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

• ClinicalTrials.gov Identifier: NCT01200758
• Recruitment Status: Completed
• First Posted: September 14, 2010
• Results First Posted: August 5, 2015
• Last Update Posted: November 27, 2018
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non-Hodgkin's Lymphoma
• Interventions: Drug: Rituximab SC; Drug: Rituximab IV; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine; Drug: Prednisone/Prednisolone
• Enrollment: 410

Participant Flow

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

Arm/Group Title	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)	Stage II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description	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.	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.	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.	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.
Period Title: Stage I
Started	64	63	0 [1]	0 [1]
Completed	46 [2]	46 [2]	0	0
Not Completed	18	17	0	0
Reason Not Completed
Death	0	1	0	0
Physician Decision	1	1	0	0
Lack of Efficacy	2	1	0	0
Adverse Event	5	5	0	0
Withdrawal by Subject	1	2	0	0
Disease Progression	9	7	0	0
[1] Different participants were randomized into different stages of the study.; [2] Participants completed treatment period.
Period Title: Stage 2
Started	0 [1]	0 [1]	141	142
Completed	0	0	100 [2]	92 [2]
Not Completed	0	0	41	50
Reason Not Completed
Disease Progression	0	0	16	21
Lack of Efficacy	0	0	4	2
Physician Decision	0	0	5	7
Adverse Event	0	0	5	9
Withdrawal by Subject	0	0	4	1
Lost to Follow-up	0	0	3	1
Protocol Violation	0	0	1	4
Death	0	0	3	5
[1] Different participants were randomized into different stages of the study.; [2] Participants completed treatment period.

Baseline Characteristics

Arm/Group Title		Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)	Total
Arm/Group Description		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.	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 of all reporting groups
Overall Number of Baseline Participants		205	205	410
Baseline Analysis Population Description		Intent-to-Treat (ITT) Population included all participants who were randomized into study irrespective whether they received study drug or not.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	205 participants	205 participants	410 participants
		56.9 (12.69)	56.1 (12.66)	56.5 (12.67)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	205 participants	205 participants	410 participants
	Female	99 48.3%	120 58.5%	219 53.4%
	Male	106 51.7%	85 41.5%	191 46.6%

Outcome Measures

1. Primary Outcome

Title	Stage I: Trough Serum Concentrations (Ctrough) of IV and SC Rituximab
Description	[Not Specified]
Time Frame	Stage I: Cycle (Cy) 7 Day (D) 21 (within 2 hours predose on Cy8) of induction treatment (1 Cy=3 weeks)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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 Number of Participants Analyzed	48	54
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: micrograms per milliliter (mcg/mL)
	83.1; (36.7%)	134.6; (43.2%)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP), Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferior Ctrough in SC formulation was demonstrated, if the lower bound of 90% confidence interval (CI) was above 0.8.
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	1.62
	Confidence Interval	(2-Sided) 90%; 1.36 to 1.94
	Estimation Comments	Geometric mean ratio adjusted for tumor load at baseline.

2. Primary Outcome

Title	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)
Description	Overall Response comprised complete response (CR), CR unconfirmed (CRu), or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and computed tomography (CT) scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by more than (>) 75% in the sum of the products of greatest diameters (SPD); PR: Greater than or equal to (≥) 50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI was estimated for one sample binomial using Pearson-Clopper.
Time Frame	Stage II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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 entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.	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.
Overall Number of Participants Analyzed	141	142
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	85.1; (78.1 to 90.5)	80.3; (72.8 to 86.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage II: Rituximab IV + Chemotherapy (CHOP/CVP), Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2835
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	-4.82
	Confidence Interval	(2-Sided) 95%; -14.0 to 4.4
	Estimation Comments	The 95% CI for the difference in response rates was estimated using the Hauck-Anderson method.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage II: Rituximab IV + Chemotherapy (CHOP/CVP), Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.38 to 1.33
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Stage I: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL
Description	Overall Response comprised CR, CRu, or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in the SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI was estimated for one sample binomial using Pearson-Clopper.
Time Frame	Stage I: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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 Number of Participants Analyzed	64	63
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	82.8; (71.3 to 91.1)	90.5; (80.4 to 96.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP), Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2047
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	7.66
	Confidence Interval	(2-Sided) 95%; -5.0 to 20.3
	Estimation Comments	The 95% CI for the difference in response rates was estimated using the Hauck-Anderson method.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP), Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.97
	Confidence Interval	(2-Sided) 95%; 0.68 to 5.71
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	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
Description	Overall Response comprised of CR, CRu, or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumour response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.
Time Frame	Stage I and II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	205	205
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	84.9; (79.2 to 89.5)	84.4; (78.7 to 89.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8911
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -7.7 to 6.8
	Estimation Comments	The 95% CI for the difference in response rates was estimated using the Hauck-Anderson.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.56 to 1.65
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Stage I: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL
Description	Complete Response was comprised CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.
Time Frame	Stage I: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)

Outcome Measure Data

Analysis Population Description

Stage I ITT Population.

Arm/Group Title	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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 Number of Participants Analyzed	64	63
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	25.0; (15.0 to 37.4)	42.9; (30.5 to 56.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP), Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0335
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in CRR
	Estimated Value	17.86
	Confidence Interval	(2-Sided) 95%; 0.8 to 35.0
	Estimation Comments	The 95% CI for the difference in response rates was estimated using the Hauck-Anderson method.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP), Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.25
	Confidence Interval	(2-Sided) 95%; 1.06 to 4.78
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL
Description	Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.
Time Frame	Stage II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)

Outcome Measure Data

Analysis Population Description

Stage II ITT Population.

