Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis, Golimumab, Methotrexate, Fully Human anti-TNFa monoclonal antibody, Simpony
Brief summary
The purpose of this study is to evaluate the efficacy and safety of golimumab, alone or in combination with methotrexate (MTX), as compared to methotrexate alone in rheumatoid arthritis (RA) patients who have active rheumatoid arthritis despite treatment with MTX.
Detailed description
This is a randomized (treatment is assigned by chance), double-blind (neither the physician nor the patient is aware of the received treatment), placebo-controlled study of multiple subcutaneous (SC) administrations of golimumab at 2 doses as monotherapy or in combination with MTX in patients with active RA despite treatment with MTX. The duration of participation in the study for an individual patient will be upto 268 weeks. The patients will be randomly assigned in a 3:3:2:2 ratio to receive golimumab 50 mg or 100 mg or placebo injections under the skin every 4 weeks through week 20 and methotrexate or placebo capsules will be given in addition. At Week 24, all subjects will receive golimumab 50mg or 100mg injections, and golimumab continues for all groups for about 4 and a half more years. At Week 16 any patient in the study who meets criteria for \< 20% improvement from baseline in both swollen and tender joint count will enter early escape in a double-blinded fashion. Treatment during the long-term extension will start at Week 52 and continue every 4 weeks thereafter for a total of approximately 5 years from the initial (Week 0) administration of study agent. Patients will return for scheduled follow-up visits generally every 12 weeks for a total length of follow-up of approximately 5 years from the first administration of the study drug.
Interventions
DRUGGolimumab 100 mg
Participants will receive subcutaneous (SC) injections of golimumab 100 mg every 4 weeks.
DRUGGolimumab 50 mg
Participants will receive subcutaneous (SC) injections of golimumab 50 mg every 4 weeks.
DRUGMethotrexate
Participants will receive methotrexate capsules weekly.
DRUGPlacebo injection
Participants will receive subcutaneous (SC) injections of placebo every 4 weeks.
DRUGPlacebo capsules
Participants will receive placebo capsules weekly
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 screening * Must 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 a MTX dose of \>=15 mg/week and \<=25 mg/week and stable for at least 4 weeks 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, 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 magnetic resonance imaging (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 * Are considered eligible according to specified tuberculosis (TB) screening criteria
Exclusion criteria
* Have inflammatory diseases other than RA that might confound the evaluation of the benefit of golimumab therapy * Have had treatment with disease-modifying anti-rheumatic drugs (DMARDs)/systemic immunosuppressives other than MTX, during the 4 weeks prior to the first administration of study agent * Have had prior treatment with biologic anti-tumor necrosis factor (TNF) drugs (infliximab, etanercept, adalimumab) * Have had history of, or ongoing, chronic or recurrent infectious disease. * Have serious infection within 2 months prior to first administration of study agent * Have a history of latent or active granulomatous infection, including TB, histoplasmosis, or coccidioidomycosis, prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 14 | Week 14 | 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 50 percentage improvement in 3 of the following 5 assessments: a. Patient's assessment of pain 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 Health Assessment Questionnaire (HAQ) Score at Week 24 | Baseline (Week 0) and Week 24 | 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). The average score across the functional areas yields an overall HAQ score which ranges from 0 (no disability) to 3 (completely disabled). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Disease Activity Index Score 28 (DAS 28) Using C-reactive Protein (CRP) Response at Week 14 | Week 14 | DAS 28 using CRP is an index to measure the 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). Participants are considered to have a DAS 28 response if they have a score of \<= 3.2 (good response) or \> 3.2 to 5.1 (moderate response). |
| Number of Participants Who Achieved American College of Rheumatology 20 (ACR 20) Response at Week 24 | Week 24 | An 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 50 percentage improvement in 3 of the following 5 assessments: a. Patient's assessment of pain (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 (CRP). |
| Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 14 | Baseline (Week 0) and 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). The average score across the functional areas yields an overall HAQ score which ranges from 0 (no disability) to 3 (completely disabled). |
| Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 24 | Baseline (Week 0) and Week 24 | The vdH-S score is the sum of joint erosion score and 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, Canada, Chile, Germany, Hungary, Mexico, New Zealand, Poland, South Korea, Taiwan, United States
Participant flow
Recruitment details
A total of 444 participants were enrolled at 60 sites in 12 countries.
