This is a Phase IIIb multicenter study to evaluate the safety and efficacy of certolizumab pegol (CZP) administered to patients with moderate-to-severe rheumatoid arthritis.
The treatment period starts with a 12-week, double-blind, placebo-controlled, randomized period followed by an open-label extension phase. In the double-blind phase, eligible patients are randomized (4:1 ratio) to receive either certolizumab pegol (CZP) or Placebo up to and including Week 10. The randomization will be stratified according to the three factors: concomitant use of methotrexate (MTX, Yes or No), prior anti-tumor necrosis factor (anti-TNF) use (Yes or No), and disease duration categories (\< 2 years or ≥ 2 years). From Week 12 all patients remaining in the study receive open-label CZP for a minimum 16 additional weeks until CZP is commercially available.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
1,648
400 mg CZP given as two 200 mg subcutaneous (sc) injections at Weeks 0, 2, and 4, followed by 200 mg CZP given as 1 sc injection on Weeks 6, 8, and 10. At Week 12 subjects enter the open label phase and receive 200 mg of CZP every other week for a minimum 16 additional weeks until CZP is commercially available.
Placebo (0.9% saline) given as 2 subcutaneous (sc) injections at Weeks 0, 2, and 4, followed by placebo given as 1 sc injection on Weeks 6, 8, and 10. At Week 12 subjects enter the open label phase and receive 200 mg of CZP every other week for a minimum 16 additional weeks until CZP is commercially available.
American College of Rheumatology 20% (ACR20) Response at Week 12
ACR20 responders are subjects with at least 20% improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS)
Time frame: Baseline, Week 12
American College of Rheumatology 20% (ACR20) Response at Week 12 for Subjects With Concomitant Methotrexate (MTX) Use.
ACR20 responders are subjects with at least 20% improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS)
Time frame: Baseline, Week 12
American College of Rheumatology 20% (ACR20) Response at Week 12 for Subjects Without Concomitant Methotrexate (MTX) Use.
ACR20 responders are subjects with at least 20% improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS)
Time frame: Baseline, Week 12
American College of Rheumatology 20% (ACR20) Response at Week 12 for Subjects With Prior Anti-tumor Necrosis (Anti-TNF) Use
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ACR20 responders are subjects with at least 20% improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS)
Time frame: Baseline, Week 12
American College of Rheumatology 20% (ACR20) Response at Week 12 for Subjects Without Prior Anti-tumor Necrosis (Anti-TNF) Use
ACR20 responders are subjects with at least 20% improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS)
Time frame: Baseline, Week 12
American College of Rheumatology 20% (ACR20) Response at Week 12 for Subjects With Disease Duration < 2 Years
ACR20 responders are subjects with at least 20% improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS)
Time frame: Baseline, Week 12
American College of Rheumatology 20% (ACR20) Response at Week 12 for Subjects With Disease Duration ≥ 2 Years.
ACR20 responders are subjects with at least 20% improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS)
Time frame: Baseline, Week 12
American College of Rheumatology 50% (ACR50) Response at Week 12
ACR50 responders are subjects with at least 50% improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS)
Time frame: Baseline, Week 12
American College of Rheumatology 70% (ACR70) Response at Week 12.
ACR70 responders are subjects with at least 70% improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS)
Time frame: Baseline, Week 12
Change From Baseline in DAS28(CRP) [Disease Activity Score-28 (C-reactive Protein)] at Week 12
DAS28(CRP) is calculated using tender joint count (TJC), swollen joint count (SJC), C-reactive protein (CRP in mg/L), and Patient's Global Assessment of Arthritis-Visual Analog Scale (PtGADA-VAS in mm). A lower score indicates less disease activity. Change from baseline is computed as Week 12 value minus baseline value. A negative value in change from baseline indicates an improvement. This analysis was carried out using the Last Observation Carried Forward (LOCF) method.
Time frame: Baseline, Week 12
Change From Baseline in SDAI (Simplified Disease Activity Index) at Week 12
SDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), C-reactive protein (CRP in mg/dL), Patient's Global Assessment of Arthritis-Visual Analog Scale (PtGADA-VAS in cm), and Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS in cm). A lower score indicates less disease activity. Change from baseline is computed as Week 12 value minus baseline value. A negative value in change from baseline indicates an improvement. This analysis was carried out using the Last Observation Carried Forward (LOCF) method.
Time frame: Baseline, Week 12
Change From Baseline in CDAI (Clinical Disease Activity Index) at Week 12
CDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), Patient's Global Assessment of Arthritis-Visual Analog Scale (PtGADA-VAS in cm), and Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS in cm). A lower score indicates less disease activity. Change from baseline is computed as Week 12 value minus baseline value. A negative value in change from baseline indicates an improvement. This analysis was carried out using the Last Observation Carried Forward (LOCF) method.