Arm/Group Title	Stage II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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 entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.	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.
Overall Number of Participants Analyzed	141	142
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	34.8; (26.9 to 43.2)	28.2; (20.9 to 36.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage II: Rituximab IV + Chemotherapy (CHOP/CVP), Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2331
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	-6.58
	Confidence Interval	(2-Sided) 95%; -17.8 to 4.6
	Estimation Comments	The 95% CI for the difference in response rates was estimated using the Hauck-Anderson method.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage II: Rituximab IV + Chemotherapy (CHOP/CVP), Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.44 to 1.22
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	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
Description	Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.
Time Frame	Stage I and II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	205	205
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	31.7; (25.4 to 38.6)	32.2; (25.9 to 39.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP), Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9157
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	0.49
	Confidence Interval	(2-Sided) 95%; -8.8 to 9.8
	Estimation Comments	The 95% CI for the difference in response rates was estimated using the Hauck-Anderson method.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.51
	Estimation Comments	[Not Specified]

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	178	172
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	57.9; (50.3 to 65.2)	50.6; (42.9 to 58.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP), Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1715
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	-7.28
	Confidence Interval	(2-Sided) 95%; -18.0 to 3.5
	Estimation Comments	The 95% CI for the difference in response rates was estimated using the Hauck-Anderson method.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.52 to 1.22
	Estimation Comments	[Not Specified]

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	178	172
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	78.1; (71.3 to 83.9)	77.9; (71.0 to 83.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP), Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9671
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -9.2 to 8.8
	Estimation Comments	The 95% CI for the difference in response rates was estimated using the Hauck-Anderson method.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.60 to 1.64
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse or Death
Description	Disease progression: ≥50% increase from nadir in the SPD of any previously identified abnormal node or appearance of any new lesion during or at the end of therapy or ≥50% increase in the greatest diameter of any previously identified node >1 cm in its short axis or in the SPD of more than one node. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to median of 27 months; up to data cutoff of 31 Oct 2017 [up to 6 years])
Time Frame	Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	205	205
Measure Type: Number; Unit of Measure: percentage of participants
	34.6	31.7

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	205	205
Median (95% Confidence Interval); Unit of Measure: days
	NA [1]; (NA to NA)	NA [2]; (NA to NA)

[1]

Data for upper limit of 95% CI were not reached due to low number (<50%) of participants with event of interest.

[2]

Data for median and corresponding 95% CI were not reached due to low number (<50%) of participants with event of interest.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP), Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5526
	Comments	[Not Specified]
	Method	Wald test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.26
	Estimation Comments	[Not Specified]

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	205	205
Measure Type: Number; Unit of Measure: percentage of participants
	36.1	35.1

13. Secondary Outcome

Title	Stage I and II (Pooled): Event-Free Survival Assessed Using International Working Group Response Criteria for NHL
Description	Event-free survival was defined as the time from randomization to disease progression/relapse, death or initiation of new NHL therapy. If the specified event (progression/relapse, death or new anti-lymphoma treatment) did not occur, event-free survival was censored at the last tumor assessment date either during treatment or follow up. Event-free survival analysis was performed using Kaplan-Meier curves. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to a median of 27 months; up to data cutoff of 31 Oct 2017 [up to 6 years])
Time Frame	Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	205	205
Median (95% Confidence Interval); Unit of Measure: days
	NA [1]; (2126 to NA)	NA [2]; (NA to NA)

[1]

Data for upper limit of 95% CI was not reached due to low number (<50%) of participants with event of interest.

[2]

Data for median and upper limit of 95% CI were not reached due to low number (<50%) of participants with event of interest.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP), Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9115
	Comments	[Not Specified]
	Method	Wald test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.71 to 1.36
	Estimation Comments	[Not Specified]

14. Secondary Outcome

Title	Percentage of Participants Who Died
Description	[Not Specified]
Time Frame	Baseline up to death (up to data cutoff of 31 Oct 2017 [up to 6 years])

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	205	205
Measure Type: Number; Unit of Measure: percentage of participants
	12.7	8.8

15. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from randomization to death due to any cause. Participants without event were censored at the time of last follow-up information for survival, ie, at the last time known to be alive.
Time Frame	Baseline up to death (up to data cutoff of 31 Oct 2017 [up to 6 years])

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	205	205
Median (95% Confidence Interval); Unit of Measure: days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Data for median and corresponding 95% CI were not reached due to low number (<10%) of participants with event of interest.

