Trial Outcomes & Findings for A Study of Rituximab (MabThera) Subcutaneous (SC) Versus Rituximab (MabThera) Intravenous in Participannts With Follicular Non-Hodgkin's Lymphoma (NCT NCT01200758)

NCT ID: NCT01200758

Last Updated: 2018-11-27

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

410 participants

Primary outcome timeframe

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

Results posted on

2018-11-27

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) Eight cycles of rituximab intravenous (IV) infusion (375 milligrams per square meter \[mg/m\^2\]; rituximab induction) in combination with up to 8 cycles of cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) or cyclophosphamide, vincristine, prednisolone (CVP) chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least partial response (PR) during induction, entered rituximab IV maintenance therapy (375 mg/m\^2) once every 8 weeks for 24 months.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 milligrams \[mg\]; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.	Stage 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.	Stage II: Rituximab SC + Chemotherapy (CHOP/CVP) First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab SC (1400 mg; 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 entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
Stage I STARTED	64	63	0	0
Stage I COMPLETED	46	46	0	0
Stage I NOT COMPLETED	18	17	0	0
Stage 2 STARTED	0	0	141	142
Stage 2 COMPLETED	0	0	100	92
Stage 2 NOT COMPLETED	0	0	41	50

Reasons for withdrawal

Reasons for withdrawal
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) Eight cycles of rituximab intravenous (IV) infusion (375 milligrams per square meter \[mg/m\^2\]; rituximab induction) in combination with up to 8 cycles of cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) or cyclophosphamide, vincristine, prednisolone (CVP) chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least partial response (PR) during induction, entered rituximab IV maintenance therapy (375 mg/m\^2) once every 8 weeks for 24 months.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 milligrams \[mg\]; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.	Stage 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.	Stage II: Rituximab SC + Chemotherapy (CHOP/CVP) First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab SC (1400 mg; 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 entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
Stage I Death	0	1	0	0
Stage I Physician Decision	1	1	0	0
Stage I Lack of Efficacy	2	1	0	0
Stage I Adverse Event	5	5	0	0
Stage I Withdrawal by Subject	1	2	0	0
Stage I Disease Progression	9	7	0	0
Stage 2 Disease Progression	0	0	16	21
Stage 2 Lack of Efficacy	0	0	4	2
Stage 2 Physician Decision	0	0	5	7
Stage 2 Adverse Event	0	0	5	9
Stage 2 Withdrawal by Subject	0	0	4	1
Stage 2 Lost to Follow-up	0	0	3	1
Stage 2 Protocol Violation	0	0	1	4
Stage 2 Death	0	0	3	5

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) n=205 Participants 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.	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP) n=205 Participants 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.	Total n=410 Participants Total of all reporting groups
Age, Continuous	56.9 years STANDARD_DEVIATION 12.69 • n=5 Participants	56.1 years STANDARD_DEVIATION 12.66 • n=7 Participants	56.5 years STANDARD_DEVIATION 12.67 • n=5 Participants
Sex: Female, Male Female	99 Participants n=5 Participants	120 Participants n=7 Participants	219 Participants n=5 Participants
Sex: Female, Male Male	106 Participants n=5 Participants	85 Participants n=7 Participants	191 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=48 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=54 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
Stage I: Trough Serum Concentrations (Ctrough) of IV and SC Rituximab	83.1 micrograms per milliliter (mcg/mL) Geometric Coefficient of Variation 36.7	134.6 micrograms per milliliter (mcg/mL) Geometric Coefficient of Variation 43.2

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=141 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=142 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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 Interval 78.1 to 90.5	80.3 percentage of participants Interval 72.8 to 86.5

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=64 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=63 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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 Interval 71.3 to 91.1	90.5 percentage of participants Interval 80.4 to 96.4

SECONDARY outcome

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

Population: ITT Population.

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.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=205 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=205 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 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	84.9 percentage of participants Interval 79.2 to 89.5	84.4 percentage of participants Interval 78.7 to 89.1

SECONDARY outcome

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

Population: Stage I ITT Population.

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.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=64 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=63 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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 Interval 15.0 to 37.4	42.9 percentage of participants Interval 30.5 to 56.0

SECONDARY outcome

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

Population: Stage II ITT Population.

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.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=141 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=142 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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 Interval 26.9 to 43.2	28.2 percentage of participants Interval 20.9 to 36.3

SECONDARY outcome

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

Population: ITT Population.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=205 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=205 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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 Interval 25.4 to 38.6	32.2 percentage of participants Interval 25.9 to 39.1

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=178 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=172 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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 Interval 50.3 to 65.2	50.6 percentage of participants Interval 42.9 to 58.3

SECONDARY outcome

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.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=178 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=172 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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 Interval 71.3 to 83.9	77.9 percentage of participants Interval 71.0 to 83.9

SECONDARY outcome

Timeframe: 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.

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 \[up to 6 years\])

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=205 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=205 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse or Death	34.6 percentage of participants	31.7 percentage of participants

SECONDARY outcome

Timeframe: 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.

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 \[up to 6 years\])

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=205 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=205 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
Stage I and II (Pooled): Progression-Free Survival (PFS) Assessed Using International Working Group Response Criteria for NHL	NA days Data for upper limit of 95% CI were not reached due to low number (\<50%) of participants with event of interest.	NA days Data for median and corresponding 95% CI were not reached due to low number (\<50%) of participants with event of interest.

SECONDARY outcome

Timeframe: 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.

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 \[up to 6 years\])

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=205 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=205 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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	35.1 percentage of participants

SECONDARY outcome

Timeframe: 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.

