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A Safety and Efficacy Study of Obinutuzumab Alone or in Combination With Chemotherapy in Participants With Chronic Lymphocytic Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01905943
Recruitment Status : Completed
First Posted : July 23, 2013
Results First Posted : October 29, 2018
Last Update Posted : December 11, 2018
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Chronic Lymphocytic Leukemia
Interventions Drug: Bendamustine
Drug: Chlorambucil
Drug: Cyclophosphamide
Drug: Fludarabine
Drug: Obinutuzumab
Enrollment 979
Recruitment Details The study was conducted at 195 centers in 31 countries
Pre-assignment Details A total of 1131 subjects were screened and 979 subjects were enrolled. Due to compliance issues a site in Romania was closed. Seven subjects were excluded from the analysis, because data integrity was impacted by the site’s non-compliance. Hence, data analysis is reported for 972 enrolled subjects.
Arm/Group Title Obinutuzumab
Hide Arm/Group Description Participants received obinutuzumab either alone as single agent, or in combination with chemotherapy (Fludarabine/Cyclophosphamide [FC], Bendamustine or Chlorambucil).
Period Title: Overall Study
Started 972
Completed 0 [1]
Not Completed 972
Reason Not Completed
Withdrawal of consent             63
Moved away from site             1
Renal cell carcinoma             1
Disease progression             2
Lost to Follow-up             9
Investigator discretion             4
Death             105
Adverse Event             10
Ongoing in study             777
[1]
All patients provide reason at final analysis
Arm/Group Title Obinutuzumab
Hide Arm/Group Description Participants received obinutuzumab either alone as single agent, or in combination with chemotherapy (Fludarabine/Cyclophosphamide [FC], Bendamustine or Chlorambucil).
Overall Number of Baseline Participants 972
Hide Baseline Analysis Population Description
The intent-to-treat (ITT) population was defined as all participants enrolled in the study regardless of whether or not they received any study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 972 participants
65.4  (10.94)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 972 participants
Female
355
  36.5%
Male
617
  63.5%
1.Primary Outcome
Title Number of Participants With Adverse Events (AEs)
Hide Description An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs, including AEs of Special Interest and AEs of Particular Interest, were reported based on the national cancer institute common terminology criteria for AEs, Version 4.0 (NCI-CTCAE, v4.0). Reported are the number of subjects with AEs, Grade 3-5 AEs, and Serious Adverse Events (SAEs).
Time Frame Baseline up to data base lock date at time of primary study completion (up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety population was defined as all participants who have received at least one dose of study medication.
Arm/Group Title Obinutuzumab
Hide Arm/Group Description:
Participants received obinutuzumab either alone as single agent, or in combination with chemotherapy (Fludarabine/Cyclophosphamide [FC], Bendamustine or Chlorambucil).
Overall Number of Participants Analyzed 971
Measure Type: Count of Participants
Unit of Measure: Participants
AEs
950
  97.8%
Grade 3-5 AEs
780
  80.3%
SAEs
516
  53.1%
2.Primary Outcome
Title Number of Participants With Adverse Events of Special Interest (AESIs)
Hide Description The following AEs were defined as AESIs: AEs with the preferred term Tumour Lysis Syndrome (TLS), Infusion-Related Reactions (IRRs) defined as AEs that occurred during or within 24 hours of the completion of obinutuzumab infusion and were assessed as related to obinutuzumab by the Investigator, Infections defined as AEs from System Organ Class (SOC) “Infections and infestations” and AEs with the preferred term Neutropenia. Reported are number of participants with total AESIs, IRRs, Infections, Neutropenia and TLS.
Time Frame Baseline up to data base lock date at time of primary study completion (up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety population was defined as all participants who have received at least one dose of study medication.
Arm/Group Title Obinutuzumab
Hide Arm/Group Description:
Participants received obinutuzumab either alone as single agent, or in combination with chemotherapy (Fludarabine/Cyclophosphamide [FC], Bendamustine or Chlorambucil).
Overall Number of Participants Analyzed 971
Measure Type: Count of Participants
Unit of Measure: Participants
Total AESIs
895
  92.2%
IRRs
635
  65.4%
Neutropenia
599
  61.7%
Infections
521
  53.7%
TLS
62
   6.4%
3.Primary Outcome
Title Number of Participants With Adverse Events of Particular Interest (AEPIs)
Hide Description The following AEs were defined as AEPIs: AEs with the preferred term Progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation defined as AEs with preferred term containing “Hepatitis B” or “hepatitis acute", thrombocytopenia defined via Roche MedDRA basket subgroup “haematopoietic thrombocytopenia”, second malignancies defined as AEs from the SOC “Neoplasms benign, malignant and unspecified” starting 6 months after the first study drug intake, second malignancies based on standardised MedDRA queries (SMQ) starting 6 months after the first study drug intake based on the MedDRA SMQ “Malignant or unspecified tumours”, in which benign neoplasms are not included, Cardiac events including AEs from the SOC “Cardiac disorders”, and hemorrhagic events defined via Roche MedDRA basket subgroup “Haemorrhagic events”. Reported are number of participants with total AEPIs and each of the AEPI categories.
Time Frame Baseline up to data base lock date at time of primary study completion (up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety population was defined as all participants who have received at least one dose of study medication.
Arm/Group Title Obinutuzumab
Hide Arm/Group Description:
Participants received obinutuzumab either alone as single agent, or in combination with chemotherapy (Fludarabine/Cyclophosphamide [FC], Bendamustine or Chlorambucil).
Overall Number of Participants Analyzed 971
Measure Type: Count of Participants
Unit of Measure: Participants
Total AEPIs
467
  48.1%
Thrombocytopenia
314
  32.3%
Cardiac events
109
  11.2%
Second malignancies
82
   8.4%
Second malignancies (SMQ)
75
   7.7%
Hemorrhagic events
69
   7.1%
Hepatitis B reactivation
3
   0.3%
PML
1
   0.1%
4.Secondary Outcome
Title Percentage of Participants With Overall Response (OR) at Final Response Assessment (FRA)
Hide Description OR: percentage of participants with complete response (CR) or CR with incomplete marrow recovery (CRi), or partial response (PR), as determined by the investigator based on International Workshop on Chronic Lymphocytic Leukemia (IWCLL) tumor response criteria. CR: Peripheral blood lymphocytes 4,000/mcL, no significant lymphadenopathy, no hepatomegaly and splenomegaly, no disease symptoms, blood counts: neutrophils >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 110 g/L and bone marrow normocellular for age. Cri: CR with persistent cytopenia. PR: >/= 50% decrease in peripheral blood lymphocyte count AND >/= 50% reduction in lymphadenopathy OR >/= 50% reduction of liver enlargement OR >/= 50% reduction of spleen PLUS one of the following: neutrophils >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 110 g/L OR >/= 50% increase in neutrophils, platelets or hemoglobin.
Time Frame 3 months after the last dose of study treatment (up to approximately 5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was defined as all participants enrolled in the study regardless of whether or not they received any study drug.
Arm/Group Title G Mono: Previously Untreated Fit G Mono: Previously Untreated Unfit G Mono: Relapsed/Refractory G-Benda: Previously Untreated Fit G-Benda: Previously Untreated Unfit G-Benda: Relapsed/Refractory G-FC: Previously Untreated Fit G-FC: Previously Untreated Unfit G-FC: Relapsed/Refractory G-Clb: Previously Untreated Fit G-Clb: Previously Untreated Unfit G-Clb: Relapsed/Refractory
Hide Arm/Group Description:
Participants with obinutuzumab monotherapy who were previously untreated fit. Fit participants were defined as having a total Cumulative Illness Rating Scale (CIRS) score ≤6 and creatinine clearance (CrCl) ≥70 mL/min.