16. Secondary Outcome

Title	Stage I: Observed Area Under the Serum Concentration-Time Curve (AUC) of Rituximab
Description	AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. Predose (within 2 hr) and 24 hrs postdose on Cy 7 (D1,3,7,15), predose (0 hr) on Cy 8 D1 (1 Cy=3 weeks); additionally within 15 minutes after end of infusion (infusion duration=30 minutes) on Cy 7 D1 for rituximab IV (up to data cutoff of 11 Apr 2012 [up to 26 months])
Time Frame	Stage I (Induction): Predose (within 2 hour [hr]) up to data cutoff of 11 Apr 2012 [up to 26 months]) (See detailed timeframe in Outcome Measure description)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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 Number of Participants Analyzed	58	55
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: mcg*day/mL
	2734.21; (32.51%)	3778.93; (37.59%)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP), Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	The ratio of observed rituximab serum was determined as AUC SC/AUC IV during Cycle 7 of induction treatment.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	1.38
	Confidence Interval	(2-Sided) 90%; 1.24 to 1.53
	Estimation Comments	[Not Specified]

17. Secondary Outcome

Title	Stage I: Maximum Serum Concentrations (Cmax) of IV and SC Rituximab
Description	Predose (within 2 hr) and 24 hrs postdose on Cy7 (D1,3,7,15), predose (0 hr) on Cy8 D1 (1 Cy=3 weeks); additionally within 15 minutes after end of infusion (infusion duration=30 minutes) on Cy7 D1 for rituximab IV (up to data cutoff of 11 Apr 2012 [up to 26 months])
Time Frame	Stage I (Induction): Predose (within 2hr) up to data cutoff of 11 Apr 2012 [up to 26 months]) (See detailed timeframe in Outcome Measure description)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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 Number of Participants Analyzed	58	59
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: mcg/mL
	250.63; (19.66%)	236.82; (31.45%)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stage I: Rituximab IV + Chemotherapy (CHOP/CVP), Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	0.941
	Confidence Interval	(2-Sided) 95%; 0.872 to 1.015
	Estimation Comments	[Not Specified]

18. Secondary Outcome

Title	Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle
Description	Stage I and II (Induction): Rituximab IV: Predose (within 2 hr) on D1 of Cy1-8 (1 Cy=3 weeks & 4 weeks for Cy8); Rituximab SC: Predose (within 2 hr) on D1 of Cy1 & Cy3-8 (1 Cy=3 weeks and 4 weeks for Cy8), predose (within 2 hr) on D0 of Cy2 (up to data cutoff of 31 Oct 2013 [up to 32 months])
Time Frame	Stage I and II (Pooled): Predose (within 2hr) up to data cutoff of 31 Oct 2013 [up to 32 months]) (See detailed timeframe in Outcome Measure description)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	198	193
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: mcg/mL
Cycle 1 (n = 198, 193)	14.00; (157.53%)	12.88; (189.70%)
Cycle 2 (n = 197, 190)	30.13; (145.36%)	40.00; (124.50%)
Cycle 3 (n = 192, 190)	45.25; (110.35%)	63.83; (101.83%)
Cycle 4 (n = 186, 185)	54.06; (108.90%)	81.71; (92.28%)
Cycle 5 (n = 185, 185)	64.68; (89.90%)	98.00; (71.91%)
Cycle 6 (n = 187, 180)	71.02; (87.60%)	109.56; (58.74%)
Cycle 7 (n = 183, 172)	78.31; (77.76%)	120.75; (55.60%)
Cycle 8 (n = 52, 54)	77.60; (70.53%)	131.48; (50.20%)

19. Secondary Outcome

Title	Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle
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])
Time Frame	Stage I and II (maintenance): Predose (within 2hr) up to data cutoff of 11 Jan 2016 [up to 6 years]) (See detailed timeframe in Outcome Measure description)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	174	170
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: mcg/mL
Cycle 8 (n = 174, 170)	37.69; (94.30%)	61.31; (65.52%)
Cycle 9 (n = 171, 168)	30.35; (75.03%)	49.47; (81.23%)
Cycle 10 (n = 164, 160)	28.44; (84.64%)	47.27; (73.03%)
Cycle 11 (n = 164, 157)	28.77; (65.28%)	46.70; (66.80%)
Cycle 12 (n = 160, 150)	28.80; (56.97%)	44.72; (68.74%)
Cycle 13 (n = 157, 150)	28.84; (54.04%)	44.32; (67.67%)
Cycle 14 (n = 153, 147)	28.09; (55.61%)	43.32; (67.97%)
Cycle 15 (n = 148, 143)	28.19; (52.69%)	44.11; (67.92%)
Cycle 16 (n = 150, 145)	28.05; (57.19%)	42.96; (64.32%)
Cycle 17 (n = 149, 143)	28.24; (57.51%)	42.82; (65.67%)
Cycle 18 (n = 143, 132)	28.59; (62.06%)	44.79; (68.56%)
Cycle 19 (n = 138, 131)	27.75; (78.26%)	43.69; (69.02%)

20. Secondary Outcome

Title	Stage I and II (Pooled): Rituximab Levels 12 Weeks, 24 Weeks, and 36 Weeks After the Last Rituximab Administration
Description	[Not Specified]
Time Frame	12 weeks, 24 weeks, and 36 weeks after the last rituximab administration (up to data cutoff of 11 Jan 2016 [up to 6 years])

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	117	118
Median (Full Range); Unit of Measure: mcg/mL
Week 12: Follow-up Visit 1 (n = 117, 118)	15.60; (0.70 to 80.40)	22.35; (0.65 to 107.00)
Week 24: Follow-up Visit 2 (n = 88, 96)	2.89; (0.58 to 17.40)	5.19; (0.69 to 62.10)
Week 36: Follow-up Visit 3 (n = 38, 53)	1.08; (0.52 to 51.40)	2.02; (0.53 to 33.90)

