Rheumatoid Arthritis
Conditions
Brief summary
This is a Phase 3 Study to Compare the Pharmacokinetics, Efficacy and Safety between CT-P10, Rituxan and MabThera in Patients with Rheumatoid Arthritis.
Interventions
BIOLOGICALCT-P10
1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusion
DRUGRituxan
US-licensed reference product, 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusion
DRUGMabThera
EU-approved reference product, 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusion
Sponsors
Celltrion
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 75 Years
Healthy volunteers
No
Inclusion criteria
1. Patient is male or female between 18 and 75 years old, inclusive. 2. Patient has a diagnosis of RA according to the revised 1987 ACR classification criteria (Arnett et al 1988) for at least 6 months prior to randomization. 3. Patient has active disease as defined by the presence of 6 or more swollen joints (of 66 assessed) and 6 or more tender joints (of 68 assessed), and serum CRP ≥1.5 mg/dL (≥15 mg/L) or an ESR ≥28 mm/hour. 4. Patient has experienced an inadequate response to previous or current treatment with the anti-TNF agents infliximab 5. Patient has a proper discontinuation period after treatment with interleukin-1 receptor (IL-1R) antagonist, interleukin-6 receptor (IL-6R) antibody, or abatacept.
Exclusion criteria
1. Patient has taken more than 2 biologic agents. 2. Patient has previously been administered Rituximab or participated in a Rituximab biosimilar study. 3. Patient has allergies or hypersensitivity to murine, chimeric, human, or humanized proteins. 4. Patient has current or past history of chronic infection with hepatitis B, hepatitis C, or infection with human immunodeficiency virus (HIV)-1 or -2 or who has a positive result to the screening test for these infections. 5. Patient has an infection requiring oral antibiotics 2 weeks before randomization, parenteral injection of antibiotics 4 weeks before randomization, other serious infection 6 months before randomization, a history of recurrent herpes zoster or other chronic or recurrent infection 6 weeks before randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Analysis of Serum AUC0-last of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA) | over the first 24 weeks | For evaluation of pharmacokinetics (PK), the primary endpoint was defined as the analysis of serum AUC0-last, AUC0-inf and Cmax of rituximab during the 1st course of the Main Study Period (over the first 24 weeks). During the 1st course of the Main Study Period, blood samples for PK analysis were collected every week from Week 0 to Week 4, every 4 weeks from Week 4 to Week 16, followed by Week 24. AUC0-last: Area under the concentration-time curve from time to the last measurable concentration over both doses of the 1st course |
| Analysis of Serum AUC0-inf of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA) | at Week 24 of the Main Study Period | For evaluation of PK, the primary endpoint was defined as the analysis of serum AUC0-last, AUC0-inf and Cmax of rituximab during the 1st course of the Main Study Period (over the first 24 weeks). During the 1st course of the Main Study Period, blood samples for PK analysis were collected every week from Week 0 to Week 4, every 4 weeks from Week 4 to Week 16, followed by Week 24. AUC0-inf: Area under the concentration-time curve from time 0 extrapolated to infinity over both doses of the 1st course |
| Analysis of Serum Cmax of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA) | at Week 24 of the Main Study Period | For evaluation of pharmacokinetics (PK), the primary endpoint was defined as the analysis of serum AUC0-last, AUC0-inf and Cmax of rituximab during the 1st course of the Main Study Period (over the first 24 weeks). During the 1st course of the Main Study Period, blood samples for PK analysis were collected every week from Week 0 to Week 4, every 4 weeks from Week 4 to Week 16, followed by Week 24. Cmax: Observed maximum concentration after the seocnd infusion of the 1st course |