Participants with obinutuzumab monotherapy who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab monotherapy who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with bendamustine who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with bendamustine who were previously untreated unfit. Non fit Participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with bendamustine who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated fit. Fit subjects were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min. This is a Protocol deviation: unfit subjects were incorrectly assigned to the G-FC treatment regimen.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with chlorambucil who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Overall Number of Participants Analyzed 31 32 64 167 180 191 140 13 40 1 67 46
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
71.0
(52.0 to 85.8)
56.3
(37.7 to 73.6)
42.2
(29.9 to 55.2)
83.8
(77.4 to 89.1)
80.0
(73.4 to 85.6)
72.8
(65.9 to 79.0)
90.0
(83.8 to 94.4)
84.6
(54.6 to 98.1)
82.5
(67.2 to 92.7)
100
(2.5 to 100.0)
82.1
(70.8 to 90.4)
54.3
(39.0 to 69.1)
5.Secondary Outcome
Title Percentage of Participants With Minimal Residual Disease (MRD)-Negativity as Assessed by Flow Cytometry
Hide Description MRD-negativity was defined as the presence of less than 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes in blood and bone marrow as assessed by flow cytometry 3 months after last dose of study treatment (i.e. at final response assessment [FRA] visit).
Time Frame 3 months after the last dose of study treatment (up to approximately 5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-ship (ITS) population included all participants whose shipment of fresh blood/bone marrow to the central laboratory for purpose of MRD analyses could occur within 48 hours. Number of participants analyzed indicates participants who took part in the analysis.
Arm/Group Title G Mono: Previously Untreated Fit G Mono: Previously Untreated Unfit G Mono: Relapsed/Refractory G-Benda: Previously Untreated Fit G-Benda: Previously Untreated Unfit G-Benda: Relapsed/Refractory G-FC: Previously Untreated Fit G-FC: Previously Untreated Unfit G-FC: Relapsed/Refractory G-Clb: Previously Untreated Fit G-Clb: Previously Untreated Unfit G-Clb: Relapsed/Refractory
Hide Arm/Group Description:
Participants with obinutuzumab monotherapy who were previously untreated fit. Fit participants were defined as having a total Cumulative Illness Rating Scale (CIRS) score ≤6 and creatinine clearance (CrCl) ≥70 mL/min.
Participants with obinutuzumab monotherapy who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab monotherapy who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with bendamustine who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with bendamustine who were previously untreated unfit. Non fit Participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with bendamustine who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated fit. Fit subjects were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min. This is a Protocol deviation: unfit subjects were incorrectly assigned to the G-FC treatment regimen.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with chlorambucil who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Overall Number of Participants Analyzed 24 26 48 148 148 162 125 12 33 0 53 32
Measure Type: Number
Unit of Measure: percentage of participants
Blood 8.3 23.1 4.2 62.8 64.9 39.5 72.0 58.3 51.5 9.4 6.3
Bone Marrow 4.2 3.8 2.1 31.8 27.0 14.8 40.0 41.7 24.2 5.7 3.1
6.Secondary Outcome
Title Percentage of Participants With Best Overall Response (BOR)
Hide Description BOR was defined as the percentage of participants with the best response obtained throughout the trial with CR, CRi, or PR, as determined by the investigator based on IWCLL tumor response criteria. CR: Peripheral blood lymphocytes 4,000/mcL, no significant lymphadenopathy, no hepatomegaly and splenomegaly, no disease symptoms, blood counts: neutrophils >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 110 g/L and bone marrow normocellular for age. Cri: CR with persistent cytopenia. PR: >/= 50% decrease in peripheral blood lymphocyte count AND >/= 50% reduction in lymphadenopathy OR >/= 50% reduction of liver enlargement OR >/= 50% reduction of spleen PLUS one of the following: neutrophils >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 110 g/L OR >/= 50% increase in neutrophils, platelets or hemoglobin.