21. Secondary Outcome

Title	Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase
Description	Depletion is defined as a cluster of differentiation (CD) 19 value <80 cells per cubic millimeter (cells/mm^3).
Time Frame	Stage I and II (induction): for rituximab IV - D1 of Cy 1 to 8 (1 Cy=3 weeks); for rituximab SC - D1 of Cy 1 and Cy 3 to 8, D0 of Cy 2

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	188	180
Measure Type: Number; Unit of Measure: percentage of participants
Cycle 1 Day 1 - Baseline (n=188, 168)	51.6	54.8
Cycle 2 Day 0 (n=183, 180)	95.1	95.0
Cycle 3 Day 1 (n=175, 175)	99.4	99.4
Cycle 4 Day 1 (n=178, 180)	99.4	100.0
Cycle 5 Day 1 (n=179, 176)	100.0	100.0
Cycle 6 Day 1 (n=173, 175)	100.0	100.0
Cycle 7 Day 1 (n=178, 173)	100.0	100.0
Cycle 8 Day 1 (n=175, 174)	100.0	100.0

22. Secondary Outcome

Title	Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase
Description	Depletion is defined as a CD19 value <80 cells/mm^3.
Time Frame	Stage I and II (maintenance): D1 of Cy 9 to 20 (1 Cy=8 weeks) (up to data cutoff of 11 Jan 2016 [up to 6 years])

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	170	164
Measure Type: Number; Unit of Measure: percentage of participants
Cycle 9 Day 1 (n=170, 161)	99.4	100.0
Cycle 10 Day 1 (n=165, 164)	99.4	100.0
Cycle 11 Day 1 (n=158, 158)	99.4	100.0
Cycle 12 Day 1 (n=151, 146)	100.0	100.0
Cycle 13 Day 1 (n=149, 143)	100.0	100.0
Cycle 14 Day 1 (n=152, 143)	100.0	100.0
Cycle 15 Day 1 (n=149, 140)	100.0	100.0
Cycle 16 Day 1 (n=142, 141)	100.0	100.0
Cycle 17 Day 1 (n=145, 142)	100.0	100.0
Cycle 18 Day 1 (n=141, 140)	100.0	100.0
Cycle 19 Day 1 (n=140, 138)	100.0	100.0
Cycle 20 Day 1 (n=139, 134)	100.0	100.0

23. Secondary Outcome

Title	Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Chimeric Antibodies (HACAs) to Rituximab
Description	Levels of HACA in serum were detected at Day 1 of each cycle up to Cycle 8 and at follow-up visit. Stage I and II: Baseline: pre-dose (72 hours prior) D1 of Cy1, Cy 3-20, D0 of Cy2 (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), post-baseline: every 12 weeks after last rituximab administration until 96 weeks (a median of 27 months; up to data cutoff of 11 Jan 2016 [up to 6 years])
Time Frame	Stage I and II: Baseline, post-baseline (See detailed timeframe in Outcome Measure description)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	208	197
Measure Type: Number; Unit of Measure: percentage of participants
Baseline (n=208, 191)	5.8	2.6
Post-Baseline (n=206, 197)	1.5	2.0

24. Secondary Outcome

Title	Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Human Antibodies (HAHAs) to Rituximab
Description	Levels of HAHA in serum were detected at Day 1 of each cycle up to Cycle 8 and at follow-up visit. Stage I and II: Baseline: pre-dose (72 hours prior) D1 of Cy1, Cy 3-20, D0 of Cy2 (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), post-baseline: every 12 weeks after last rituximab administration until 96 weeks (a median of 27 months; up to data cutoff of 11 Jan 2016 [up to 6 years])
Time Frame	Stage I and II: Baseline, post-baseline (See detailed timeframe in Outcome Measure description)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	68	197
Measure Type: Number; Unit of Measure: percentage of participants
Baseline (n=68, 188)	10.3	11.2
Post-Baseline (n=66, 197)	7.6	13.2

25. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	All Participants
Arm/Group Description:	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP): First cycle rituximab IV infusion (375 mg/m^2) + 7 cycles of rituximab SC 1400 mg in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months. Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP): Eight cycles of rituximab IV infusion (375 mg/m^2; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.
Overall Number of Participants Analyzed	166
Measure Type: Number; Unit of Measure: percentage of responses
After Cy8: <1 hour (n=166)	11
After Cy8: ≥1 to <2 hours (n=166)	20
After Cy8: ≥2 to <3 hours (n=166)	35
After Cy8: ≥3 to <4 hours (n=166)	18
After Cy8: ≥4 hours (n=166)	16
After Cy15: <1 hour (n=130)	13
After Cy15: ≥1 to <2 hours (n=130)	17
After Cy15: ≥2 to <3 hours (n=126)	34
After Cy15: ≥3 to <4 hours (n=130)	14
After Cy15: ≥4 hours (n=130)	22
After Cy20: <1 hour (n=126)	14
After Cy20: ≥1 to <2 hours (n=126)	32
After Cy20: ≥2 to <3 hours (n=126)	21
After Cy20: ≥3 to <4 hours (n=126)	13
After Cy20: ≥4 hours (n=126)	19

