rituximab: PK Similarity Prospective Phase 3 Study in Patients With Rheumatoid Arthritis

• Sponsor: Celltrion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02149121
• Collaborator: (none)
• Enrollment: 384
• Arms: 3
• Actual Duration (Months): 29

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Biological: CT-P10; Drug: Rituxan; Drug: MabThera	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 384 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Aug 1, 2014
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Jan 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CT-P10 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; 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusion; Other Names: rituximab
Active Comparator: Rituxan US-licensed referece product, 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusions	Biological: CT-P10; 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusion; Other Names: rituximab ; Drug: Rituxan; US-licensed reference product, 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusion; Other Names: rituximab
Active Comparator: MabThera EU-approved reference product, 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusions	Biological: CT-P10; 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusion; Other Names: rituximab ; Drug: MabThera; EU-approved reference product, 1000mg by intravenous infusion. 2 infusions with a 2-week interval between the first and second infusion; Other Names: rituximab

Outcome Measures

Primary Outcome Measures

1. 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

2. 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

3. 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

4. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Celltrion

Investigators

• Principal Investigator: DaeHyun Yoo, M.D., Ph.D, Hanyang University

Study Documents (Full-Text)

• Study Protocol - Apr 1, 2016
• Statistical Analysis Plan - Mar 2, 2017

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Celltrion
• ClinicalTrials.gov Identifier: NCT02149121
• Other Study ID Numbers: CT-P10 3.2; 2013-004555-21
• First Posted: May 29, 2014
• Last Update Posted: Dec 16, 2021
• Last Verified: May 1, 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Rituximab

Study Results

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 Detail	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.

Arm/Group Title	CT-P10 (Main Study Period)	Rituxan (Main Study Period)	MabThera (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)
Arm/Group Description	This group received 1000mg rituximab (CT-P10; experimental drug) by intravenous (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, Methotrexate (MTX) (7.5-25 mg/week orally or parenterally) and folic acid (≥ 5 mg/week) were coadministered.	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.	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.	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.	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.	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.	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.
Period Title: Main Study Period
STARTED	161	151	60	0	0	0	0
COMPLETED	140	134	56	0	0	0	0
NOT COMPLETED	21	17	4	0	0	0	0
Period Title: Main Study Period
STARTED	0	0	0	122	64	62	47
COMPLETED	0	0	0	121	64	60	47
NOT COMPLETED	0	0	0	1	0	2	0

Baseline Characteristics

Arm/Group Title	CT-P10 (Main Study Period)	Rituxan (Main Study Period)	MabThera (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
Arm/Group Description	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.	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.	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.	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.	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.	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.	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.	Total of all reporting groups
Overall Participants	161	151	60	122	64	62	47	667
Age (Count of Participants)
<=18 years	1 0.6%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 0.1%
Between 18 and 65 years	142 88.2%	127 84.1%	56 93.3%	0 0%	0 0%	0 0%	0 0%	325 48.7%
>=65 years	18 11.2%	24 15.9%	4 6.7%	0 0%	0 0%	0 0%	0 0%	46 6.9%
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	1 0.8%	0 0%	0 0%	0 0%	1 0.1%
Between 18 and 65 years	0 0%	0 0%	0 0%	105 86.1%	57 89.1%	52 83.9%	44 93.6%	258 38.7%
>=65 years	0 0%	0 0%	0 0%	16 13.1%	7 10.9%	10 16.1%	3 6.4%	36 5.4%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	53.0	53.0	51.5	53.0
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	52.5	52.5	53.0	50.0	52.0
Sex: Female, Male (Count of Participants)
Female	138 85.7%	130 86.1%	50 83.3%	318 260.7%
Male	23 14.3%	21 13.9%	10 16.7%	54 44.3%
Sex: Female, Male (Count of Participants)
Female	100 62.1%	54 35.8%	55 91.7%	40 32.8%	249 389.1%
Male	22 13.7%	10 6.6%	7 11.7%	7 5.7%	46 71.9%

Outcome Measures

1. Primary Outcome

Title	Analysis of Serum AUC0-last of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	CT-P10 (Main Study Period)	Rituxan (Main Study Period)	MabThera (Main Study Period)
Arm/Group Description	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.	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.	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.
Measure Participants	62	60	59
Geometric Least Squares Mean (Standard Error) [h*μg/mL]	162414.81 (1.073)	167309.07 (1.073)	172450.97 (1.075)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT-P10 (Main Study Period), Rituxan (Main Study Period)
	Comments	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.
	Type of Statistical Test	Equivalence
	Comments	The equivalence of PK was to be concluded if the 90% CI for the ratio of geometric means in AUC0-last, AUC0-inf, and Cmax was entirely contained within the PK equivalence bounds of 80% and 125% for the following comparisons: CT-P10 versus Rituxan, CT-P10 versus MabThera, and Rituxan versus MabThera.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric least squares means
	Estimated Value	97.07
	Confidence Interval	(2-Sided) 90%; 88.08 to 106.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimates (geometric least squares means and ratios of geometric means) were calculated by back-transforming the least squares means.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CT-P10 (Main Study Period), MabThera (Main Study Period)
	Comments	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.
	Type of Statistical Test	Equivalence
	Comments	The equivalence of PK was to be concluded if the 90% CI for the ratio of geometric means in AUC0-last, AUC0-inf, and Cmax was entirely contained within the PK equivalence bounds of 80% and 125% for the following comparisons: CT-P10 versus Rituxan, CT-P10 versus MabThera, and Rituxan versus MabThera.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric least squares means
	Estimated Value	94.18
	Confidence Interval	(2-Sided) 90%; 85.40 to 103.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimates (geometric least squares means and ratios of geometric means) were calculated by back-transforming the least squares means.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Rituxan (Main Study Period), MabThera (Main Study Period)
	Comments	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.
	Type of Statistical Test	Equivalence
	Comments	The equivalence of PK was to be concluded if the 90% CI for the ratio of geometric means in AUC0-last, AUC0-inf, and Cmax was entirely contained within the PK equivalence bounds of 80% and 125% for the following comparisons: CT-P10 versus Rituxan, CT-P10 versus MabThera, and Rituxan versus MabThera.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric least squares means
	Estimated Value	103.07
	Confidence Interval	(2-Sided) 90%; 93.32 to 113.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimates (geometric least squares means and ratios of geometric means) were calculated by back-transforming the least squares means.

2. Primary Outcome

Title	Analysis of Serum AUC0-inf of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	CT-P10 (Main Study Period)	Rituxan (Main Study Period)	MabThera (Main Study Period)
Arm/Group Description	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.	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.	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.
Measure Participants	59	60	56
Geometric Least Squares Mean (Standard Error) [h*μg/mL]	162377.28 (1.068)	169480.80 (1.069)	180637.81 (1.072)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT-P10 (Main Study Period), Rituxan (Main Study Period)
	Comments	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.
	Type of Statistical Test	Equivalence
	Comments	The equivalence of PK was to be concluded if the 90% CI for the ratio of geometric means in AUC0-last, AUC0-inf, and Cmax was entirely contained within the PK equivalence bounds of 80% and 125% for the following comparisons: CT-P10 versus Rituxan, CT-P10 versus MabThera, and Rituxan versus MabThera.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric least squares means
	Estimated Value	95.81
	Confidence Interval	(2-Sided) 90%; 87.39 to 105.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimates (geometric least squares means and ratios of geometric means) were calculated by back-transforming the least squares means.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CT-P10 (Main Study Period), MabThera (Main Study Period)
	Comments	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.
	Type of Statistical Test	Equivalence
	Comments	The equivalence of PK was to be concluded if the 90% CI for the ratio of geometric means in AUC0-last, AUC0-inf, and Cmax was entirely contained within the PK equivalence bounds of 80% and 125% for the following comparisons: CT-P10 versus Rituxan, CT-P10 versus MabThera, and Rituxan versus MabThera.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric least squares means
	Estimated Value	89.89
	Confidence Interval	(2-Sided) 90%; 81.85 to 98.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimates (geometric least squares means and ratios of geometric means) were calculated by back-transforming the least squares means.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Rituxan (Main Study Period), MabThera (Main Study Period)
	Comments	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.
	Type of Statistical Test	Equivalence
	Comments	The equivalence of PK was to be concluded if the 90% CI for the ratio of geometric means in AUC0-last, AUC0-inf, and Cmax was entirely contained within the PK equivalence bounds of 80% and 125% for the following comparisons: CT-P10 versus Rituxan, CT-P10 versus MabThera, and Rituxan versus MabThera.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric least squares means
	Estimated Value	106.58
	Confidence Interval	(2-Sided) 90%; 97.03 to 117.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimates (geometric least squares means and ratios of geometric means) were calculated by back-transforming the least squares means.

