 2 or 4 Weeks | Number of Participants Meeting the American College of Rheumatology 20 (ACR 20) Response at Week 16 | 27 Participants |
| Combined: Groups II, III, IV & V | Number of Participants Meeting the American College of Rheumatology 20 (ACR 20) Response at Week 16 | 84 Participants |
Comparison: Null hypothesis: No difference in ACR 20 response at Week 16 between combined golimumab groups and Placebo +MTX group. Sample of 35 participants per treatment groups (140 in combined golimumab group and 35 in Placebo +MTX group) provides greater than 90% power assuming 60% golimumab response and 25 % response in Placebo +MTX.p-value: 0.01Cochran-Mantel-Haenszel
Comparison: Null hypothesis: No difference in ACR 20 response at Wk 16 between golimumab 50 mg every 4 weeks and Placebo + MTX. Sample of 35 participants per treatment groups (140 in combined golimumab group and 35 in Placebo +MTX group) provides greater than 90% power assuming 60% golimumab response and 25% response in placebo.p-value: 0.056Cochran-Mantel-Haenszel
Comparison: Null hypothesis: No difference in ACR 20 response at Wk 16 between Golimumab 50 mg every 2 or 4 Weeks and Placebo + MTX. Sample of 35 participants per treatment groups (140 in combined golimumab group and 35 in Placebo +MTX group) provides greater than 90% power assuming 60% golimumab response and 25% response in placebo.p-value: 0.281Cochran-Mantel-Haenszel
Comparison: Null hypothesis: No difference in ACR 20 response at Wk 16 between Golimumab 100 mg every 4 weeks and Placebo + MTX. Sample of 35 participants per treatment groups (140 in combined golimumab group and 35 in Placebo +MTX group) provides greater than 90% power assuming 60% golimumab response and 25% response in placebo.p-value: 0.119Cochran-Mantel-Haenszel
Comparison: Null hypothesis: No difference in ACR 20 response at Wk 16 between Golimumab 100 mg every 2 or 4 Weeks and Placebo + MTX. Sample of 35 participants per treatment groups (140 in combined golimumab group and 35 in Placebo +MTX group) provides greater than 90% power assuming 60% golimumab response and 25% response in placebo.p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Summary of ACR-N, Index of Improvement at Week 16
The ACR-N index of improvement is the minimum of the following: 1) the percent decrease from baseline in tender joint counts; 2) the percent decrease from baseline in swollen joint counts; 3) the median percent decrease from baseline for the following: a. Patient's assessment of pain as measured on a 10 cm visual assessment scale (0-10, 10 worst pain) Patient's global assessment of disease activity (VAS 0-10); c. Physician's global assessment of disease activity (VAS 0-10) d. Physical function as measured by the Health Assessment Questionnaire; e. C-Reactive Protein measurement.
Time frame: Week 16
Population: Intent-to-treat (ITT) and missing ACR components were imputed by LOCF unless all ACR components are missing in which case considered non-responders. The joint evaluability rules were also applied.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Placebo Crossover to Infliximab | Summary of ACR-N, Index of Improvement at Week 16 | 0.0 Scores on scale |
| Group II: Golimumab 50 mg Every 4 Weeks | Summary of ACR-N, Index of Improvement at Week 16 | 37.4 Scores on scale |
| Group III: Golimumab 50 mg Every 2 or 4 Weeks | Summary of ACR-N, Index of Improvement at Week 16 | 19.4 Scores on scale |
| Group IV: Golibumab 100 mg Every 4 Weeks | Summary of ACR-N, Index of Improvement at Week 16 | 22.3 Scores on scale |
| Group V: Golimumab 100 mg Every 2 or 4 Weeks | Summary of ACR-N, Index of Improvement at Week 16 | 35.6 Scores on scale |
| Combined: Groups II, III, IV & V | Summary of ACR-N, Index of Improvement at Week 16 | 33.3 Scores on scale |
Comparison: No difference in ACRn scores measured as percentage of improvement from baseline at Week 16 between Placebo + MTX and combined golimumab groups.p-value: 0.001ANOVA on van der Waerden normal scores.
Comparison: No difference in ACRn scores measured as percentage of improvement from baseline at Week 16 between Placebo + MTX and Golimumab 50 mg every 4 weeksp-value: 0.006ANOVA on van der Waerden normal scores.
Comparison: No difference in ACRn scores measured as percentage of improvement from baseline at Week 16 between Placebo + MTX and Golimumab 50 mg every 2 or 4 Weeksp-value: 0.095ANOVA on van der Waerden normal scores.
Comparison: No difference in ACRn scores measured as percentage of improvement from baseline at Week 16 between Placebo + MTX Golibumab 100 mg every 4 weeksp-value: 0.01ANOVA on van der Waerden normal scores.
Comparison: No difference in ACRn scores measured as percentage of improvement from baseline at Week 16 between Placebo + MTX Golimumab 100 mg every 2 or 4 Weeksp-value: <0.001ANOVA on van der Waerden normal scores.