26. Secondary Outcome

Title	Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion
Description	All investigator physicians and nurses involved in this study were asked to complete question i.e. "Which formulation of rituximab (SC or IV) do you think is more convenient?" based on their experience with the rituximab SC and IV formulations across all participants and presented as rituximab SC is much more convenient; rituximab SC is a little more convenient; both formulations are equally convenient; rituximab IV is a little more convenient; and rituximab IV is much more convenient.
Time Frame	After Cycle 8 of induction treatment (24 weeks) and during the maintenance part of the study after 12 months (i.e., Cycle 15), and after the end of the maintenance treatment, (i.e., Cycle 20) (1 Cycle=4 weeks for Cycle 8 and 8 weeks for Cycles 15 and 20)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	All Participants
Arm/Group Description:	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP): First cycle rituximab IV infusion (375 mg/m^2) + 7 cycles of rituximab SC 1400 mg in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months. Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP): Eight cycles of rituximab IV infusion (375 mg/m^2; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.
Overall Number of Participants Analyzed	166
Measure Type: Number; Unit of Measure: percentage of responses
Cy8: Rituximab SC much more convenient (n=166)	81
Cy8: Rituximab SC little more convenient (n=166)	13
Cy8: Both formulations equally convenient (n=166)	2
Cy8: Rituximab IV little more convenient (n=166)	4
Cy8: Rituximab IV much more convenient (n=166)	0
Cy15: Rituximab SC much more convenient (n=130)	88
Cy15: Rituximab SC little more convenient (n=130)	7
Cy15: Both formulations equally convenient (n=130)	5
Cy15: Rituximab IV little more convenient (n=130)	0
Cy15: Rituximab IV much more convenient (n=130)	0
Cy20: Rituximab SC much more convenient (n=126)	88
Cy20: Rituximab SC little more convenient (n=126)	9
Cy20: Both formulations equally convenient (n=126)	2
Cy20: Rituximab IV little more convenient (n=126)	1
Cy20: Rituximab IV much more convenient (n=126)	0