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 \[up to 6 years\])

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=205 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=205 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
Stage I and II (Pooled): Event-Free Survival Assessed Using International Working Group Response Criteria for NHL	NA days Interval 2126.0 to Data for upper limit of 95% CI was not reached due to low number (\<50%) of participants with event of interest.	NA days Data for median and upper limit of 95% CI were not reached due to low number (\<50%) of participants with event of interest.

SECONDARY outcome

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

Population: ITT population.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=205 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=205 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
Percentage of Participants Who Died	12.7 percentage of participants	8.8 percentage of participants

SECONDARY outcome

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

Population: ITT population.

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.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=205 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=205 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
Overall Survival (OS)	NA days Data for median and corresponding 95% CI were not reached due to low number (\<10%) of participants with event of interest.	NA days Data for median and corresponding 95% CI were not reached due to low number (\<10%) of participants with event of interest.

SECONDARY outcome

Timeframe: 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.

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 \[up to 26 months\])

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=58 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=55 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
Stage I: Observed Area Under the Serum Concentration-Time Curve (AUC) of Rituximab	2734.21 mcg*day/mL Geometric Coefficient of Variation 32.51	3778.93 mcg*day/mL Geometric Coefficient of Variation 37.59

SECONDARY outcome

Timeframe: 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.

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 \[up to 26 months\])

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=58 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=59 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
Stage I: Maximum Serum Concentrations (Cmax) of IV and SC Rituximab	250.63 mcg/mL Geometric Coefficient of Variation 19.66	236.82 mcg/mL Geometric Coefficient of Variation 31.45

SECONDARY outcome

Timeframe: 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)

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.

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 \[up to 32 months\])

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=198 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=193 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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	131.48 mcg/mL Geometric Coefficient of Variation 50.20
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	12.88 mcg/mL Geometric Coefficient of Variation 189.70
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	40.00 mcg/mL Geometric Coefficient of Variation 124.50
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	63.83 mcg/mL Geometric Coefficient of Variation 101.83
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 108.90	81.71 mcg/mL Geometric Coefficient of Variation 92.28
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 89.90	98.00 mcg/mL Geometric Coefficient of Variation 71.91
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 87.60	109.56 mcg/mL Geometric Coefficient of Variation 58.74
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	120.75 mcg/mL Geometric Coefficient of Variation 55.60

SECONDARY outcome

Timeframe: 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 \[up to 6 years\])

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=174 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=170 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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 94.30	61.31 mcg/mL Geometric Coefficient of Variation 65.52
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	49.47 mcg/mL Geometric Coefficient of Variation 81.23
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	47.27 mcg/mL Geometric Coefficient of Variation 73.03
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	46.70 mcg/mL Geometric Coefficient of Variation 66.80
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	44.72 mcg/mL Geometric Coefficient of Variation 68.74
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	44.32 mcg/mL Geometric Coefficient of Variation 67.67
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	43.32 mcg/mL Geometric Coefficient of Variation 67.97
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	44.11 mcg/mL Geometric Coefficient of Variation 67.92
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	42.96 mcg/mL Geometric Coefficient of Variation 64.32
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	42.82 mcg/mL Geometric Coefficient of Variation 65.67
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	44.79 mcg/mL Geometric Coefficient of Variation 68.56
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	43.69 mcg/mL Geometric Coefficient of Variation 69.02

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=117 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=118 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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 Interval 0.7 to 80.4	22.35 mcg/mL Interval 0.65 to 107.0
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 Interval 0.58 to 17.4	5.19 mcg/mL Interval 0.69 to 62.1
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 Interval 0.52 to 51.4	2.02 mcg/mL Interval 0.53 to 33.9

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=188 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=180 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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	54.8 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase Cycle 2 Day 0 (n=183, 180)	95.1 percentage of participants	95.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase Cycle 3 Day 1 (n=175, 175)	99.4 percentage of participants	99.4 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase Cycle 4 Day 1 (n=178, 180)	99.4 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase Cycle 5 Day 1 (n=179, 176)	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase Cycle 6 Day 1 (n=173, 175)	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase Cycle 7 Day 1 (n=178, 173)	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase Cycle 8 Day 1 (n=175, 174)	100.0 percentage of participants	100.0 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=170 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=164 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase Cycle 16 Day 1 (n=142, 141)	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase Cycle 9 Day 1 (n=170, 161)	99.4 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase Cycle 10 Day 1 (n=165, 164)	99.4 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase Cycle 11 Day 1 (n=158, 158)	99.4 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase Cycle 12 Day 1 (n=151, 146)	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase Cycle 13 Day 1 (n=149, 143)	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase Cycle 14 Day 1 (n=152, 143)	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase Cycle 15 Day 1 (n=149, 140)	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase Cycle 17 Day 1 (n=145, 142)	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase Cycle 18 Day 1 (n=141, 140)	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase Cycle 19 Day 1 (n=140, 138)	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase Cycle 20 Day 1 (n=139, 134)	100.0 percentage of participants	100.0 percentage of participants

SECONDARY outcome

Timeframe: 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.

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 \[up to 6 years\])

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=208 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=197 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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	2.6 percentage of participants
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	2.0 percentage of participants

SECONDARY outcome

Timeframe: 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.

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 \[up to 6 years\])

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=68 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) n=197 Participants First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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	11.2 percentage of participants
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	13.2 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=166 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 outcome

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.

Outcome measures

Outcome measures
Measure	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) n=166 Participants 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.	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) First cycle of rituximab IV (375 mg/m\^2) + 7 cycles of rituximab subcutaneously (SC) (1400 mg; 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 SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—
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	—

Adverse Events

Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)

Serious events: 76 serious events

Other events: 187 other events

Deaths: 0 deaths

Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)

Serious events: 74 serious events

Other events: 186 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER