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A Study to Compare Subcutaneous Versus Intravenous MabThera (Rituximab) in Combination With Chemotherapy in Patients With Chronic Lymphocytic Leukemia

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ClinicalTrials.gov Identifier: NCT01292603
Recruitment Status : Completed
First Posted : February 9, 2011
Results First Posted : December 15, 2015
Last Update Posted : December 18, 2017
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Lymphocytic Leukemia, Chronic
Interventions Drug: Cyclophosphamide
Drug: Fludarabine
Drug: rituximab [MabThera]
Enrollment 240
Recruitment Details  
Pre-assignment Details In Part 1 a single dose of subcutaneous (SC) rituximab was administered at Cycle 6 to select a dose resulting in trough concentration (Ctrough) non-inferior to intravenous (IV) dose. In Part 2, participants were randomized to receive rituximab IV or SC, to demonstrate non-inferiority of rituximab Ctrough levels of SC dose compared with IV dose.
Arm/Group Title Part 1: Rituximab SC 1400 Milligrams (mg) Part 1: Rituximab SC 1600 mg Part 1: Rituximab SC 1870 mg No SC Dose Received Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Hide Arm/Group Description

Participant could have been enrolled any time during their treatment with rituximab IV in combination with fludarabine/cyclophosphamide (FC) prior to Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 milligrams per square meter (mg/m^2) on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1400 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participant could have been enrolled any time during their treatment with rituximab IV in combination with FC prior to Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1600 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participant could have been enrolled any time during their treatment with rituximab IV in combination with FC prior to Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1870 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

These participants were withdrawn prior to SC treatment.

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: IV rituximab 500 mg/m^2 on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: SC rituximab 1600 mg on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Period Title: Part 1: Pilot Dose Selection Period
Started 16 17 23 [1] 8 [2] 0 0
Completed 16 17 23 0 0 0
Not Completed 0 0 0 8 0 0
Reason Not Completed
Adverse Event             0             0             0             4             0             0
Death             0             0             0             1             0             0
Protocol Violation             0             0             0             2             0             0
Withdrawal by Subject             0             0             0             1             0             0
[1]
1 participant received a dose of 1000mg of rituximab by oversight.
[2]
These participants were withdrawn prior to SC treatment.
Period Title: Part 1: Regular Follow-Up Period
Started 16 17 23 0 0 0
Completed 0 [1] 0 [1] 0 [1] 0 0 0
Not Completed 16 17 23 0 0 0
Reason Not Completed
Ongoing Regular Follow-Up             11             15             19             0             0             0
Death             1             0             2             0             0             0
Disease Progression             3             2             2             0             0             0
Adverse Event             1             0             0             0             0             0
[1]
Participants withdrawn from regular follow-up who were still alive entered survival follow-up
Period Title: Part 1: Survival Follow-Up
Started 4 2 2 0 0 0
Completed 0 0 0 0 0 0
Not Completed 4 2 2 0 0 0
Reason Not Completed
Death             1             0             1             0             0             0
Ongoing Survival Follow-UP             3             2             1             0             0             0
Period Title: Part 2: Dose Confirmation Period
Started 0 0 0 0 88 88
Completed 0 0 0 0 72 73
Not Completed 0 0 0 0 16 15
Reason Not Completed
Death             0             0             0             0             1             0
Physician Decision             0             0             0             0             2             0
Withdrawn Prior to Treatment             0             0             0             0             1             1
Adverse Event             0             0             0             0             7             9
Protocol Violation             0             0             0             0             5             3
Withdrawal by Subject             0             0             0             0             0             2
Period Title: Part 2: Regular Follow-Up
Started 0 0 0 0 78 78
Completed 0 0 0 0 0 0
Not Completed 0 0 0 0 78 78
Reason Not Completed
Death             0             0             0             0             2             2
Ongoing Regular Follow-Up             0             0             0             0             73             72
Disease Progression             0             0             0             0             2             4
Noncompliance             0             0             0             0             1             0
Period Title: Part 2: Survival Follow-UP
Started 0 0 0 0 11 13
Completed 0 0 0 0 0 0
Not Completed 0 0 0 0 11 13
Reason Not Completed
Death             0             0             0             0             1             3
Ongoing survival Follow-Up             0             0             0             0             10             10
Arm/Group Title Part 1: Rituximab SC 1400 Milligrams (mg) Part 1: Rituximab SC 1600 mg Part 1: Rituximab SC 1870 mg Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg Total
Hide Arm/Group Description