3. Primary Outcome

Title	Analysis of Serum Cmax of Rituximab During the 1st Course of the Main Study Period (Over the First 24 Weeks) (ANCOVA)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	CT-P10 (Main Study Period)	Rituxan (Main Study Period)	MabThera (Main Study Period)
Arm/Group Description	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.	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..	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.
Measure Participants	62	59	59
Geometric Least Squares Mean (Standard Error) [ug/mL]	367.03 (1.042)	386.65 (1.042)	412.40 (1.043)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT-P10 (Main Study Period), Rituxan (Main Study Period)
	Comments	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.
	Type of Statistical Test	Equivalence
	Comments	The equivalence of PK was to be concluded if the 90% CI for the ratio of geometric means in AUC0-last, AUC0-inf, and Cmax was entirely contained within the PK equivalence bounds of 80% and 125% for the following comparisons: CT-P10 versus Rituxan, CT-P10 versus MabThera, and Rituxan versus MabThera.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric least squares means
	Estimated Value	94.92
	Confidence Interval	(2-Sided) 90%; 89.61 to 100.55
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimates (geometric least squares means and ratios of geometric means) were calculated by back-transforming the least squares means.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CT-P10 (Main Study Period), MabThera (Main Study Period)
	Comments	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.
	Type of Statistical Test	Equivalence
	Comments	The equivalence of PK was to be concluded if the 90% CI for the ratio of geometric means in AUC0-last, AUC0-inf, and Cmax was entirely contained within the PK equivalence bounds of 80% and 125% for the following comparisons: CT-P10 versus Rituxan, CT-P10 versus MabThera, and Rituxan versus MabThera.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric least squares means
	Estimated Value	89.00
	Confidence Interval	(2-Sided) 90%; 84.01 to 94.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimates (geometric least squares means and ratios of geometric means) were calculated by back-transforming the least squares means.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Rituxan (Main Study Period), MabThera (Main Study Period)
	Comments	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.
	Type of Statistical Test	Equivalence
	Comments	The equivalence of PK was to be concluded if the 90% CI for the ratio of geometric means in AUC0-last, AUC0-inf, and Cmax was entirely contained within the PK equivalence bounds of 80% and 125% for the following comparisons: CT-P10 versus Rituxan, CT-P10 versus MabThera, and Rituxan versus MabThera.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric least squares means
	Estimated Value	106.66
	Confidence Interval	(2-Sided) 90%; 100.56 to 113.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimates (geometric least squares means and ratios of geometric means) were calculated by back-transforming the least squares means.

4. Primary Outcome

Title	Analysis of Change From Baseline of DAS28 (CRP) at Week 24 (ANCOVA)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	CT-P10 (Main Study Period)	Reference Products (Main Study Period)
Arm/Group Description	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.	Reference products group: The combined Rituxan and MabThera groups. This group received 1000mg rituximab (Rituxan and MabThera) 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.
Measure Participants	138	196
Least Squares Mean (Standard Error) [score on a scale]	-2.11 (0.176)	-2.10 (0.178)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT-P10 (Main Study Period), Rituxan (Main Study Period)
	Comments	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.
	Type of Statistical Test	Equivalence
	Comments	Therapeutic equivalence was to be concluded if the 90% CI for the treatment difference in the change from baseline of DAS28 (CRP) at Week 24 was entirely within the equivalence margin of ±0.50.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 90%; -0.22 to 0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted least squares means and standard error, estimate of treatment difference [CT-P10 - (Rituxan + MabThera)] and 2-sided 90% confidence interval calculated from the ANCOVA model.

