A Study of Rituximab (MabThera) Subcutaneous (SC) Versus Rituximab (MabThera) Intravenous in Participannts With Follicular Non-Hodgkin's Lymphoma

A Two-Stage Phase III, International, Multi-Center, Randomized, Controlled, Open-Label Study to Investigate the Pharmacokinetics, Efficacy and Safety of Rituximab SC in Combination With CHOP or CVP Versus Rituximab IV in Combination With CHOP or CVP in Patients With Previously Untreated Follicular Lymphoma Followed by Maintenance Treatment With Either Rituximab SC or Rituximab IV

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01200758

Enrollment

410

Registered

2010-09-14

Start date

2011-02-15

Completion date

2017-10-31

Last updated

2018-11-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Non-Hodgkin's Lymphoma

Brief summary

This two-stage, multi-center, randomized, controlled, open-label study will investigate the pharmacokinetics, efficacy and safety of rituximab SC versus rituximab IV in participants with previously untreated follicular non-Hodgkin's lymphoma. Participants will be randomized to receive 375 milligrams per meter square (mg/m\^2) rituximab as IV infusion or 1400 milligrams (mg) rituximab SC. In addition, participants will receive standard chemotherapy. Participants who achieved a complete or partial response (PR) after 8 treatment cycles, will receive maintenance treatment for a further maximum number of 12 cycles. Maintenance treatment cycles will be repeated every 8 weeks. This is a two-stage study. Stage 1 was designed to confirm the chosen rituximab SC dose resulting in comparable rituximab serum Ctrough levels compared with rituximab IV, when given as part of induction treatment every 3 weeks. Enrollment for Stage 2 started after the rituximab SC dose was established in Stage 1. Stage 2 aimed to further investigate the efficacy and safety of rituximab SC compared with rituximab IV. The anticipated time on study treatment is 96 weeks.

Interventions

DRUGRituximab SC

First cycle of rituximab IV infusion (375 mg/m\^2) + 7 cycles of rituximab SC (1400 mg; rituximab induction) in administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.

DRUGRituximab IV

Eight cycles of rituximab IV infusion (375 mg/m\^2; rituximab induction) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m\^2) once every 8 weeks for 24 months.

DRUGCyclophosphamide

Eight cycles of cyclophosphamide (750 mg/m\^2 IV) administered every 3 weeks.

DRUGDoxorubicin

Eight cycles of doxorubicin (50 mg/m\^2 IV) administered every 3 weeks.

DRUGVincristine

Eight cycles of doxorubicin (1.4 mg/m\^2 IV) administered every 3 weeks.

DRUGPrednisone/Prednisolone

Eight cycles of prednisone/prednisolone (100 mg/day or 40 mg/m\^2/day IV/orally) administered Days 1 to 5 of every 21 days cycle.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Cluster of differentiation 20 (CD20)-positive, follicular Non-Hodgkin's lymphoma grade 1, 2, 3a. A tumor biopsy must have been performed within 6 months before study entry with material available for central review * No prior treatment * Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Exclusion criteria

* Grade 3b follicular lymphoma * Transformation to high-grade lymphoma secondary to follicular lymphoma * Types of Non-Hodgkin's lymphoma other than follicular lymphoma * Presence or history of central nervous system (CNS) disease * Corticoid therapy during the last 4 weeks, except prednisone treatment less than (\<) 20 milligrams per day (mg per day) * Known active bacterial, viral, fungal, or mycobacterial, or any major episode of infections requiring hospitalization or treatment with IV antibiotics within 4 weeks of start of study medication, or oral antibiotics within 2 weeks prior to start of study medication

Design outcomes

Primary

Measure	Time frame	Description
Stage I: Trough Serum Concentrations (Ctrough) of IV and SC Rituximab	Stage I: Cycle (Cy) 7 Day (D) 21 (within 2 hours predose on Cy8) of induction treatment (1 Cy=3 weeks)	—
Stage II: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for Non-Hodgkin Lymphoma (NHL)	Stage II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)	Overall Response comprised complete response (CR), CR unconfirmed (CRu), or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and computed tomography (CT) scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by more than (\>) 75% in the sum of the products of greatest diameters (SPD); PR: Greater than or equal to (≥) 50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI was estimated for one sample binomial using Pearson-Clopper.

