Rheumatoid Arthritis
Conditions
Keywords
Cimzia, Early RA, Certolizumab Pegol
Brief summary
The objective of this study is to assess the efficacy of certolizumab pegol (CZP) with methotrexate (MTX) compared with MTX-alone in patients with early-stage rheumatoid arthritis (RA) who are naive to MTX and have with poor prognostic factors, using inhibition of radiographically confirmed joint damage progression over a one-year period as a primary endpoint. Following a year of treatment with CZP plus MTX treatment, CZP will be discontinued, and the subjects will be monitored for one more year (the follow-up period) to investigate the sustainability of efficacy of CZP during the MTX monotherapy for exploratory purposes.
Detailed description
This study was initiated by Otsuka Pharmaceutical Co., Ltd and transferred to Astellas on 12/04/2012.
Interventions
DRUGPlacebo
Subcutaneous (SC)
DRUGCZP
SC
DRUGmethotrexate (MTX)
oral
Sponsors
UCB Japan Co. Ltd.
Astellas Pharma Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with RA as defined by the ACR/EULAR criteria (2010) who meet all of the following criteria: 1. Subjects who developed RA within one year after onset of RA. 2. Subjects who have never received MTX before (MTX naive) 3. Subjects whose disease activity is moderate or higher (DAS28(ESR) ≥ 3.2） 4. Subjects must satisfy at least two of the three criteria (Anti-CCP antibody positive, Rheumatoid factor positive, Presence of X-ray erosion） for poor prognostic factors. The anti-CCP antibody positive is essential for every patient.
Exclusion criteria
* Patients who have a diagnosis of any other type of inflammatory arthritis. * Patients who have a secondary, non-inflammatory type of arthritis. * Patients who have used with MTX, reflunomide, or any other biologics prior to the start of study drug administration. * Patients who have NYHA (New York Heart Association) Class III or IV congestive heart failure * Patients who currently have, or who have a history of, tuberculosis. * Patients who have a high risk of infection (with a current infectious disease, a chronic infectious disease, a history of serious infectious disease) * Patients who currently have, or have a history of, malignant tumor * Female patients who are breastfeeding or pregnant, who are of childbearing potential
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52 | Baseline and Week 52 | Radiographs/X-rays of hands and feet (posteroanterior views of both hands and dorsoplantar views of both feet) were independently assessed by two radiographic readers. The degree of joint damage was graded by assessing bone erosion in 44 joints and joint space narrowing (JSN) in 42 joints. The bone erosion score is a summary of erosion severity in 32 joints of the hands and 12 joints in the feet. Each joint was scored, according to the surface area involved, from 0 (no erosion) to 5 (complete collapse of bone). The score for erosion ranges from 0 to 160 in the hands and from 0 to 120 in the feet (the maximum erosion score for a joint in the foot is 10). The JSN score summarizes the severity of JSN in 30 joints of the hands and 12 joints of the feet. JSN, including subluxation, was scored from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation), with a maximum JSN score of 168. The mTSS ranges from 0 (normal) to 448 (worst). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in mTSS at Week 24 | Baseline and Week 24 | Radiographs/X-rays of hands and feet (posteroanterior views of both hands and dorsoplantar views of both feet) were independently assessed by two radiographic readers. The degree of joint damage was graded by assessing bone erosion in 44 joints and joint space narrowing (JSN) in 42 joints. The bone erosion score is a summary of erosion severity in 32 joints of the hands and 12 joints in the feet. Each joint was scored, according to the surface area involved, from 0 (no erosion) to 5 (complete collapse of bone). The score for erosion ranges from 0 to 160 in the hands and from 0 to 120 in the feet (the maximum erosion score for a joint in the foot is 10). The JSN score summarizes the severity of JSN in 30 joints of the hands and 12 joints of the feet. JSN, including subluxation, was scored from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation), with a maximum JSN score of 168. The mTSS ranges from 0 (normal) to 448 (worst). |
| Clinical Remission Rate: Percentage of Participants Meeting the Disease Activity Score-28 Joint Count (DAS28) Erythrocyte Sedimentation Rate (ESR) (DAS28[ESR]) Remission Criteria at Weeks 24 and 52 | Week 24 and Week 52 | The DAS28(ESR) measures the severity of disease at a specific time and is derived from the following variables: •28 tender joint count (TJC); •28 swollen joint count (SJC); •ESR; •Patient's global assessment of disease activity (PtGADA). To obtain the tender joint count and swollen joint count, 28 joints of the shoulder, elbow, wrist, metacarpophalangeal joints, thumb interphalangeal joints, proximal interphalangeal joints, and knee joints were examined. DAS28(ESR) scores range from 0 to approximately 10, with the upper bound dependent on the highest possible ESR. A participant was considered to be in remission if DAS28(ESR) \<2.6. Last Observation Carried Forward (LOCF) was applied. |