Time frame: Baseline, Week 12
DAS28(CRP) [Disease Activity Score-28 (C-reactive Protein)] Remission (<2.6) at Week 12
DAS28(CRP) is calculated using tender joint count (TJC), swollen joint count (SJC), C-reactive protein (CRP in mg/L), and Patient's Global Assessment of Arthritis-Visual Analog Scale (PtGADA-VAS in mm). A lower score indicates less disease activity.
Time frame: Week 12
SDAI (Simplified Disease Activity Index) Remission (≤3.3) at Week 12
SDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), C-reactive protein (CRP in mg/dL), Patient's Global Assessment of Arthritis-Visual Analog Scale (PtGADA-VAS in cm), and Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS in cm). A lower score indicates less disease activity.
Time frame: Week 12
CDAI (Clinical Disease Activity Index) Remission (≤2.8) at Week 12
CDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), Patient's Global Assessment of Arthritis-Visual Analog Scale (PtGADA-VAS in cm), and Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS in cm). A lower score indicates less disease activity.
Time frame: Week 12
Change From Baseline in Tender Joint Count (TJC) at Week 12
TJC is calculated based on tenderness response of 28 joints. TJC possible values range from 0 to 28. A lower TJC indicates less joint tenderness. Change from baseline is computed as Week 12 value minus baseline value. A negative value in change from baseline indicates an improvement. This analysis was carried out using the Last Observation Carried Forward (LOCF) method.
Time frame: Baseline, Week 12
Change From Baseline in Swollen Joint Count (SJC) at Week 12
SJC is calculated based on swelling response of 28 joints. SJC possible values range from 0 to 28. A lower SJC indicates less joint swelling. Change from baseline is computed as Week 12 value minus baseline value. A negative value in change from baseline indicates an improvement. This analysis was carried out using the Last Observation Carried Forward (LOCF) method.
Time frame: Baseline, Week 12
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12
HAQ-DI is derived based on the mean of individual scores in 8 categories of daily living actives (using 20 questions). Each question is scored 0-3 (0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, and 3 = unable to do). Change from baseline is computed as Week 12 value minus baseline value. A negative value in change from baseline indicates an improvement. This analysis was carried out using the Last Observation Carried Forward (LOCF) method.
Time frame: Baseline, Week 12
Change From Baseline in C-reactive Protein (CRP) at Week 12
Change from baseline in CRP (mg/L) is computed as the ratio of Week 12 value divided by baseline value. A ratio less then 1 indicates an improvement. This analysis was carried out using the Last Observation Carried Forward (LOCF) method.
Time frame: Baseline, Week 12
Change From Baseline in Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS) at Week 12
Change from Baseline in PAAP-VAS (0 to 100 mm visual analog scale, 0 being no pain and 100 being most severe pain) is computed as Week 12 value minus baseline value. A negative value in change from baseline indicates an improvement. This analysis was carried out using the Last Observation Carried Forward (LOCF) method.
Time frame: Baseline, Week 12
Change From Baseline in Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS) at Week 12
Change from Baseline in PtGADA-VAS (0 to 100 mm visual analog scale, 0 being no symptoms and 100 being severe symptoms) is computed as Week 12 value minus baseline value. A negative value in change from baseline indicates an improvement. This analysis was carried out using the Last Observation Carried Forward (LOCF) method.
Time frame: Baseline, Week 12
Change From Baseline in Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS) at Week 12
Change from Baseline in PhGADA-VAS (0 to 100 mm visual analog scale, 0 being no symptoms and 100 being severe symptoms) is computed as Week 12 value minus baseline value. A negative value in change from baseline indicates an improvement. This analysis was carried out using the Last Observation Carried Forward (LOCF) method.
Time frame: Baseline, Week 12
Time to Sustained American College of Rheumatology 20% (ACR20) Response
The time from randomization to sustained ACR20 response at 2 consecutive visits (at the latest on Week 12).
Time frame: Baseline up to Week 12
European League Against Rheumatism (EULAR) Response at Week 12
EULAR response (good response, moderate response, or no response) is defined based on the present value and improvement from baseline in DAS28(CRP) \[Disease Activity Score-28 (C-reactive protein)\].
Time frame: Baseline, Week 12
American College of Rheumatology 20% (ACR20) Response at Week 28
ACR20 responders are subjects with at least 20% improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS). This analysis was carried out using imputation.
Time frame: Baseline, Week 28
American College of Rheumatology 50% (ACR50) Response at Week 28
ACR50 responders are subjects with at least 50% improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS). This analysis was carried out using imputation.
Time frame: Baseline, Week 28
American College of Rheumatology 70% (ACR70) Response at Week 28
ACR70 responders are subjects with at least 70% improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS). This analysis was carried out using imputation.
Time frame: Baseline, Week 28
Change From Baseline in DAS28(CRP) [Disease Activity Score-28 (C-reactive Protein)] at Week 28
DAS28(CRP) is calculated using tender joint count (TJC), swollen joint count (SJC), C-reactive protein (CRP in mg/L), and Patient's Global Assessment of Arthritis-Visual Analog Scale (PtGADA-VAS in mm). A lower score indicates less disease activity. Change from Baseline is computed as the value at Week 28 minus Baseline value. A negative value in change from Baseline indicates an improvement. This analysis was done using a Mixed Effects Repeated Measures Model (MMRM).