Secondary

Measure	Time frame	Description
Stage I: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	Stage I: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)	Complete Response was comprised CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by \>75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.
Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	Stage II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)	Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by \>75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.
Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	Stage I and II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)	Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by \>75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.
Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL	Stage I and II: Baseline up to 57 days after last maintenance dose (last maintenance dose: maintenance Cy12/Study Cy20 [30 months]) (up to data cutoff of 31 Oct 2017 [up to 6 years]) (1 Cy=8 weeks)	Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by \>75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.
Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL	Stage I and II: Baseline up to 57 days after last maintenance dose (last maintenance dose: maintenance Cy12/Study Cy20 [30 months]) (up to data cutoff of 31 Oct 2017 [up to 6 years]) (1 Cy=8 weeks)	Overall Response comprised of CR, CRu, or PR . A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by \>75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.
Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse or Death	Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)	Disease progression: ≥50% increase from nadir in the SPD of any previously identified abnormal node or appearance of any new lesion during or at the end of therapy or ≥50% increase in the greatest diameter of any previously identified node \>1 cm in its short axis or in the SPD of more than one node. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to median of 27 months; up to data cutoff of 31 Oct 2017 \[up to 6 years\])
Stage I and II (Pooled): Progression-Free Survival (PFS) Assessed Using International Working Group Response Criteria for NHL	Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)	PFS was defined as the time from randomization to disease progression/relapse or death due to any cause. If the specified event (disease progression/relapse, death) did not occur, PFS was censored at the last tumor assessment date showing no disease progression, either during treatment or follow-up. Disease progression: ≥50% increase from nadir in the SPD of any previously identified abnormal node or appearance of any new lesion during or at the end of therapy or ≥50% increase in the greatest diameter of any previously identified node \>1 cm in its short axis or in the SPD of more than one node. PFS analysis was performed using Kaplan - Meier curves. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to median of 27 months; up to data cutoff of 31 Oct 2017 \[up to 6 years\])
Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse, New Anti-Lymphoma Treatment or Death Assessed Using International Working Group Response Criteria for NHL	Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)	Disease progression: ≥50% increase from nadir in the SPD of any previously identified abnormal node or appearance of any new lesion during or at the end of therapy or ≥50% increase in the greatest diameter of any previously identified node \>1 cm in its short axis or in the SPD of more than one node. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to a median of 27 months; up to data cutoff of 31 Oct 2017 \[up to 6 years\])
Stage I and II (Pooled): Event-Free Survival Assessed Using International Working Group Response Criteria for NHL	Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)	Event-free survival was defined as the time from randomization to disease progression/relapse, death or initiation of new NHL therapy. If the specified event (progression/relapse, death or new anti-lymphoma treatment) did not occur, event-free survival was censored at the last tumor assessment date either during treatment or follow up. Event-free survival analysis was performed using Kaplan-Meier curves. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to a median of 27 months; up to data cutoff of 31 Oct 2017 \[up to 6 years\])
Percentage of Participants Who Died	Baseline up to death (up to data cutoff of 31 Oct 2017 [up to 6 years])	—
Overall Survival (OS)	Baseline up to death (up to data cutoff of 31 Oct 2017 [up to 6 years])	OS was defined as the time from randomization to death due to any cause. Participants without event were censored at the time of last follow-up information for survival, ie, at the last time known to be alive.
Stage I: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	Stage I: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)	Overall Response comprised CR, CRu, or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by \>75% in the SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI was estimated for one sample binomial using Pearson-Clopper.
Stage I: Maximum Serum Concentrations (Cmax) of IV and SC Rituximab	Stage I (Induction): Predose (within 2hr) up to data cutoff of 11 Apr 2012 [up to 26 months]) (See detailed timeframe in Outcome Measure description)	Predose (within 2 hr) and 24 hrs postdose on Cy7 (D1,3,7,15), predose (0 hr) on Cy8 D1 (1 Cy=3 weeks); additionally within 15 minutes after end of infusion (infusion duration=30 minutes) on Cy7 D1 for rituximab IV (up to data cutoff of 11 Apr 2012 \[up to 26 months\])
Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Stage I and II (Pooled): Predose (within 2hr) up to data cutoff of 31 Oct 2013 [up to 32 months]) (See detailed timeframe in Outcome Measure description)	Stage I and II (Induction): Rituximab IV: Predose (within 2 hr) on D1 of Cy1-8 (1 Cy=3 weeks & 4 weeks for Cy8); Rituximab SC: Predose (within 2 hr) on D1 of Cy1 & Cy3-8 (1 Cy=3 weeks and 4 weeks for Cy8), predose (within 2 hr) on D0 of Cy2 (up to data cutoff of 31 Oct 2013 \[up to 32 months\])
Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Stage I and II (maintenance): Predose (within 2hr) up to data cutoff of 11 Jan 2016 [up to 6 years]) (See detailed timeframe in Outcome Measure description)	Stage I and II (maintenance): D29 of Cy8 (induction; 1 Cy=4 weeks), predose (within 2 hr) on D1 of Cy9 to 19 (maintenance Cy1 to 12 \[1 Cy=8 weeks\]; up to data cutoff of 11 Jan 2016 \[up to 6 years\])
Stage I and II (Pooled): Rituximab Levels 12 Weeks, 24 Weeks, and 36 Weeks After the Last Rituximab Administration	12 weeks, 24 weeks, and 36 weeks after the last rituximab administration (up to data cutoff of 11 Jan 2016 [up to 6 years])	—
Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Stage I and II (induction): for rituximab IV - D1 of Cy 1 to 8 (1 Cy=3 weeks); for rituximab SC - D1 of Cy 1 and Cy 3 to 8, D0 of Cy 2	Depletion is defined as a cluster of differentiation (CD) 19 value \<80 cells per cubic millimeter (cells/mm\^3).
Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Stage I and II (maintenance): D1 of Cy 9 to 20 (1 Cy=8 weeks) (up to data cutoff of 11 Jan 2016 [up to 6 years])	Depletion is defined as a CD19 value \<80 cells/mm\^3.
Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Chimeric Antibodies (HACAs) to Rituximab	Stage I and II: Baseline, post-baseline (See detailed timeframe in Outcome Measure description)	Levels of HACA in serum were detected at Day 1 of each cycle up to Cycle 8 and at follow-up visit. Stage I and II: Baseline: pre-dose (72 hours prior) D1 of Cy1, Cy 3-20, D0 of Cy2 (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), post-baseline: every 12 weeks after last rituximab administration until 96 weeks (a median of 27 months; up to data cutoff of 11 Jan 2016 \[up to 6 years\])
Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Human Antibodies (HAHAs) to Rituximab	Stage I and II: Baseline, post-baseline (See detailed timeframe in Outcome Measure description)	Levels of HAHA in serum were detected at Day 1 of each cycle up to Cycle 8 and at follow-up visit. Stage I and II: Baseline: pre-dose (72 hours prior) D1 of Cy1, Cy 3-20, D0 of Cy2 (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), post-baseline: every 12 weeks after last rituximab administration until 96 weeks (a median of 27 months; up to data cutoff of 11 Jan 2016 \[up to 6 years\])
Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cycle 8 of induction treatment (24 weeks) and during the maintenance part of the study after 12 months (i.e., Cycle 15), and after the end of the maintenance treatment, (i.e., Cycle 20) (1 Cycle=4 weeks for Cycle 8 and 8 weeks for Cycles 15 and 20)	All investigator physicians and nurses involved in this study were asked to provide the staff time that could be saved with each administration of rituximab SC as compared with rituximab IV to participants in routine practice afetr Cy 8, 15, 20 and categorized as less than (\<) 1 hr, at least 1 hr but \<2 hrs, at least 2 hrs but \<3 hrs, at least 3 hrs but \<4 hrs, \>/=4 hrs. Staff were asked not to consider the time needed for the first IV administration. Analysis was done in all participants to show a comparison on the time saved by staffs when administered via SC and IV.
Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	After Cycle 8 of induction treatment (24 weeks) and during the maintenance part of the study after 12 months (i.e., Cycle 15), and after the end of the maintenance treatment, (i.e., Cycle 20) (1 Cycle=4 weeks for Cycle 8 and 8 weeks for Cycles 15 and 20)	All investigator physicians and nurses involved in this study were asked to complete question i.e. Which formulation of rituximab (SC or IV) do you think is more convenient? based on their experience with the rituximab SC and IV formulations across all participants and presented as rituximab SC is much more convenient; rituximab SC is a little more convenient; both formulations are equally convenient; rituximab IV is a little more convenient; and rituximab IV is much more convenient.
Stage I: Observed Area Under the Serum Concentration-Time Curve (AUC) of Rituximab	Stage I (Induction): Predose (within 2 hour [hr]) up to data cutoff of 11 Apr 2012 [up to 26 months]) (See detailed timeframe in Outcome Measure description)	AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. Predose (within 2 hr) and 24 hrs postdose on Cy 7 (D1,3,7,15), predose (0 hr) on Cy 8 D1 (1 Cy=3 weeks); additionally within 15 minutes after end of infusion (infusion duration=30 minutes) on Cy 7 D1 for rituximab IV (up to data cutoff of 11 Apr 2012 \[up to 26 months\])
Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	Stage I and II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)	Overall Response comprised of CR, CRu, or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumour response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by \>75% in SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.