Participant could have been enrolled any time during their treatment with rituximab IV in combination with fludarabine/cyclophosphamide (FC) prior to Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1400 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participant could have been enrolled any time during their treatment with rituximab IV in combination with FC prior to Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1600 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participant could have been enrolled any time during their treatment with rituximab IV in combination with FC prior to Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1870 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: IV rituximab 500 mg/m^2 on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: SC rituximab 1600 mg on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Total of all reporting groups
Overall Number of Baseline Participants 16 17 22 89 85 229
Hide Baseline Analysis Population Description
Safety Analysis Population (SAP): all participants who received at least one dose of study medication whether prematurely withdrawn or not. In Part 2 two participants randomized to the rituximab SC 1600 mg arm were included in Rituximab IV 500 mg/m^2 arm as they received only the first cycle of rituximab IV 375 mg/m^2.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 16 participants 17 participants 22 participants 89 participants 85 participants 229 participants
56.6  (10.13) 60.4  (8.18) 56.9  (6.79) 58.7  (9.03) 59.0  (8.88) 58.8  (8.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 17 participants 22 participants 89 participants 85 participants 229 participants
Female
6
  37.5%
2
  11.8%
7
  31.8%
36
  40.4%
25
  29.4%
76
  33.2%
Male
10
  62.5%
15
  88.2%
15
  68.2%
53
  59.6%
60
  70.6%
153
  66.8%
1.Primary Outcome
Title Part 1: Subcutaneous Rituximab Dose Resulting in Trough Concentration (Ctrough) Levels Non-Inferior to Intravenous Rituximab
Hide Description Ctrough is defined as the trough or minimum serum concentration. Pharmacokinetic parameters for rituximab were assessed during Cycles 5 (IV rituximab) and 6 (SC rituximab). Rituximab pharmacokinetic (PK) data from Part 1 were integrated into a population PK model using parametric, nonlinear, mixed-effects modelling. Rituximab IV 500 mg/m^2 administered once every 4 weeks was compared to fixed doses of rituximab SC between 1400 mg and 1870 mg. The dose selection was performed on Ctrough concentrations at Cycle 5 (pre-dose Cycle 6). A test of the probability of success was applied to each of the 100 replicates, and the percentage of replicates with a positive test corresponded to the probability of success of the trial.
Time Frame Pre-dose and post-dose (15 minutes to end of infusion) on Day 1 and on Days 2, 5, 11 and 15 of Cycle 5 and Pre-dose, Post-dose on Days 2, 3, 5,11, 15 and 29 of Cycle 6; Pre-dose was taken 2 hours prior rituximab dose
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Enrolled (non-randomized) Pharmacokinetic Evaluable Population (Part 1) included all participants from Part 1 who did not significantly violate the inclusion or exclusion criteria, deviate significantly from the protocol or have unavailable or incomplete data which could influence the pharmacokinetic analysis.
Arm/Group Title Part 1: Rituximab SC
Hide Arm/Group Description:

Participant could have been enrolled any time during their treatment with rituximab IV in combination with FC prior to Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1400, 1600 or 1870 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Overall Number of Participants Analyzed 56
Measure Type: Number
Unit of Measure: mg
1600
2.Primary Outcome
Title Part 2: Rituximab C Trough Levels at Cycle 5
Hide Description Ctrough is defined as the trough or minimum serum concentration in a given cycle of treatment. The objective of Part 2 was to demonstrate the comparability of the observed Ctrough of rituximab SC 1600 mg and rituximab IV 500 mg/m2 at Cycle 5, as assessed by a non-inferiority test with a lower boundary of at least 0.8 for the 90% CI.
Time Frame +/- 25hours around the 28th day post the 5th Cycle of Rituximab administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only participants who entered Part 2 of the study and had pharmacokinetic (PK) data available were included in the analysis.
Arm/Group Title Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Hide Arm/Group Description:

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: IV rituximab 500 mg/m^2 on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: SC rituximab 1600 mg on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Overall Number of Participants Analyzed 69 65
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: μg/mL
61.50
(89.54%)
97.53
(55.27%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2 : Rituximab IV 500 mg/m^2, Part 2: Rituximab SC 1600 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments A standard non-inferiority margin of 0.8 for the ratio of Ctrough was used. The non-inferiority limit corresponds to a maximal 20 percent (%) loss in Ctrough which is considered acceptable given the high variability and range of Ctrough data, with an 80% power and a one-sided alpha of 0.05.
Method of Estimation Estimation Parameter Adjusted geometric mean ratio
Estimated Value 1.533
Confidence Interval (2-Sided) 90%
1.269 to 1.852
Estimation Comments Ratio based on geometric scale and adjusted for the covariate N_TMLD ("Tumor Load at Baseline").
3.Secondary Outcome
Title Part 2: Observed Area Under the Serum Concentration-Curve (AUC) of Rituximab at Cycle 6
Hide Description

AUC values were calculated by numerical integration using the linear trapezoidal rule. AUC levels were analyzed using the model below:

Ln(AUC) = μ + τi + BlTLij + εij wherein, Ln is the natural log, μ denotes the overall mean effect, τi the effect in each treatment group, BlTLij the tumor load at baseline for each patient and εij a random error variable with normal distribution and mean 0. The treatment effect therein was based on a contrast statement in the model to calculate 90 % confidence intervals for ln(AUC SC)– ln(AUC IV).

Time Frame Rituximab IV arm: pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6; Rituximab SC arm: pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only participants who entered Part 2 of the study and had PK data available were included in the analysis.
Arm/Group Title Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Hide Arm/Group Description:

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: IV rituximab 500 mg/m^2 on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: SC rituximab 1600 mg on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Overall Number of Participants Analyzed 58 51
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: μg*day/mL
3630.43
(38.61%)
4088.78
(37.52%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2 : Rituximab IV 500 mg/m^2, Part 2: Rituximab SC 1600 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted geometric mean ratio
Estimated Value 1.102
Confidence Interval (2-Sided) 90%
0.979 to 1.242
Estimation Comments Ratio based on geometric scale and adjusted for the covariate: N_TMLD ("Tumor Load at Baseline").
4.Secondary Outcome
Title Part 2: Maximum Observed Concentration (Cmax) of Rituximab at Cycle 6
Hide Description Cmax was obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration of rituximab in the blood samplings.
Time Frame Rituximab IV arm: pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6; Rituximab SC arm: pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only participants who entered Part 2 of the study and had PK data available were included in the analysis.
Arm/Group Title Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Hide Arm/Group Description:

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: IV rituximab 500 mg/m^2 on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: SC rituximab 1600 mg on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Overall Number of Participants Analyzed 58 51
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: μg/mL
279.78
(23.96%)
202.16
(36.10%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2 : Rituximab IV 500 mg/m^2, Part 2: Rituximab SC 1600 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted geometric mean ratio
Estimated Value 0.719
Confidence Interval (2-Sided) 90%
0.653 to 0.792
Estimation Comments Ratio based on geometric scale and adjusted for the covariate: N_TMLD.
5.Secondary Outcome
Title Part 2: Time to Cmax (Tmax) of Rituximab at Cycle 6
Hide Description Multiple blood samples were obtained at pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6 in Rituximab IV arm, and at pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6 in Rituximab SC arm and time to peak plasma concentration of rituximab was determined.
Time Frame Rituximab IV arm: pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6; Rituximab SC arm: pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only participants who entered Part 2 of the study and had PK data available were included in the analysis.
Arm/Group Title Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Hide Arm/Group Description:

