Arthritis, Rheumatoid
Conditions
Keywords
Rheumatoid Arthritis, Anti-TNFa agents, subcutaneous injection
Brief summary
The purpose of this study is to evaluate the efficacy and safety of golimumab (CNTO 148) in subjects who have active rheumatoid arthritis and have been treated previously with at least 1 dose of a biologic anti-TNFa agent (etanercept, adalimumab or infliximab).
Detailed description
Golimumab is a fully human protein (antibody) which binds to tumor necrosis factor-alpha (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 in subjects with active RA previously treated with at least 1 dose of a biologic anti-TNFa agent (etanercept, adalimumab or infliximab). Concomitant therapy with methotrexate, sulfasalazine and/or hydroxychloroquine is permitted if the subject has tolerated these medications for at least 12 weeks prior to the first administration of study drug and is on a stable dose for at least 4 weeks prior to the first administration of study agent. The study hypothesis is that golimumab will be a safe and effective treatment for RA in subjects with active RA previously treated with at least one biologic anti-TNFa agent as measured by the American College of Rheumatology (ACR) response criteria, the Disease Activity Score 28 (DAS28) responses and the change from baseline in Health Assessment Questionnaire (HAQ), without causing unacceptable significant adverse effects. The ACR response criteria were designed to assess the level of improvement in the signs and symptoms of RA. The DAS28 responses also measure improvement in the signs and symptoms of RA using the joint examination and laboratory testing. The HAQ is a series of questions that measure a subject's impairment in physical function caused by RA. Patients will receive golimumab 50 mg or 100 mg or placebo injections under the skin every 4 weeks until Week 24. After Week 24, all subjects receive golimumab 50 mg or 100 mg injections, and golimumab continues for all groups every 4 weeks for about 4 and a half more years.
Interventions
DRUGPlacebo
SC injections
BIOLOGICALGolimumab 50 mg
SC injections
BIOLOGICALGolimumab 100 mg
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
* Patients have a diagnosis of rheumatoid arthritis (RA) (according to the revised 1987 criteria of the ACR) for at least 3 months prior to screening * 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 * Must have been previously treated with at least one dose of etanercept, adalimumab, or infliximab * If currently using methotrexate, sulfasalazine and/or hydroxychloroquine must have tolerated these agents for at least 12 weeks and be on a stable dose for at least 4 weeks prior to the first administration of study agent * If using NSAIDs or other analgesics must be on a stable dose for at least 2 weeks prior to the first administration of study agent * 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 * Are considered eligible according to specified tuberculosis (TB) screening criteria.
Exclusion criteria
* Patients cannot have other inflammatory diseases other than RA that might interfere with the evaluation of the benefit of golimumab therapy * No history of treatment with natalizumab, rituximab or cytotoxic agents * No history of demyelinating diseases such as multiple sclerosis or optic neuritis or of concurrent congestive heart failure (CHF), lymphoproliferative disease, known malignancy or history of malignancy within the previous 5 years (with the exception of a nonmelanoma skin cancer that has been treated with no evidence of recurrence) * 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 |
|---|---|---|
| American College of Rheumatology (ACR) 20 Response at Week 14. | Week 14 | ACR 20 response is an improvement of \>= 20% from baseline in both the tender and swollen joint count and in at least 3 of the 5 assessments ( patient's assessment of pain visual analog scale (VAS), patient's global assessment of disease activity VAS scale, Physician's global assessment of disease activity VAS scale, Health Assessment Questionnaire and C-reactive protein) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| American College of Rheumatology (ACR) 50 Response at Week 14 | Week 14 | Number of patients who achieved an ACR 50 response at Week (Wk) 14. ACR 50 response is an improvement of \>= 50% from baseline in both the tender and swollen joint count and in at least 3 of the 5 assessments ( patient's assessment of pain visual analog scale (VAS), patient's global assessemnt of disease activity VAS scale, Physician's global assessment of disease activity VAS scale, Health Assessment Questionnaire and C-reactive protein). |
| Disease Activity Index Score 28 (DAS 28) (Using C-reactive Protein) Response at Week 14 | Week 14 | DAS 28 using C-reactive protein (CRP) is an index to measure disease activity in participants with rheumatoid arthritis which combines tender joint count (28 joints), swollen joint count (28 joints), CRP value, and participant's global assessment of disease activity (using a Visual Analog Scale of 0 to 100 mm). The DAS 28 score ranges from 0 (best) to 10 (worst). |
| American College of Rheumatology (ACR) 20 at Week 24 | From Baseline to Week 24 | Number of patients who achieved ACR 20 response at Week (Wk) 24. ACR 20 response is an improvement of \>= 20% from baseline in both the tender and swollen joint count and in at least 3 of the 5 assessments ( patient's assessment of pain visual analog scale (VAS), patient's global assessemnt of disease activity VAS scale, Physician's global assessment of disease activity VAS scale,HAQ and CRP) |
| Health Assessment Questionnaire (HAQ) Score at Week 24 | From Baseline to Week 24 | Improvement from baseline in HAQ score at Week 24. This 20-question instrument 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, indicating no difficulty, to 3, indicating inability to perform a task in that area based on the worst score from the questions that pertain to that task. The HAQ score is determined by the average of the 8 scores; HAQ ranges from 0 to 3. |
Countries
Australia, Austria, Canada, Finland, Germany, Netherlands, New Zealand, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 461 participants were enrolled at 86 sites in North America, Europe, Australia and New Zealand.
Participants by arm
| Arm | Count |
|---|---|
| Group 1: Placebo Placebo Subcutaneous (SC) injections every 4 weeks (wks) thru Wk 20 (unless early escape at Wk 16); Golimumab - if early escape, 50 mg SC injections from Wk 16 up to 5 yrs; Golimumab - 50 mg SC injections beginning Wk 24 up to 5 yrs (unless early escape); 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-24 database lock. | 155 |
| Group 2: Golimumab 50 mg Golimumab 50 mg SC injections every 4 wks from Wk 0 up to 5 yrs (unless early escape at Wk 16); Golimumab - if early escape, 100 mg SC injections every 4 wks beginning Wk 16 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-24 database lock. | 153 |
| Group 3: Golimumab 100 mg Golimumab 100 mg SC injections every 4 wks from Wk 0 up to 5 yrs; Golimumab - Dr's discretion after unblinding, dose adjusted from 100 to 50 mg. Duration of the blinded period was until the week-24 database lock. | 153 |
| Total | 461 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 37 | 22 | 27 |
| Overall Study | Death | 3 | 2 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 | 5 |
| Overall Study | Not treated | 0 | 1 | 1 |
| Overall Study | Other | 24 | 26 | 19 |
| Overall Study | Unsatisfactory therapeutic effect | 34 | 39 | 34 |
Baseline characteristics
| Characteristic | Group 1: Placebo | Group 2: Golimumab 50 mg | Group 3: Golimumab 100 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 54.8 years STANDARD_DEVIATION 13.07 | 53.9 years STANDARD_DEVIATION 11.47 | 53.7 years STANDARD_DEVIATION 12.26 | 54.1 years STANDARD_DEVIATION 12.27 |
| Sex: Female, Male Female | 132 Participants | 113 Participants | 122 Participants | 367 Participants |
| Sex: Female, Male Male | 23 Participants | 40 Participants | 31 Participants | 94 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 | 76 / 98 | 117 / 138 | 172 / 195 |
| serious Total, serious adverse events | 34 / 98 | 46 / 138 | 71 / 195 |
Outcome results
Primary
American College of Rheumatology (ACR) 20 Response at Week 14.
ACR 20 response is an improvement of \>= 20% from baseline in both the tender and swollen joint count and in at least 3 of the 5 assessments ( patient's assessment of pain visual analog scale (VAS), patient's global assessment of disease activity VAS scale, Physician's global assessment of disease activity VAS scale, Health Assessment Questionnaire and C-reactive protein)
Time frame: Week 14
Population: Randomized participants (excluding 1 site). 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 | American College of Rheumatology (ACR) 20 Response at Week 14. | 27 participants |
| Group 2: Golimumab 50 mg | American College of Rheumatology (ACR) 20 Response at Week 14. | 51 participants |
| Group 3: Golimumab 100 mg | American College of Rheumatology (ACR) 20 Response at Week 14. | 54 participants |
| Combined Golimumab | American College of Rheumatology (ACR) 20 Response at Week 14. | 105 participants |
Comparison: Null hypothesis: No difference in ACR 20 response at Wk 14 comparing Group 1 vs. Combined Groups 2 and 3. A sample size of 140 patients per group provides a \>90% power assuming 50% of patients used Methotrexate (MTX) at baseline and 30% ACR 20 response in placebo and 40\~55% ACR 20 response in golimumab groups.p-value: <0.001Cochran-Mantel-Haenszel
Comparison: Null Hypothesis: No difference in ACR 20 response at Wk 14 between Group 1: Placebo and Group 2: 50 mg.p-value: 0.001Cochran-Mantel-Haenszel
Comparison: Null Hypothesis: No difference in ACR 20 response at Wk 14 between Group 1: Placebo and Group 3 :100 mg.p-value: <0.001Cochran-Mantel-Haenszel
Secondary
American College of Rheumatology (ACR) 20 at Week 24
Number of patients who achieved ACR 20 response at Week (Wk) 24. ACR 20 response is an improvement of \>= 20% from baseline in both the tender and swollen joint count and in at least 3 of the 5 assessments ( patient's assessment of pain visual analog scale (VAS), patient's global assessemnt of disease activity VAS scale, Physician's global assessment of disease activity VAS scale,HAQ and CRP)
Time frame: From Baseline to Week 24
Population: Randomized participants (excluding 1 site). Participants considered non-responders if used any prohibited medications or discontinued SC study agent due to lack of efficacy. Missing ACR components imputed by LOCF unless all components were missing; in which case considered non-responders. Wk 16 ACR response used for change in study tx.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Placebo | American College of Rheumatology (ACR) 20 at Week 24 | 24 participants |
| Group 2: Golimumab 50 mg | American College of Rheumatology (ACR) 20 at Week 24 | 46 participants |
| Group 3: Golimumab 100 mg | American College of Rheumatology (ACR) 20 at Week 24 | 63 participants |
| Combined Golimumab | American College of Rheumatology (ACR) 20 at Week 24 | 109 participants |
p-value: <0.001Cochran-Mantel-Haenszel
p-value: 0.002Cochran-Mantel-Haenszel
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
American College of Rheumatology (ACR) 50 Response at Week 14
Number of patients who achieved an ACR 50 response at Week (Wk) 14. ACR 50 response is an improvement of \>= 50% from baseline in both the tender and swollen joint count and in at least 3 of the 5 assessments ( patient's assessment of pain visual analog scale (VAS), patient's global assessemnt of disease activity VAS scale, Physician's global assessment of disease activity VAS scale, Health Assessment Questionnaire and C-reactive protein).