| Analysis of Change From Baseline of DAS28 (CRP) at Week 24 (ANCOVA) | at Week 24 of the Main Study Period | For evaluation of efficacy, the primary endpoint was defined as the analysis of change from baseline in disease activity measured by disease activity score 28 (DAS 28) C-reactive protein (CRP) at Week 24 between 2 treatment groups, CT-P10 and reference products (combined Rituxan and MabThera) groups. During the 1st course of the Main Study Period, DAS28 was assessed every 4 weeks from Week 0 to Week 24. DAS28 (CRP) was calculated using the following formula: DAS28 (CRP) = 0.56 X SQRT(TJC28) + 0.28 X SQRT(SJC28) + 0.36 X ln(CRP+1) + 0.014 X GH on VAS + 0.96. DAS28 (CRP) provides a number on a scale from 0 to 10 with higher values indicating greater RA disease activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period | at Week 24 of the Main Study Period | For evaluation of efficacy, the secondary endpoint was defined as descriptive statistics of mean change from baseline in disease activity measured by DAS 28 (CRP) and DAS28 erythrocyte sedimentation rate (ESR) at Week 24 (efficacy population) and Week 48 (efficacy population - 2nd treatment course in Main Study Period subset) for the Main Study Period between 2 treatment groups, CT-P10 and reference products (combined Rituxan and MabThera) groups. DAS28 was assessed every 4 weeks from Week 0 to Week 24 during the 1st treatment course of the Main Study Period and every 8 weeks from Week 24 to Week 48 during the 2nd treatment course of the Main Study Period. DAS28 (CRP) was calculated using the following formula: DAS28 (CRP) = 0.56 X SQRT(TJC28) + 0.28 X SQRT(SJC28) + 0.36 X ln(CRP+1) + 0.014 X GH on VAS + 0.96. DAS28 (CRP) provides a number on a scale from 0 to 10 with higher values indicating greater RA disease activity. |
| Analysis of B-cell Counts at Week 24 of the Main Study Period (ANCOVA) | Week 24 | For evaluation of pharmacodynamics (PD), the endpoint was defined as B-cell counts at Week 24 between 2 treatment groups, CT-P10 and reference products (combined Rituxan and MabThera) groups. During the 1st course of the Main Study Period, B-cell kinetics blood samples were collected every week from Week 0 to Week 4, every 4 weeks from Week 4 to Week 16, followed by Week 24. |
| Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Extension Study Period | at Week 24 of the Main Study Period | For evaluation of efficacy, the secondary endpoint was defined as descriptive statistics of mean change from baseline in disease activity measured by DAS28 (CRP) and DAS28 (ESR) at Week 72 (efficacy population-Extension Study Period subset) for the Extension Study Period between 4 treatment groups, CT-P10/CT-P10, Rituxan/Rituxan, Rituxan/CT-P10 and MabThera/CT-P10 groups. DAS28 was assessed every 8 weeks from Week 48 (Week 0 of the Extension Study Period) to Week 72 (Week 24 of the Extension Study Period) during the Extension Study Period. DAS28 (CRP) was calculated using the following formula: DAS28 (CRP) = 0.56 X SQRT(TJC28) + 0.28 X SQRT(SJC28) + 0.36 X ln(CRP+1) + 0.014 X GH on VAS + 0.96. DAS28 (CRP) provides a number on a scale from 0 to 10 with higher values indicating greater RA disease activity. |
| Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period | at Week 24 of the Main Study Period | For evaluation of efficacy, the secondary endpoint was defined as descriptive statistics of mean change from baseline in disease activity measured by DAS 28 (CRP) and DAS28 (ESR) at Week 24 (efficacy population) and Week 48 (efficacy population - 2nd treatment course in Main Study Period subset) for the Main Study Period between 2 treatment groups, CT-P10 and reference products (combined Rituxan and MabThera) groups. DAS28 was assessed every 4 weeks from Week 0 to Week 24 during the 1st treatment course of the Main Study Period and every 8 weeks from Week 24 to Week 48 during the 2nd treatment course of the Main Study Period. DAS28 (ESR) was calculated using the following formula: DAS28 (CRP) = 0.56 X SQRT(TJC28) + 0.28 X SQRT(SJC28) + 0.36 X ln(ESR) + 0.014 X GH on VAS. DAS28 (ESR) provides a number on a scale from 0 to 10 with higher values indicating greater RA disease activity. |
| Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Extension Study Period | at Week 24 of the Main Study Period | For evaluation of efficacy, the secondary endpoint was defined as descriptive statistics of mean change from baseline in disease activity measured by DAS28 (CRP) and DAS28 (ESR) at Week 72 (efficacy population-Extension Study Period subset) for the Extension Study Period between 4 treatment groups, CT-P10/CT-P10, Rituxan/Rituxan, Rituxan/CT-P10 and MabThera/CT-P10 groups. DAS28 was assessed every 8 weeks from Week 48 (Week 0 of the Extension Study Period) to Week 72 (Week 24 of the Extension Study Period) during the Extension Study Period. DAS28 (ESR) was calculated using the following formula: DAS28 (CRP) = 0.56 X SQRT(TJC28) + 0.28 X SQRT(SJC28) + 0.36 X ln(ESR) + 0.014 X GH on VAS. DAS28 (ESR) provides a number on a scale from 0 to 10 with higher values indicating greater RA disease activity. |
Participant flow
Recruitment details
Participants recruited from 76 study centers (including 1 GCP noncompliant study center) in Europe, Asia Pacific, and Latin America.