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: IV rituximab 500 mg/m^2 on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: SC rituximab 1600 mg on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Overall Number of Participants Analyzed 58 51
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: days
0.22
(130.84%)
3.14
(87.62%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2 : Rituximab IV 500 mg/m^2, Part 2: Rituximab SC 1600 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted geometric mean ratio
Estimated Value 14.884
Confidence Interval (2-Sided) 90%
11.215 to 19.755
Estimation Comments Ratio based on geometric scale and adjusted for the covariate: N_TMLD.
6.Secondary Outcome
Title Part 2: Terminal Half-Life of Rituximab at Cycle 6
Hide Description The terminal half-life (t1/2) of rituximab is defined as the time required for the plasma concentration of rituximab to reach half of its original concentration.
Time Frame Rituximab IV arm: pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6; Rituximab SC arm: pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only participants who entered Part 2 of the study and had PK data available were included in the analysis.
Arm/Group Title Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Hide Arm/Group Description:

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: IV rituximab 500 mg/m^2 on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: SC rituximab 1600 mg on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Overall Number of Participants Analyzed 58 50
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: days
30.09
(41.86%)
30.71
(33.19%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2 : Rituximab IV 500 mg/m^2, Part 2: Rituximab SC 1600 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted geometric mean ratio
Estimated Value 1.010
Confidence Interval (2-Sided) 90%
0.895 to 1.139
Estimation Comments Ratio based on geometric scale and adjusted for the covariate: N_TMLD
7.Secondary Outcome
Title Part 1: Percentage of Participants and Nurses Recording a Preference For Either SC or IV Administration
Hide Description In part 1 of the trial, upon completion of dosing in cycle 6, participants and their treating nurses were asked whether they have a preference of dosing route, IV vs SC
Time Frame Days 4 to 5 in Cycle 6
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants in Part 1 were included in this analysis including 8 participants that did not receive SC rituximab.
Arm/Group Title Part 1: Rituximab SC 1400 mg Part 1: Rituximab SC 1600 mg Part 1: Rituximab SC 1870 mg
Hide Arm/Group Description:

Participant could have been enrolled any time during treatment with rituximab IV in combination with fludarabine/cyclophosphamide (FC) prior to Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1400 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1600 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1870 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Overall Number of Participants Analyzed 16 17 23
Measure Type: Number
Unit of Measure: percentage of participants or nurses
Participants who preferred SC 88.0 100.0 91.0
Participants who preferred IV 13.0 0.0 9.0
Nurses who preferred SC 88.0 100.0 91.0
Nurses who preferred IV 13.0 0.0 9.0
8.Secondary Outcome
Title Part 2: Physician/Nurse Opinion on Time Savings With Rituximab SC Compared With Rituximab IV
Hide Description

Physicians and nurses who administered rituximab were asked to answer the following question: " If used in routine practice, on average, how much staff time could be saved with each administration of rituximab SC as compared to rituximab IV? (Please do not consider the time needed for the first IV administration, consider only the subsequent ones). Percentage of participants with specified answers were reported.

  • A- Less than 1 hour
  • B- At least 1 hour but less than 2 hours
  • C- At least 2 hours but less than 3 hours
  • D- At least 3 hours but less than 4 hours
  • E- 4 or more hours
Time Frame Days 4-5 in Cycle 6
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All the physicians and nurses who responded to the questionnaire were included in the analysis. number (n) = number of physicians or nurses that responded to the survey.
Arm/Group Title Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Hide Arm/Group Description:

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: IV rituximab 500 mg/m^2 on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: SC rituximab 1600 mg on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Overall Number of Participants Analyzed 78 81
Measure Type: Number
Unit of Measure: percentage of participants in the survey
Nurse: A (n=70,70) 13.0 16.0
Physician: A (n=78,81) 10.0 7.0
Nurse: B (n=70,70) 17.0 11.0
Physician: B (n=78,81) 22.0 19.0
Nurse: C (n=70,70) 26.0 23.0
Physician: C (n=78,81) 24.0 26.0
Nurse: D (n=70,70) 23.0 29.0
Physician: D (n=78,81) 23.0 26.0
Nurse: E (n=70,70) 21.0 21.0
Physician: E (n=78,81) 21.0 22.0
9.Secondary Outcome
Title Part 2: Physician/Nurse Opinion on Convenience of Rituximab SC Compared With Rituximab IV
Hide Description

Physicians and nurses who administered rituximab were asked to answer the following question: Which formulation of rituximab (SC or IV) do you think is more convenient? with pre-specified responses as below. Percentage of participants with specified answers were reported.

  • A - Rituximab SC is much more convenient.
  • B - Rituximab SC is a little more convenient.
  • C - Both formulations are equally convenient.
  • D - Rituximab IV is a little more convenient.
  • E - Rituximab IV is much more convenient
Time Frame Days 4-5 in Cycle 6
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All the physicians and nurses who responded to the questionnaire were included in the analysis. n = number of physicians or nurses that responded to the survey.
Arm/Group Title Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Hide Arm/Group Description:

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: IV rituximab 500 mg/m^2 on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: SC rituximab 1600 mg on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Overall Number of Participants Analyzed 78 81
Measure Type: Number
Unit of Measure: percentage of participants in the survey
Nurse: A (n=70,70) 81.0 77.0
Physician: A (n=78,81) 78.0 80.0
Nurse: B (n=70,70) 7.0 9.0
Physician: B (n=78,81) 15.0 14.0
Nurse: C (n=70,70 9.0 4.0
Physician: C (n=78,81) 6.0 6.0
Nurse: D (n=70,70 3.0 10.0
Physician: D (n=78,81) 0.0 0.0
Nurse: E (n=70,70 0.0 0.0
Physician: E (n=78,81) 0.0 0.0
10.Secondary Outcome
Title Part 1: Percentage of Participants With Anti-Rituximab Antibodies
Hide Description Blood samples for the assessment of antibodies against rituximab (HACAs) were drawn pre-dose at Cycle 5 and Cycle 6 in Part 1 and at each follow up visit until 24 months after the last dose.
Time Frame Predose at Cycles 5 and 6 and at each follow up visit until 24 months after the last dose
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Population (SAP): all participants who received at least one dose of study medication, whether prematurely withdrawn from the study or not. This included 8 participants that did not receive SC rituximab. n = number of participants analyzed.
Arm/Group Title Part 1: Rituximab SC
Hide Arm/Group Description:

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1400, 1600 or 1870 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Overall Number of Participants Analyzed 64
Measure Type: Number
Unit of Measure: percentage of participants
Pre-Dose Cycle 5: positive for HACAs n=59) 0.0
Pre-Dose Cycle 5: negative for HACAs n=59) 100.0
Post-Dose: positive for HACAs (n=61) 5.0
Post-Dose: negative for HACAs (n=61) 95.1
11.Secondary Outcome
Title Part 2: Percentage of Participants With Anti-Rituximab Antibodies
Hide Description In Part 2, samples for the HACA assay were collected at each treatment cycle prior to the administration of rituximab and at each follow-up visit until 24 months after the last dose of rituximab.
Time Frame Day 0 of Cycle 1 and Day 1 of Cycles 1, 2, 3, 4, 5, and 6 and at each follow-up visit until 24 months after the last dose of rituximab.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
SAP; n = number of participants analyzed for the specific parameter.
Arm/Group Title Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Hide Arm/Group Description:

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: IV rituximab 500 mg/m^2 on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: SC rituximab 1600 mg on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Overall Number of Participants Analyzed 89 85
Measure Type: Number
Unit of Measure: percentage of participants
Baseline pre Cycle 1: positive for HACAs (n=87,85) 0.0 2.4
Baseline pre Cycle 1: negative for HACAs (n=87,85) 100.0 97.6
Post-Baseline: positive for HACAs (n=89,85) 6.7 2.4
Post-Baseline: negative for HACAs (n=89,85) 93.3 97.6
12.Secondary Outcome
Title Part 1: Total Cluster Differentiation19 Positive (CD19+) B-Cell Counts by Visit
Hide Description CD 19 is a surface antigen (protein) present on B-lymphocytes.
Time Frame Day 1 of Cycles 5 and 6 and Follow-up Days 28 and 56 and Follow-up Visits at Months 3, 6, 9, 12, 15,18, 21 and 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part 1 SAP; n = number of participants analyzed at the specified visit.
Arm/Group Title Part 1: Rituximab SC 1400 Milligrams (mg) Part 1: Rituximab SC 1600 mg Part 1: Rituximab SC 1870 mg Part 1: Rituximab SC 1000 mg No SC Dose Received
Hide Arm/Group Description:

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1400 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1600 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1870 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1000 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

These participants were withdrawn prior to SC treatment.
Overall Number of Participants Analyzed 16 17 22 1 8
Median (Full Range)
Unit of Measure: cells per microliter (cells/μL)
Cycle 5 Day 1 (n=15,13,19,1,2)
2
(0 to 157)
3
(0 to 419)
0
(0 to 19)
84 [1] 
(NA to NA)
2
(1 to 2)
Cycle 6 Day 1 (n=15,14,18,1,0)
1
(0 to 90)
2
(0 to 22)
1
(0 to 5)
27 [1] 
(NA to NA)
NA [2] 
(NA to NA)
FU 28 Day Visit (n=15,11,19,1,0)
2
(0 to 113)
2
(0 to 8)
0
(0 to 7)
7 [1] 
(NA to NA)
NA [2] 
(NA to NA)
FU 56 Day Visit (n=15,9,15,1,0)
1
(0 to 215)
3
(1 to 42)
0
(0 to 2)
14 [1] 
(NA to NA)
NA [2] 
(NA to NA)
FU 3 Month Visit (n=16,8,18,0,0)
3
(0 to 469)
1
(0 to 5)
1
(0 to 6)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
FU 6 Month Visit (n=15,13,17,1,0)
2
(0 to 5929)
1
(0 to 265)
2
(0 to 96)
51 [1] 
(NA to NA)
NA [2] 
(NA to NA)
FU 9 Month Visit (n=15,13,15,1,0)
66
(0 to 15727)
19
(1 to 728)
29
(0 to 1153)
74 [1] 
(NA to NA)
NA [2] 
(NA to NA)
FU 12 Month Visit (n=14,14,20,0,0)
126
(4 to 1457)
31
(0 to 2775)
90
(2 to 1281)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
FU 15 Month Visit (n=14,11,15,0,0)
175
(14 to 2426)
41
(3 to 6588)
106
(29 to 500)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
FU 18 Month Visit (n=13,14,15,0,0)
175
(15 to 5871)
82
(16 to 13749)
189
(22 to 478)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
FU 21 Month Visit (n=13,12,16,0,0)
128
(27 to 10679)
78
(9 to 314)
149
(57 to 783)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
FU 24 Month Visit(n=12, 4,16,0,0)
238
(29 to 11989)
110
(25 to 2225)
232
(69 to 1343)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
[1]
Only 1 participant was analyzed in this group.
[2]
No participants were analyzed in this group.
13.Secondary Outcome
Title Part 1: Percentage of Participants With Total B-Cell Depletion by Visit
Hide Description Total B-cell depletion (normal B-cell plus Malignant B-cell depletion) was defined for each individual participant when the sum of CD5-/CD19+ (normal B-cells) and CD5+/CD19+ (malignant B-cells) cell counts decreased below 80 cells/μL.
Time Frame Day 1 pre-dose of Cycles 5 and 6 and Follow-up Days 28 and 56 and Follow-up Visits at Months 3, 6, 9, 12, 15, 18, 21 and 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part 1 SAP; n = number of participants analyzed at the specified visit.
Arm/Group Title Part 1: Rituximab SC 1400 mg Part 1: Rituximab SC 1600 mg Part 1: Rituximab SC 1870 mg Rituximab SC 1000 mg No SC Dose Received
Hide Arm/Group Description:

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1400 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1600 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1870 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1000 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

These participants were withdrawn prior to SC treatment.
Overall Number of Participants Analyzed 16 17 22 1 8
Measure Type: Number
Unit of Measure: percentage of participants
Cycle 5 Day 1 (n=15,1319,1,2) 93.3 92.3 100.0 0.0 100.0
Cycle 6 Day 1(n= 15,14,18,1,0) 93.3 100.0 100.0 100.0 NA [1] 
FU 28 Day Visit (n=15,11,19,1,0) 93.3 100.0 100.0 100.0 NA [1] 
FU 56 Day Visit (n=15,9,15,1,0) 93.3 100.0 100.0 100.0 NA [1] 
FU 3 Month Visit (n=16,8,18,0,0) 93.8 100.0 100.0 NA [1]  NA [1] 
FU 6 Month Visit (n=15,13,17,1,0) 86.7 92.3 94.1 100.0 NA [1] 
FU 9 Month Visit (n=15,13,15,1,0) 53.3 84.6 60.0 100.0 NA [1] 
FU 12 Month Visit (n=14,14,20,0,0) 28.6 85.7 45.0 NA [1]  NA [1] 
FU 15 Month Visit (n=14,11,15,0,0) 35.7 54.5 40.0 NA [1]  NA [1] 
FU 18 Month Visit (n=13,14,15,0,0) 30.8 50.0 26.7 NA [1]  NA [1] 
FU 21 Month Visit (n=13,12,16,0,0) 30.8 50.0 18.8 NA [1]  NA [1] 
FU 24 Month Visit (n=12,14,16,0,0) 25.0 21.4 18.8 NA [1]  NA [1] 
[1]
No participants were analyzed in this group.
14.Secondary Outcome
Title Part 2: Total CD19+ B-Cell Counts by Visit
Hide Description CD 19 is a surface antigen (protein) present on B-lymphocytes.
Time Frame Cycle 1 pre-dose, 60 minutes post-dose, Days 2 and 3 in Cycle 2, day 1 pre-dose in Cycles 3, 4, 5 and 6, Follow-up Days 28 and 56, and Follow-up Visits at Months 3, 6, 9, 12, 15, and 18 and Withdrawal Visit
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part 2 SAP; n = number of participants analyzed at the specified visit.
Arm/Group Title Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Hide Arm/Group Description:

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: IV rituximab 500 mg/m^2 on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: SC rituximab 1600 mg on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Overall Number of Participants Analyzed 89 85
Median (Full Range)
Unit of Measure: cells/μL
Cycle 1 - Baseline (n=79,80)
69930
(0 to 277645)
50565
(640 to 453292)
Cycle 2 - Pre-dose (n=71,73)
338
(2 to 38252)
246
(1 to 92469)
Cycle 2 - Post-dose (n=65, 65)
163
(3 to 13026)
166
(1 to 32615)
Cycle 2 Day 2 (n=54, 59)
154
(6 to 10416)
266
(0 to 40815)
Cycle 2 Day 3 (n=48, 54)
87
(0 to 14769)
125
(0 to 13229)
Cycle 3 Day 1 (n=67,67)
12
(0 to 13118)
8
(1 to 22392)
Cycle 4 Day 1 (n=71,69)
4
(0 to 17827)
4
(0 to 18672)
Cycle 5 Day 1 (n=68,67)
2
(0 to 7146)
2
(0 to 8542)
Cycle 6 Day 1 (n=71,63)
3
(0 to 3612)
3
(0 to 4234)
FU 28 Day Visit (n=66,63)
2
(0 to 1299)
2
(0 to 2749)
FU 56 Day Visit (n=63,67)
2
(0 to 14331)
2
(0 to 3539)
FU 3 Month Visit (n=65,67)
2
(0 to 39037)
2
(0 to 16413)
FU 6 Month Visit (n=60,68)
3
(0 to 1356)
3
(0 to 22630)
FU 9 Month Visit (n=50,45)
30
(1 to 2721)
16
(0 to 890)
FU 12 Month Visit (n=21,18)
119
(9 to 2951)
66
(4 to 1770)
FU 15 Month Visit (n=3,0)
140
(59 to 370)
NA [1] 
(NA to NA)
FU 18 Month Visit (n=1,1)
497 [2] 
(NA to NA)
165 [2] 
(NA to NA)
Withdrawn/Termination (n=13,12)
61
(2 to 16952)
5
(0 to 35325)
[1]
No participants were analyzed in this group.
[2]
The range is not calculated since there was only a single participant at this time point.
15.Secondary Outcome
Title Part 2: Percentage of Participants With Total B-Cell Depletion by Visit
Hide Description Total B-cell depletion (normal B-cell plus Malignant B-cell depletion) was defined for each individual participant when the sum of CD5-/CD19+ (normal B-cells) and CD5+/CD19+ (malignant B-cells) cell counts decreased below 80 cells/μL.
Time Frame Cycle 1 Pre-dose, 60 minutes post-dose, Days 2 and 3 in Cycle 2, day 1 in Cycles 3, 4, 5 and 6, Follow-up Days 28 and 56, and Follow-up Visits at Months 3, 6, 9, 12, 15, and 18 and Withdrawal Visit
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Part 2 SAP; n= number of participants analyzed at the specified visit.
Arm/Group Title Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Hide Arm/Group Description:

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: IV rituximab 500 mg/m^2 on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: SC rituximab 1600 mg on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Overall Number of Participants Analyzed 89 85
Measure Type: Number
Unit of Measure: percentage of participants
Cycle 1 - Baseline (n=79,80)) 1.3 0.0
Cycle 2 - Pre-dose (n=71, 73) 23.9 31.5
Cycle 2 - Post-dose (n=65, 65) 32.3 38.5
Cycle 2 Day 2 (n=54, 59) 35.2 30.5
Cycle 2 Day 3 (n=48, 54) 50.0 37.0
Cycle 3 Day 1 (n=67,67) 73.1 76.1
Cycle 4 Day 1 (n=71,69) 83.1 84.1
Cycle 5 Day 1 (n=68,67) 88.2 89.6
Cycle 6 Day 1 (n=71,63) 95.8 95.2
FU 28 Day Visit (n=66,63) 95.5 96.8
FU 56 Day Visit (n=63,67) 92.1 97.0
FU 3 Month Visit (n=65,67) 95.4 92.5
FU 6 Month Visit (n=60,68) 88.3 91.2
FU 9 Month Visit (n=50,45) 66.0 66.7
FU 12 Month Visit (n=21,18) 33.3 50.0
FU 15 Month Visit (n=3,0) 33.3 NA [1] 
FU 18 Month Visit (n=1,1) 0.0 0.0
Withdrawn/Termination (n=13,12) 53.8 83.3
[1]
No participants were analyzed in this group.
Time Frame Adverse Events were recorded from the time of initiation of treatment until 28 days after completion of study treatment in Cycle 6.
Adverse Event Reporting Description New infections and all unrelated SAEs were reported until 9 months after the last dose of study treatment. All related SAEs were reported indefinitely. Secondary malignancies were reported until the end of the study or initiation of a new anti-leukemia treatment, whichever was earlier.
 
Arm/Group Title Part 1: Rituximab SC 1400 mg Part 1: Rituximab SC 1600 mg Part 1: Rituximab SC 1870 mg Part 1: Rituximab SC 1000 mg No SC Dose Received Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Hide Arm/Group Description

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1400 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1600 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

PParticipant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1870 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m^2 on Day 1 Cycle 6: SC rituximab 1000 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

These participants were withdrawn prior to SC treatment.

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: IV rituximab 500 mg/m^2 on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

Participants received the following in 28-day cycles.

Cycle 1: IV rituximab 375 mg/m^2 on Day 0

Cycles 2-6: SC rituximab 1600 mg on Day 1

Cycles 1-6: IV fludarabine 25 mg/m^2 on Days 1−3 (or as an oral dose of 24 mg/m^2 on Days 1-5 or 30-40 mg/m^2 on Days 1-3), and IV cyclophosphamide 250 mg/m^2 on Days 1−3 (or as an oral dose of 150 mg/m^2 on Days 1−5 or 200-250 mg/m^2 on Days 1−3).

All-Cause Mortality
Part 1: Rituximab SC 1400 mg Part 1: Rituximab SC 1600 mg Part 1: Rituximab SC 1870 mg Part 1: Rituximab SC 1000 mg No SC Dose Received Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Part 1: Rituximab SC 1400 mg Part 1: Rituximab SC 1600 mg Part 1: Rituximab SC 1870 mg Part 1: Rituximab SC 1000 mg No SC Dose Received Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/16 (31.25%)   7/17 (41.18%)   4/22 (18.18%)   1/1 (100.00%)   3/8 (37.50%)   29/89 (32.58%)   25/85 (29.41%) 
Blood and lymphatic system disorders               
Febrile Neutropenia * 1  0/16 (0.00%)  1/17 (5.88%)  2/22 (9.09%)  1/1 (100.00%)  1/8 (12.50%)  4/89 (4.49%)  9/85 (10.59%) 
Anaemia * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  3/89 (3.37%)  0/85 (0.00%) 
Bone Marrow Failure * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  1/1 (100.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Neutropenia * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  8/89 (8.99%)  1/85 (1.18%) 
Thrombocytopenia * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  1/1 (100.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Haemolytic Anaemia * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  1/85 (1.18%) 
Leukopenia * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  1/85 (1.18%) 
Pancytopenia * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Tachycardia * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Cardiac disorders               
Cardiac Failure * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Arrhythmia * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Ear and labyrinth disorders               
Vertigo * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Eye disorders               
Diabetic Retinal Oedema * 1  0/16 (0.00%)  0/17 (0.00%)  1/22 (4.55%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Gastrointestinal disorders               
Diarrhoea * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Neutropenic Colitis * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
General disorders               
Pyrexia * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  1/89 (1.12%)  3/85 (3.53%) 
Death * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/89 (0.00%)  0/85 (0.00%) 
Localised Oedema * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Ulcer * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Hepatobiliary disorders               
Cholecystitis * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Cholelithiasis * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Hepatitis Toxic * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Immune system disorders               
Drug Hypersensitivity * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Hypersensitivity * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/89 (0.00%)  0/85 (0.00%) 
Infections and infestations               
Peumonia * 1  1/16 (6.25%)  1/17 (5.88%)  1/22 (4.55%)  0/1 (0.00%)  1/8 (12.50%)  1/89 (1.12%)  1/85 (1.18%) 
Gastroenteritis * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Pelvic Infection * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Skin Infection * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Upper Respiratory Tract Infection * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  2/89 (2.25%)  1/85 (1.18%) 
Bronchopneumonia * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  1/85 (1.18%) 
Lower Respiratory Tract Infection * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  2/89 (2.25%)  0/85 (0.00%) 
Cellulitis * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Hepatitis B * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Herpes Zoster * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Influenza * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Listeriosis * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Lobar Pneumonia * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Lung Infection * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Meningitis * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Meningitis Cryptococcal * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Oesophageal Infection * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Progressive Multifocal Leukoencephalopathy * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Pulpitis Dental * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Respiratory tract infection * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Staphylococcal Sepsis * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Tuberculosis * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Wound Infection * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Injury, poisoning and procedural complications               
Wound Dehiscene * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Meniscus Injury * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Metabolism and nutrition disorders               
Tumor Lysis Syndrome * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/89 (0.00%)  0/85 (0.00%) 
Musculoskeletal and connective tissue disorders               
Osteitis * 1  0/16 (0.00%)  0/17 (0.00%)  1/22 (4.55%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Pain in extremity * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Adenocarcinoma Gastric * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Brain Neoplasm * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Malignant Melanoma * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Metastases to Peritoneum * 1  0/16 (0.00%)  0/17 (0.00%)  1/22 (4.55%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Squamous Cell Carcinoma * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Nervous system disorders               
Guillain- Barre Syndrome * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/89 (0.00%)  0/85 (0.00%) 
Meralgia Paraesthetica * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Syncope * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Renal and urinary disorders               
Cystitis Haemorrhagic * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Nephrolithiasis * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Renal Failure Acute * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Reproductive system and breast disorders               
Bartholinitis * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Interstitial Lung Disease * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Pulmonary Embolism * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Bronchitis Chronic * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Dyspnoea * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Hypoxia * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Skin and subcutaneous tissue disorders               
Dermatitis Allergic * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
Rash Maculo- Papular * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  1/85 (1.18%) 
Vascular disorders               
Hypertension * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  0/85 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (17.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Part 1: Rituximab SC 1400 mg Part 1: Rituximab SC 1600 mg Part 1: Rituximab SC 1870 mg Part 1: Rituximab SC 1000 mg No SC Dose Received Part 2 : Rituximab IV 500 mg/m^2 Part 2: Rituximab SC 1600 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   13/16 (81.25%)   16/17 (94.12%)   20/22 (90.91%)   1/1 (100.00%)   7/8 (87.50%)   77/89 (86.52%)   81/85 (95.29%) 
Blood and lymphatic system disorders               
Neutropenia * 1  7/16 (43.75%)  8/17 (47.06%)  9/22 (40.91%)  1/1 (100.00%)  3/8 (37.50%)  51/89 (57.30%)  54/85 (63.53%) 
Leukopenia * 1  3/16 (18.75%)  6/17 (35.29%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  14/89 (15.73%)  15/85 (17.65%) 
Anaemia * 1  2/16 (12.50%)  2/17 (11.76%)  1/22 (4.55%)  1/1 (100.00%)  2/8 (25.00%)  20/89 (22.47%)  11/85 (12.94%) 
Thrombocytopenia * 1  0/16 (0.00%)  3/17 (17.65%)  2/22 (9.09%)  1/1 (100.00%)  1/8 (12.50%)  23/89 (25.84%)  19/85 (22.35%) 
Agranulocytosis * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Febrile Neutropenia * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Granulocytopenia * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Cardiac disorders               
Palpitations * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Tachycardia * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Eye disorders               
Diplopia * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/89 (0.00%)  0/85 (0.00%) 
Ocular hyperaemia * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Gastrointestinal disorders               
Nausea * 1  2/16 (12.50%)  6/17 (35.29%)  4/22 (18.18%)  0/1 (0.00%)  2/8 (25.00%)  31/89 (34.83%)  32/85 (37.65%) 
Vomiting * 1  2/16 (12.50%)  2/17 (11.76%)  7/22 (31.82%)  0/1 (0.00%)  2/8 (25.00%)  20/89 (22.47%)  18/85 (21.18%) 