Countries

Australia, Belgium, Bosnia and Herzegovina, Brazil, Bulgaria, Canada, Colombia, Croatia, Denmark, Finland, France, Georgia, Germany, Greece, Italy, Malaysia, Mexico, New Zealand, North Macedonia, Peru, Romania, Russia, Serbia, Singapore, Slovakia, South Africa, Spain, Thailand, Turkey (Türkiye), United Kingdom

Participant flow

Pre-assignment details

Screening/baseline tests were performed within 28 days before randomization. Randomization was centralized in a 1:1 fashion using the Pocock and Simon dynamic randomization algorithm. The study was conducted in 2 stages: Stage I & II. All participants irrespective of the treatment period completion commenced follow-up period in both Stage I and II.

Participants by arm

Arm	Count
Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Eight cycles of rituximab IV infusion (375 mg/m\^2; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m\^2) once every 8 weeks for 24 months.	205
Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP) First cycle rituximab IV infusion (375 mg/m\^2) + 7 cycles of rituximab SC 1400 mg in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.	205
Total	410

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Stage 2	Adverse Event	0	0	5	9
Stage 2	Death	0	0	3	5
Stage 2	Disease Progression	0	0	16	21
Stage 2	Lack of Efficacy	0	0	4	2
Stage 2	Lost to Follow-up	0	0	3	1
Stage 2	Physician Decision	0	0	5	7
Stage 2	Protocol Violation	0	0	1	4
Stage 2	Withdrawal by Subject	0	0	4	1
Stage I	Adverse Event	5	5	0	0
Stage I	Death	0	1	0	0
Stage I	Disease Progression	9	7	0	0
Stage I	Lack of Efficacy	2	1	0	0
Stage I	Physician Decision	1	1	0	0
Stage I	Withdrawal by Subject	1	2	0	0

Baseline characteristics

Characteristic	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)	Total
Age, Continuous	56.9 years STANDARD_DEVIATION 12.69	56.1 years STANDARD_DEVIATION 12.66	56.5 years STANDARD_DEVIATION 12.67
Sex: Female, Male Female	99 Participants	120 Participants	219 Participants
Sex: Female, Male Male	106 Participants	85 Participants	191 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	187 / 210	186 / 197
serious Total, serious adverse events	76 / 210	74 / 197

Outcome results

Primary

Stage II: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for Non-Hodgkin Lymphoma (NHL)

Overall Response comprised complete response (CR), CR unconfirmed (CRu), or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and computed tomography (CT) scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by more than (\>) 75% in the sum of the products of greatest diameters (SPD); PR: Greater than or equal to (≥) 50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI was estimated for one sample binomial using Pearson-Clopper.

Time frame: Stage II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)

Population: Stage II ITT Population included all participants who were randomized in Stage II irrespective whether they received study drug or not.