Pre-assignment details
A total of 495 participants were screened for the study. Of theses, 111 participants were excluded from the study due to screening failure and 384 participants were enrolled in the study. Of these 384 participants, 12 participants from the significantly GCP noncompliant study center were excluded from all analysis populations.
Participants by arm
| Arm | Count |
|---|---|
| CT-P10 (Main Study Period) This group received 1000mg rituximab (CT-P10; experimental drug) by IV infusion. Each participant received up to 3 treatment courses (2 treatment courses in the Main Study Period, and 1 additional treatment course in the Extension Study Period), if they met predefined eligibility criteria. Each course consisted of 2 infusions with a 2-week interval between the first and second infusions of a 24-week course. Throughout the study, MTX (7.5-25 mg/week orally or parenterally) and folic acid (≥ 5 mg/week) were coadministered. | 161 |
| Rituxan (Main Study Period) This group received 1000mg rituximab (Rituxan; US-licensed reference product) by IV infusion. Each participant received up to 3 treatment courses (2 treatment courses in the Main Study Period, and 1 additional treatment course in the Extension Study Period), if they met predefined eligibility criteria. Each course consisted of 2 infusions with a 2-week interval between the first and second infusions of a 24-week course. Throughout the study, MTX (7.5-25 mg/week orally or parenterally) and folic acid (≥ 5 mg/week) were coadministered. | 151 |
| MabThera (Main Study Period) This group received 1000mg rituximab (MabThera; EU-approved reference product) by IV infusion. Each participant received up to 3 treatment courses (2 treatment courses in the Main Study Period, and 1 additional treatment course in the Extension Study Period), if they met predefined eligibility criteria. Each course consisted of 2 infusions with a 2-week interval between the first and second infusions of a 24-week course. Throughout the study, MTX (7.5-25 mg/week orally or parenterally) and folic acid (≥ 5 mg/week) were coadministered. | 60 |
| CT-P10/CT-P10 (Extension Study Period) For the Extension Study Period, participants, who were assigned to receive CT-P10 with their first infusion in the Main Study Period, were considered as CT-P10/CT-P10 group and maintained CT-P10 for the treatment course of the Extension Study Period at Extension Week 0. This group received 1000mg rituximab (CT-P10; experimental drug) by IV infusion with a 2-week interval between the first and second infusions of a 24-week course in the Extension Study Period followed by 1000mg rituximab (CT-P10; experimental drug) infusions in the Main Study Period. Throughout the study, MTX (7.5-25 mg/week orally or parenterally) and folic acid (≥ 5 mg/week) were coadministered. | 122 |
| Rituxan/Rituxan (Extension Study Period) For the Extension Study Period, participants, who were assigned to receive Rituxan with their first infusion in the Main Study Period, were randomized in a 1:1 ratio to Rituxan/Rituxan group and Rituxan/CT-P10 group at Extension Week 0. This group is for participants who were assigned as Rituxan/Rituxan group and received 1000mg rituximab (Rituxan; US-licensed reference product) by IV infusion with a 2-week interval between the first and second infusions of a 24-week course in the Extension Study Period followed by 1000mg rituximab (Rituxan; US-licensed reference product) infusions in the Main Study Period. Throughout the study, MTX (7.5-25 mg/week orally or parenterally) and folic acid (≥ 5 mg/week) were coadministered. | 64 |
| Rituxan/CT-P10 (Extension Study Period) For the Extension Study Period, participants, who were assigned to receive Rituxan with their first infusion in the Main Study Period, were randomized in a 1:1 ratio to Rituxan/Rituxan group and Rituxan/CT-P10 group at Extension Week 0. This group is for participants who were assigned as Rituxan/CT-P10 group and received 1000mg rituximab (CT-P10; experimental drug) by IV infusion with a 2-week interval between the first and second infusions of a 24-week course in the Extension Study Period followed by 1000mg rituximab (Rituxan; US-licensed reference product) infusions in the Main Study Period. Throughout the study, MTX (7.5-25 mg/week orally or parenterally) and folic acid (≥ 5 mg/week) were coadministered. | 62 |