Time Frame Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was defined as all participants enrolled in the study regardless of whether or not they received any study drug.
Arm/Group Title G Mono: Previously Untreated Fit G Mono: Previously Untreated Unfit G Mono: Relapsed/Refractory G-Benda: Previously Untreated Fit G-Benda: Previously Untreated Unfit G-Benda: Relapsed/Refractory G-FC: Previously Untreated Fit G-FC: Previously Untreated Unfit G-FC: Relapsed/Refractory G-Clb: Previously Untreated Fit G-Clb: Previously Untreated Unfit G-Clb: Relapsed/Refractory
Hide Arm/Group Description:
Participants with obinutuzumab monotherapy who were previously untreated fit. Fit participants were defined as having a total Cumulative Illness Rating Scale (CIRS) score ≤6 and creatinine clearance (CrCl) ≥70 mL/min.
Participants with obinutuzumab monotherapy who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab monotherapy who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with bendamustine who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with bendamustine who were previously untreated unfit. Non fit Participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with bendamustine who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated fit. Fit subjects were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min. This is a Protocol deviation: unfit subjects were incorrectly assigned to the G-FC treatment regimen.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with chlorambucil who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Overall Number of Participants Analyzed 31 32 64 167 180 191 140 13 40 1 67 46
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
83.9
(66.3 to 94.5)
71.9
(53.3 to 86.3)
62.5
(49.5 to 74.3)
92.2
(87.1 to 95.8)
93.3
(88.6 to 96.5)
86.4
(80.7 to 90.9)
95.7
(90.9 to 98.4)
84.6
(54.6 to 98.1)
97.5
(86.8 to 99.9)
100
(2.5 to 100.0)
92.5
(83.4 to 97.5)
84.8
(71.1 to 93.7)
7.Secondary Outcome
Title Median Time to Progression-Free Survival (PFS)
Hide Description Kaplan Meier estimate of the median PFS was defined as the time at which half of the participants have progressed (progressive disease [PD]) based on IWCLL tumor response criteria or died from any cause, whichever occurred first. PD: at least one of the following: >/= 50% increase in the absolute number of circulating lymphocytes to at least 5,000/mcL, appearance of new palpable lymph nodes, >/= 50% increase in the longest diameter of any previous site of clinically significant lymphadenopathy, >/= 50% increase in the enlargement of the liver and/or spleen, transformation to more aggressive histology, progression of any cytopenia, decrease of hemoglobin levels by more than 20 g/L or to less than 100 g/L, decrease of platelet counts by more than 50% or to less than 100,000 /mcL, decrease of neutrophil counts by more than 50% or to less than 1,000/mcL.
Time Frame Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was defined as all participants enrolled in the study regardless of whether or not they received any study drug.
Arm/Group Title G Mono: Previously Untreated Fit G Mono: Previously Untreated Unfit G Mono: Relapsed/Refractory G-Benda: Previously Untreated Fit G-Benda: Previously Untreated Unfit G-Benda: Relapsed/Refractory G-FC: Previously Untreated Fit G-FC: Previously Untreated Unfit G-FC: Relapsed/Refractory G-Clb: Previously Untreated Fit G-Clb: Previously Untreated Unfit G-Clb: Relapsed/Refractory
Hide Arm/Group Description:
Participants with obinutuzumab monotherapy who were previously untreated fit. Fit participants were defined as having a total Cumulative Illness Rating Scale (CIRS) score ≤6 and creatinine clearance (CrCl) ≥70 mL/min.
Participants with obinutuzumab monotherapy who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab monotherapy who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with bendamustine who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with bendamustine who were previously untreated unfit. Non fit Participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with bendamustine who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated fit. Fit subjects were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min. This is a Protocol deviation: unfit subjects were incorrectly assigned to the G-FC treatment regimen.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with chlorambucil who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Overall Number of Participants Analyzed 31 32 64 167 180 191 140 13 40 1 67 46
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(15.6 to NA)
NA [1] 
(14.5 to NA)
17.6
(12.5 to 20.8)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
25.8
(22.6 to 30.1)
NA [2] 
(NA to NA)
NA [1] 
(17.8 to NA)
28.1 [3] 
(20.9 to NA)
NA [2] 
(NA to NA)
27.5 [3] 
(21.6 to NA)
14.1
(10.8 to 22.1)
[1]
Median and upper bound of 95% CI could not be estimated as too few patients had an event.