Arm	Measure	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage II: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for Non-Hodgkin Lymphoma (NHL)	85.1 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage II: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for Non-Hodgkin Lymphoma (NHL)	80.3 percentage of participants

p-value: 0.283595% CI: [-14, 4.4]Chi-squared

95% CI: [0.38, 1.33]

Primary

Stage I: Trough Serum Concentrations (Ctrough) of IV and SC Rituximab

Time frame: Stage I: Cycle (Cy) 7 Day (D) 21 (within 2 hours predose on Cy8) of induction treatment (1 Cy=3 weeks)

Population: Stage I pharmacokinetic (PK) evaluable population comprised all participants with data for Ctrough available at Cycle 7 and/or observed area under the serum concentration-time curve (AUC) available at Cycle 7. Participants were analyzed as per treatment received. Number of participants analyzed = participants analyzed for this outcome measure.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I: Trough Serum Concentrations (Ctrough) of IV and SC Rituximab	83.1 micrograms per milliliter (mcg/mL)	Geometric Coefficient of Variation 36.7
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I: Trough Serum Concentrations (Ctrough) of IV and SC Rituximab	134.6 micrograms per milliliter (mcg/mL)	Geometric Coefficient of Variation 43.2

90% CI: [1.36, 1.94]

Secondary

Overall Survival (OS)

OS was defined as the time from randomization to death due to any cause. Participants without event were censored at the time of last follow-up information for survival, ie, at the last time known to be alive.

Time frame: Baseline up to death (up to data cutoff of 31 Oct 2017 [up to 6 years])

Population: ITT population.

Arm	Measure	Value (MEDIAN)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Overall Survival (OS)	NA days
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Overall Survival (OS)	NA days

Secondary

Percentage of Participants Who Died

Time frame: Baseline up to death (up to data cutoff of 31 Oct 2017 [up to 6 years])

Population: ITT population.

Arm	Measure	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants Who Died	12.7 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants Who Died	8.8 percentage of participants

Secondary

Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase

Depletion is defined as a cluster of differentiation (CD) 19 value \<80 cells per cubic millimeter (cells/mm\^3).

Time frame: Stage I and II (induction): for rituximab IV - D1 of Cy 1 to 8 (1 Cy=3 weeks); for rituximab SC - D1 of Cy 1 and Cy 3 to 8, D0 of Cy 2

Population: ITT Population. Here, number of participants analyzed = participants evaluable for the outcome measure. Here n = number of participants evaluable for this outcome measure at specified timepoint.

Arm	Measure	Group	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 1 Day 1 - Baseline (n=188, 168)	51.6 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 2 Day 0 (n=183, 180)	95.1 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 3 Day 1 (n=175, 175)	99.4 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 4 Day 1 (n=178, 180)	99.4 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 5 Day 1 (n=179, 176)	100.0 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 6 Day 1 (n=173, 175)	100.0 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 7 Day 1 (n=178, 173)	100.0 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 8 Day 1 (n=175, 174)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 8 Day 1 (n=175, 174)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 1 Day 1 - Baseline (n=188, 168)	54.8 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 5 Day 1 (n=179, 176)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 2 Day 0 (n=183, 180)	95.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 7 Day 1 (n=178, 173)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 3 Day 1 (n=175, 175)	99.4 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 6 Day 1 (n=173, 175)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Cycle 4 Day 1 (n=178, 180)	100.0 percentage of participants

Secondary

Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase

Depletion is defined as a CD19 value \<80 cells/mm\^3.

Time frame: Stage I and II (maintenance): D1 of Cy 9 to 20 (1 Cy=8 weeks) (up to data cutoff of 11 Jan 2016 [up to 6 years])

Arm	Measure	Group	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 10 Day 1 (n=165, 164)	99.4 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 9 Day 1 (n=170, 161)	99.4 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 11 Day 1 (n=158, 158)	99.4 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 12 Day 1 (n=151, 146)	100.0 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 13 Day 1 (n=149, 143)	100.0 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 14 Day 1 (n=152, 143)	100.0 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 15 Day 1 (n=149, 140)	100.0 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 16 Day 1 (n=142, 141)	100.0 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 17 Day 1 (n=145, 142)	100.0 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 18 Day 1 (n=141, 140)	100.0 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 19 Day 1 (n=140, 138)	100.0 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 20 Day 1 (n=139, 134)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 19 Day 1 (n=140, 138)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 15 Day 1 (n=149, 140)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 9 Day 1 (n=170, 161)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 10 Day 1 (n=165, 164)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 18 Day 1 (n=141, 140)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 11 Day 1 (n=158, 158)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 16 Day 1 (n=142, 141)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 12 Day 1 (n=151, 146)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 20 Day 1 (n=139, 134)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 13 Day 1 (n=149, 143)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 17 Day 1 (n=145, 142)	100.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Cycle 14 Day 1 (n=152, 143)	100.0 percentage of participants

Secondary

Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion

All investigator physicians and nurses involved in this study were asked to complete question i.e. Which formulation of rituximab (SC or IV) do you think is more convenient? based on their experience with the rituximab SC and IV formulations across all participants and presented as rituximab SC is much more convenient; rituximab SC is a little more convenient; both formulations are equally convenient; rituximab IV is a little more convenient; and rituximab IV is much more convenient.