| MabThera/CT-P10 (Extension Study Period) For the Extension Study Period, participants, who were assigned to receive MabThera with their first infusion in the Main Study Period, were considered as MabThera/CT-P10 group and received CT-P10 for the treatment course of the Extension Study Period at Extension Week 0. This group received 1000mg rituximab (CT-P10; experimental drug) by IV infusion with a 2-week interval between the first and second infusions of a 24-week course in the Extension Study Period followed by 1000mg rituximab (Rituxan; US-licensed reference product) infusions in the Main Study Period. Throughout the study, MTX (7.5-25 mg/week orally or parenterally) and folic acid (≥ 5 mg/week) were coadministered. | 47 |
| Total | 667 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Extension Study Period | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 2 | 0 |
| Main Study Period | Adverse Event | 2 | 5 | 1 | 0 | 0 | 0 | 0 |
| Main Study Period | Death | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Main Study Period | Developed any malignancy | 0 | 1 | 1 | 0 | 0 | 0 | 0 |
| Main Study Period | Disease progression | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Main Study Period | Lack of Efficacy | 2 | 2 | 1 | 0 | 0 | 0 | 0 |
| Main Study Period | Lost to Follow-up | 2 | 1 | 0 | 0 | 0 | 0 | 0 |
| Main Study Period | Physician Decision | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Main Study Period | Protocol Violation | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Main Study Period | Unmet predefined eligibility criteria | 2 | 2 | 0 | 0 | 0 | 0 | 0 |
| Main Study Period | Withdrawal by Subject | 9 | 5 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Rituxan (Main Study Period) | MabThera (Main Study Period) | CT-P10 (Main Study Period) | CT-P10/CT-P10 (Extension Study Period) | Rituxan/Rituxan (Extension Study Period) | Rituxan/CT-P10 (Extension Study Period) | MabThera/CT-P10 (Extension Study Period) | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 16 Participants | 7 Participants | 10 Participants | 3 Participants | 36 Participants |
| Age, Categorical Between 18 and 65 years | 127 Participants | 56 Participants | 142 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 325 Participants |
| Age, Continuous | 53.0 years | 51.5 years | 53.0 years | 52.5 years | 52.5 years | 53.0 years | 50.0 years | 53.0 years |
| Sex: Female, Male Female | 130 Participants | 50 Participants | 138 Participants | 100 Participants | 54 Participants | 55 Participants | 40 Participants | 318 Participants |
| Sex: Female, Male Male | 21 Participants | 10 Participants | 23 Participants | 22 Participants | 10 Participants | 7 Participants | 7 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 161 | 0 / 151 | 0 / 60 | 0 / 122 | 0 / 64 | 0 / 62 | 0 / 47 |
| other Total, other adverse events | 88 / 161 | 72 / 151 | 29 / 60 | 27 / 122 | 16 / 64 | 17 / 62 | 7 / 47 |
| serious Total, serious adverse events | 13 / 161 | 14 / 151 | 4 / 60 | 4 / 122 | 0 / 64 | 1 / 62 | 0 / 47 |
Outcome results
Primary
Analysis of Change From Baseline of DAS28 (CRP) at Week 24 (ANCOVA)
For evaluation of efficacy, the primary endpoint was defined as the analysis of change from baseline in disease activity measured by disease activity score 28 (DAS 28) C-reactive protein (CRP) at Week 24 between 2 treatment groups, CT-P10 and reference products (combined Rituxan and MabThera) groups. During the 1st course of the Main Study Period, DAS28 was assessed every 4 weeks from Week 0 to Week 24. DAS28 (CRP) was calculated using the following formula: DAS28 (CRP) = 0.56 X SQRT(TJC28) + 0.28 X SQRT(SJC28) + 0.36 X ln(CRP+1) + 0.014 X GH on VAS + 0.96. DAS28 (CRP) provides a number on a scale from 0 to 10 with higher values indicating greater RA disease activity.
