PK Similarity Prospective Phase 3 Study in Patients With Rheumatoid Arthritis

Study Overview
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Brief Summary
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This is a Phase 3 Study to Compare the Pharmacokinetics, Efficacy and Safety between CT-P10, Rituxan and MabThera in Patients with Rheumatoid Arthritis.

Official Title
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A Randomized, Controlled, Double-Blind, Parallel-Group, Phase 3 Study to Compare the Pharmacokinetics, Efficacy and Safety Between CT-P10, Rituxan and MabThera in Patients With Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: CT-P10
* Drug: Rituxan
* Drug: MabThera


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is male or female between 18 and 75 years old, inclusive. 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. 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. Patient has experienced an inadequate response to previous or current treatment with the anti-TNF agents infliximab 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: Patient has taken more than 2 biologic agents. Patient has previously been administered Rituximab or participated in a Rituximab biosimilar study. Patient has allergies or hypersensitivity to murine, chimeric, human, or humanized proteins. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CT-P10<br>rituximab, CT-P10(experimental drug), 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusion | Biological: CT-P10<br>* 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusion<br>* Other names: rituximab;|
| Active Comparator: Rituxan<br>US-licensed referece product, 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusions | Biological: CT-P10<br>* 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusion<br>* Other names: rituximab;Drug: Rituxan<br>* US-licensed reference product, 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusion<br>* Other names: rituximab;|
| Active Comparator: MabThera<br>EU-approved reference product, 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusions | Biological: CT-P10<br>* 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusion<br>* Other names: rituximab;Drug: MabThera<br>* EU-approved reference product, 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusion<br>* Other names: rituximab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | over the first 24 weeks | 
| 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 | at Week 24 of the Main Study Period | 
| 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 | at Week 24 of the Main Study Period | 
| 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. | at Week 24 of the Main Study Period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | at Week 24 of the 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 | 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. | at Week 24 of the Main Study Period | 
| 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. | at Week 24 of the Main Study Period | 
| 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. | at Week 24 of the Main Study Period | 
| 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. | Week 24 |