Time frame: After Cycle 8 of induction treatment (24 weeks) and during the maintenance part of the study after 12 months (i.e., Cycle 15), and after the end of the maintenance treatment, (i.e., Cycle 20) (1 Cycle=4 weeks for Cycle 8 and 8 weeks for Cycles 15 and 20)

Arm	Measure	Group	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy8: Rituximab SC much more convenient (n=166)	81 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy8: Rituximab SC little more convenient (n=166)	13 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy8: Both formulations equally convenient (n=166)	2 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy8: Rituximab IV little more convenient (n=166)	4 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy8: Rituximab IV much more convenient (n=166)	0 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy15: Rituximab SC much more convenient (n=130)	88 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy15: Rituximab SC little more convenient (n=130)	7 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy15: Both formulations equally convenient (n=130)	5 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy15: Rituximab IV little more convenient (n=130)	0 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy15: Rituximab IV much more convenient (n=130)	0 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy20: Rituximab SC much more convenient (n=126)	88 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy20: Rituximab SC little more convenient (n=126)	9 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy20: Both formulations equally convenient (n=126)	2 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy20: Rituximab IV little more convenient (n=126)	1 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	Cy20: Rituximab IV much more convenient (n=126)	0 percentage of responses

Secondary

Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle

Stage I and II (Induction): Rituximab IV: Predose (within 2 hr) on D1 of Cy1-8 (1 Cy=3 weeks & 4 weeks for Cy8); Rituximab SC: Predose (within 2 hr) on D1 of Cy1 & Cy3-8 (1 Cy=3 weeks and 4 weeks for Cy8), predose (within 2 hr) on D0 of Cy2 (up to data cutoff of 31 Oct 2013 \[up to 32 months\])

Time frame: Stage I and II (Pooled): Predose (within 2hr) up to data cutoff of 31 Oct 2013 [up to 32 months]) (See detailed timeframe in Outcome Measure description)

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 1 (n = 198, 193)	14.00 mcg/mL	Geometric Coefficient of Variation 157.53
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 2 (n = 197, 190)	30.13 mcg/mL	Geometric Coefficient of Variation 145.36
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 3 (n = 192, 190)	45.25 mcg/mL	Geometric Coefficient of Variation 110.35
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 4 (n = 186, 185)	54.06 mcg/mL	Geometric Coefficient of Variation 108.9
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 5 (n = 185, 185)	64.68 mcg/mL	Geometric Coefficient of Variation 89.9
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 6 (n = 187, 180)	71.02 mcg/mL	Geometric Coefficient of Variation 87.6
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 7 (n = 183, 172)	78.31 mcg/mL	Geometric Coefficient of Variation 77.76
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 8 (n = 52, 54)	77.60 mcg/mL	Geometric Coefficient of Variation 70.53
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 8 (n = 52, 54)	131.48 mcg/mL	Geometric Coefficient of Variation 50.2
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 1 (n = 198, 193)	12.88 mcg/mL	Geometric Coefficient of Variation 189.7
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 5 (n = 185, 185)	98.00 mcg/mL	Geometric Coefficient of Variation 71.91
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 2 (n = 197, 190)	40.00 mcg/mL	Geometric Coefficient of Variation 124.5
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 7 (n = 183, 172)	120.75 mcg/mL	Geometric Coefficient of Variation 55.6
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 3 (n = 192, 190)	63.83 mcg/mL	Geometric Coefficient of Variation 101.83
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 6 (n = 187, 180)	109.56 mcg/mL	Geometric Coefficient of Variation 58.74
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Cycle 4 (n = 186, 185)	81.71 mcg/mL	Geometric Coefficient of Variation 92.28

Secondary

Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle

Stage I and II (maintenance): D29 of Cy8 (induction; 1 Cy=4 weeks), predose (within 2 hr) on D1 of Cy9 to 19 (maintenance Cy1 to 12 \[1 Cy=8 weeks\]; up to data cutoff of 11 Jan 2016 \[up to 6 years\])

Time frame: Stage I and II (maintenance): Predose (within 2hr) up to data cutoff of 11 Jan 2016 [up to 6 years]) (See detailed timeframe in Outcome Measure description)

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 8 (n = 174, 170)	37.69 mcg/mL	Geometric Coefficient of Variation 94.3
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 9 (n = 171, 168)	30.35 mcg/mL	Geometric Coefficient of Variation 75.03
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 10 (n = 164, 160)	28.44 mcg/mL	Geometric Coefficient of Variation 84.64
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 11 (n = 164, 157)	28.77 mcg/mL	Geometric Coefficient of Variation 65.28
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 12 (n = 160, 150)	28.80 mcg/mL	Geometric Coefficient of Variation 56.97
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 13 (n = 157, 150)	28.84 mcg/mL	Geometric Coefficient of Variation 54.04
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 14 (n = 153, 147)	28.09 mcg/mL	Geometric Coefficient of Variation 55.61
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 15 (n = 148, 143)	28.19 mcg/mL	Geometric Coefficient of Variation 52.69
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 16 (n = 150, 145)	28.05 mcg/mL	Geometric Coefficient of Variation 57.19
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 17 (n = 149, 143)	28.24 mcg/mL	Geometric Coefficient of Variation 57.51
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 18 (n = 143, 132)	28.59 mcg/mL	Geometric Coefficient of Variation 62.06
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 19 (n = 138, 131)	27.75 mcg/mL	Geometric Coefficient of Variation 78.26
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 18 (n = 143, 132)	44.79 mcg/mL	Geometric Coefficient of Variation 68.56
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 8 (n = 174, 170)	61.31 mcg/mL	Geometric Coefficient of Variation 65.52
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 14 (n = 153, 147)	43.32 mcg/mL	Geometric Coefficient of Variation 67.97
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 9 (n = 171, 168)	49.47 mcg/mL	Geometric Coefficient of Variation 81.23
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 17 (n = 149, 143)	42.82 mcg/mL	Geometric Coefficient of Variation 65.67
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 10 (n = 164, 160)	47.27 mcg/mL	Geometric Coefficient of Variation 73.03
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 15 (n = 148, 143)	44.11 mcg/mL	Geometric Coefficient of Variation 67.92
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 11 (n = 164, 157)	46.70 mcg/mL	Geometric Coefficient of Variation 66.8
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 19 (n = 138, 131)	43.69 mcg/mL	Geometric Coefficient of Variation 69.02
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 12 (n = 160, 150)	44.72 mcg/mL	Geometric Coefficient of Variation 68.74
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 16 (n = 150, 145)	42.96 mcg/mL	Geometric Coefficient of Variation 64.32
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Cycle 13 (n = 157, 150)	44.32 mcg/mL	Geometric Coefficient of Variation 67.67

