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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Rituximab SC
* Drug: Rituximab IV
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone/Prednisolone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)<br>Eight cycles of rituximab IV infusion (375 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 PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months. | Drug: Rituximab IV<br>* 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.<br>* Other names: MabThera;Drug: Cyclophosphamide<br>* Eight cycles of cyclophosphamide (750 mg/m^2 IV) administered every 3 weeks.<br>Drug: Doxorubicin<br>* Eight cycles of doxorubicin (50 mg/m^2 IV) administered every 3 weeks.<br>Drug: Vincristine<br>* Eight cycles of doxorubicin (1.4 mg/m^2 IV) administered every 3 weeks.<br>Drug: Prednisone/Prednisolone<br>* 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.<br>|
| Experimental: Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)<br>First cycle of rituximab IV infusion (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. | Drug: Rituximab SC<br>* 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.<br>* Other names: MabThera;Drug: Cyclophosphamide<br>* Eight cycles of cyclophosphamide (750 mg/m^2 IV) administered every 3 weeks.<br>Drug: Doxorubicin<br>* Eight cycles of doxorubicin (50 mg/m^2 IV) administered every 3 weeks.<br>Drug: Vincristine<br>* Eight cycles of doxorubicin (1.4 mg/m^2 IV) administered every 3 weeks.<br>Drug: Prednisone/Prednisolone<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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. | Stage II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Stage I: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks) | 
| 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. | Stage I and II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks) | 
| 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. | Stage I: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks) | 
| Stage II: 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. | Stage II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks) | 
| 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. | Stage I and II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks) | 
| 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 | 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: 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) | 
| 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. | 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) | 
| 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]) | 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) | 
| 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]) | 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) | 
| 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]) | 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) | 
| 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]) | 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) | 
| Percentage of Participants Who Died |  | Baseline up to death (up to data cutoff of 31 Oct 2017 [up to 6 years]) | 
| 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. | Baseline up to death (up to data cutoff of 31 Oct 2017 [up to 6 years]) | 
| 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]) | 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) | 
| 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]) | 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) | 
| 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]) | 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 (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]) | 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 (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 | Depletion is defined as a cluster of differentiation (CD) 19 value <80 cells per cubic millimeter (cells/mm^3). | 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 | 
| Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase | Depletion is defined as a CD19 value <80 cells/mm^3. | 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]) | 
| 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]) | Stage I and II: Baseline, post-baseline (See detailed timeframe in Outcome Measure description) | 
| 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]) | Stage I and II: Baseline, post-baseline (See detailed timeframe in Outcome Measure description) | 
| 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. | 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) | 
| 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. | 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) |