Time frame: at Week 24 of the Main Study Period
Population: Efficacy population - The efficacy analysis set for the Main Study Period consisted of all who received at least 1 full dose (1000mg) of study drug (CT-P10, Rituxan or MabThera), who had at least 1 post-treatment efficacy result and who did not have any major protocol violation including a violation of the inclusion and exclusion criteria.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CT-P10 (Main Study Period) | Analysis of Change From Baseline of DAS28 (CRP) at Week 24 (ANCOVA) | -2.11 score on a scale | Standard Error 0.176 |
| Rituxan (Main Study Period) | Analysis of Change From Baseline of DAS28 (CRP) at Week 24 (ANCOVA) | -2.10 score on a scale | Standard Error 0.178 |
Comparison: Primary efficacy analysis were analyzed using an ANCOVA model with treatment group as a fixed effect and gender, region, race, study part, interaction of treatment group with study part, prior anti TNF alpha blocker status at baseline (intolerance case versus inadequate response), and RF or anti-CCP status fitted as covariates.90% CI: [-0.22, 0.2]
Primary
Analysis of Serum AUC0-inf of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA)
For evaluation of PK, the primary endpoint was defined as the analysis of serum AUC0-last, AUC0-inf and Cmax of rituximab during the 1st course of the Main Study Period (over the first 24 weeks). During the 1st course of the Main Study Period, blood samples for PK analysis were collected every week from Week 0 to Week 4, every 4 weeks from Week 4 to Week 16, followed by Week 24. AUC0-inf: Area under the concentration-time curve from time 0 extrapolated to infinity over both doses of the 1st course
Time frame: at Week 24 of the Main Study Period
Population: PK population - The PK analysis set for the Main Study Period consisted of all patients who received 2 full doses (Week 0 and Week 2) of the study drug and provided at least 1 post-treatment PK concentration result during the 1st course in the Main Study Period.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CT-P10 (Main Study Period) | Analysis of Serum AUC0-inf of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA) | 162377.28 h*μg/mL | Standard Error 1.068 |
| Rituxan (Main Study Period) | Analysis of Serum AUC0-inf of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA) | 169480.80 h*μg/mL | Standard Error 1.069 |
| MabThera (Main Study Period) | Analysis of Serum AUC0-inf of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA) | 180637.81 h*μg/mL | Standard Error 1.072 |
Comparison: Primary PK analysis were analyzed using an ANCOVA model with treatment group as a fixed effect and gender, region, race, prior anti TNF alpha blocker status, and RF or anti-CCP status fitted as covariates.90% CI: [87.39, 105.04]
Comparison: Primary PK analysis were analyzed using an ANCOVA model with treatment group as a fixed effect and gender, region, race, prior anti TNF alpha blocker status, and RF or anti-CCP status fitted as covariates.90% CI: [81.85, 98.72]
Comparison: Primary PK analysis were analyzed using an ANCOVA model with treatment group as a fixed effect and gender, region, race, prior anti TNF alpha blocker status, and RF or anti-CCP status fitted as covariates.90% CI: [97.03, 117.08]
Primary
Analysis of Serum AUC0-last of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA)
For evaluation of pharmacokinetics (PK), the primary endpoint was defined as the analysis of serum AUC0-last, AUC0-inf and Cmax of rituximab during the 1st course of the Main Study Period (over the first 24 weeks). During the 1st course of the Main Study Period, blood samples for PK analysis were collected every week from Week 0 to Week 4, every 4 weeks from Week 4 to Week 16, followed by Week 24. AUC0-last: Area under the concentration-time curve from time to the last measurable concentration over both doses of the 1st course
Time frame: over the first 24 weeks
Population: PK population - The PK analysis set for the Main Study Period consisted of all patients who received 2 full doses (Week 0 and Week 2) of the study drug and provided at least 1 post-treatment PK concentration result during the 1st course in the Main Study Period.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CT-P10 (Main Study Period) | Analysis of Serum AUC0-last of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA) | 162414.81 h*μg/mL | Standard Error 1.073 |
| Rituxan (Main Study Period) | Analysis of Serum AUC0-last of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA) | 167309.07 h*μg/mL | Standard Error 1.073 |
| MabThera (Main Study Period) | Analysis of Serum AUC0-last of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA) | 172450.97 h*μg/mL | Standard Error 1.075 |
Comparison: Primary PK analysis were analyzed using analysis of covariance (ANCOVA) model with treatment group as a fixed effect and gender, region, race, prior anti TNF alpha blocker status, and RF or anti-CCP status fitted as covariates.90% CI: [88.08, 106.99]