Secondary

Stage I and II (Pooled): Event-Free Survival Assessed Using International Working Group Response Criteria for NHL

Event-free survival was defined as the time from randomization to disease progression/relapse, death or initiation of new NHL therapy. If the specified event (progression/relapse, death or new anti-lymphoma treatment) did not occur, event-free survival was censored at the last tumor assessment date either during treatment or follow up. Event-free survival analysis was performed using Kaplan-Meier curves. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to a median of 27 months; up to data cutoff of 31 Oct 2017 \[up to 6 years\])

Time frame: Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)

Population: ITT population.

Arm	Measure	Value (MEDIAN)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Event-Free Survival Assessed Using International Working Group Response Criteria for NHL	NA days
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Event-Free Survival Assessed Using International Working Group Response Criteria for NHL	NA days

p-value: 0.911595% CI: [0.71, 1.36]Wald test

Secondary

Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Chimeric Antibodies (HACAs) to Rituximab

Levels of HACA in serum were detected at Day 1 of each cycle up to Cycle 8 and at follow-up visit. Stage I and II: Baseline: pre-dose (72 hours prior) D1 of Cy1, Cy 3-20, D0 of Cy2 (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), post-baseline: every 12 weeks after last rituximab administration until 96 weeks (a median of 27 months; up to data cutoff of 11 Jan 2016 \[up to 6 years\])

Time frame: Stage I and II: Baseline, post-baseline (See detailed timeframe in Outcome Measure description)

Population: Safety Analysis Population: included 6 participants who were randomized under Rituximab SC arm but withdrew after Cy1 and then analyzed under Rituximab IV arm. Here, number of participants analyzed = participants evaluable for the outcome measure. Here n = number of participants evaluable for this outcome measure at specified timepoint.

Arm	Measure	Group	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Chimeric Antibodies (HACAs) to Rituximab	Baseline (n=208, 191)	5.8 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Chimeric Antibodies (HACAs) to Rituximab	Post-Baseline (n=206, 197)	1.5 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Chimeric Antibodies (HACAs) to Rituximab	Baseline (n=208, 191)	2.6 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Chimeric Antibodies (HACAs) to Rituximab	Post-Baseline (n=206, 197)	2.0 percentage of participants

Secondary

Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Human Antibodies (HAHAs) to Rituximab

Levels of HAHA in serum were detected at Day 1 of each cycle up to Cycle 8 and at follow-up visit. Stage I and II: Baseline: pre-dose (72 hours prior) D1 of Cy1, Cy 3-20, D0 of Cy2 (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), post-baseline: every 12 weeks after last rituximab administration until 96 weeks (a median of 27 months; up to data cutoff of 11 Jan 2016 \[up to 6 years\])

Time frame: Stage I and II: Baseline, post-baseline (See detailed timeframe in Outcome Measure description)

Population: Safety Analysis Population. Here, number of participants analyzed = participants evaluable for the outcome measure. Here n = number of participants evaluable for this outcome measure at specified timepoint.

Arm	Measure	Group	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Human Antibodies (HAHAs) to Rituximab	Baseline (n=68, 188)	10.3 percentage of participants
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Human Antibodies (HAHAs) to Rituximab	Post-Baseline (n=66, 197)	7.6 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Human Antibodies (HAHAs) to Rituximab	Baseline (n=68, 188)	11.2 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Human Antibodies (HAHAs) to Rituximab	Post-Baseline (n=66, 197)	13.2 percentage of participants

Secondary

Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL

Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by \>75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.

Time frame: Stage I and II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)

Population: ITT Population.

Arm	Measure	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	31.7 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	32.2 percentage of participants

p-value: 0.915795% CI: [-8.8, 9.8]Chi-squared

95% CI: [0.66, 1.51]

Secondary

Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL

Time frame: Stage I and II: Baseline up to 57 days after last maintenance dose (last maintenance dose: maintenance Cy12/Study Cy20 [30 months]) (up to data cutoff of 31 Oct 2017 [up to 6 years]) (1 Cy=8 weeks)

Population: ITT population; only participants who entered the maintenance phase and received at least 1 cycle of rituximab maintenance treatment from Cycle 9 to Cycle 20 were included in the analysis.

Arm	Measure	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL	57.9 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL	50.6 percentage of participants

p-value: 0.171595% CI: [-18, 3.5]Chi-squared

95% CI: [0.52, 1.22]

Secondary

Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse, New Anti-Lymphoma Treatment or Death Assessed Using International Working Group Response Criteria for NHL

Disease progression: ≥50% increase from nadir in the SPD of any previously identified abnormal node or appearance of any new lesion during or at the end of therapy or ≥50% increase in the greatest diameter of any previously identified node \>1 cm in its short axis or in the SPD of more than one node. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to a median of 27 months; up to data cutoff of 31 Oct 2017 \[up to 6 years\])

Time frame: Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)

Population: ITT population.