[2]
Median and corresponding 95% CI could not be estimated as too few patients had an event.
[3]
Upper bound of 95% CI could not be estimated as too few patients had an event.
8.Secondary Outcome
Title Median Time to Response (TTR)
Hide Description Kaplan Meier estimate of median TTR was defined as the time at which half of the participants reached CR or PR based on IWCLL tumor response criteria. CR: Peripheral blood lymphocytes 4,000/mcL, no significant lymphadenopathy, no hepatomegaly and splenomegaly, no disease symptoms, blood counts: neutrophils >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 110 g/L and bone marrow normocellular for age. PR: >/= 50% decrease in peripheral blood lymphocyte count AND >/= 50% reduction in lymphadenopathy OR >/= 50% reduction of liver enlargement OR >/= 50% reduction of spleen PLUS one of the following: neutrophils >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 110 g/L OR >/= 50% increase in neutrophils, platelets or hemoglobin.
Time Frame Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was defined as all participants enrolled in the study regardless of whether or not they received any study drug.
Arm/Group Title G Mono: Previously Untreated Fit G Mono: Previously Untreated Unfit G Mono: Relapsed/Refractory G-Benda: Previously Untreated Fit G-Benda: Previously Untreated Unfit G-Benda: Relapsed/Refractory G-FC: Previously Untreated Fit G-FC: Previously Untreated Unfit G-FC: Relapsed/Refractory G-Clb: Previously Untreated Fit G-Clb: Previously Untreated Unfit G-Clb: Relapsed/Refractory
Hide Arm/Group Description:
Participants with obinutuzumab monotherapy who were previously untreated fit. Fit participants were defined as having a total Cumulative Illness Rating Scale (CIRS) score ≤6 and creatinine clearance (CrCl) ≥70 mL/min.
Participants with obinutuzumab monotherapy who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab monotherapy who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with bendamustine who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with bendamustine who were previously untreated unfit. Non fit Participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with bendamustine who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated fit. Fit subjects were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min. This is a Protocol deviation: unfit subjects were incorrectly assigned to the G-FC treatment regimen.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with chlorambucil who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Overall Number of Participants Analyzed 31 32 64 167 180 191 140 13 40 1 67 46
Median (95% Confidence Interval)
Unit of Measure: months
3.6
(3.2 to 3.8)
3.6
(3.3 to 3.9)
3.9
(3.7 to 4.4)
3.5
(3.4 to 3.6)
3.5
(3.5 to 3.6)
3.7
(3.5 to 3.7)
3.6
(3.5 to 3.7)
4.1
(3.3 to 7.9)
3.6
(3.4 to 3.7)
3.3 [1] 
(NA to NA)
3.6
(3.4 to 3.6)
3.7
(0.1 to 15.5)
[1]
The corresponding 95% CI could not be estimated as too few patients had an event.
9.Secondary Outcome
Title Median Time to Event-Free Survival (EFS)
Hide Description Kaplan Meier estimate of median EFS is the time at which half of the participants have progressed as assessed by investigator based on IWCLL tumor response criteria, or have initiated a non-protocol-specified anti-leukemia therapy or died, whichever occurs first. PD: at least 1 of the following: >/= 50% increase in absolute number of circulating lymphocytes to at least 5,000/mcL, appearance of new palpable lymph nodes, >/= 50% increase in longest diameter of any previous site of clinically significant lymphadenopathy, >/= 50% increase in enlargement of liver and/or spleen, transformation to more aggressive histology, progression of any cytopenia, decrease of hemoglobin levels by more than 20 g/L or to less than 100 g/L, decrease of platelet counts by more than 50% or to less than 100,000 /mcL, decrease of neutrophil counts by more than 50% or to less than 1,000/mcL.