Adverse Events

Time Frame	Baseline up to data cutoff date of 31 Oct 2017 (up to 6 years)
Adverse Event Reporting Description	Safety Analysis Population included all participants who received at least one dose of rituximab, either IV or SC. Safety Analysis Population included 6 participants who were randomized under Rituximab SC arm but withdrew after Cy1 and then analyzed under Rituximab IV arm.
Arm/Group Title	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
Arm/Group Description	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.	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.
All-Cause Mortality
	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	76/210 (36.19%)	74/197 (37.56%)
Blood and lymphatic system disorders
Febrile neutropenia * 1	10/210 (4.76%)	12/197 (6.09%)
Neutropenia * 1	4/210 (1.90%)	6/197 (3.05%)
Anaemia * 1	1/210 (0.48%)	2/197 (1.02%)
Thrombocytopenia * 1	1/210 (0.48%)	0/197 (0.00%)
Cardiac disorders
Acute coronary syndrome * 1	1/210 (0.48%)	0/197 (0.00%)
Atrial fibrillation * 1	0/210 (0.00%)	2/197 (1.02%)
Myocardial infarction * 1	1/210 (0.48%)	1/197 (0.51%)
Acute myocardial infarction * 1	0/210 (0.00%)	1/197 (0.51%)
Cardiac arrest * 1	1/210 (0.48%)	0/197 (0.00%)
Cardiac failure congestive * 1	1/210 (0.48%)	1/197 (0.51%)
Myocardial ischaemia * 1	1/210 (0.48%)	0/197 (0.00%)
Bradycardia * 2	1/210 (0.48%)	0/197 (0.00%)
Ear and labyrinth disorders
Vertigo * 2	1/210 (0.48%)	2/197 (1.02%)
Gastrointestinal disorders
Abdominal pain * 1	2/210 (0.95%)	2/197 (1.02%)
Constipation * 1	3/210 (1.43%)	0/197 (0.00%)
Ascites * 1	1/210 (0.48%)	0/197 (0.00%)
Oral lichen planus * 1	1/210 (0.48%)	0/197 (0.00%)
Pancreatitis * 1	1/210 (0.48%)	0/197 (0.00%)
Colitis ulcerative * 1	0/210 (0.00%)	1/197 (0.51%)
Diarrhoea * 1	0/210 (0.00%)	1/197 (0.51%)
Duodenal ulcer * 1	1/210 (0.48%)	0/197 (0.00%)
Enteritis * 1	1/210 (0.48%)	0/197 (0.00%)
Ileus paralytic * 1	0/210 (0.00%)	1/197 (0.51%)
Mouth ulceration * 1	0/210 (0.00%)	1/197 (0.51%)
Proctalgia * 1	1/210 (0.48%)	0/197 (0.00%)
Vomiting * 1	0/210 (0.00%)	1/197 (0.51%)
Mesenteric vein thrombosis * 2	1/210 (0.48%)	0/197 (0.00%)
Abdominal wall haematoma * 2	1/210 (0.48%)	0/197 (0.00%)
Colitis * 2	0/210 (0.00%)	1/197 (0.51%)
Large intestine polyp * 2	1/210 (0.48%)	0/197 (0.00%)
General disorders
Pyrexia * 1	5/210 (2.38%)	6/197 (3.05%)
Malaise * 1	1/210 (0.48%)	0/197 (0.00%)
Multi-organ failure * 1	1/210 (0.48%)	0/197 (0.00%)
Death * 2	2/210 (0.95%)	0/197 (0.00%)
Hepatobiliary disorders
Cholangitis * 1	0/210 (0.00%)	1/197 (0.51%)
Cholecystitis acute * 1	1/210 (0.48%)	0/197 (0.00%)
Jaundice * 2	0/210 (0.00%)	1/197 (0.51%)
Infections and infestations
Pneumonia * 1	7/210 (3.33%)	11/197 (5.58%)
Neutropenic sepsis * 1	4/210 (1.90%)	1/197 (0.51%)
Cystitis * 1	1/210 (0.48%)	2/197 (1.02%)
Lower respiratory tract infection * 1	2/210 (0.95%)	2/197 (1.02%)
Urinary tract infection * 1	1/210 (0.48%)	2/197 (1.02%)
Bronchitis * 1	2/210 (0.95%)	1/197 (0.51%)
Infection * 1	2/210 (0.95%)	0/197 (0.00%)
Sepsis * 1	1/210 (0.48%)	3/197 (1.52%)
Bacterial prostatitis * 1	0/210 (0.00%)	1/197 (0.51%)
Creutzfeldt-Jakob disease * 1	0/210 (0.00%)	1/197 (0.51%)
Empyema * 1	0/210 (0.00%)	1/197 (0.51%)
Gastroenteritis norovirus * 1	1/210 (0.48%)	0/197 (0.00%)
Giardiasis * 1	0/210 (0.00%)	1/197 (0.51%)
Meningitis * 1	0/210 (0.00%)	2/197 (1.02%)
Otitis externa * 1	1/210 (0.48%)	0/197 (0.00%)
Pneumocystis jirovecii pneumonia * 1	1/210 (0.48%)	0/197 (0.00%)
Pneumonia mycoplasmal * 1	0/210 (0.00%)	1/197 (0.51%)
Postoperative wound infection * 1	0/210 (0.00%)	1/197 (0.51%)
Respiratory tract infection * 1	1/210 (0.48%)	1/197 (0.51%)
Upper respiratory tract infection * 1	0/210 (0.00%)	1/197 (0.51%)
Urinary tract infection bacterial * 1	0/210 (0.00%)	1/197 (0.51%)
Appendicitis * 2	1/210 (0.48%)	1/197 (0.51%)
Cellulitis * 2	1/210 (0.48%)	1/197 (0.51%)
Urosepsis * 2	0/210 (0.00%)	2/197 (1.02%)
Abscess * 2	1/210 (0.48%)	0/197 (0.00%)
Bacteraemia * 2	0/210 (0.00%)	1/197 (0.51%)
Chronic hepatitis B * 2	0/210 (0.00%)	1/197 (0.51%)
Erysipelas * 2	0/210 (0.00%)	1/197 (0.51%)
Hepatitis viral * 2	0/210 (0.00%)	1/197 (0.51%)
Intestinal sepsis * 2	1/210 (0.48%)	0/197 (0.00%)
Pulmonary tuberculosis * 2	1/210 (0.48%)	0/197 (0.00%)
Pyelonephritis * 2	1/210 (0.48%)	0/197 (0.00%)
Respiratory tract infection fungal * 2	1/210 (0.48%)	0/197 (0.00%)
Cellulitis gangrenous * 2	1/210 (0.48%)	0/197 (0.00%)