Comparison: Primary PK analysis were analyzed using an ANCOVA model with treatment group as a fixed effect and gender, region, race, prior anti TNF alpha blocker status, and RF or anti-CCP status fitted as covariates.90% CI: [85.4, 103.86]
Comparison: Primary PK analysis were analyzed using an ANCOVA model with treatment group as a fixed effect and gender, region, race, prior anti TNF alpha blocker status, and RF or anti-CCP status fitted as covariates.90% CI: [93.32, 113.85]
Primary
Analysis of Serum Cmax of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA)
For evaluation of pharmacokinetics (PK), the primary endpoint was defined as the analysis of serum AUC0-last, AUC0-inf and Cmax of rituximab during the 1st course of the Main Study Period (over the first 24 weeks). During the 1st course of the Main Study Period, blood samples for PK analysis were collected every week from Week 0 to Week 4, every 4 weeks from Week 4 to Week 16, followed by Week 24. Cmax: Observed maximum concentration after the seocnd infusion of the 1st course
Time frame: at Week 24 of the Main Study Period
Population: PK population - The PK analysis set for the Main Study Period consisted of all patients who received 2 full doses (Week 0 and Week 2) of the study drug and provided at least 1 post-treatment PK concentration result during the 1st course in the Main Study Period.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CT-P10 (Main Study Period) | Analysis of Serum Cmax of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA) | 367.03 ug/mL | Standard Error 1.042 |
| Rituxan (Main Study Period) | Analysis of Serum Cmax of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA) | 386.65 ug/mL | Standard Error 1.042 |
| MabThera (Main Study Period) | Analysis of Serum Cmax of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA) | 412.40 ug/mL | Standard Error 1.043 |
Comparison: Primary PK analysis were analyzed using an ANCOVA model with treatment group as a fixed effect and gender, region, race, prior anti TNF alpha blocker status, and RF or anti-CCP status fitted as covariates.90% CI: [89.61, 100.55]
Comparison: Primary PK analysis were analyzed using an ANCOVA model with treatment group as a fixed effect and gender, region, race, prior anti TNF alpha blocker status, and RF or anti-CCP status fitted as covariates.90% CI: [84.01, 94.28]
Comparison: Primary PK analysis were analyzed using an ANCOVA model with treatment group as a fixed effect and gender, region, race, prior anti TNF alpha blocker status, and RF or anti-CCP status fitted as covariates.90% CI: [100.56, 113.13]
Secondary
Analysis of B-cell Counts at Week 24 of the Main Study Period (ANCOVA)
For evaluation of pharmacodynamics (PD), the endpoint was defined as B-cell counts at Week 24 between 2 treatment groups, CT-P10 and reference products (combined Rituxan and MabThera) groups. During the 1st course of the Main Study Period, B-cell kinetics blood samples were collected every week from Week 0 to Week 4, every 4 weeks from Week 4 to Week 16, followed by Week 24.
Time frame: Week 24
Population: PD population - The PD analysis set for the Main Study Period consisted of all patients who received at least 1 full dose (1000mg) of study drug and provided at least 1 post-treatment PD result during the 1st course in the Main Study Period.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CT-P10 (Main Study Period) | Analysis of B-cell Counts at Week 24 of the Main Study Period (ANCOVA) | 25.29 cells/mcL | Standard Error 1.074 |
| Rituxan (Main Study Period) | Analysis of B-cell Counts at Week 24 of the Main Study Period (ANCOVA) | 24.70 cells/mcL | Standard Error 1.073 |
Comparison: Secondary PD analysis were analyzed using an ANCOVA model with results as the response, treatment group, as fixed effect and baseline values, gender, region, race, study part, interaction of treatment group with study part, prior anti-TNF alpha blocker status, and RF or anti-CCP status fitted as covariates.95% CI: [92.46, 113.33]
Secondary
Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Extension Study Period
For evaluation of efficacy, the secondary endpoint was defined as descriptive statistics of mean change from baseline in disease activity measured by DAS28 (CRP) and DAS28 (ESR) at Week 72 (efficacy population-Extension Study Period subset) for the Extension Study Period between 4 treatment groups, CT-P10/CT-P10, Rituxan/Rituxan, Rituxan/CT-P10 and MabThera/CT-P10 groups. DAS28 was assessed every 8 weeks from Week 48 (Week 0 of the Extension Study Period) to Week 72 (Week 24 of the Extension Study Period) during the Extension Study Period. DAS28 (ESR) was calculated using the following formula: DAS28 (CRP) = 0.56 X SQRT(TJC28) + 0.28 X SQRT(SJC28) + 0.36 X ln(ESR) + 0.014 X GH on VAS. DAS28 (ESR) provides a number on a scale from 0 to 10 with higher values indicating greater RA disease activity.
Time frame: at Week 24 of the Main Study Period
Population: Efficacy - Extension Study Period subset: The efficacy - Extension Study Period subset consisted of all patients in the efficacy population who received at least 1 full dose (1000 mg) of study drug and provided at least 1 post-treatment efficacy result during the Extension Study Period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CT-P10 (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Extension Study Period | -3.3 score on a scale | Standard Deviation 1.24 |
| Rituxan (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Extension Study Period | -3.3 score on a scale | Standard Deviation 1.41 |
| MabThera (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Extension Study Period | -3.2 score on a scale | Standard Deviation 1.36 |
| Reference Products (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Extension Study Period | -3.2 score on a scale | Standard Deviation 1.15 |
Secondary
Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period
For evaluation of efficacy, the secondary endpoint was defined as descriptive statistics of mean change from baseline in disease activity measured by DAS 28 (CRP) and DAS28 (ESR) at Week 24 (efficacy population) and Week 48 (efficacy population - 2nd treatment course in Main Study Period subset) for the Main Study Period between 2 treatment groups, CT-P10 and reference products (combined Rituxan and MabThera) groups. DAS28 was assessed every 4 weeks from Week 0 to Week 24 during the 1st treatment course of the Main Study Period and every 8 weeks from Week 24 to Week 48 during the 2nd treatment course of the Main Study Period. DAS28 (ESR) was calculated using the following formula: DAS28 (CRP) = 0.56 X SQRT(TJC28) + 0.28 X SQRT(SJC28) + 0.36 X ln(ESR) + 0.014 X GH on VAS. DAS28 (ESR) provides a number on a scale from 0 to 10 with higher values indicating greater RA disease activity.
Time frame: at Week 24 of the Main Study Period
Population: Weeks 0 and 24 data were analysed by efficacy population who received at least 1 full dose of study drug and provided at least 1 post treatment efficacy result during 1st course. Week 48 data were analysed by 'efficacy-2nd course subset' who received at least 1 full dose and provided at least 1 post treatment efficacy result during 2nd course.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CT-P10 (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period | Week 0 (Baseline) | 6.7 score on a scale | Standard Deviation 0.83 |
| CT-P10 (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period | Week 48 (2nd course Week 24) | -2.9 score on a scale | Standard Deviation 1.29 |
| CT-P10 (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period | Week 24 (1st course Week 24) | -2.5 score on a scale | Standard Deviation 1.13 |
| Rituxan (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period | Week 0 (Baseline) | 6.7 score on a scale | Standard Deviation 0.84 |
| Rituxan (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period | Week 48 (2nd course Week 24) | -2.8 score on a scale | Standard Deviation 1.42 |
| Rituxan (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period | Week 24 (1st course Week 24) | -2.5 score on a scale | Standard Deviation 1.13 |
| MabThera (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period | Week 24 (1st course Week 24) | -2.3 score on a scale | Standard Deviation 1.31 |
| MabThera (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period | Week 0 (Baseline) | 6.8 score on a scale | Standard Deviation 0.75 |
| MabThera (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period | Week 48 (2nd course Week 24) | -2.9 score on a scale | Standard Deviation 1.32 |
| Reference Products (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period | Week 0 (Baseline) | 6.7 score on a scale | Standard Deviation 0.81 |
| Reference Products (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period | Week 48 (2nd course Week 24) | -2.8 score on a scale | Standard Deviation 1.39 |
| Reference Products (Main Study Period) | Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period | Week 24 (1st course Week 24) | -2.5 score on a scale | Standard Deviation 1.18 |
Secondary
Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Extension Study Period
For evaluation of efficacy, the secondary endpoint was defined as descriptive statistics of mean change from baseline in disease activity measured by DAS28 (CRP) and DAS28 (ESR) at Week 72 (efficacy population-Extension Study Period subset) for the Extension Study Period between 4 treatment groups, CT-P10/CT-P10, Rituxan/Rituxan, Rituxan/CT-P10 and MabThera/CT-P10 groups. DAS28 was assessed every 8 weeks from Week 48 (Week 0 of the Extension Study Period) to Week 72 (Week 24 of the Extension Study Period) during the Extension Study Period. DAS28 (CRP) was calculated using the following formula: DAS28 (CRP) = 0.56 X SQRT(TJC28) + 0.28 X SQRT(SJC28) + 0.36 X ln(CRP+1) + 0.014 X GH on VAS + 0.96. DAS28 (CRP) provides a number on a scale from 0 to 10 with higher values indicating greater RA disease activity.
