Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis, Methotrexate Naïve, subcutaneous injection
Brief summary
The purpose of this study is to evaluate the efficacy and safety of golimumab, alone or in combination with methotrexate, as compared to methotrexate alone in rheumatoid arthritis subjects who have not been previously treated with methotrexate.
Detailed description
Golimumab is a fully human protein (antibody) which binds to tumor necrosis factor (TNFa). TNFa is increased in patients with rheumatoid arthritis (RA), and plays a major role in causing the joint pain, swelling, and damage from RA. Other marketed drugs that target TNFa (anti-TNFa drugs) have been shown to be effective in reducing the symptoms, signs, and joint damage of RA, but have limitations with respect to safety and ease of use. This is a randomized, double-blind, placebo-controlled trial of the efficacy and safety of a new anti-TNFa drug, golimumab, at 2 doses, injected under the skin every 4 weeks, alone or in combination with methotrexate, compared with methotrexate alone, in subjects with active RA who have not been previously treated with methotrexate. The study hypothesis is that golimumab, alone or in combination with methotrexate, will be more effective in treatment of RA than methotrexate alone, as measured by the American College of Rheumatology (ACR) response criteria and change from baseline in van der Heide Modified Sharp (vdH-S) score, without causing unacceptable significant adverse effects. The ACR response criteria were designed to determine the percentage of subjects who have achieved a certain level of improvement in their signs and symptoms of rheumatoid arthritis. The vdH-S score is a measurement of the amount of joint damage in a subject as seen by x-ray. Other secondary measures of effectiveness include the Health Assessment Questionnaire (HAQ), which is a series of questions that measure a subject's impairment in physical function caused by RA. Golimumab 50 mg or 100 mg, or placebo injections under the skin every 4 weeks until Week52. Methotrexate (MTX) or placebo capsules will be given in addition. At Week52, subjects on MTX alone with joint pain or swelling get golimumab 50mg, and all subjects receive golimumab for about 4 more years.
Interventions
SC injections
DRUGPlacebo capsules
Placebo capsules will be filled with microcrystalline cellulose (Avicel PH 102).
DRUGMethotrexate capsules
Methotrexate capsules will be filled with microcrystalline cellulose (Avicel PH 102) and a 2.5 mg methotrexate tablet.
BIOLOGICALGolimumab 50 mg injections
SC injections
BIOLOGICALGolimumab 100 mg injections
SC injections
Sponsors
Schering-Plough
Centocor, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have a diagnosis of rheumatoid arthritis (RA) (according to the revised 1987 criteria of the ACR) for at least 3 months prior to first administration of study agent * Are methotrexate (MTX)-naïve (ie, have not received more than 3 weekly doses of MTX for RA at any time) * Have active RA as defined by persistent disease activity with at least 4 swollen and 4 tender joints, at the time of screening and baseline, and at least 2 of the following 4 criteria: a) C-reactive protein (CRP) \>=1.5 mg/dL at screening or erythrocyte sedimentation rate (ESR) by Westergren method of \>= 28 mm in the first hour at screening or baseline, b)Morning stiffness of \>= 30 minutes at screening and baseline, c)Bone erosion by x-ray and/or MRI prior to first administration of study agent, d)Anti-cyclic citrullinated peptide (anti-CCP) antibody-positive or rheumatoid factor (RF) positive at screening * If using oral corticosteroids, must be on a stable dose equivalent to \<= 10 mg of prednisone/day for at least 2 weeks prior to first administration of study agent.