Time Frame Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was defined as all participants enrolled in the study regardless of whether or not they received any study drug.
Arm/Group Title G Mono: Previously Untreated Fit G Mono: Previously Untreated Unfit G Mono: Relapsed/Refractory G-Benda: Previously Untreated Fit G-Benda: Previously Untreated Unfit G-Benda: Relapsed/Refractory G-FC: Previously Untreated Fit G-FC: Previously Untreated Unfit G-FC: Relapsed/Refractory G-Clb: Previously Untreated Fit G-Clb: Previously Untreated Unfit G-Clb: Relapsed/Refractory
Hide Arm/Group Description:
Participants with obinutuzumab monotherapy who were previously untreated fit. Fit participants were defined as having a total Cumulative Illness Rating Scale (CIRS) score ≤6 and creatinine clearance (CrCl) ≥70 mL/min.
Participants with obinutuzumab monotherapy who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab monotherapy who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with bendamustine who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with bendamustine who were previously untreated unfit. Non fit Participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with bendamustine who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated fit. Fit subjects were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min. This is a Protocol deviation: unfit subjects were incorrectly assigned to the G-FC treatment regimen.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with chlorambucil who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Overall Number of Participants Analyzed 31 32 64 167 180 191 140 13 40 1 67 46
Median (95% Confidence Interval)
Unit of Measure: months
30.2 [1] 
(12.3 to NA)
17.0 [1] 
(14.5 to NA)
14.4
(9.1 to 19.1)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
25.0
(20.9 to 28.9)
NA [2] 
(NA to NA)
NA [3] 
(17.8 to NA)
24.8 [1] 
(18.7 to NA)
NA [2] 
(NA to NA)
27.5
(0.0 to 34.4)
13.7
(0.3 to 30.6)
[1]
Upper bound of 95% CI could not be estimated as too few patients had an event.
[2]
Median and corresponding 95% CI could not be estimated as too few patients had an event.
[3]
Median and upper bound of 95% CI could not be estimated as too few patients had an event.
10.Secondary Outcome
Title Median Time to Overall Survival (OS)
Hide Description Kaplan Meier estimate of median OS was defined as the time at which half of the participants had died, regardless of the cause of death.
Time Frame Baseline until death (Approximately up to 5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was defined as all participants enrolled in the study regardless of whether or not they received any study drug.
Arm/Group Title G Mono: Previously Untreated Fit G Mono: Previously Untreated Unfit G Mono: Relapsed/Refractory G-Benda: Previously Untreated Fit G-Benda: Previously Untreated Unfit G-Benda: Relapsed/Refractory G-FC: Previously Untreated Fit G-FC: Previously Untreated Unfit G-FC: Relapsed/Refractory G-Clb: Previously Untreated Fit G-Clb: Previously Untreated Unfit G-Clb: Relapsed/Refractory
Hide Arm/Group Description:
Participants with obinutuzumab monotherapy who were previously untreated fit. Fit participants were defined as having a total Cumulative Illness Rating Scale (CIRS) score ≤6 and creatinine clearance (CrCl) ≥70 mL/min.
Participants with obinutuzumab monotherapy who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab monotherapy who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with bendamustine who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with bendamustine who were previously untreated unfit. Non fit Participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with bendamustine who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated fit. Fit subjects were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min. This is a Protocol deviation: unfit subjects were incorrectly assigned to the G-FC treatment regimen.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with chlorambucil who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Overall Number of Participants Analyzed 31 32 64 167 180 191 140 13 40 1 67 46
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
NA [2] 
(NA to NA)
NA [3] 
(27.3 to NA)
NA [4] 
(NA to NA)
NA [1] 
(NA to NA)
NA [3] 
(35.3 to NA)
NA [1] 
(NA to NA)
NA [3] 
(28.6 to NA)
NA [3] 
(29.8 to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [3] 
(30.6 to NA)
[1]
Median and corresponding 95% CI could not be estimated as too few patients had an event.
[2]
Median and corresponding 95% CI could not be estimated as too few patients had an event
[3]
Median and upper bound of 95% CI could not be estimated as too few patients had an event.
[4]
.Median and corresponding 95% CI could not be estimated as too few patients had an event.
11.Secondary Outcome
Title Median Time to New Anti-Leukemia Therapy (TTNT)
Hide Description Kaplan Meier estimate of median TTNT was defined as the time at which half of the participants have initiated a new treatment.
Time Frame Baseline until end of study (up to approximately 5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was defined as all participants enrolled in the study regardless of whether or not they received any study drug.
Arm/Group Title G Mono: Previously Untreated Fit G Mono: Previously Untreated Unfit G Mono: Relapsed/Refractory G-Benda: Previously Untreated Fit G-Benda: Previously Untreated Unfit G-Benda: Relapsed/Refractory G-FC: Previously Untreated Fit G-FC: Previously Untreated Unfit G-FC: Relapsed/Refractory G-Clb: Previously Untreated Fit G-Clb: Previously Untreated Unfit G-Clb: Relapsed/Refractory
Hide Arm/Group Description:
Participants with obinutuzumab monotherapy who were previously untreated fit. Fit participants were defined as having a total Cumulative Illness Rating Scale (CIRS) score ≤6 and creatinine clearance (CrCl) ≥70 mL/min.
Participants with obinutuzumab monotherapy who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab monotherapy who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with bendamustine who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with bendamustine who were previously untreated unfit. Non fit Participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with bendamustine who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated fit. Fit subjects were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min. This is a Protocol deviation: unfit subjects were incorrectly assigned to the G-FC treatment regimen.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with chlorambucil who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Overall Number of Participants Analyzed 31 32 64 167 180 191 140 13 40 1 67 46
Median (95% Confidence Interval)
Unit of Measure: months
33.2 [1] 
(25.0 to NA)
NA [2] 
(20.8 to NA)
22.1
(14.8 to 29.0)
NA [3] 
(NA to NA)
NA [4] 
(NA to NA)
NA [2] 
(33.1 to NA)
NA [3] 
(NA to NA)
NA [3] 
(NA to NA)
32.4 [1] 
(28.2 to NA)
NA [3] 
(NA to NA)
NA [3] 
(NA to NA)
20.4 [1] 
(12.2 to NA)
[1]
Upper bound of 95% CI could not be estimated as too few patients had an event.
[2]
Median and upper bound of 95% CI could not be estimated as too few patients had an event.
[3]
Median and corresponding 95% CI could not be estimated as too few patients had an event.
[4]
Median and corresponding 95% CI could not be estimated as too few patients had an event
12.Secondary Outcome
Title Median Time to Duration of Response (DoR)
Hide Description Kaplan Meier estimate of median DoR was defined as the time at which half of the responding (PR or CR) participants had progressed (PD) or died from any cause, whichever occurred first. PR: >/= 50% decrease in peripheral blood lymphocyte count AND >/= 50% reduction in lymphadenopathy OR >/= 50% reduction of liver enlargement OR >/= 50% reduction of spleen PLUS one of the following: neutrophils >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 110 g/L OR >/= 50% increase in neutrophils, platelets or hemoglobin. CR: Peripheral blood lymphocytes 4,000/mcL, no significant lymphadenopathy, no hepatomegaly and splenomegaly, no disease symptoms, blood counts: neutrophils >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 110 g/L and bone marrow normocellular for age. PD: as defined in the description for Event-Free Survival outcome measure.
Time Frame Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was defined as all participants enrolled in the study regardless of whether or not they received any study drug. Number of participants analyzed indicates participants who took part in the analysis.