| Clinical Remission Rate: Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Simplified Disease Activity Index (SDAI)-Based Remission Criteria at Weeks 24 and 52 | Week 24 and Week 52 | The ACR/EULAR SDAI remission rate measures the severity of disease at a specific time and is derived from the following variables: •28 tender joint count (TJC); •28 swollen joint count (SJC); •Patient's global assessment of disease activity (PtGADA); •Physician's Global Assessment of Disease Activity (PhGADA); •C-reactive protein (CRP) To obtain the tender joint count and swollen joint count, 28 joints of the shoulder, elbow, wrist, metacarpophalangeal joints, thumb interphalangeal joints, proximal interphalangeal joints, and knee joints were examined. A participant was considered to be in remission if SDAI ≤3.3. Last Observation Carried Forward (LOCF) was applied. |
| Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean-based Remission Criteria at Weeks 24 and 52 | Week 24 and Week 52 | The ACR/EULAR Boolean-based remission rate measures the severity of disease at a specific time and is derived from the following variables: •28 tender joint count (TJC); •28 swollen joint count (SJC); •Patient's global assessment of disease activity (PtGADA); •C-reactive protein (CRP) To obtain the tender joint count and swollen joint count, 28 joints of the shoulder, elbow, wrist, metacarpophalangeal joints, thumb interphalangeal joints, proximal interphalangeal joints, and knee joints were examined. A participant was considered to be in remission if all the criteria for each variable was met:TJC (in 28 joints) ≤1; SJC (in 28 joints) ≤1; CRP ≤1 mg/dl; PtGADA ≤1. Last Observation Carried Forward (LOCF) was applied |
Countries
Japan
Participant flow
Recruitment details
Participants with early rheumatoid arthritis (RA), methotrexate (MTX)-naïve and had poor prognostic factors were recruited for this study.
Participants by arm
| Arm | Count |
|---|---|
| PBO + MTX Participants who received placebo subcutaneously every two weeks (Q2W) at Weeks 0, 2, and 4; followed by placebo subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards | 157 |
| CZP + MTX Participants who received certolizumab pegol (CZP) subcutaneously at a loading dose of CZP 400 mg every 2 weeks (Q2W) at Weeks 0, 2, and 4; followed by a dose of CZP 200 mg subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards | 159 |
| Total | 316 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Treatment Period | Adverse Event | 6 | 9 |
| Double-blind Treatment Period | Consent Withdrawn | 3 | 2 |
| Double-blind Treatment Period | Did not receive treatment | 1 | 2 |
| Double-blind Treatment Period | HBV-DNA positive (during the DB Period) | 0 | 1 |
| Double-blind Treatment Period | Investigator decision | 2 | 0 |
| Double-blind Treatment Period | Lack of Efficacy | 71 | 36 |
| Double-blind Treatment Period | Missing study medication ≥6 times | 1 | 0 |
| Double-blind Treatment Period | Violation of eligibility criteria | 1 | 0 |
| Post-treatment Period | Adverse Event | 0 | 1 |
| Post-treatment Period | Consent withdrawn | 2 | 4 |
| Post-treatment Period | Investigator decision | 0 | 1 |
| Post-treatment Period | Lack of Efficacy | 12 | 28 |
Baseline characteristics
| Characteristic | PBO + MTX | CZP + MTX | Total |
|---|---|---|---|
| Age, Continuous | 49.0 years STANDARD_DEVIATION 10.3 | 49.4 years STANDARD_DEVIATION 10.6 | 49.2 years STANDARD_DEVIATION 10.5 |
| Sex: Female, Male Female | 127 Participants | 129 Participants | 256 Participants |
| Sex: Female, Male Male | 30 Participants | 30 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 139 / 157 | 146 / 159 |
| serious Total, serious adverse events | 18 / 157 | 17 / 159 |
Outcome results
Primary
Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52
Radiographs/X-rays of hands and feet (posteroanterior views of both hands and dorsoplantar views of both feet) were independently assessed by two radiographic readers. The degree of joint damage was graded by assessing bone erosion in 44 joints and joint space narrowing (JSN) in 42 joints. The bone erosion score is a summary of erosion severity in 32 joints of the hands and 12 joints in the feet. Each joint was scored, according to the surface area involved, from 0 (no erosion) to 5 (complete collapse of bone). The score for erosion ranges from 0 to 160 in the hands and from 0 to 120 in the feet (the maximum erosion score for a joint in the foot is 10). The JSN score summarizes the severity of JSN in 30 joints of the hands and 12 joints of the feet. JSN, including subluxation, was scored from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation), with a maximum JSN score of 168. The mTSS ranges from 0 (normal) to 448 (worst).
Time frame: Baseline and Week 52
Population: FAS with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBO + MTX | Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52 | 1.58 units on a scale | Standard Deviation 4.86 |
| CZP + MTX | Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52 | 0.36 units on a scale | Standard Deviation 2.7 |
Comparison: The mTSS was analyzed using LINEAR for the imputation of missing data at Week 52.The primary Week 52 analysis assessed whether treatment up to Week 52 with the CZP group was superior to the placebo group in mTSS at Week 52. The 2-sided null and alternative hypotheses were: H0: πC = πM Ha: πC ≠ πM where πC represented subjects in the CZP group at Week 52 and πM represented subjects in the placebo group at Week 52.p-value: <0.00195% CI: [0, 0]ANCOVA
Secondary
Change From Baseline in mTSS at Week 24
Radiographs/X-rays of hands and feet (posteroanterior views of both hands and dorsoplantar views of both feet) were independently assessed by two radiographic readers. The degree of joint damage was graded by assessing bone erosion in 44 joints and joint space narrowing (JSN) in 42 joints. The bone erosion score is a summary of erosion severity in 32 joints of the hands and 12 joints in the feet. Each joint was scored, according to the surface area involved, from 0 (no erosion) to 5 (complete collapse of bone). The score for erosion ranges from 0 to 160 in the hands and from 0 to 120 in the feet (the maximum erosion score for a joint in the foot is 10). The JSN score summarizes the severity of JSN in 30 joints of the hands and 12 joints of the feet. JSN, including subluxation, was scored from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation), with a maximum JSN score of 168. The mTSS ranges from 0 (normal) to 448 (worst).
Time frame: Baseline and Week 24
Population: FAS with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBO + MTX | Change From Baseline in mTSS at Week 24 | 0.86 units on a scale | Standard Deviation 2.37 |
| CZP + MTX | Change From Baseline in mTSS at Week 24 | 0.26 units on a scale | Standard Deviation 1.55 |
Comparison: The mTSS was analyzed using LINEAR for the imputation of missing data at Week 24.p-value: 0.00395% CI: [0, 0]ANCOVA
Secondary
Clinical Remission Rate: Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Simplified Disease Activity Index (SDAI)-Based Remission Criteria at Weeks 24 and 52
The ACR/EULAR SDAI remission rate measures the severity of disease at a specific time and is derived from the following variables: •28 tender joint count (TJC); •28 swollen joint count (SJC); •Patient's global assessment of disease activity (PtGADA); •Physician's Global Assessment of Disease Activity (PhGADA); •C-reactive protein (CRP) To obtain the tender joint count and swollen joint count, 28 joints of the shoulder, elbow, wrist, metacarpophalangeal joints, thumb interphalangeal joints, proximal interphalangeal joints, and knee joints were examined. A participant was considered to be in remission if SDAI ≤3.3. Last Observation Carried Forward (LOCF) was applied.