Exclusion criteria
* Can not have inflammatory diseases other than RA that might confound the evaluation of the benefit of golimumab therapy * No treatment with disease-modifying anti-rheumatic drugs (DMARDs)/systemic immunosuppressives during the 4 weeks prior to the first administration of study agent * No prior treatment with biologic anti-TNF drugs (infliximab, etanercept, adalimumab) * No history of, or ongoing, chronic or recurrent infectious disease * No serious infection within 2 months prior to first administration of study agent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | Week 24 | ACR 50 response is defined as a greater than or equal to 50 percent improvement from baseline in: 1. Swollen joint count (66 joints) and tender joint count (68 joints) 2. greater than or equal to 50 percentage improvement in 3 of the following 5 assessments: a. Patient's assessment of pain by the Visual Analogue Scale (VAS) (0-10 cm) b.Patient's Global Assessment of Disease activity VAS (0-10 cm) c. Physician's Global Assessment of Disease Activity VAS (0-10 cm) d. Patient's assessment of physical function as measured by the Health Assessment Questionnaire (HAQ) e. C reactive protein. |
| Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 | Baseline and Week 52 | The vdH-S score is the sum of the joint erosion score and the joint-space narrowing (JSN) score. The total score ranges from 0 (best) to 448 (worst) with higher scores indicating more joint damage. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 24 | Week 24 | ACR 20 response is defined as a greater than or equal to 20 percent improvement from baseline in: 1. Swollen joint count (66 joints) and tender joint count (68 joints) 2. greater than or equal to 20 percentage improvement in 3 of the following 5 assessments: a. Patient's assessment of pain by the Visual Analogue Scale (VAS) (0-10 cm) b.Patient's Global Assessment of Disease activity VAS (0-10 cm) c. Physician's Global Assessment of Disease Activity VAS (0-10 cm) d. Patient's assessment of physical function as measured by the Health Assessment Questionnaire (HAQ) e. C reactive protein. |
| Number of Patients With Abnormal Baseline C-reactive Protein (CRP) Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | Week 24 | ACR 50 response is defined as a greater than or equal to 50 percent improvement from baseline in: 1. Swollen joint count (66 joints) and tender joint count (68 joints) 2. greater than or equal to 50 percentage improvement in 3 of the following 5 assessments: a. Patient's assessment of pain by the Visual Analogue Scale (VAS) (0-10 cm) b.Patient's Global Assessment of Disease activity VAS (0-10 cm) c. Physician's Global Assessment of Disease Activity VAS (0-10 cm) d. Patient's assessment of physical function as measured by the Health Assessment Questionnaire (HAQ) e. C reactive protein. |
| Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 in Patients With Abnormal C-reactive Protein (CRP Greater Than 1.0 mg/dL) at Baseline | Baseline and Week 52 | The vdH-S score is the sum of the joint erosion score and the joint-space narrowing (JSN) score. The total score ranges from 0 (best) to 448 (worst) with higher scores indicating more joint damage. |
Countries
Argentina, Australia, Austria, Belgium, Canada, Chile, Hungary, India, Malaysia, New Zealand, Philippines, Poland, Russia, Singapore, South Korea, Spain, Taiwan, Thailand, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 637 participants were enrolled at 90 centers: 25 sites in Asia, 34 sites in Europe/Australia/New Zealand, 10 sites in Latin America and 21 sites in North America.
Participants by arm
| Arm | Count |
|---|---|
| Group 1: Placebo + Methotrexate Placebo subcutaneous injections (SC) every 4 weeks from Week 0 for up to 5 years (unless early escape at week 28); Methotrexate - 10 to 20 mg weekly from Week 0 for up to 5 years; Golimumab - if early escape, 50 mg SC injections every 4 weeks from Week 28 up to 5 years; Golimumab - Dr's discretion after unblinding (in participants receiving methotrexate plus placebo), 50 mg SC injections every 4 weeks up to 5 years; Golimumab- Dr's discretion after unblinding, dose adjusted from 50 to 100 mg and from 100 to 50mg. Duration of the blinded period was until the week-52 database lock. | 160 |
| Group 2: Golimumab 100 mg + Placebo Golimumab 100 mg SC injections every 4 weeks from Week 0 for up to 5 years; placebo capsules weekly from Week 0 for up to 5 years (unless early escape at Week 28); Methotrexate - if early escape, 10 to 20 mg weekly from Week 28 up to 5 years; Methotrexate - Dr's discretion after unblinding (in participants receiving golimumab plus placebo) 10 to 20 mg weekly for up to 5 years; Golimumab - Dr's discretion after unblinding, dose adjusted from 100 to 50mg. Duration of the blinded period was until the week-52 database lock. | 159 |