Injury, poisoning and procedural complications
Stress fracture * 1	1/210 (0.48%)	0/197 (0.00%)
Ankle fracture * 2	1/210 (0.48%)	0/197 (0.00%)
Femoral neck fracture * 2	1/210 (0.48%)	0/197 (0.00%)
Foreign body * 1	1/210 (0.48%)	0/197 (0.00%)
Multiple injuries * 1	1/210 (0.48%)	0/197 (0.00%)
Skull fracture * 2	0/210 (0.00%)	1/197 (0.51%)
Fall * 2	0/210 (0.00%)	1/197 (0.51%)
Lumbar vertebral fracture * 2	0/210 (0.00%)	1/197 (0.51%)
Procedural pain * 2	0/210 (0.00%)	1/197 (0.51%)
Traumatic intracranial haemorrhage * 2	1/210 (0.48%)	0/197 (0.00%)
Wrist fracture * 2	0/210 (0.00%)	1/197 (0.51%)
Investigations
Eastern Cooperative Oncology Group performance status worsened * 1	1/210 (0.48%)	0/197 (0.00%)
International normalised ratio increased * 2	0/210 (0.00%)	1/197 (0.51%)
Metabolism and nutrition disorders
Hyponatraemia * 2	0/210 (0.00%)	2/197 (1.02%)
Tumour lysis syndrome * 2	0/210 (0.00%)	1/197 (0.51%)
Musculoskeletal and connective tissue disorders
Back pain * 1	1/210 (0.48%)	2/197 (1.02%)
Osteoarthritis * 1	2/210 (0.95%)	0/197 (0.00%)
Arthralgia * 1	0/210 (0.00%)	2/197 (1.02%)
Flank pain * 1	0/210 (0.00%)	1/197 (0.51%)
Pain in extremity * 1	1/210 (0.48%)	0/197 (0.00%)
Pathological fracture * 1	0/210 (0.00%)	1/197 (0.51%)
Arthritis * 2	0/210 (0.00%)	1/197 (0.51%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma * 1	1/210 (0.48%)	0/197 (0.00%)
Prostate cancer * 2	1/210 (0.48%)	1/197 (0.51%)
Rectal adenocarcinoma * 2	1/210 (0.48%)	0/197 (0.00%)
Squamous cell carcinoma of lung * 1	1/210 (0.48%)	0/197 (0.00%)
Squamous cell carcinoma of skin * 1	1/210 (0.48%)	1/197 (0.51%)
Thyroid cancer * 1	1/210 (0.48%)	0/197 (0.00%)
Adenocarcinoma of colon * 2	0/210 (0.00%)	1/197 (0.51%)
Cervix Carcinoma Stage 0 * 2	0/210 (0.00%)	1/197 (0.51%)
Colon cancer * 2	1/210 (0.48%)	1/197 (0.51%)
Kaposi's sarcoma * 2	0/210 (0.00%)	1/197 (0.51%)
Lung neoplasm malignant * 2	1/210 (0.48%)	0/197 (0.00%)
Myelodysplastic syndrome * 2	1/210 (0.48%)	0/197 (0.00%)
Renal cell carcinoma * 2	0/210 (0.00%)	1/197 (0.51%)
Uterine leiomyoma * 2	0/210 (0.00%)	1/197 (0.51%)
Adenocarcinoma * 2	1/210 (0.48%)	0/197 (0.00%)
Breast cancer * 2	0/210 (0.00%)	1/197 (0.51%)
Plasma cell myeloma * 2	0/210 (0.00%)	1/197 (0.51%)
Squamous cell carcinoma * 2	0/210 (0.00%)	1/197 (0.51%)
Nervous system disorders
Coma hepatic * 1	1/210 (0.48%)	0/197 (0.00%)
Hydrocephalus * 1	0/210 (0.00%)	1/197 (0.51%)
Migraine * 1	1/210 (0.48%)	0/197 (0.00%)
Paraesthesia * 1	0/210 (0.00%)	1/197 (0.51%)
Sciatica * 1	1/210 (0.48%)	0/197 (0.00%)
Cognitive disorder * 2	2/210 (0.95%)	0/197 (0.00%)
Hypoglycaemic coma * 2	1/210 (0.48%)	0/197 (0.00%)
Transient ischaemic attack * 2	1/210 (0.48%)	0/197 (0.00%)
Psychiatric disorders
Major depression * 2	1/210 (0.48%)	0/197 (0.00%)
Bipolar disorder * 2	1/210 (0.48%)	0/197 (0.00%)
Renal and urinary disorders
Hydronephrosis * 1	0/210 (0.00%)	2/197 (1.02%)
Urinary retention * 2	1/210 (0.48%)	0/197 (0.00%)
Calculus bladder * 2	1/210 (0.48%)	0/197 (0.00%)
Reproductive system and breast disorders
Pelvic cyst * 2	0/210 (0.00%)	1/197 (0.51%)
Ovarian cyst * 2	0/210 (0.00%)	1/197 (0.51%)
Uterovaginal prolapse * 2	0/210 (0.00%)	1/197 (0.51%)
Uterine polyp * 2	0/210 (0.00%)	1/197 (0.51%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea * 1	3/210 (1.43%)	2/197 (1.02%)
Pulmonary embolism * 1	4/210 (1.90%)	1/197 (0.51%)
Pleural effusion * 1	1/210 (0.48%)	1/197 (0.51%)
Acute respiratory failure * 1	1/210 (0.48%)	1/197 (0.51%)
Pneumothorax * 1	1/210 (0.48%)	0/197 (0.00%)
Bronchitis chronic * 2	1/210 (0.48%)	0/197 (0.00%)
Skin and subcutaneous tissue disorders
Hyperhidrosis * 1	1/210 (0.48%)	0/197 (0.00%)
Lichen planus * 1	1/210 (0.48%)	0/197 (0.00%)
Rash * 1	1/210 (0.48%)	0/197 (0.00%)
Skin ulcer * 1	1/210 (0.48%)	0/197 (0.00%)
Surgical and medical procedures
Bladder calculus removal * 2	1/210 (0.48%)	0/197 (0.00%)
Hysterectomy * 2	0/210 (0.00%)	1/197 (0.51%)
Vascular disorders
Arterial occlusive disease * 1	0/210 (0.00%)	1/197 (0.51%)
Deep vein thrombosis * 2	1/210 (0.48%)	0/197 (0.00%)
Hypertensive crisis * 2	1/210 (0.48%)	1/197 (0.51%)
Vena cava thrombosis * 1	0/210 (0.00%)	1/197 (0.51%)
Subclavian artery occlusion * 2	0/210 (0.00%)	1/197 (0.51%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (16.1); 2 Term from vocabulary, MedDRA (18.1)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)	Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	187/210 (89.05%)	186/197 (94.42%)