Participants by arm
| Arm | Count |
|---|---|
| Group 1: Placebo + Methotrexate Placebo subcutaneous (SC) injections every 4 weeks from Week 0 to Week 20 (early escape at Week 16); Methotrexate - 15 to 25mg weekly from Week 0 up to 5 yrs; Golimumab - if early escape, 50mg SC injections every 4 weeks from Week 16 up to 5 years; Golimumab - 50 mg SC injections every 4 weeks from Week 24 up to 5 yrs (unless early escape); Methotrexate - Dr's discretion, weekly dose adjusted after unblinding; Golimumab - Dr's discretion after unblinding, dose adjusted from 50 to 100mg and from 100 to 50mg. Duration of the blinded period was until the week-52 database lock. | 133 |
| Group 2: Golimumab 100 mg + Placebo Golimumab 100 mg SC injections every 4 weeks from Week 0 up to 5 yrs; Placebo - 7 to 10 capsules weekly during blinded period (or Week 16 if early escape); Methotrexate - if early escape, 15 to 25mg weekly from Week 16 up to 5 yrs; Methotrexate - Dr's discretion, weekly dose adjusted after unblinding; Golimumab - Dr's discretion after unblinding, dose adjusted from 100 to 50mg. Duration of the blinded period was until the week-52 database lock. | 133 |
| Group 3: Golimumab 50 mg + Methotrexate Golimumab 50 mg SC injections every 4 weeks from Week 0 up to 5 yrs (unless early escape at Week 16); Methotrexate - 15 to 25 mg weekly from Week 0 up to 5 years; Golimumab - if early escape, 100 mg SC injections every 4 weeks from Week 16 up to 5 yrs; Methotrexate - Dr's discretion, weekly dose adjusted after unblinding; Golimumab - Dr's discretion after unblinding, dose adjusted from 50 to100mg and from 100 to 50mg. Duration of the blinded period was until the week-52 database lock. | 89 |
| Group 4: Golimumab 100 mg + Methotrexate Golimumab100 mg SC injections every 4 weeks from Week 0 up to 5 yrs; Methotrexate - 15 to 25 mg weekly from Week 0 up to 5 yrs; Methotrexate - Dr's discretion, weekly dose adjusted after unblinding; Golimumab - Dr's discretion after unblinding, dose adjusted from 100 to 50mg. Duration of the blinded period was until the week-52 database lock. | 89 |
| Total | 444 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 23 | 18 | 9 | 14 |
| Overall Study | Death | 0 | 3 | 0 | 0 |
| Overall Study | Discontinued oral study agent | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 3 | 1 | 1 | 1 |
| Overall Study | Other | 13 | 7 | 3 | 9 |
| Overall Study | Unsatisfactory therapeutic effect | 4 | 11 | 4 | 6 |
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 | 51.2 years STANDARD_DEVIATION 11.96 | 50 years STANDARD_DEVIATION 11.47 | 50.3 years STANDARD_DEVIATION 10.98 | 50 years STANDARD_DEVIATION 10.78 | 50.4 years STANDARD_DEVIATION 11.36 |
| Sex: Female, Male Female | 109 Participants | 105 Participants | 72 Participants | 72 Participants | 358 Participants |
| Sex: Female, Male Male | 24 Participants | 28 Participants | 17 Participants | 17 Participants | 86 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 | 96 / 105 | 160 / 184 | 118 / 145 |
| serious Total, serious adverse events | 33 / 105 | 84 / 184 | 55 / 145 |
Outcome results
Primary
Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 24
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). The average score across the functional areas yields an overall HAQ score which ranges from 0 (no disability) to 3 (completely disabled).
Time frame: Baseline (Week 0) and Week 24
Population: All participants randomly assigned to each treatment group
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1: Placebo + Methotrexate | Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 24 | 0.1250 Units on a scale |
| Group 2: Golimumab 100 mg + Placebo | Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 24 | 0.1250 Units on a scale |
| Group 3: Golimumab 50 mg + Methotrexate | Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 24 | 0.3750 Units on a scale |
| Group 4: Golimumab 100 mg + Methotrexate | Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 24 | 0.5000 Units on a scale |
| Combined Golimumab + Methotrexate | Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 24 | 0.4375 Units on a scale |
Comparison: Null hypothesis: No difference in HAQ response at Wk 24 comparing Groups I and Combined Golimumab + Methotrexate (MTX) at 0.05 level of significance.p-value: <0.001ANOVA on van der Waerden normal scores.
Comparison: Null hypothesis: No difference in HAQ response at Wk 24 comparing Groups I and III at 0.05 level of significance.p-value: <0.001ANOVA on van der Waerden normal scores.
Comparison: Null hypothesis: No difference in HAQ response at Wk 24 comparing Groups I and IV at 0.05 level of significance.p-value: <0.001ANOVA on van der Waerden normal scores.
Comparison: Null hypothesis: No difference in HAQ response at Wk 24 comparing Groups I and II at 0.05 level of significance.p-value: 0.24ANOVA on van der Waerden normal scores.
Primary
Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 14
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 50 percentage improvement in 3 of the following 5 assessments: a. Patient's assessment of pain 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 14
Population: All participants randomly assigned to each treatment group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Placebo + Methotrexate | Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 14 | 44 Participants |
| Group 2: Golimumab 100 mg + Placebo | Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 14 | 59 Participants |
| Group 3: Golimumab 50 mg + Methotrexate | Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 14 | 49 Participants |
| Group 4: Golimumab 100 mg + Methotrexate | Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 14 | 50 Participants |
| Combined Golimumab + Methotrexate | Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 14 | 99 Participants |
Comparison: Null hypothesis: No difference in ACR 20 response at Wk 14 comparing Groups I vs III and Groups I vs IV at 0.05 level of significance. Assuming greater than 90 % power, ACR 20 response for Group I, Group III and Group IV (120, 80, and 80 participants, respectively) as 35 % for Group I and 55 % for Groups III and IV.p-value: <0.001Chi-squared
Comparison: Null hypothesis: No difference in ACR 20 response at Wk 14 comparing Groups I vs III and Groups I vs IV at 0.05 level of significance. Samples of sizes 120, 80, 80 patients in Group I, III, and IV provide \>90% power assuming 35% response in Group I and 55% ACR 20 response in golimumab groups(III \& IV).p-value: 0.001Chi-squared
Comparison: Null hypothesis: No difference in ACR 20 response at Wk 14 comparing Groups I vs III and Groups I vs IV at 0.05 level of significance. Samples of sizes 120, 80, 80 patients in Group I, III, and IV provide \>90% power assuming 35% response in Group I and 55% ACR 20 response in golimumab groups(III \& IV).p-value: <0.001Chi-squared
Comparison: Null hypothesis: No difference between Group II and Group I with respect of ACR 20 at Wk 14. Superiority of golimumab alone vs MTX alone will be demonstrated if 2-sided test is significant. Sample of 120 patients in each Group I \& II provides \>85% power assuming 35% ACR 20 response in Group I and 55% ACR 20 in Group II.p-value: 0.059Chi-squared
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). The average score across the functional areas yields an overall HAQ score which ranges from 0 (no disability) to 3 (completely disabled).
Time frame: Baseline (Week 0) and Week 14
Population: All participants randomly assigned to each treatment group
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1: Placebo + Methotrexate | Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 14 | 0.1250 Units on a scale |
| Group 2: Golimumab 100 mg + Placebo | Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 14 | 0.2500 Units on a scale |
| Group 3: Golimumab 50 mg + Methotrexate | Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 14 | 0.3750 Units on a scale |
| Group 4: Golimumab 100 mg + Methotrexate | Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 14 | 0.3750 Units on a scale |
| Combined Golimumab + Methotrexate | Change From Baseline in Health Assessment Questionnaire (HAQ) Score at Week 14 | 0.3750 Units on a scale |
p-value: <0.001ANOVA on van der Waerden noramal
p-value: <0.001ANOVA on van der Waerden normal scores
p-value: <0.001ANOVA on van der Waerden normal scores
p-value: 0.097ANOVA on van der Waerden normal scores
Secondary
Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 24
The vdH-S score is the sum of joint erosion score and 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 (Week 0) and Week 24
Population: All participants randomly assigned to each treatment group
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Group 1: Placebo + Methotrexate | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 24 | 0.00 Units on a scale | Inter-Quartile Range 2.354 |
| Group 2: Golimumab 100 mg + Placebo | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 24 | 0.00 Units on a scale | Inter-Quartile Range 1.598 |
| Group 3: Golimumab 50 mg + Methotrexate | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 24 | 0.00 Units on a scale | Inter-Quartile Range 2.74 |
| Group 4: Golimumab 100 mg + Methotrexate | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 24 | 0.00 Units on a scale | Inter-Quartile Range 1.342 |
| Combined Golimumab + Methotrexate | Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 24 | 0.00 Units on a scale | Inter-Quartile Range 2.159 |
p-value: 0.551ANOVA on van der Waerden normal
p-value: 0.953ANOVA on van der Waerden normal scores
p-value: 0.293ANOVA on van der waerden normal scores
p-value: 0.361ANOVA on van der Waerden normal scores
Secondary
Number of Participants Who Achieved American College of Rheumatology 20 (ACR 20) Response at Week 24
An 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 50 percentage improvement in 3 of the following 5 assessments: a. Patient's assessment of pain (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 (CRP).
Time frame: Week 24
Population: All participants randomly assigned to each treatment group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Placebo + Methotrexate | Number of Participants Who Achieved American College of Rheumatology 20 (ACR 20) Response at Week 24 | 37 Participants |
| Group 2: Golimumab 100 mg + Placebo | Number of Participants Who Achieved American College of Rheumatology 20 (ACR 20) Response at Week 24 | 47 Participants |
| Group 3: Golimumab 50 mg + Methotrexate | Number of Participants Who Achieved American College of Rheumatology 20 (ACR 20) Response at Week 24 | 53 Participants |
| Group 4: Golimumab 100 mg + Methotrexate | Number of Participants Who Achieved American College of Rheumatology 20 (ACR 20) Response at Week 24 | 53 Participants |
| Combined Golimumab + Methotrexate | Number of Participants Who Achieved American College of Rheumatology 20 (ACR 20) Response at Week 24 | 106 Participants |
p-value: <0.001Chi-squared
p-value: <0.001Chi-squared
p-value: <0.001Chi-squared
p-value: 0.187Chi-squared
Secondary
Number of Participants With Disease Activity Index Score 28 (DAS 28) Using C-reactive Protein (CRP) Response at Week 14
DAS 28 using CRP is an index to measure the 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). Participants are considered to have a DAS 28 response if they have a score of \<= 3.2 (good response) or \> 3.2 to 5.1 (moderate response).
Time frame: Week 14
Population: All participants randomly assigned to each treatment group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Placebo + Methotrexate | Number of Participants With Disease Activity Index Score 28 (DAS 28) Using C-reactive Protein (CRP) Response at Week 14 | 67 Participants |
| Group 2: Golimumab 100 mg + Placebo | Number of Participants With Disease Activity Index Score 28 (DAS 28) Using C-reactive Protein (CRP) Response at Week 14 | 84 Participants |
| Group 3: Golimumab 50 mg + Methotrexate | Number of Participants With Disease Activity Index Score 28 (DAS 28) Using C-reactive Protein (CRP) Response at Week 14 | 64 Participants |
| Group 4: Golimumab 100 mg + Methotrexate | Number of Participants With Disease Activity Index Score 28 (DAS 28) Using C-reactive Protein (CRP) Response at Week 14 | 67 Participants |
| Combined Golimumab + Methotrexate | Number of Participants With Disease Activity Index Score 28 (DAS 28) Using C-reactive Protein (CRP) Response at Week 14 | 131 Participants |
p-value: <0.001Chi-squared
p-value: 0.001Chi-squared
p-value: <0.001Chi-squared
p-value: 0.035Chi-squared