Time frame: Week 14
Population: Randomized participants (excluding 1 site). 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 | American College of Rheumatology (ACR) 50 Response at Week 14 | 10 participants |
| Group 2: Golimumab 50 mg | American College of Rheumatology (ACR) 50 Response at Week 14 | 22 participants |
| Group 3: Golimumab 100 mg | American College of Rheumatology (ACR) 50 Response at Week 14 | 27 participants |
| Combined Golimumab | American College of Rheumatology (ACR) 50 Response at Week 14 | 49 participants |
p-value: 0.003Cochran-Mantel-Haenszel
p-value: 0.021Cochran-Mantel-Haenszel
p-value: 0.002Cochran-Mantel-Haenszel
Secondary
Disease Activity Index Score 28 (DAS 28) (Using C-reactive Protein) Response at Week 14
DAS 28 using C-reactive protein (CRP) is an index to measure disease activity in participants with rheumatoid arthritis which combines tender joint count (28 joints), swollen joint count (28 joints), CRP value, and participant's global assessment of disease activity (using a Visual Analog Scale of 0 to 100 mm). The DAS 28 score ranges from 0 (best) to 10 (worst).
Time frame: Week 14
Population: Randomized participants (excluding 1 site). Participants considered non-responders if used any prohibited medications or discontinued subcutaneous study agent due to lack of efficacy. Missing DAS 28 components imputed by Last Observation Carried Forward unless all components were missing; in which case considered non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Placebo | Disease Activity Index Score 28 (DAS 28) (Using C-reactive Protein) Response at Week 14 | 44 participants |
| Group 2: Golimumab 50 mg | Disease Activity Index Score 28 (DAS 28) (Using C-reactive Protein) Response at Week 14 | 82 participants |
| Group 3: Golimumab 100 mg | Disease Activity Index Score 28 (DAS 28) (Using C-reactive Protein) Response at Week 14 | 87 participants |
| Combined Golimumab | Disease Activity Index Score 28 (DAS 28) (Using C-reactive Protein) Response at Week 14 | 169 participants |
p-value: <0.001Cochran-Mantel-Haenszel
p-value: <0.001Cochran-Mantel-Haenszel
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Health Assessment Questionnaire (HAQ) Score at Week 24
Improvement from baseline in HAQ score at Week 24. This 20-question instrument 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, indicating no difficulty, to 3, indicating inability to perform a task in that area based on the worst score from the questions that pertain to that task. The HAQ score is determined by the average of the 8 scores; HAQ ranges from 0 to 3.
Time frame: From Baseline to Week 24
Population: Randomized participants (excluding 1 site). Missing scores imputed by Last Observation Carried Forward. Week 16 scores were used for participants with change in study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1: Placebo | Health Assessment Questionnaire (HAQ) Score at Week 24 | 0.0000 scores on a scale |
| Group 2: Golimumab 50 mg | Health Assessment Questionnaire (HAQ) Score at Week 24 | 0.1250 scores on a scale |
| Group 3: Golimumab 100 mg | Health Assessment Questionnaire (HAQ) Score at Week 24 | 0.2500 scores on a scale |
| Combined Golimumab | Health Assessment Questionnaire (HAQ) Score at Week 24 | 0.2500 scores on a scale |
p-value: <0.001ANOVA on van der Waerden normal scores.
p-value: <0.001ANOVA on van der Waerden normal scores.
p-value: <0.001ANOVA on van der Waerden normal scores.