Blood and lymphatic system disorders
Neutropenia * 2	57/210 (27.14%)	65/197 (32.99%)
Anaemia * 2	26/210 (12.38%)	30/197 (15.23%)
Leukopenia * 2	23/210 (10.95%)	13/197 (6.60%)
Gastrointestinal disorders
Nausea * 1	47/210 (22.38%)	65/197 (32.99%)
Constipation * 1	55/210 (26.19%)	50/197 (25.38%)
Diarrhoea * 2	35/210 (16.67%)	34/197 (17.26%)
Vomiting * 2	27/210 (12.86%)	29/197 (14.72%)
Abdominal pain * 2	25/210 (11.90%)	29/197 (14.72%)
Dyspepsia * 2	14/210 (6.67%)	16/197 (8.12%)
Abdominal pain upper * 2	11/210 (5.24%)	11/197 (5.58%)
Stomatitis * 2	11/210 (5.24%)	12/197 (6.09%)
General disorders
Injection site erythema * 1	0/210 (0.00%)	27/197 (13.71%)
Fatigue * 2	38/210 (18.10%)	42/197 (21.32%)
Asthenia * 2	27/210 (12.86%)	35/197 (17.77%)
Pyrexia * 2	29/210 (13.81%)	29/197 (14.72%)
Chills * 2	18/210 (8.57%)	16/197 (8.12%)
Mucosal inflammation * 2	12/210 (5.71%)	9/197 (4.57%)
Chest pain * 1	7/210 (3.33%)	14/197 (7.11%)
Injection site pain * 2	0/210 (0.00%)	16/197 (8.12%)
Oedema peripheral * 2	13/210 (6.19%)	10/197 (5.08%)
Influenza like illness * 2	12/210 (5.71%)	5/197 (2.54%)
Infections and infestations
Upper respiratory tract infection * 1	26/210 (12.38%)	30/197 (15.23%)
Urinary tract infection * 1	28/210 (13.33%)	16/197 (8.12%)
Nasopharyngitis * 1	25/210 (11.90%)	22/197 (11.17%)
Bronchitis * 1	15/210 (7.14%)	15/197 (7.61%)
Sinusitis * 1	10/210 (4.76%)	14/197 (7.11%)
Conjunctivitis * 2	12/210 (5.71%)	9/197 (4.57%)
Influenza * 2	14/210 (6.67%)	9/197 (4.57%)
Pneumonia * 2	4/210 (1.90%)	12/197 (6.09%)
Musculoskeletal and connective tissue disorders
Bone pain * 2	16/210 (7.62%)	20/197 (10.15%)
Back pain * 2	25/210 (11.90%)	18/197 (9.14%)
Myalgia * 2	10/210 (4.76%)	16/197 (8.12%)
Arthralgia * 2	22/210 (10.48%)	26/197 (13.20%)
Pain in extremity * 2	11/210 (5.24%)	22/197 (11.17%)
Muscle spasms * 2	7/210 (3.33%)	17/197 (8.63%)
Nervous system disorders
Paraesthesia * 2	27/210 (12.86%)	30/197 (15.23%)
Neuropathy peripheral * 2	30/210 (14.29%)	24/197 (12.18%)
Dizziness * 2	15/210 (7.14%)	16/197 (8.12%)
Headache * 1	20/210 (9.52%)	27/197 (13.71%)
Hypoaesthesia * 2	7/210 (3.33%)	10/197 (5.08%)
Psychiatric disorders
Insomnia * 1	19/210 (9.05%)	19/197 (9.64%)
Anxiety * 2	7/210 (3.33%)	11/197 (5.58%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	32/210 (15.24%)	49/197 (24.87%)
Oropharyngeal pain * 1	16/210 (7.62%)	16/197 (8.12%)
Dyspnoea * 1	13/210 (6.19%)	21/197 (10.66%)
Skin and subcutaneous tissue disorders
Alopecia * 2	23/210 (10.95%)	28/197 (14.21%)
Erythema * 2	11/210 (5.24%)	19/197 (9.64%)
Pruritus * 2	25/210 (11.90%)	20/197 (10.15%)
Rash * 2	14/210 (6.67%)	20/197 (10.15%)
Vascular disorders
Hypertension * 2	13/210 (6.19%)	12/197 (6.09%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (16.1); 2 Term from vocabulary, MedDRA (18.1)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Medical Communications
• Organization: Hoffmann-La Roche
• Phone: 800-821-8590
• EMail: global-roche-genentech-trials@gene.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Davies A, Merli F, Mihaljevic B, Mercadal S, Siritanaratkul N, Solal-Celigny P, Boehnke A, Berge C, Genevray M, Zharkov A, Dixon M, Brewster M, Barrett M, MacDonald D. Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol. 2017 Jun;4(6):e272-e282. doi: 10.1016/S2352-3026(17)30078-9. Epub 2017 May 2.

Davies A, Merli F, Mihaljevic B, Siritanaratkul N, Solal-Celigny P, Barrett M, Berge C, Bittner B, Boehnke A, McIntyre C, Macdonald D. Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study. Lancet Oncol. 2014 Mar;15(3):343-52. doi: 10.1016/S1470-2045(14)70005-1. Epub 2014 Feb 10.

Mao CP, Brovarney MR, Dabbagh K, Birnbock HF, Richter WF, Del Nagro CJ. Subcutaneous versus intravenous administration of rituximab: pharmacokinetics, CD20 target coverage and B-cell depletion in cynomolgus monkeys. PLoS One. 2013 Nov 12;8(11):e80533. doi: 10.1371/journal.pone.0080533. eCollection 2013.

Shpilberg O, Jackisch C. Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase. Br J Cancer. 2013 Sep 17;109(6):1556-61. doi: 10.1038/bjc.2013.371. Epub 2013 Sep 3.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01200758
• Other Study ID Numbers: BO22334; 2010-021377-36
• First Submitted: September 10, 2010
• First Posted: September 14, 2010
• Results First Submitted: July 7, 2015
• Results First Posted: August 5, 2015
• Last Update Posted: November 27, 2018