Arthritis, Rheumatoid
Conditions
Keywords
Arthritis, Rheumatoid, Active rheumatoid arthritis, Golimumab, CNTO148, Anti-TNFalpha monoclonal antibody, Methotrexate, Intravenous
Brief summary
The purpose of this study is to evaluate clinical effectiveness and safety of golimumab with methotrexate (MTX) in the treatment of rheumatoid arthritis (RA) when compared to MTX alone.
Detailed description
This is a randomized (study medication is assigned by chance), double-blind (neither physician nor participants knows the treatment that the participant receives), placebo-controlled (an inactive substance is compared with a medication to test whether the medication has a real effect in a clinical study), multicenter, 2-arm (2 groups) study of golimumab in participants with active RA despite concurrent MTX therapy. Approximately 564 participants will be randomly allocated to 1 of 2 treatment groups in a 2:1 ratio ie, Group 1(approximately 376 participants will receive golimumab + MTX) and Group 2 (approximately 188 participants will receive MTX + placebo). Total duration of study for each participant is 112 weeks. Safety will be evaluated by assessment of adverse events, tuberculosis testing and blood testing.
Interventions
DRUGGolimumab
Participants will receive 2 mg/kg of golimumab intravenously over 30 ± 10 minutes. Group 1: at Weeks 0, 4, and every 8 weeks thereafter (up to Week 100). Group II: Weeks 24, 28, and every 8 weeks thereafter (up to Week 100); Early escape: at Week 16, 20 and every 8 weeks thereafter (up to Week 100).
OTHERPlacebo
Participants will receive placebo intravenous infusion over 30 ± 10 minutes as: Group I: at Week 16 and 24; Group II: at Weeks 0, 4, 12, 16, and 20; and for early escape: at Week 24.
DRUGmethotrexate (MTX)
Participants will be maintained on their stable dose of commercial MTX (between 15 to 25 mg/week) throughout the study.
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
* Diagnosis of rheumatoid arthritis (RA) for at least 3 months prior to screening * Have been treated with and tolerated methotrexate (MTX) at a dose of at least 15 mg/week for at least 3 months prior to screening, and have been on a stable MTX dose of 15 mg/week to 25 mg/week for at least 4 weeks prior to screening * Have an active RA, as defined by disease activity with at least 6 swollen and 6 tender joints, at the time of screening and at baseline * C-Reactive Protein greater than or equal to 1.0 mg/dL at screening * No history of latent or active tuberculosis prior to screening
Exclusion criteria
* Other inflammatory diseases, including but not limited to psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, or lyme disease * Treated with disease modifying agents (other than methotrexate)/systemic immunosuppressives (eg, D-penicillamine, hydroxychloroquine, chloroquine, oral or parenteral gold, sulfasalazine, leflunomide, azathioprine, cyclosporine, mycophenolate mofetil) during the 4 weeks prior to first administration of study agent * Received intra-articular (in the joint), intramuscular (in the muscle), or intravenous corticosteroids, including adrenocorticotropic hormone, during the 4 weeks prior to first administration of study agent * Known allergy to human immunoglobulin proteins or other components of golimumab * Received any commercial or investigational anti-tumor necrosis factor alpha therapy such as but not exclusively infliximab, golimumab, adalimumab or etanercept
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With an American College of Rheumatology (ACR) 20 Response at Week 14 | Week 14 | An ACR 20 response is defined as a greater than or equal to 20 percent improvement from baseline in: 1. Swollen (66 joints) and tender (68 joints) joint counts; 2. greater than or equal to 20 percentage improvement in at least 3 of the following 5 assessments: a. Participant's assessment of pain by Visual Analog Scale (VAS), (0 \[no pain\] to 10 \[worst pain\]) b. Participant's global assessment of disease activity by VAS c. Physician's global assessment of disease activity by VAS d. Participant's assessment of physical function as measured by the Health Assessment Questionnaire (HAQ) e. C-reactive protein. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Moderate or Good Response in Disease Activity Index Score 28 (DAS28) Using C-reactive Protein (CRP) at Week 14 | Week 14 | DAS28 using CRP is an index to measure the disease activity in participants with rheumatoid arthritis combining tender joints (28 joints), swollen joints (28 joints), CRP, and participant's global assessment of disease activity. The DAS28 score ranges from 0 (best) to 10 (worst). DAS28 score above 5.1 means high disease activity whereas a DAS28 below 3.2 indicates low disease activity. Higher scores indicate worsening. A decrease in DAS28 score \>1.2 is being referred to as a good response and a decrease of 0.6-1.2 as a moderate response. |
| Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 14 | Week 14 | The HAQ is 20-question instrument that assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0 (no difficulty), to 3 (inability to perform a task in that area). HAQscore on a scale ranges from 0 (no disability) to 3 (completely disabled). Higher scores indicate worsening. |
| Proportion of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | Week 24 | An ACR 50 response is defined as a greater than or equal to 50 percent improvement from baseline in: 1. Swollen (66 joints) and tender (68 joints) joint counts; 2. greater than or equal to 50 percentage improvement in 3 of the following 5 assessments: a. Participant's assessment of pain by Visual Analog Scale (VAS) (0-10 cm) b. Participant's global assessment of disease activity by VAS (0-10 cm) c. Physician's global assessment of disease activity by VAS (0-10 cm) d. Participant'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 24. | Week 24 | Total vdH-S score is sum of joint erosion score and joint-space narrowing (JSN) score. Joint erosion score summarizes erosion severity in 32 joints of hands and 12 joints of feet. Each joint scored from 0 (no erosion) to 5 (extensive loss of bone from more than one half of the articulating bone). Maximal erosion score is 280. JSN score summarizes severity of JSN in 30 joints of hands and 12 joints of feet. Assessment of JSN, including subluxation, is scored from 0 (normal) to 4 (bony ankylosis or complete luxation). Maximal JSN score is 168. Thus, the worst possible vdH-S score is 448. |
Countries
Argentina, Australia, Colombia, Hungary, Lithuania, Malaysia, Mexico, New Zealand, Poland, Russia, South Korea, Ukraine, United States
Participant flow
Recruitment details
This study evaluated the efficacy and safety of intravenous administration of Golimumab 2mg/kg + methotrexate (MTX) in patients with Active Rheumatoid Arthritis despite treatment with MTX therapy. It was conducted between 14 September 2009 and 08 February 2013 and recruited participants at 92 sites in 13 countries worldwide.
Pre-assignment details
592 participants were randomly allocated to 2 treatment arms. At Week 16 some participants in Placebo arm switched to Golimumab earlier than the rest at Week 24. Thus, the Adverse Events are presented based upon the time when participants began to receive Golimumab in the following manner: Golimumab from Day 0, from Week 16 and from Week 24.
Participants by arm
| Arm | Count |
|---|---|
| Group I: Placebo + Methotrexate (MTX) Participants randomized to receive their stable dose of commercial MTX (between 15-25 mg/week) and placebo IV infusions at Weeks 0, 4, 12, 16, and 20. Participants will be crossed over to Golimumab 2 mg/kg at Week 24, and receive administrations at Weeks 24, 28 and q8 weeks thereafter up to Week 100. Subjects randomized to Group I (Placebo + MTX) will have the opportunity to enter early escape at Week 16 and initiate Golimumab 2 mg/kg infusions (Weeks 16, 20, and q8 weeks up to Week 100) if they demonstrate a \< 10% improvement in both tender and swollen joint count. | 197 |
| Group II: Golimumab 2 mg/kg + Methotrexate (MTX) Participants randomized to receive 2 mg/kg of Golimumab intravenously at Weeks 0, 4, and q8 weeks up to Week 100. Participants will be maintained on their stable dose of commercial MTX (between 15 and 25 mg/week) throughout the study. Participants will receive a placebo infusion at Week 16 and Week 24 to maintain the blind. | 395 |
| Total | 592 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 32 |
| Overall Study | Death | 2 | 2 |
| Overall Study | Lack of Efficacy | 5 | 7 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Other | 1 | 7 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Withdrawal by Subject | 15 | 16 |
Baseline characteristics
| Characteristic | Group I: Placebo + Methotrexate (MTX) | Group II: Golimumab 2 mg/kg + Methotrexate (MTX) | Total |
|---|---|---|---|
| Age, Continuous | 51.4 years STANDARD_DEVIATION 11.26 | 51.9 years STANDARD_DEVIATION 12.55 | 51.8 years STANDARD_DEVIATION 12.13 |
| Region of Enrollment Argentina | 28 participants | 54 participants | 82 participants |
| Region of Enrollment Australia | 3 participants | 6 participants | 9 participants |
| Region of Enrollment Columbia | 12 participants | 25 participants | 37 participants |
| Region of Enrollment Hungary | 10 participants | 21 participants | 31 participants |
| Region of Enrollment Korea, Republic of | 4 participants | 12 participants | 16 participants |
| Region of Enrollment Lithuania | 20 participants | 44 participants | 64 participants |
| Region of Enrollment Malaysia | 8 participants | 18 participants | 26 participants |
| Region of Enrollment Mexico | 13 participants | 25 participants | 38 participants |
| Region of Enrollment New Zealand | 2 participants | 4 participants | 6 participants |
| Region of Enrollment Poland | 36 participants | 65 participants | 101 participants |
| Region of Enrollment Russian Federation | 23 participants | 46 participants | 69 participants |
| Region of Enrollment Ukraine | 32 participants | 58 participants | 90 participants |
| Region of Enrollment United States | 6 participants | 17 participants | 23 participants |
| Sex: Female, Male Female | 157 Participants | 326 Participants | 483 Participants |
| Sex: Female, Male Male | 40 Participants | 69 Participants | 109 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 34 / 68 | 38 / 121 | 199 / 395 | 271 / 584 |
| serious Total, serious adverse events | 11 / 68 | 17 / 121 | 78 / 395 | 106 / 584 |
Outcome results
Primary
Proportion of Participants With an American College of Rheumatology (ACR) 20 Response at Week 14
An ACR 20 response is defined as a greater than or equal to 20 percent improvement from baseline in: 1. Swollen (66 joints) and tender (68 joints) joint counts; 2. greater than or equal to 20 percentage improvement in at least 3 of the following 5 assessments: a. Participant's assessment of pain by Visual Analog Scale (VAS), (0 \[no pain\] to 10 \[worst pain\]) b. Participant's global assessment of disease activity by VAS c. Physician's global assessment of disease activity by VAS d. Participant's assessment of physical function as measured by the Health Assessment Questionnaire (HAQ) e. C-reactive protein.
Time frame: Week 14
Population: Intent-to-treat: all patients analyzed according to the treatment for which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo + Methotrexate (MTX) | Proportion of Participants With an American College of Rheumatology (ACR) 20 Response at Week 14 | 24.9 Percentage of Participants |
| Group II: Golimumab 2 mg/kg + Methotrexate (MTX) | Proportion of Participants With an American College of Rheumatology (ACR) 20 Response at Week 14 | 58.5 Percentage of Participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 14
The HAQ is 20-question instrument that assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0 (no difficulty), to 3 (inability to perform a task in that area). HAQscore on a scale ranges from 0 (no disability) to 3 (completely disabled). Higher scores indicate worsening.
Time frame: Week 14
Population: Intent-to-treat: all patients analyzed according to the treatment for which they were randomized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group I: Placebo + Methotrexate (MTX) | Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 14 | 0.1250 Scores on a scale | Standard Deviation 0.5577 |
| Group II: Golimumab 2 mg/kg + Methotrexate (MTX) | Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 14 | 0.5000 Scores on a scale | Standard Deviation 0.57706 |
p-value: <0.001ANOVA of van der Waerden scores
Secondary
Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 24.
Total vdH-S score is sum of joint erosion score and joint-space narrowing (JSN) score. Joint erosion score summarizes erosion severity in 32 joints of hands and 12 joints of feet. Each joint scored from 0 (no erosion) to 5 (extensive loss of bone from more than one half of the articulating bone). Maximal erosion score is 280. JSN score summarizes severity of JSN in 30 joints of hands and 12 joints of feet. Assessment of JSN, including subluxation, is scored from 0 (normal) to 4 (bony ankylosis or complete luxation). Maximal JSN score is 168. Thus, the worst possible vdH-S score is 448.
Time frame: Week 24
Population: Intent-to-treat: all patients analyzed according to the treatment for which they were randomized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group I: Placebo + Methotrexate (MTX) | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 24. | 1.09 Scores on a scale | Standard Deviation 3.194 |
| Group II: Golimumab 2 mg/kg + Methotrexate (MTX) | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 24. | 0.03 Scores on a scale | Standard Deviation 1.899 |
p-value: <0.001ANOVA of van der Waerden scores
Secondary
Proportion of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24
An ACR 50 response is defined as a greater than or equal to 50 percent improvement from baseline in: 1. Swollen (66 joints) and tender (68 joints) joint counts; 2. greater than or equal to 50 percentage improvement in 3 of the following 5 assessments: a. Participant's assessment of pain by Visual Analog Scale (VAS) (0-10 cm) b. Participant's global assessment of disease activity by VAS (0-10 cm) c. Physician's global assessment of disease activity by VAS (0-10 cm) d. Participant's assessment of physical function as measured by the Health Assessment Questionnaire (HAQ) e. C reactive protein.
Time frame: Week 24
Population: Intent-to-treat: all patients analyzed according to the treatment for which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo + Methotrexate (MTX) | Proportion of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | 13.2 Percentage of Participants |
| Group II: Golimumab 2 mg/kg + Methotrexate (MTX) | Proportion of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 | 34.9 Percentage of Participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Proportion of Participants With Moderate or Good Response in Disease Activity Index Score 28 (DAS28) Using C-reactive Protein (CRP) at Week 14
DAS28 using CRP is an index to measure the disease activity in participants with rheumatoid arthritis combining tender joints (28 joints), swollen joints (28 joints), CRP, and participant's global assessment of disease activity. The DAS28 score ranges from 0 (best) to 10 (worst). DAS28 score above 5.1 means high disease activity whereas a DAS28 below 3.2 indicates low disease activity. Higher scores indicate worsening. A decrease in DAS28 score \>1.2 is being referred to as a good response and a decrease of 0.6-1.2 as a moderate response.
Time frame: Week 14
Population: Intent-to-treat: all patients analyzed according to the treatment for which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo + Methotrexate (MTX) | Proportion of Participants With Moderate or Good Response in Disease Activity Index Score 28 (DAS28) Using C-reactive Protein (CRP) at Week 14 | 40.1 Percentage of Participants |
| Group II: Golimumab 2 mg/kg + Methotrexate (MTX) | Proportion of Participants With Moderate or Good Response in Disease Activity Index Score 28 (DAS28) Using C-reactive Protein (CRP) at Week 14 | 81.3 Percentage of Participants |
p-value: <0.001Cochran-Mantel-Haenszel