Arm	Measure	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse, New Anti-Lymphoma Treatment or Death Assessed Using International Working Group Response Criteria for NHL	36.1 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse, New Anti-Lymphoma Treatment or Death Assessed Using International Working Group Response Criteria for NHL	35.1 percentage of participants

Secondary

Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse or Death

Disease progression: ≥50% increase from nadir in the SPD of any previously identified abnormal node or appearance of any new lesion during or at the end of therapy or ≥50% increase in the greatest diameter of any previously identified node \>1 cm in its short axis or in the SPD of more than one node. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to median of 27 months; up to data cutoff of 31 Oct 2017 \[up to 6 years\])

Time frame: Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)

Population: ITT Population.

Arm	Measure	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse or Death	34.6 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse or Death	31.7 percentage of participants

Secondary

Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL

Overall Response comprised of CR, CRu, or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumour response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by \>75% in SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.

Time frame: Stage I and II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)

Population: ITT Population.

Arm	Measure	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	84.9 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	84.4 percentage of participants

p-value: 0.891195% CI: [-7.7, 6.8]Chi-squared

95% CI: [0.56, 1.65]

Secondary

Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL

Overall Response comprised of CR, CRu, or PR . A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by \>75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.

Arm	Measure	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL	78.1 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL	77.9 percentage of participants

p-value: 0.967195% CI: [-9.2, 8.8]Chi-squared

95% CI: [0.6, 1.64]

Secondary

Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20

All investigator physicians and nurses involved in this study were asked to provide the staff time that could be saved with each administration of rituximab SC as compared with rituximab IV to participants in routine practice afetr Cy 8, 15, 20 and categorized as less than (\<) 1 hr, at least 1 hr but \<2 hrs, at least 2 hrs but \<3 hrs, at least 3 hrs but \<4 hrs, \>/=4 hrs. Staff were asked not to consider the time needed for the first IV administration. Analysis was done in all participants to show a comparison on the time saved by staffs when administered via SC and IV.

Arm	Measure	Group	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy8: <1 hour (n=166)	11 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy8: ≥1 to <2 hours (n=166)	20 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy8: ≥2 to <3 hours (n=166)	35 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy8: ≥3 to <4 hours (n=166)	18 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy8: ≥4 hours (n=166)	16 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy15: <1 hour (n=130)	13 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy15: ≥1 to <2 hours (n=130)	17 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy15: ≥2 to <3 hours (n=126)	34 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy15: ≥3 to <4 hours (n=130)	14 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy15: ≥4 hours (n=130)	22 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy20: <1 hour (n=126)	14 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy20: ≥1 to <2 hours (n=126)	32 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy20: ≥2 to <3 hours (n=126)	21 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy20: ≥3 to <4 hours (n=126)	13 percentage of responses
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	After Cy20: ≥4 hours (n=126)	19 percentage of responses

Secondary

Stage I and II (Pooled): Progression-Free Survival (PFS) Assessed Using International Working Group Response Criteria for NHL

PFS was defined as the time from randomization to disease progression/relapse or death due to any cause. If the specified event (disease progression/relapse, death) did not occur, PFS was censored at the last tumor assessment date showing no disease progression, either during treatment or follow-up. Disease progression: ≥50% increase from nadir in the SPD of any previously identified abnormal node or appearance of any new lesion during or at the end of therapy or ≥50% increase in the greatest diameter of any previously identified node \>1 cm in its short axis or in the SPD of more than one node. PFS analysis was performed using Kaplan - Meier curves. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to median of 27 months; up to data cutoff of 31 Oct 2017 \[up to 6 years\])

Time frame: Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)

Population: ITT Population.

Arm	Measure	Value (MEDIAN)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Progression-Free Survival (PFS) Assessed Using International Working Group Response Criteria for NHL	NA days
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Progression-Free Survival (PFS) Assessed Using International Working Group Response Criteria for NHL	NA days

p-value: 0.552695% CI: [0.64, 1.26]Wald test

Secondary

Stage I and II (Pooled): Rituximab Levels 12 Weeks, 24 Weeks, and 36 Weeks After the Last Rituximab Administration

Time frame: 12 weeks, 24 weeks, and 36 weeks after the last rituximab administration (up to data cutoff of 11 Jan 2016 [up to 6 years])

Population: Safety Analysis Population included all participants who received at least one dose of rituximab, either IV or SC. Participants were analyzed as treated. Here, number of participants analyzed = participants evaluable for the outcome measure. Here n = number of participants evaluable for this outcome measure at specified timepoint.

Arm	Measure	Group	Value (MEDIAN)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Rituximab Levels 12 Weeks, 24 Weeks, and 36 Weeks After the Last Rituximab Administration	Week 12: Follow-up Visit 1 (n = 117, 118)	15.60 mcg/mL
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Rituximab Levels 12 Weeks, 24 Weeks, and 36 Weeks After the Last Rituximab Administration	Week 24: Follow-up Visit 2 (n = 88, 96)	2.89 mcg/mL
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Rituximab Levels 12 Weeks, 24 Weeks, and 36 Weeks After the Last Rituximab Administration	Week 36: Follow-up Visit 3 (n = 38, 53)	1.08 mcg/mL
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Rituximab Levels 12 Weeks, 24 Weeks, and 36 Weeks After the Last Rituximab Administration	Week 12: Follow-up Visit 1 (n = 117, 118)	22.35 mcg/mL
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Rituximab Levels 12 Weeks, 24 Weeks, and 36 Weeks After the Last Rituximab Administration	Week 24: Follow-up Visit 2 (n = 88, 96)	5.19 mcg/mL
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I and II (Pooled): Rituximab Levels 12 Weeks, 24 Weeks, and 36 Weeks After the Last Rituximab Administration	Week 36: Follow-up Visit 3 (n = 38, 53)	2.02 mcg/mL

Secondary

Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL

Time frame: Stage II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)

Population: Stage II ITT Population.