5. Secondary Outcome

Title	Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Main Study Period
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	CT-P10 (Main Study Period)	Rituxan (Main Study Period)	MabThera (Main Study Period)	Reference Products (Main Study Period)
Arm/Group Description	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.	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..	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.	Reference products group: The combined Rituxan and MabThera groups. This group received 1000mg rituximab (Rituxan and MabThera) 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.
Measure Participants	155	144	59	203
Week 0 (Baseline)	5.8 (0.91)	5.8 (0.92)	6.0 (0.87)	5.8 (0.91)
Week 24 (1st course Week 24)	-2.3 (1.06)	-2.3 (1.11)	-2.3 (1.30)	-2.3 (1.17)
Week 48 (2nd course Week 24)	-2.7 (1.17)	-2.6 (1.32)	-2.7 (1.32)	-2.6 (1.32)

6. Secondary Outcome

Title	Descriptive Statistics for Means (SD) for Baseline Value and Change From Baseline in Disease Activity Measured by DAS28 (CRP) of the Extension Study Period
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	CT-P10/CT-P10 (Extension Study Period)	Rituxan/Rituxan (Extension Study Period)	Rituxan/CT-P10 (Extension Study Period)	MabThera/CT-P10 (Extension Study Period)
Arm/Group Description	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.	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.	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.	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.
Measure Participants	120	64	60	47
Mean (Standard Deviation) [score on a scale]	-3.0 (1.20)	-3.0 (1.32)	-2.9 (1.27)	-3.0 (1.11)

7. Secondary Outcome

Title	Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Main Study Period
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	CT-P10 (Main Study Period)	Rituxan (Main Study Period)	MabThera (Main Study Period)	Reference Products (Main Study Period)
Arm/Group Description	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.	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..	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.	Reference products group: The combined Rituxan and MabThera groups. This group received 1000mg rituximab (Rituxan and MabThera) 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.
Measure Participants	155	144	59	203
Week 0 (Baseline)	6.7 (0.83)	6.7 (0.84)	6.8 (0.75)	6.7 (0.81)
Week 24 (1st course Week 24)	-2.5 (1.13)	-2.5 (1.13)	-2.3 (1.31)	-2.5 (1.18)
Week 48 (2nd course Week 24)	-2.9 (1.29)	-2.8 (1.42)	-2.9 (1.32)	-2.8 (1.39)

8. Secondary Outcome

Title	Descriptive Statistics for Actual Value and Change From Baseline in Disease Activity Measured by DAS28 (ESR) of the Extension Study Period
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	CT-P10/CT-P10 (Extension Study Period)	Rituxan/Rituxan (Extension Study Period)	Rituxan/CT-P10 (Extension Study Period)	MabThera/CT-P10 (Extension Study Period)
Arm/Group Description	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.	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.	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.	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.
Measure Participants	120	64	60	47
Mean (Standard Deviation) [score on a scale]	-3.3 (1.24)	-3.3 (1.41)	-3.2 (1.36)	-3.2 (1.15)

9. Secondary Outcome

Title	Analysis of B-cell Counts at Week 24 of the Main Study Period (ANCOVA)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	CT-P10 (Main Study Period)	Reference Products (Main Study Period)
Arm/Group Description	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.	Reference products group: The combined Rituxan and MabThera groups. This group received 1000mg rituximab (Rituxan and MabThera) 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.
Measure Participants	123	173
Geometric Least Squares Mean (Standard Error) [cells/mcL]	25.29 (1.074)	24.70 (1.073)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT-P10 (Main Study Period), Rituxan (Main Study Period)
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric least squares means
	Estimated Value	102.37
	Confidence Interval	(2-Sided) 95%; 92.46 to 113.33
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Estimate of Geometric Least Square Mean and ratio of Geometric Least Square Means (CT-P10/reference products) were obtained from back transforming the least square means from the ANCOVA.

Adverse Events

Time Frame	Serious adverse events (SAEs) and adverse events (AEs) were assessed from the date the informed consent form was signed until the participant's last visit, up to week 24 of extension period (up to week 72).
Adverse Event Reporting Description	At each level of summarization, a participant is counted only once if they reported one or more events. Only the most severe event is counted. SAEs and AEs are considered to have occurred in the Main Study Period if start date is before the first infusion of the Extension Study Period or if participant did not enter the Extension Study Period, and considered to have occurred in the Extension Study Period if the start date is on or after the date of first infusion of the Extension Study Period.
Arm/Group Title	CT-P10 (Main Study Period)		Rituxan (Main Study Period)		MabThera (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)
Arm/Group Description	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.		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.		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.		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. Throughout the study, MTX (7.5-25 mg/week orally or parenterally) and folic acid (≥ 5 mg/week) were coadministered.		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 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. Throughout the study, MTX (7.5-25 mg/week orally or parenterally) and folic acid (≥ 5 mg/week) were coadministered.		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 received 1000mg rituximab (CT-P10) by IV infusion 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.		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) by IV infusion 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.
All Cause Mortality
	CT-P10 (Main Study Period)		Rituxan (Main Study Period)		MabThera (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)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/161 (0.6%)		0/151 (0%)		0/60 (0%)		0/122 (0%)		0/64 (0%)		0/62 (0%)		0/47 (0%)
Serious Adverse Events
	CT-P10 (Main Study Period)		Rituxan (Main Study Period)		MabThera (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)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/161 (8.1%)		14/151 (9.3%)		4/60 (6.7%)		4/122 (3.3%)		0/64 (0%)		1/62 (1.6%)		0/47 (0%)
Blood and lymphatic system disorders
Leukopenia	0/161 (0%)	0	0/151 (0%)	0	1/60 (1.7%)	1	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Pancytopenia	1/161 (0.6%)	1	1/151 (0.7%)	1	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Gastrointestinal disorders
Colitis ischaemic	0/161 (0%)	0	1/151 (0.7%)	1	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Intestinal obstruction	0/161 (0%)	0	1/151 (0.7%)	1	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
General disorders
Chest pain	1/161 (0.6%)	1	0/151 (0%)	0	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Hepatobiliary disorders
Cholecystitis	1/161 (0.6%)	1	0/151 (0%)	0	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Cholelithiasis	1/161 (0.6%)	1	0/151 (0%)	0	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Infections and infestations
Cellulitis	1/161 (0.6%)	1	1/151 (0.7%)	1	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Localised infection	0/161 (0%)	0	1/151 (0.7%)	1	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Lower respiratory tract infection	0/161 (0%)	0	1/151 (0.7%)	1	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Pneumonia	1/161 (0.6%)	1	1/151 (0.7%)	1	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	1/62 (1.6%)	1	0/47 (0%)	0
Injury, poisoning and procedural complications
Fracture	4/161 (2.5%)	4	2/151 (1.3%)	2	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Injury	0/161 (0%)	0	2/151 (1.3%)	2	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Joint dislocation	0/161 (0%)	0	1/151 (0.7%)	1	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Infusion related reaction	0/161 (0%)	0	0/151 (0%)	0	0/60 (0%)	0	1/122 (0.8%)	1	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Ligament sprain	0/161 (0%)	0	0/151 (0%)	0	0/60 (0%)	0	1/122 (0.8%)	2	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/161 (0%)	0	1/151 (0.7%)	1	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Hand deformity	1/161 (0.6%)	1	0/151 (0%)	0	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Osteoarthritis	0/161 (0%)	0	0/151 (0%)	0	0/60 (0%)	0	3/122 (2.5%)	3	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	0/161 (0%)	0	0/151 (0%)	0	1/60 (1.7%)	1	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Bladder cancer	0/161 (0%)	0	1/151 (0.7%)	1	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Breast cancer	0/161 (0%)	0	1/151 (0.7%)	1	1/60 (1.7%)	1	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Lymphangioma	0/161 (0%)	0	0/151 (0%)	0	1/60 (1.7%)	1	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Nervous system disorders
Tremor	1/161 (0.6%)	1	0/151 (0%)	0	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Vertebrobasilar insufficiency	0/161 (0%)	0	1/151 (0.7%)	1	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Renal and urinary disorders
Acute kidney injury	1/161 (0.6%)	1	0/151 (0%)	0	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional	1/161 (0.6%)	1	0/151 (0%)	0	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Other (Not Including Serious) Adverse Events
	CT-P10 (Main Study Period)		Rituxan (Main Study Period)		MabThera (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)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	88/161 (54.7%)		72/151 (47.7%)		29/60 (48.3%)		27/122 (22.1%)		16/64 (25%)		17/62 (27.4%)		7/47 (14.9%)
Blood and lymphatic system disorders
Anaemia	6/161 (3.7%)	7	5/151 (3.3%)	5	2/60 (3.3%)	2	1/122 (0.8%)	1	0/64 (0%)	0	3/62 (4.8%)	3	1/47 (2.1%)	1
Gastrointestinal disorders
Abdominal pain	4/161 (2.5%)	4	5/151 (3.3%)	6	1/60 (1.7%)	3	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Infections and infestations
Upper respiratory tract infection	24/161 (14.9%)	32	30/151 (19.9%)	31	9/60 (15%)	12	10/122 (8.2%)	10	10/64 (15.6%)	10	8/62 (12.9%)	10	0/47 (0%)	0
Urinary tract infection	15/161 (9.3%)	23	8/151 (5.3%)	14	2/60 (3.3%)	2	8/122 (6.6%)	10	2/64 (3.1%)	2	2/62 (3.2%)	3	1/47 (2.1%)	1
Lower respiratory tract infection	10/161 (6.2%)	11	7/151 (4.6%)	9	3/60 (5%)	3	1/122 (0.8%)	1	3/64 (4.7%)	3	2/62 (3.2%)	2	2/47 (4.3%)	3
Rhinitis	3/161 (1.9%)	4	6/151 (4%)	6	1/60 (1.7%)	1	0/122 (0%)	0	1/64 (1.6%)	1	0/62 (0%)	0	0/47 (0%)	0
Infleunza	2/161 (1.2%)	2	0/151 (0%)	0	2/60 (3.3%)	2	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Gastroenteritis	3/161 (1.9%)	3	2/151 (1.3%)	2	0/60 (0%)	0	0/122 (0%)	0	0/64 (0%)	0	2/62 (3.2%)	2	0/47 (0%)	0
Vaginal infection	1/161 (0.6%)	1	1/151 (0.7%)	1	1/60 (1.7%)	1	0/122 (0%)	0	2/64 (3.1%)	2	0/62 (0%)	0	0/47 (0%)	0
Injury, poisoning and procedural complications
Infusion-related reaction	33/161 (20.5%)	39	12/151 (7.9%)	15	13/60 (21.7%)	15	4/122 (3.3%)	5	3/64 (4.7%)	3	2/62 (3.2%)	2	2/47 (4.3%)	3
Investigations
Alanine aminotransferase increased	5/161 (3.1%)	5	7/151 (4.6%)	10	0/60 (0%)	0	1/122 (0.8%)	1	0/64 (0%)	0	1/62 (1.6%)	2	0/47 (0%)	0
Metabolism and nutrition disorders
Hypertriglyceridaemia	7/161 (4.3%)	7	4/151 (2.6%)	5	1/60 (1.7%)	1	1/122 (0.8%)	1	1/64 (1.6%)	1	0/62 (0%)	0	0/47 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	5/161 (3.1%)	5	4/151 (2.6%)	5	1/60 (1.7%)	1	2/122 (1.6%)	2	0/64 (0%)	0	1/62 (1.6%)	1	0/47 (0%)	0
Nervous system disorders
Headache	8/161 (5%)	9	8/151 (5.3%)	9	2/60 (3.3%)	3	1/122 (0.8%)	1	0/64 (0%)	0	0/62 (0%)	0	1/47 (2.1%)	1
Psychiatric disorders
Depression	1/161 (0.6%)	1	1/151 (0.7%)	1	2/60 (3.3%)	2	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	3/161 (1.9%)	3	1/151 (0.7%)	1	3/60 (5%)	3	0/122 (0%)	0	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0
Vascular disorders
Hypertension	6/161 (3.7%)	6	4/151 (2.6%)	5	0/60 (0%)	0	1/122 (0.8%)	1	0/64 (0%)	0	0/62 (0%)	0	0/47 (0%)	0

Limitations/Caveats

[Not Specified]

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