Time frame: at Week 24 of the Main Study Period
Population: Efficacy - Extension Study Period subset: The efficacy - Extension Study Period subset consisted of all patients in the efficacy population who received at least 1 full dose (1000 mg) of study drug and provided at least 1 post-treatment efficacy result during the Extension Study Period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CT-P10 (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Extension Study Period | -3.0 score on a scale | Standard Deviation 1.2 |
| Rituxan (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Extension Study Period | -3.0 score on a scale | Standard Deviation 1.32 |
| MabThera (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Extension Study Period | -2.9 score on a scale | Standard Deviation 1.27 |
| Reference Products (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Extension Study Period | -3.0 score on a scale | Standard Deviation 1.11 |
Secondary
Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period
For evaluation of efficacy, the secondary endpoint was defined as descriptive statistics of mean change from baseline in disease activity measured by DAS 28 (CRP) and DAS28 erythrocyte sedimentation rate (ESR) at Week 24 (efficacy population) and Week 48 (efficacy population - 2nd treatment course in Main Study Period subset) for the Main Study Period between 2 treatment groups, CT-P10 and reference products (combined Rituxan and MabThera) groups. DAS28 was assessed every 4 weeks from Week 0 to Week 24 during the 1st treatment course of the Main Study Period and every 8 weeks from Week 24 to Week 48 during the 2nd treatment course of the Main Study Period. DAS28 (CRP) was calculated using the following formula: DAS28 (CRP) = 0.56 X SQRT(TJC28) + 0.28 X SQRT(SJC28) + 0.36 X ln(CRP+1) + 0.014 X GH on VAS + 0.96. DAS28 (CRP) provides a number on a scale from 0 to 10 with higher values indicating greater RA disease activity.
Time frame: at Week 24 of the Main Study Period
Population: Weeks 0 and 24 data were analysed by efficacy population who received at least 1 full dose of study drug and provided at least 1 post treatment efficacy result during 1st course. Week 48 data were analysed by 'efficacy-2nd course subset' who received at least 1 full dose and provided at least 1 post treatment efficacy result during 2nd course.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CT-P10 (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period | Week 24 (1st course Week 24) | -2.3 score on a scale | Standard Deviation 1.06 |
| CT-P10 (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period | Week 0 (Baseline) | 5.8 score on a scale | Standard Deviation 0.91 |
| CT-P10 (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period | Week 48 (2nd course Week 24) | -2.7 score on a scale | Standard Deviation 1.17 |
| Rituxan (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period | Week 0 (Baseline) | 5.8 score on a scale | Standard Deviation 0.92 |
| Rituxan (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period | Week 24 (1st course Week 24) | -2.3 score on a scale | Standard Deviation 1.11 |
| Rituxan (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period | Week 48 (2nd course Week 24) | -2.6 score on a scale | Standard Deviation 1.32 |
| MabThera (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period | Week 0 (Baseline) | 6.0 score on a scale | Standard Deviation 0.87 |
| MabThera (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period | Week 48 (2nd course Week 24) | -2.7 score on a scale | Standard Deviation 1.32 |
| MabThera (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period | Week 24 (1st course Week 24) | -2.3 score on a scale | Standard Deviation 1.3 |
| Reference Products (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period | Week 24 (1st course Week 24) | -2.3 score on a scale | Standard Deviation 1.17 |
| Reference Products (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period | Week 0 (Baseline) | 5.8 score on a scale | Standard Deviation 0.91 |
| Reference Products (Main Study Period) | Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period | Week 48 (2nd course Week 24) | -2.6 score on a scale | Standard Deviation 1.32 |