| Group 3: Golimumab 50 mg + Methotrexate Golimumab 50 mg SC injections every 4 weeks from Week 0 for up to 5 years (unless early escape at week 28); Methotrexate - 10 to 20 mg weekly from Week 0 for up to 5 years; Golimumab - if early escape, 100 mg SC injections every 4 weeks from Week 28 for up to 5 yrs; Golimumab - Dr's discretion after unblinding, dose adjusted from 50 to 100 mg and from 100 to 50mg. Duration of the blinded period was until the week-52 database lock. | 159 |
| Group 4: Golimumab 100 mg + Methotrexate Golimumab 100 mg SC injections every 4 weeks from Week 0 for up to 5 years; Methotrexate - 10 to 20 mg weekly from Week 0 for up to 5 years; Golimumab - Dr's discretion after unblinding, dose adjusted from 100 to 50mg. Duration of the blinded period was until the week-52 database lock. | 159 |
| Total | 637 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 21 | 32 | 24 | 34 |
| Overall Study | Death | 0 | 3 | 3 | 2 |
| Overall Study | Lost to Follow-up | 3 | 4 | 7 | 6 |
| Overall Study | Not treated | 0 | 2 | 1 | 0 |
| Overall Study | Other | 21 | 11 | 10 | 11 |
| Overall Study | Unsatisfactory therapeutic effect | 5 | 6 | 5 | 7 |
Baseline characteristics
| Characteristic | Group 1: Placebo + Methotrexate | Group 2: Golimumab 100 mg + Placebo | Group 3: Golimumab 50 mg + Methotrexate | Group 4: Golimumab 100 mg + Methotrexate | Total |
|---|---|---|---|---|---|
| Age, Continuous | 48.6 years STANDARD_DEVIATION 12.91 | 48.2 years STANDARD_DEVIATION 12.85 | 50.9 years STANDARD_DEVIATION 11.32 | 50.2 years STANDARD_DEVIATION 11.87 | 49.5 years STANDARD_DEVIATION 12.28 |
| Sex: Female, Male Female | 134 Participants | 134 Participants | 135 Participants | 125 Participants | 528 Participants |
| Sex: Female, Male Male | 26 Participants | 25 Participants | 24 Participants | 34 Participants | 109 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 139 / 172 | 215 / 243 | 174 / 201 |
| serious Total, serious adverse events | 55 / 172 | 94 / 243 | 55 / 201 |
Outcome results
Primary
Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52
The vdH-S score is the sum of the joint erosion score and the joint-space narrowing (JSN) score. The total score ranges from 0 (best) to 448 (worst) with higher scores indicating more joint damage.
Time frame: Baseline and Week 52
Population: All participants randomly assigned to each treatment group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Placebo + Methotrexate | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 | 1.37 Scores on a scale | Standard Deviation 4.555 |
| Group 2: Golimumab 100 mg + Placebo | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 | 1.25 Scores on a scale | Standard Deviation 6.155 |
| Group 3: Golimumab 50 mg + Methotrexate | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 | 0.74 Scores on a scale | Standard Deviation 5.233 |
| Group 4: Golimumab 100 mg + Methotrexate | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 | 0.07 Scores on a scale | Standard Deviation 1.833 |
| Combined Golimumab + Methotrexate | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 | 0.41 Scores on a scale | Standard Deviation 3.929 |
Comparison: Null Hypothesis: No difference in vdH-S score comparing Groups 1 vs Groups 3 and 4 combined. The sample size of 150 subjects in each treatment group (Group 1, Group 3, Group 4) will provide \> 95% power to detect a difference in the vdH-S score between treatment groups using a 2-sided t-test on van der Waerden normal scores of change from baseline in vdH-S score at α = 0.05, assuming a mean change from baseline in vdH-S score of 3.5 for the placebo group and 1 for Groups 3 and 4.p-value: 0.006ANOVA
Comparison: Null hypothesis: No difference in vdH-S score comparing Groups 1 vs 3.p-value: 0.015ANOVA
Comparison: Null hypothesis: No difference in vdH-S score comparing Groups 1 vs 4.p-value: 0.025ANOVA
Primary
Number of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24
ACR 50 response is defined as a greater than or equal to 50 percent improvement from baseline in: 1. Swollen joint count (66 joints) and tender joint count (68 joints) 2. greater than or equal to 50 percentage improvement in 3 of the following 5 assessments: a. Patient's assessment of pain by the Visual Analogue Scale (VAS) (0-10 cm) b.Patient's Global Assessment of Disease activity VAS (0-10 cm) c. Physician's Global Assessment of Disease Activity VAS (0-10 cm) d. Patient's assessment of physical function as measured by the Health Assessment Questionnaire (HAQ) e. C reactive protein.
Time frame: Week 24
Population: All participants randomly assigned to each treatment group. Participants considered non-responders if used any prohibited medications or discontinued subcutaneous study agent due to lack of efficacy. Missing ACR components imputed by Last Observation Carried Forward unless all ACR components were missing; in which case considered non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Placebo + Methotrexate | Number of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | 47 Participants |
| Group 2: Golimumab 100 mg + Placebo | Number of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | 52 Participants |
| Group 3: Golimumab 50 mg + Methotrexate | Number of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | 64 Participants |
| Group 4: Golimumab 100 mg + Methotrexate | Number of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | 58 Participants |
| Combined Golimumab + Methotrexate | Number of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | 122 Participants |
Comparison: Null hypothesis: No difference in ACR 50 response comparing Group 1 vs combined Groups 3 and 4. The sample size of 150 patients per treatment group will provide \>98% power to detect a difference in ACR 50 response between treatment groups at alpha=0.05, assuming 50% of patients with screening C-reactive protein (CRP)\<1.5mg/dL, and the difference in ACR 50 response of 15-20% in patients with screening CRP\<1.5mg/dL and 20-25% in subjects with screening CRP\>=1.5mg/dL, between Groups 1 vs 3 or 4p-value: 0.053Cochran-Mantel-Haenszel
Comparison: Null hypothesis: No difference in ACR 50 response comparing Groups 1 vs 3.p-value: 0.042Cochran-Mantel-Haenszel
Comparison: Null hypothesis: No difference in ACR 50 response comparing Groups 1 vs 4.p-value: 0.177Cochran-Mantel-Haenszel
Comparison: Null hypothesis: Group 2 is inferior to Group 1. Noninferiority of golimumab will be demonstrated if the lower bound of the 2-sided 95% CI is above -10%. The 10% non-inferiority margin was chosen because this difference is not clinically admissible. Under the above noted assumed response rates, this corresponds to preservation of at least 70% \[(33% - 10%)/33%\*100\] of the expected MTX benefit.p-value: 0.521Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 in Patients With Abnormal C-reactive Protein (CRP Greater Than 1.0 mg/dL) at Baseline
The vdH-S score is the sum of the joint erosion score and the joint-space narrowing (JSN) score. The total score ranges from 0 (best) to 448 (worst) with higher scores indicating more joint damage.
Time frame: Baseline and Week 52
Population: All participants randomly assigned to each treatment group who had C-reactive protein \> 1.0 mg/dl at baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Placebo + Methotrexate | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 in Patients With Abnormal C-reactive Protein (CRP Greater Than 1.0 mg/dL) at Baseline | 2.16 Scores on a scale | Standard Deviation 5.642 |
| Group 2: Golimumab 100 mg + Placebo | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 in Patients With Abnormal C-reactive Protein (CRP Greater Than 1.0 mg/dL) at Baseline | 2.19 Scores on a scale | Standard Deviation 7.967 |
| Group 3: Golimumab 50 mg + Methotrexate | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 in Patients With Abnormal C-reactive Protein (CRP Greater Than 1.0 mg/dL) at Baseline | 1.29 Scores on a scale | Standard Deviation 6.991 |
| Group 4: Golimumab 100 mg + Methotrexate | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 in Patients With Abnormal C-reactive Protein (CRP Greater Than 1.0 mg/dL) at Baseline | 0.16 Scores on a scale | Standard Deviation 2.195 |
| Combined Golimumab + Methotrexate | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 in Patients With Abnormal C-reactive Protein (CRP Greater Than 1.0 mg/dL) at Baseline | 0.74 Scores on a scale | Standard Deviation 5.235 |
p-value: 0.003ANOVA
p-value: 0.01ANOVA
p-value: 0.014ANOVA
p-value: 0.545ANOVA
Secondary
Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 24
ACR 20 response is defined as a greater than or equal to 20 percent improvement from baseline in: 1. Swollen joint count (66 joints) and tender joint count (68 joints) 2. greater than or equal to 20 percentage improvement in 3 of the following 5 assessments: a. Patient's assessment of pain by the Visual Analogue Scale (VAS) (0-10 cm) b.Patient's Global Assessment of Disease activity VAS (0-10 cm) c. Physician's Global Assessment of Disease Activity VAS (0-10 cm) d. Patient's assessment of physical function as measured by the Health Assessment Questionnaire (HAQ) e. C reactive protein.
Time frame: Week 24
Population: All participants randomly assigned to each treatment group. Participants considered non-responders if used any prohibited medications or discontinued subcutaneous study agent due to lack of efficacy. Missing ACR components imputed by Last Observation Carried Forward unless all ACR components were missing; in which case considered non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Placebo + Methotrexate | Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 24 | 79 Participants |
| Group 2: Golimumab 100 mg + Placebo | Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 24 | 82 Participants |
| Group 3: Golimumab 50 mg + Methotrexate | Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 24 | 98 Participants |
| Group 4: Golimumab 100 mg + Methotrexate | Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 24 | 98 Participants |
| Combined Golimumab + Methotrexate | Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 24 | 196 Participants |
p-value: 0.011Cochran-Mantel-Haenszel
p-value: 0.028Cochran-Mantel-Haenszel
p-value: 0.028Cochran-Mantel-Haenszel
p-value: 0.677Cochran-Mantel-Haenszel
Secondary
Number of Patients With Abnormal Baseline C-reactive Protein (CRP) Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24
ACR 50 response is defined as a greater than or equal to 50 percent improvement from baseline in: 1. Swollen joint count (66 joints) and tender joint count (68 joints) 2. greater than or equal to 50 percentage improvement in 3 of the following 5 assessments: a. Patient's assessment of pain by the Visual Analogue Scale (VAS) (0-10 cm) b.Patient's Global Assessment of Disease activity VAS (0-10 cm) c. Physician's Global Assessment of Disease Activity VAS (0-10 cm) d. Patient's assessment of physical function as measured by the Health Assessment Questionnaire (HAQ) e. C reactive protein.
Time frame: Week 24
Population: Randomized participants with abnormal baseline CRP. Participants considered non-responders if used any prohibited medications or discontinued subcutaneous study agent due to lack of efficacy. Missing ACR components imputed by Last Observation Carried Forward unless all ACR components were missing; in which case considered non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Placebo + Methotrexate | Number of Patients With Abnormal Baseline C-reactive Protein (CRP) Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | 34 Participants |
| Group 2: Golimumab 100 mg + Placebo | Number of Patients With Abnormal Baseline C-reactive Protein (CRP) Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | 26 Participants |
| Group 3: Golimumab 50 mg + Methotrexate | Number of Patients With Abnormal Baseline C-reactive Protein (CRP) Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | 38 Participants |
| Group 4: Golimumab 100 mg + Methotrexate | Number of Patients With Abnormal Baseline C-reactive Protein (CRP) Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | 37 Participants |
| Combined Golimumab + Methotrexate | Number of Patients With Abnormal Baseline C-reactive Protein (CRP) Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | 75 Participants |
p-value: 0.178Cochran-Mantel-Haenszel
p-value: 0.25Cochran-Mantel-Haenszel
p-value: 0.24Cochran-Mantel-Haenszel
p-value: 0.339Cochran-Mantel-Haenszel