Time frame: Week 24 and Week 52
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PBO + MTX | Clinical Remission Rate: Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Simplified Disease Activity Index (SDAI)-Based Remission Criteria at Weeks 24 and 52 | Week 24 | 29.3 percentage of participants |
| PBO + MTX | Clinical Remission Rate: Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Simplified Disease Activity Index (SDAI)-Based Remission Criteria at Weeks 24 and 52 | Week 52 | 33.8 percentage of participants |
| CZP + MTX | Clinical Remission Rate: Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Simplified Disease Activity Index (SDAI)-Based Remission Criteria at Weeks 24 and 52 | Week 24 | 48.4 percentage of participants |
| CZP + MTX | Clinical Remission Rate: Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Simplified Disease Activity Index (SDAI)-Based Remission Criteria at Weeks 24 and 52 | Week 52 | 57.9 percentage of participants |
p-value: <0.001Fisher Exact
Secondary
Clinical Remission Rate: Percentage of Participants Meeting the Disease Activity Score-28 Joint Count (DAS28) Erythrocyte Sedimentation Rate (ESR) (DAS28[ESR]) Remission Criteria at Weeks 24 and 52
The DAS28(ESR) measures the severity of disease at a specific time and is derived from the following variables: •28 tender joint count (TJC); •28 swollen joint count (SJC); •ESR; •Patient's global assessment of disease activity (PtGADA). To obtain the tender joint count and swollen joint count, 28 joints of the shoulder, elbow, wrist, metacarpophalangeal joints, thumb interphalangeal joints, proximal interphalangeal joints, and knee joints were examined. DAS28(ESR) scores range from 0 to approximately 10, with the upper bound dependent on the highest possible ESR. A participant was considered to be in remission if DAS28(ESR) \<2.6. Last Observation Carried Forward (LOCF) was applied.
Time frame: Week 24 and Week 52
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PBO + MTX | Clinical Remission Rate: Percentage of Participants Meeting the Disease Activity Score-28 Joint Count (DAS28) Erythrocyte Sedimentation Rate (ESR) (DAS28[ESR]) Remission Criteria at Weeks 24 and 52 | Week 24 | 30.6 percentage of participants |
| PBO + MTX | Clinical Remission Rate: Percentage of Participants Meeting the Disease Activity Score-28 Joint Count (DAS28) Erythrocyte Sedimentation Rate (ESR) (DAS28[ESR]) Remission Criteria at Weeks 24 and 52 | Week 52 | 36.9 percentage of participants |
| CZP + MTX | Clinical Remission Rate: Percentage of Participants Meeting the Disease Activity Score-28 Joint Count (DAS28) Erythrocyte Sedimentation Rate (ESR) (DAS28[ESR]) Remission Criteria at Weeks 24 and 52 | Week 24 | 52.8 percentage of participants |
| CZP + MTX | Clinical Remission Rate: Percentage of Participants Meeting the Disease Activity Score-28 Joint Count (DAS28) Erythrocyte Sedimentation Rate (ESR) (DAS28[ESR]) Remission Criteria at Weeks 24 and 52 | Week 52 | 57.2 percentage of participants |
p-value: <0.001Fisher Exact
Secondary
Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean-based Remission Criteria at Weeks 24 and 52
The ACR/EULAR Boolean-based remission rate measures the severity of disease at a specific time and is derived from the following variables: •28 tender joint count (TJC); •28 swollen joint count (SJC); •Patient's global assessment of disease activity (PtGADA); •C-reactive protein (CRP) To obtain the tender joint count and swollen joint count, 28 joints of the shoulder, elbow, wrist, metacarpophalangeal joints, thumb interphalangeal joints, proximal interphalangeal joints, and knee joints were examined. A participant was considered to be in remission if all the criteria for each variable was met:TJC (in 28 joints) ≤1; SJC (in 28 joints) ≤1; CRP ≤1 mg/dl; PtGADA ≤1. Last Observation Carried Forward (LOCF) was applied
Time frame: Week 24 and Week 52
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PBO + MTX | Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean-based Remission Criteria at Weeks 24 and 52 | Week 24 | 22.3 percentage of participants |
| PBO + MTX | Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean-based Remission Criteria at Weeks 24 and 52 | Week 52 | 28.0 percentage of participants |
| CZP + MTX | Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean-based Remission Criteria at Weeks 24 and 52 | Week 24 | 36.5 percentage of participants |
| CZP + MTX | Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean-based Remission Criteria at Weeks 24 and 52 | Week 52 | 45.3 percentage of participants |
p-value: 0.002Fisher Exact