Diarrhoea * 1  1/16 (6.25%)  3/17 (17.65%)  3/22 (13.64%)  0/1 (0.00%)  1/8 (12.50%)  9/89 (10.11%)  10/85 (11.76%) 
Abdominal pain upper * 1  0/16 (0.00%)  2/17 (11.76%)  2/22 (9.09%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Constipation * 1  1/16 (6.25%)  2/17 (11.76%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  7/89 (7.87%)  7/85 (8.24%) 
Abdominal pain * 1  1/16 (6.25%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  5/89 (5.62%)  8/85 (9.41%) 
Dyspepsia * 1  0/16 (0.00%)  1/17 (5.88%)  1/22 (4.55%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Gastrooesophageal reflux disease * 1  1/16 (6.25%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Mouth ulceration * 1  0/16 (0.00%)  2/17 (11.76%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Abdominal discomfort * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Gingival erythema * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Gingival pain * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Haemorrhoids * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Odynophagia * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Painful defaecation * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
General disorders               
Pyrexia * 1  1/16 (6.25%)  5/17 (29.41%)  1/22 (4.55%)  0/1 (0.00%)  1/8 (12.50%)  22/89 (24.72%)  25/85 (29.41%) 
Chills * 1  1/16 (6.25%)  4/17 (23.53%)  1/22 (4.55%)  0/1 (0.00%)  1/8 (12.50%)  9/89 (10.11%)  11/85 (12.94%) 
Injection site pain * 1  0/16 (0.00%)  3/17 (17.65%)  3/22 (13.64%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  14/85 (16.47%) 
Injection site erythema * 1  0/16 (0.00%)  2/17 (11.76%)  4/22 (18.18%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  22/85 (25.88%) 
Asthenia * 1  1/16 (6.25%)  2/17 (11.76%)  1/22 (4.55%)  0/1 (0.00%)  0/8 (0.00%)  15/89 (16.85%)  7/85 (8.24%) 
Fatigue * 1  0/16 (0.00%)  3/17 (17.65%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  9/89 (10.11%)  9/85 (10.59%) 
Chest discomfort * 1  1/16 (6.25%)  2/17 (11.76%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Chest pain * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Feeling hot * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Injection site discolouration * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Injection site swelling * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Oedema * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Hepatobiliary disorders               
Hepatotoxicity * 1  1/16 (6.25%)  0/17 (0.00%)  1/22 (4.55%)  0/1 (0.00%)  1/8 (12.50%)  0/89 (0.00%)  0/85 (0.00%) 
Infections and infestations               
Sinusitis * 1  0/16 (0.00%)  2/17 (11.76%)  4/22 (18.18%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Nasopharyngitis * 1  1/16 (6.25%)  0/17 (0.00%)  3/22 (13.64%)  0/1 (0.00%)  1/8 (12.50%)  0/89 (0.00%)  0/85 (0.00%) 
Upper respiratory tract infection * 1  0/16 (0.00%)  1/17 (5.88%)  3/22 (13.64%)  0/1 (0.00%)  0/8 (0.00%)  11/89 (12.36%)  10/85 (11.76%) 
Herpes zoster * 1  1/16 (6.25%)  2/17 (11.76%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Urinary tract infection * 1  1/16 (6.25%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  7/89 (7.87%)  2/85 (2.35%) 
Bronchitis * 1  1/16 (6.25%)  0/17 (0.00%)  1/22 (4.55%)  0/1 (0.00%)  0/8 (0.00%)  5/89 (5.62%)  6/85 (7.06%) 
Rhinitis * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Fungal infection * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Gastroenteritis viral * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Giardiasis * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Laryngitis * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Respiratory tract infection * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  3/89 (3.37%)  7/85 (8.24%) 
Upper respiratory tract infection bacterial * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Vulvovaginal candidiasis * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Vulvovaginitis trichomonal * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Injury, poisoning and procedural complications               
Procedural pain * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Investigations               
Weight decreased * 1  0/16 (0.00%)  1/17 (5.88%)  1/22 (4.55%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Immunoglobulins decreased * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Serum ferritin decreased * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Metabolism and nutrition disorders               
Hyperglycaemia * 1  1/16 (6.25%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/89 (0.00%)  0/85 (0.00%) 
Hypokalaemia * 1  1/16 (6.25%)  1/17 (5.88%)  1/22 (4.55%)  0/1 (0.00%)  1/8 (12.50%)  0/89 (0.00%)  0/85 (0.00%) 
Decreased appetite * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/89 (0.00%)  0/85 (0.00%) 
Diabetes mellitus * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Hypomagnesaemia * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Musculoskeletal and connective tissue disorders               
Musculoskeletal chest pain * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Musculoskeletal discomfort * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Myalgia * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Arthralgia * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  1/89 (1.12%)  8/85 (9.41%) 
Bone pain * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  2/89 (2.25%)  5/85 (5.88%) 
Pain in extremity * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  2/89 (2.25%)  5/85 (5.88%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Colon adenoma * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Haemangioma * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Mycosis fungoides * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Renal oncocytoma * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Nervous system disorders               
Headache * 1  2/16 (12.50%)  3/17 (17.65%)  3/22 (13.64%)  0/1 (0.00%)  0/8 (0.00%)  8/89 (8.99%)  6/85 (7.06%) 
Dizziness * 1  0/16 (0.00%)  1/17 (5.88%)  1/22 (4.55%)  0/1 (0.00%)  1/8 (12.50%)  0/89 (0.00%)  0/85 (0.00%) 
Paraesthesia * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  1/8 (12.50%)  0/89 (0.00%)  0/85 (0.00%) 
Psychiatric disorders               
Anxiety * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Insomnia * 1  0/16 (0.00%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  6/89 (6.74%)  1/85 (1.18%) 
Reproductive system and breast disorders               
Vaginal discharge * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Cough * 1  1/16 (6.25%)  1/17 (5.88%)  3/22 (13.64%)  0/1 (0.00%)  0/8 (0.00%)  10/89 (11.24%)  11/85 (12.94%) 
Dyspnoea * 1  1/16 (6.25%)  3/17 (17.65%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  6/89 (6.74%)  3/85 (3.53%) 
Oropharyngeal pain * 1  1/16 (6.25%)  1/17 (5.88%)  1/22 (4.55%)  0/1 (0.00%)  0/8 (0.00%)  3/89 (3.37%)  5/85 (5.88%) 
Rhinorrhoea * 1  0/16 (0.00%)  1/17 (5.88%)  1/22 (4.55%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Bronchospasm * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Dysphonia * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Dyspnoea exertional * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Skin and subcutaneous tissue disorders               
Erythema * 1  1/16 (6.25%)  0/17 (0.00%)  2/22 (9.09%)  0/1 (0.00%)  0/8 (0.00%)  6/89 (6.74%)  13/85 (15.29%) 
Hyperhidrosis * 1  1/16 (6.25%)  2/17 (11.76%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Pruritus * 1  0/16 (0.00%)  1/17 (5.88%)  2/22 (9.09%)  0/1 (0.00%)  0/8 (0.00%)  4/89 (4.49%)  7/85 (8.24%) 
Rash * 1  0/16 (0.00%)  2/17 (11.76%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  9/89 (10.11%)  10/85 (11.76%) 
Panniculitis * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Pityriasis * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Rash erythematous * 1  0/16 (0.00%)  1/17 (5.88%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Rash pruritic * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Skin lesion * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
Vascular disorders               
Hypotension * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  6/89 (6.74%)  1/85 (1.18%) 
Thrombophlebitis * 1  1/16 (6.25%)  0/17 (0.00%)  0/22 (0.00%)  0/1 (0.00%)  0/8 (0.00%)  0/89 (0.00%)  0/85 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (17.0)
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- LaRoche
Phone: 1-800-821-8590
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01292603     History of Changes
Other Study ID Numbers: BO25341
2010-021380-32 ( EudraCT Number )
First Submitted: February 8, 2011
First Posted: February 9, 2011
Results First Submitted: September 23, 2015
Results First Posted: December 15, 2015
Last Update Posted: December 18, 2017