Time frame: Baseline, Week 28
Change From Baseline in SDAI (Simplified Disease Activity Index) at Week 28
SDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), C-reactive protein (CRP in mg/dL), Patient's Global Assessment of Arthritis-Visual Analog Scale (PtGADA-VAS in cm), and Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS in cm). A lower score indicates less disease activity. Change from Baseline is computed as the value at Week 28 minus the Baseline value. A negative value in change from Baseline indicates an improvement. This analysis was done using a Mixed Effects Repeated Measures Model (MMRM).
Time frame: Baseline, Week 28
Change From Baseline in CDAI (Clinical Disease Activity Index) at Week 28
CDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), Patient's Global Assessment of Arthritis-Visual Analog Scale (PtGADA-VAS in cm), and Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS in cm). A lower score indicates less disease activity. Change from Baseline is computed as value at Week 28 minus the Baseline value. A negative value in change from Baseline indicates an improvement. This analysis was done using a Mixed Effects Repeated Measures Model (MMRM).
Time frame: Baseline, Week 28
DAS28(CRP) [Disease Activity Score-28 (C-reactive Protein)] Remission (<2.6) at Week 28
DAS28(CRP) is calculated using tender joint count (TJC), swollen joint count (SJC), C-reactive protein (CRP in mg/L), and Patient's Global Assessment of Arthritis-Visual Analog Scale (PtGADA-VAS in mm). A lower score indicates less disease activity. This analysis was carried out using imputation.
Time frame: Week 28
SDAI (Simplified Disease Activity Index) Remission (≤3.3) at Week 28
SDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), C-reactive protein (CRP in mg/dL), Patient's Global Assessment of Arthritis-Visual Analog Scale (PtGADA-VAS in cm), and Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS in cm). A lower score indicates less disease activity. This analysis was carried out using imputation.
Time frame: Week 28
CDAI (Clinical Disease Activity Index) Remission (≤2.8) at Week 28
CDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), Patient's Global Assessment of Arthritis-Visual Analog Scale (PtGADA-VAS in cm), and Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS in cm). A lower score indicates less disease activity. This analysis was carried out using imputation.
Time frame: Week 28
Change From Baseline in Tender Joint Count (TJC) at Week 28
TJC is calculated based on tenderness response of 28 joints. TJC possible values range from 0 to 28. A lower TJC indicates less joint tenderness. Change from Baseline is computed as the value at Week 28 minus the Baseline value. A negative value in change from Baseline indicates an improvement. This analysis was done using a Mixed Effects Repeated Measures Model (MMRM).
Time frame: Baseline, Week 28
Change From Baseline in Swollen Joint Count (SJC) at Week 28
SJC is calculated based on swelling response of 28 joints. SJC possible values range from 0 to 28. A lower SJC indicates less joint swelling. Change from baseline is computed as the value at Week 28 minus the baseline value. A negative value in change from baseline indicates an improvement. This analysis was done using a Mixed Effects Repeated Measures Model (MMRM).
Time frame: Baseline, Week 28
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 28
HAQ-DI is derived based on the mean of individual scores in 8 categories of daily living actives (using 20 questions). Each question is scored 0-3 (0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, and 3 = unable to do). Change from baseline is computed as the value at Week 28 minus the baseline value. A negative value in change from baseline indicates an improvement. This analysis was done using a Mixed Effects Repeated Measures Model (MMRM).
Time frame: Baseline, Week 28
Change From Baseline in C-reactive Protein (CRP) at Week 28
Change from Baseline in CRP (mg/L) is computed as the ratio of the value at Week 28 divided by Baseline value. A ratio less then 1 indicates an improvement. This analysis was done using a Mixed Effects Repeated Measures Model (MMRM).
Time frame: Baseline, Week 28
Change From Baseline in Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS) at Week 28
Change from Baseline in PAAP-VAS (0 to 100 mm visual analog scale, 0 being no pain and 100 being most severe pain) is computed as the value at Week 28 minus the Baseline value. A negative value in change from Baseline indicates an improvement. This analysis was done using a Mixed Effects Repeated Measures Model (MMRM).
Time frame: Baseline, Week 28
Change From Baseline in Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS) at Week 28
Change from Baseline in PtGADA-VAS (0 to 100 mm visual analog scale, 0 being no symptoms and 100 being severe symptoms) is computed as the value at Week 28 minus the Baseline value. A negative value in change from Baseline indicates an improvement. This analysis was done using a Mixed Effects Repeated Measures Model (MMRM).
Time frame: Baseline, Week 28
Change From Baseline in Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS) at Week 28
Change from Baseline in PhGADA-VAS (0 to 100 mm visual analog scale, 0 being no symptoms and 100 being severe symptoms) is computed as the value at Week 28 minus the Baseline value. A negative value in change from Baseline indicates an improvement. This analysis was done using a Mixed Effects Repeated Measures Model (MMRM).
Time frame: Baseline, Week 28