Arm	Measure	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	34.8 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	28.2 percentage of participants

p-value: 0.233195% CI: [-17.8, 4.6]Chi-squared

95% CI: [0.44, 1.22]

Secondary

Stage I: Maximum Serum Concentrations (Cmax) of IV and SC Rituximab

Predose (within 2 hr) and 24 hrs postdose on Cy7 (D1,3,7,15), predose (0 hr) on Cy8 D1 (1 Cy=3 weeks); additionally within 15 minutes after end of infusion (infusion duration=30 minutes) on Cy7 D1 for rituximab IV (up to data cutoff of 11 Apr 2012 \[up to 26 months\])

Time frame: Stage I (Induction): Predose (within 2hr) up to data cutoff of 11 Apr 2012 [up to 26 months]) (See detailed timeframe in Outcome Measure description)

Population: Stage 1 PK Evaluable Population. Here, number of participants analyzed = participants evaluable for this outcome measure.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I: Maximum Serum Concentrations (Cmax) of IV and SC Rituximab	250.63 mcg/mL	Geometric Coefficient of Variation 19.66
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I: Maximum Serum Concentrations (Cmax) of IV and SC Rituximab	236.82 mcg/mL	Geometric Coefficient of Variation 31.45

95% CI: [0.872, 1.015]

Secondary

Stage I: Observed Area Under the Serum Concentration-Time Curve (AUC) of Rituximab

AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. Predose (within 2 hr) and 24 hrs postdose on Cy 7 (D1,3,7,15), predose (0 hr) on Cy 8 D1 (1 Cy=3 weeks); additionally within 15 minutes after end of infusion (infusion duration=30 minutes) on Cy 7 D1 for rituximab IV (up to data cutoff of 11 Apr 2012 \[up to 26 months\])

Time frame: Stage I (Induction): Predose (within 2 hour [hr]) up to data cutoff of 11 Apr 2012 [up to 26 months]) (See detailed timeframe in Outcome Measure description)

Population: Stage I PK evaluable population. Here, number of participants analyzed = participants evaluable for this outcome measure.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I: Observed Area Under the Serum Concentration-Time Curve (AUC) of Rituximab	2734.21 mcg*day/mL	Geometric Coefficient of Variation 32.51
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I: Observed Area Under the Serum Concentration-Time Curve (AUC) of Rituximab	3778.93 mcg*day/mL	Geometric Coefficient of Variation 37.59

Comparison: The ratio of observed rituximab serum was determined as AUC SC/AUC IV during Cycle 7 of induction treatment.90% CI: [1.24, 1.53]

Secondary

Stage I: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL

Complete Response was comprised CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by \>75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.

Time frame: Stage I: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)

Population: Stage I ITT Population.

Arm	Measure	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	25.0 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	42.9 percentage of participants

p-value: 0.033595% CI: [0.8, 35]Chi-squared

95% CI: [1.06, 4.78]

Secondary

Stage I: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL

Overall Response comprised CR, CRu, or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by \>75% in the SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI was estimated for one sample binomial using Pearson-Clopper.

Time frame: Stage I: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)

Population: Stage I ITT Population included all participants who were randomized in Stage I irrespective whether they received study drug or not.

Arm	Measure	Value (NUMBER)
Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	82.8 percentage of participants
Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage I: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	90.5 percentage of participants

p-value: 0.204795% CI: [-5, 20.3]Chi-squared

95% CI: [0.68, 5.71]

Source: ClinicalTrials.gov · Data processed: Mar 21, 2026

A Study of Rituximab (MabThera) Subcutaneous (SC) Versus Rituximab (MabThera) Intravenous in Participannts With Follicular Non-Hodgkin's Lymphoma

Conditions

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Stage II: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for Non-Hodgkin Lymphoma (NHL)

Stage I: Trough Serum Concentrations (Ctrough) of IV and SC Rituximab

Overall Survival (OS)

Percentage of Participants Who Died

Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase

Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase

Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion

Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle

Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle

Stage I and II (Pooled): Event-Free Survival Assessed Using International Working Group Response Criteria for NHL

Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Chimeric Antibodies (HACAs) to Rituximab

Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Human Antibodies (HAHAs) to Rituximab

Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL

Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL

Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse, New Anti-Lymphoma Treatment or Death Assessed Using International Working Group Response Criteria for NHL

Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse or Death

Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL

Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL

Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20

Stage I and II (Pooled): Progression-Free Survival (PFS) Assessed Using International Working Group Response Criteria for NHL

Stage I and II (Pooled): Rituximab Levels 12 Weeks, 24 Weeks, and 36 Weeks After the Last Rituximab Administration

Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL

Stage I: Maximum Serum Concentrations (Cmax) of IV and SC Rituximab

Stage I: Observed Area Under the Serum Concentration-Time Curve (AUC) of Rituximab

Stage I: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL

Stage I: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL