Trial Outcomes & Findings for Comparative Pharmacokinetic, Pharmacodynamic, Safety and Efficacy Study of Three Anti-CD20 Monoclonal Antibodies in Patients With Moderate to Severe Rheumatoid Arthritis (NCT NCT02296775)

Last Updated: 2020-01-13

Results Overview

PK samples were collected pre-infusion; 3 hours post infusion; EOI; and at 1, 6, 24, 48, 168 hours post End of Infusion. A PK sample at 336 hours post EOI were also to be collected after the second dose.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

276 participants

Primary outcome timeframe

2 weeks

Results posted on

2020-01-13

Participant Flow

The study was conducted in 2 parts, a treatment and evaluation period (Part 1) and a recovery and follow-up period (Part 2). Study period was between November 2014 to June 2017 in a total of 29 sites across India and Ukraine.

The study was having 6 weeks screening period to accommodate 4 weeks washout/run-in stabilization and screening procedures.

Participant milestones

Participant milestones
Measure	DRL_RI (DRL Rituximab-Test Product Arm) DRL\_RI 500 mg/50 mL solution in a single-use vial. On Day 1, all randomized patients were received one dose of 1000 mg of assigned study drug as a slow IV infusion. The second infusion was administered on Day 15.	Rituxan® (US Licensed Reference Product) Rituxan® 500 mg/50 mL solution in a single-use vial. On Day 1, all randomized patients were received one dose of 1000 mg of assigned study drug as a slow IV infusion. The second infusion was administered on Day 15.	MabThera® (EU Approved Reference Medicinal Product) MabThera® 500 mg/50 mL solution in a single-use vial. On Day 1, all randomized patients were received one dose of 1000 mg of assigned study drug as a slow IV infusion. The second infusion was administered on Day 15.
Treatment and Evaluation STARTED	91	92	93
Treatment and Evaluation COMPLETED	87	84	83
Treatment and Evaluation NOT COMPLETED	4	8	10
Recovery and Follow-up STARTED	87	84	83
Recovery and Follow-up COMPLETED	82	79	79
Recovery and Follow-up NOT COMPLETED	5	5	4

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

All patients who receive at least one dose of study drug and provide at least the baseline (pre-infusion of infusion and one post-baseline assessment of PD endpoints will be included in the PD population. Patients with relevant protocol deviations thought to affect the evaluations of PD endpoints will not be included in the PD population.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	DRL- Rituximab-DRL_RI n=91 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=92 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=93 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Total n=276 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=91 Participants	0 Participants n=92 Participants	0 Participants n=93 Participants	0 Participants n=276 Participants
Age, Categorical Between 18 and 65 years	91 Participants n=91 Participants	92 Participants n=92 Participants	93 Participants n=93 Participants	276 Participants n=276 Participants
Age, Categorical >=65 years	0 Participants n=91 Participants	0 Participants n=92 Participants	0 Participants n=93 Participants	0 Participants n=276 Participants
Age, Continuous	44.1 years STANDARD_DEVIATION 10.96 • n=91 Participants	44.0 years STANDARD_DEVIATION 10.36 • n=92 Participants	45.5 years STANDARD_DEVIATION 10.41 • n=93 Participants	44.5 years STANDARD_DEVIATION 10.56 • n=276 Participants
Sex: Female, Male Female	81 Participants n=91 Participants	81 Participants n=92 Participants	81 Participants n=93 Participants	243 Participants n=276 Participants
Sex: Female, Male Male	10 Participants n=91 Participants	11 Participants n=92 Participants	12 Participants n=93 Participants	33 Participants n=276 Participants
Region of Enrollment Ukraine	13 Participants n=91 Participants	14 Participants n=92 Participants	15 Participants n=93 Participants	42 Participants n=276 Participants
Region of Enrollment India	78 Participants n=91 Participants	78 Participants n=92 Participants	78 Participants n=93 Participants	234 Participants n=276 Participants
Disease Activity Score-C Reactive Protein (DAS28-CRP)	6.031 Score on a scale STANDARD_DEVIATION 0.6702 • n=86 Participants • All patients who receive at least one dose of study drug and provide at least the baseline (pre-infusion of infusion and one post-baseline assessment of PD endpoints will be included in the PD population. Patients with relevant protocol deviations thought to affect the evaluations of PD endpoints will not be included in the PD population.	5.719 Score on a scale STANDARD_DEVIATION 0.7603 • n=86 Participants • All patients who receive at least one dose of study drug and provide at least the baseline (pre-infusion of infusion and one post-baseline assessment of PD endpoints will be included in the PD population. Patients with relevant protocol deviations thought to affect the evaluations of PD endpoints will not be included in the PD population.	5.831 Score on a scale STANDARD_DEVIATION 0.7024 • n=85 Participants • All patients who receive at least one dose of study drug and provide at least the baseline (pre-infusion of infusion and one post-baseline assessment of PD endpoints will be included in the PD population. Patients with relevant protocol deviations thought to affect the evaluations of PD endpoints will not be included in the PD population.	5.786 Score on a scale STANDARD_DEVIATION 0.7233 • n=257 Participants • All patients who receive at least one dose of study drug and provide at least the baseline (pre-infusion of infusion and one post-baseline assessment of PD endpoints will be included in the PD population. Patients with relevant protocol deviations thought to affect the evaluations of PD endpoints will not be included in the PD population.

PRIMARY outcome

Timeframe: 2 weeks

Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=218

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=74 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=72 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=72 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Area Under the Concentration-Time Curve From Time 0 to 336 Hours (AUC0-336) Post First Dose	49000 ug*h/ml Geometric Coefficient of Variation 27.1	49000 ug*h/ml Geometric Coefficient of Variation 25.4	51400 ug*h/ml Geometric Coefficient of Variation 24.1

PRIMARY outcome

Timeframe: 16 weeks

Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=212

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=73 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=71 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=68 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
AUC0-∞ Over the Entire Course of Therapy (2 Doses) From Day 1 Through Week 16.	189000 ug*h/ml Geometric Coefficient of Variation 33.2	189000 ug*h/ml Geometric Coefficient of Variation 34.0	201000 ug*h/ml Geometric Coefficient of Variation 30.1

PRIMARY outcome

Timeframe: 16 weeks

Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=220

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=76 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=71 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=73 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Area Under Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-t) (Second Dose).	139000 ug*h/ml Geometric Coefficient of Variation 37.3	137000 ug*h/ml Geometric Coefficient of Variation 37.2	146000 ug*h/ml Geometric Coefficient of Variation 33.5

SECONDARY outcome

Timeframe: 2 weeks

Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=218.

Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) ,and 168 hours (post-EOI).

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=74 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=72 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=72 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Maximum Plasma Concentration (Cmax) After First Dose	405.452 ug/ml Geometric Coefficient of Variation 24.5	388.017 ug/ml Geometric Coefficient of Variation 24.4	405.200 ug/ml Geometric Coefficient of Variation 30.1

SECONDARY outcome

Timeframe: 2 weeks

Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=224

Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI),6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , 168 (post-EOI), and 336 hours post EOI.

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=78 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=72 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=74 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Maximum Plasma Concentration (Cmax) After Second Dose	490.182 ug/ml Geometric Coefficient of Variation 28.1	470.237 ug/ml Geometric Coefficient of Variation 26.8	478.149 ug/ml Geometric Coefficient of Variation 24.7

SECONDARY outcome

Timeframe: 2 weeks

Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=218

Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , and 168 hours (post-EOI).

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=74 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=72 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=72 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Time to Cmax (Tmax) After First Dose.	5.25 Hours Interval 3.0 to 10.25	5.25 Hours Interval 4.25 to 10.33	5.25 Hours Interval 3.0 to 29.05

SECONDARY outcome

Timeframe: 2 weeks

Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=224

Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , and 168 hours (post-EOI).

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=78 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=72 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=74 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Time to Cmax (Tmax) After Second Dose	5.25 Hours Interval 3.0 to 10.33	5.25 Hours Interval 3.08 to 52.0	5.25 Hours Interval 3.0 to 27.25

SECONDARY outcome

Timeframe: 24 weeks

Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=230

Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , 168 (post-EOI), 336 hours (post-EOI), 4 weeks, 6 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, and 22 weeks relative to infusion.

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=79 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=73 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=78 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Volume of Distribution (Vz)	5.69 L Geometric Coefficient of Variation 26.3	5.76 L Geometric Coefficient of Variation 23.1	5.55 L Geometric Coefficient of Variation 26.4

SECONDARY outcome

Timeframe: 24 weeks

Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=230

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=79 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=73 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=78 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Systemic Clearance (CL)	0.254 L/day Geometric Coefficient of Variation 33.2	0.254 L/day Geometric Coefficient of Variation 33.9	0.238 L/day Geometric Coefficient of Variation 30.0

SECONDARY outcome

Timeframe: 24 weeks

Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=230

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=79 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=73 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=78 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Terminal Half-life (t1/2)	374 h Geometric Coefficient of Variation 30.1	378 h Geometric Coefficient of Variation 25.0	391 h Geometric Coefficient of Variation 23.9

SECONDARY outcome

Timeframe: Baseline and 4 weeks

In clinical studies, Disease Activity Score (DAS) is used to assess improvement in disease activity in RA patients over time. The assessment involved an examination of 28 joints for swelling, tenderness, blood C-reactive protein (CRP), and a one on one consultation between the patient and healthcare professional. The results were combined to produce a score which indicated how active the RA was at that particular time. The disease activity is interpreted as low (DAS \<2.6), mild (2.6 to \<3.2), moderate (3.2 to \<5.1), and severe with DAS \> 5.1. A DAS score between 0 and 2.6 corresponds to remission. The analysis of DAS28-CRP was based on a generalized estimating equation model in RA patients with DAS28 score \> 3.2. The mean change was calculated from two time points (Value at 4 weeks minus baseline value).

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=85 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=85 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=83 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Mean Change in Disease Activity Score-C Reactive Protein (DAS28-CRP) From Baseline Per Unit Time at Weeks 4	-1.004 units on a scale Standard Deviation 0.9955	-0.871 units on a scale Standard Deviation 0.7918	-0.96 units on a scale Standard Deviation 0.9125

SECONDARY outcome

Timeframe: Baseline and 8 weeks

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=85 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=85 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=83 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Mean Change in DAS28-CRP From Baseline Per Unit Time at 8 Weeks.	-1.379 units on a scale Standard Deviation 1.0274	-1.192 units on a scale Standard Deviation 0.8635	-1.424 units on a scale Standard Deviation 1.1764

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=82 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=84 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=82 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Mean Change in DAS28-CRP From Baseline Per Unit Time at Week 12.	-1.652 units on a scale Standard Deviation 1.1405	1.443 units on a scale Standard Deviation 0.9648	-1.718 units on a scale Standard Deviation 1.153

SECONDARY outcome

Timeframe: Baseline and 16 weeks

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=83 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=85 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=82 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Mean Change in Disease Activity Score- C Reactive Protein (DAS28-CRP) From Baseline Per Unit Time at Week 16.	-1.892 units on a scale Standard Deviation 1.1257	-1.49 units on a scale Standard Deviation 1.0222	-1.814 units on a scale Standard Deviation 1.2105

SECONDARY outcome

Timeframe: 48 hours

The time to depletion and repletion of peripheral blood cell counts (determined by CD19+ cell counts) as well as the B-cell counts at selected time points (taking into consideration the patient baseline count) were used to assess the PD of the study drugs.

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=86 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=87 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=86 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Percentage of Patients With B-cell Counts 20% Below the Lower Limit of Normal	98.8 Percentage of participants	100 Percentage of participants	100 Percentage of participants

SECONDARY outcome

Timeframe: 16 weeks

Analysis of the PD parameter peripheral B-Cell count was performed by evaluating the 95% CI for the difference between treatment arms in the percentage of patients with B-cell depletion at 48 hours after dose 1, Week 16, and at Week 24. Percentage of patients with B-cell repletion at each evaluation time is also reported and descriptively compared.

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=86 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=87 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=86 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Percentage of Patients With Peripheral B-cell Counts Depletion at Week 16.	10.0 percentage of participants	4.9 percentage of participants	10.1 percentage of participants

SECONDARY outcome

Timeframe: 24 weeks

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=86 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=87 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=86 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Percentage of Patients With Peripheral B-cell Counts Depletion at Week 24.	0.0 percentage of participants	3.7 percentage of participants	1.3 percentage of participants

SECONDARY outcome

Timeframe: 24 weeks

Percentage of the patients with at least 20% improvement in counts of tender, swollen joints and in 3 of the following: patient's assessment of pain, patient's global assessment of disease activity, patient's assessment of physical function, the physician's global assessment of disease activity, and acute phase reactant. Adjusted response rates for the treatment arms using the logistic regression analysis including treatment, gender and region as fixed effects and patients as random effect in the model.

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=59 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=56 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=54 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Percentage of Patients With ACR20 at Week 24	72 Percentage of participants	69.1 Percentage of participants	68.4 Percentage of participants

SECONDARY outcome

Timeframe: 24 weeks

Percentage of the patients with at least 50% improvement in counts of tender, swollen joints and in 3 of the following: patient's assessment of pain, patient's global assessment of disease activity, patient's assessment of physical function, the physician's global assessment of disease activity, and acute phase reactant. Adjusted Response rates for the treatment arms using the logistic regression analysis including treatment, gender and region as fixed effects and patients as random effect in the model.

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=36 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=32 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=34 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Percentage of Patients With ACR50 at Week 24	43.9 Percentage of participants	39.5 Percentage of participants	43.0 Percentage of participants

SECONDARY outcome

Timeframe: 24 weeks

Percentage of the patients with at least 70% improvement in counts of tender, swollen joints and in 3 of the following: patient's assessment of pain, patient's global assessment of disease activity, patient's assessment of physical function, the physician's global assessment of disease activity, and acute phase reactant. Adjusted Response rates for the treatment arms using the logistic regression analysis including treatment, gender and region as fixed effects and patients as random effect in the model.

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=14 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=12 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=12 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Percentage of Patients With ACR70 Response at Week 24	17.1 Percentage of participants	14.8 Percentage of participants	15.2 Percentage of participants

SECONDARY outcome

Timeframe: 24 weeks

The health assessment questionnaire disability index (HAQ-DI) was assessed at Week 24. The disability assessment component of the HAQ, the HAQ-DI, assessed a patient's level of functional ability and included questions about fine movements of the upper extremities, locomotor activities of the lower extremities, and activities that involved both upper and lower extremities. There were 20 questions in 8 categories of functioning which represented a comprehensive set of functional activities-dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. The stem of each item asked over the past week "Were you able to" perform a particular task. The patient's responses were made on a scale from 0 (no disability) to 3 (completely disabled). Each category contained at least 2 specific component questions. Physical function was measured using the HAQ-DI Scores, which range from 0-3, with lower scores reflecting better physical function and thus, less disability.

Outcome measures

Outcome measures
Measure	DRL- Rituximab-DRL_RI n=82 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=81 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=79 Participants On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Change From Baseline in HAQ-DI at Week 24.	0.742 score on a scale Standard Deviation 0.60603	0.691 score on a scale Standard Deviation 0.62598	0.726 score on a scale Standard Deviation 0.5659

Adverse Events

DRL- Rituximab-DRL_RI

Serious events: 3 serious events

Other events: 60 other events

Deaths: 2 deaths

Rituxan® (US Licensed Reference Product): RP

Serious events: 5 serious events

Other events: 58 other events

Deaths: 0 deaths

MabThera® (EU Approved Reference Medicinal Product): RMP

Serious events: 10 serious events

Other events: 66 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Dr. Ankit Ranpura, MD (Associate Director- Clinical Development)

Dr. Reddy's Laboratories Ltd, Biologics Survey No. 47, Bachupally Village, Bachupally Mandal, Medchal Malkajgiri District Telangana, India - 500 090

Phone: 040 4464 4000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	DRL- Rituximab-DRL_RI n=91 participants at risk On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	Rituxan® (US Licensed Reference Product): RP n=92 participants at risk On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.	MabThera® (EU Approved Reference Medicinal Product): RMP n=93 participants at risk On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen.
Infections and infestations H1N1 Influenza	0.00% 0/91 • Baseline up to end of the study (52 weeks)	0.00% 0/92 • Baseline up to end of the study (52 weeks)	1.1% 1/93 • Number of events 1 • Baseline up to end of the study (52 weeks)
Infections and infestations Penumonia	1.1% 1/91 • Number of events 1 • Baseline up to end of the study (52 weeks)	0.00% 0/92 • Baseline up to end of the study (52 weeks)	0.00% 0/93 • Baseline up to end of the study (52 weeks)
Infections and infestations Urinary Tract Infection	0.00% 0/91 • Baseline up to end of the study (52 weeks)	0.00% 0/92 • Baseline up to end of the study (52 weeks)	1.1% 1/93 • Number of events 1 • Baseline up to end of the study (52 weeks)
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/91 • Baseline up to end of the study (52 weeks)	0.00% 0/92 • Baseline up to end of the study (52 weeks)	1.1% 1/93 • Number of events 1 • Baseline up to end of the study (52 weeks)
Injury, poisoning and procedural complications Forearm fracture	0.00% 0/91 • Baseline up to end of the study (52 weeks)	0.00% 0/92 • Baseline up to end of the study (52 weeks)	1.1% 1/93 • Number of events 1 • Baseline up to end of the study (52 weeks)
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/91 • Baseline up to end of the study (52 weeks)	1.1% 1/92 • Number of events 1 • Baseline up to end of the study (52 weeks)	0.00% 0/93 • Baseline up to end of the study (52 weeks)
Injury, poisoning and procedural complications Infusion related reaction	0.00% 0/91 • Baseline up to end of the study (52 weeks)	1.1% 1/92 • Number of events 1 • Baseline up to end of the study (52 weeks)	0.00% 0/93 • Baseline up to end of the study (52 weeks)
Blood and lymphatic system disorders Febile neutropenia	0.00% 0/91 • Baseline up to end of the study (52 weeks)	1.1% 1/92 • Number of events 1 • Baseline up to end of the study (52 weeks)	0.00% 0/93 • Baseline up to end of the study (52 weeks)
Blood and lymphatic system disorders Neutropenia	0.00% 0/91 • Baseline up to end of the study (52 weeks)	1.1% 1/92 • Number of events 1 • Baseline up to end of the study (52 weeks)	0.00% 0/93 • Baseline up to end of the study (52 weeks)
Cardiac disorders Atrial fibrillation	0.00% 0/91 • Baseline up to end of the study (52 weeks)	1.1% 1/92 • Number of events 1 • Baseline up to end of the study (52 weeks)	1.1% 1/93 • Number of events 1 • Baseline up to end of the study (52 weeks)
Cardiac disorders Cardio-respiratory arrest	0.00% 0/91 • Baseline up to end of the study (52 weeks)	0.00% 0/92 • Baseline up to end of the study (52 weeks)	1.1% 1/93 • Number of events 1 • Baseline up to end of the study (52 weeks)
General disorders Pyrexia	0.00% 0/91 • Baseline up to end of the study (52 weeks)	0.00% 0/92 • Baseline up to end of the study (52 weeks)	1.1% 1/93 • Number of events 1 • Baseline up to end of the study (52 weeks)
General disorders Sudden death	1.1% 1/91 • Number of events 1 • Baseline up to end of the study (52 weeks)	0.00% 0/92 • Baseline up to end of the study (52 weeks)	0.00% 0/93 • Baseline up to end of the study (52 weeks)
Gastrointestinal disorders Intestinal obstruction	0.00% 0/91 • Baseline up to end of the study (52 weeks)	1.1% 1/92 • Number of events 1 • Baseline up to end of the study (52 weeks)	0.00% 0/93 • Baseline up to end of the study (52 weeks)
Respiratory, thoracic and mediastinal disorders Intestitial lung disease	0.00% 0/91 • Baseline up to end of the study (52 weeks)	0.00% 0/92 • Baseline up to end of the study (52 weeks)	1.1% 1/93 • Number of events 1 • Baseline up to end of the study (52 weeks)
Infections and infestations Cellulitis	0.00% 0/91 • Baseline up to end of the study (52 weeks)	0.00% 0/92 • Baseline up to end of the study (52 weeks)	1.1% 1/93 • Number of events 1 • Baseline up to end of the study (52 weeks)
Infections and infestations Gastroenteritis viral	0.00% 0/91 • Baseline up to end of the study (52 weeks)	0.00% 0/92 • Baseline up to end of the study (52 weeks)	1.1% 1/93 • Number of events 1 • Baseline up to end of the study (52 weeks)
Infections and infestations Pyelonephritis acute	0.00% 0/91 • Baseline up to end of the study (52 weeks)	0.00% 0/92 • Baseline up to end of the study (52 weeks)	1.1% 1/93 • Number of events 1 • Baseline up to end of the study (52 weeks)
Injury, poisoning and procedural complications Spinal cord compression fracture	0.00% 0/91 • Baseline up to end of the study (52 weeks)	1.1% 1/92 • Number of events 1 • Baseline up to end of the study (52 weeks)	0.00% 0/93 • Baseline up to end of the study (52 weeks)
Musculoskeletal and connective tissue disorders Spondylolisthesis	0.00% 0/91 • Baseline up to end of the study (52 weeks)	0.00% 0/92 • Baseline up to end of the study (52 weeks)	1.1% 1/93 • Number of events 1 • Baseline up to end of the study (52 weeks)
General disorders Death	1.1% 1/91 • Number of events 1 • Baseline up to end of the study (52 weeks)	0.00% 0/92 • Baseline up to end of the study (52 weeks)	0.00% 0/93 • Baseline up to end of the study (52 weeks)