Arm/Group Title G Mono: Previously Untreated Fit G Mono: Previously Untreated Unfit G Mono: Relapsed/Refractory G-Benda: Previously Untreated Fit G-Benda: Previously Untreated Unfit G-Benda: Relapsed/Refractory G-FC: Previously Untreated Fit G-FC: Previously Untreated Unfit G-FC: Relapsed/Refractory G-Clb: Previously Untreated Fit G-Clb: Previously Untreated Unfit G-Clb: Relapsed/Refractory
Hide Arm/Group Description:
Participants with obinutuzumab monotherapy who were previously untreated fit. Fit participants were defined as having a total Cumulative Illness Rating Scale (CIRS) score ≤6 and creatinine clearance (CrCl) ≥70 mL/min.
Participants with obinutuzumab monotherapy who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab monotherapy who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with bendamustine who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with bendamustine who were previously untreated unfit. Non fit Participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with bendamustine who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated fit. Fit subjects were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min. This is a Protocol deviation: unfit subjects were incorrectly assigned to the G-FC treatment regimen.
Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Participants with obinutuzumab in combination with chlorambucil who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.
Participants with obinutuzumab in combination with chlorambucil who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).
Overall Number of Participants Analyzed 31 32 64 167 180 191 140 13 40 1 67 46
Median (95% Confidence Interval)
Unit of Measure: months
26.3 [1] 
(12.0 to NA)
NA [2] 
(11.5 to NA)
15.7
(12.3 to 19.9)
NA [3] 
(NA to NA)
NA [3] 
(NA to NA)
24.1
(21.0 to 27.2)
NA [3] 
(NA to NA)
NA [2] 
(14.5 to NA)
21.2 [1] 
(15.1 to NA)
NA [3] 
(NA to NA)
24.0 [1] 
(18.2 to NA)
14.4
(7.8 to 22.8)
[1]
Upper bound of 95% CI could not be estimated as too few patients had an event.
[2]
Median and upper bound of 95% CI could not be estimated as too few patients had an event.
[3]
Median and corresponding 95% CI could not be estimated as too few patients had an event.
Time Frame Up to 3 years
Adverse Event Reporting Description The safety population was defined as all participants who received at least one dose of study medication. AEs that were entered into the data base at the time of the data base lock were included in the AE analysis. A small set of AEs was not entered and will be included at the time of final analysis.
 
Arm/Group Title G-Mono G-Benda G-FC G-Clb
Hide Arm/Group Description Participants received obinutuzumab alone as single agent. Participants received obinutuzumab in combination with bendamustine. Participants received obinutuzumab in combination with fludarabine/cyclophosphamide (FC). Participants received obinutuzumab in combination with chlorambucil.
All-Cause Mortality
G-Mono G-Benda G-FC G-Clb
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
G-Mono G-Benda G-FC G-Clb
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   67/126 (53.17%)   305/538 (56.69%)   87/193 (45.08%)   57/114 (50.00%) 
Blood and lymphatic system disorders         
Anaemia  1  2/126 (1.59%)  4/538 (0.74%)  3/193 (1.55%)  1/114 (0.88%) 
Autoimmune haemolytic anaemia  1  2/126 (1.59%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Febrile neutropenia  1  6/126 (4.76%)  40/538 (7.43%)  20/193 (10.36%)  2/114 (1.75%) 
Haemolytic anaemia  1  1/126 (0.79%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Neutropenia  1  9/126 (7.14%)  62/538 (11.52%)  28/193 (14.51%)  6/114 (5.26%) 
Thrombocytopenia  1  2/126 (1.59%)  17/538 (3.16%)  7/193 (3.63%)  5/114 (4.39%) 
Pancytopenia  1  0/126 (0.00%)  4/538 (0.74%)  1/193 (0.52%)  0/114 (0.00%) 
Leukopenia  1  0/126 (0.00%)  3/538 (0.56%)  2/193 (1.04%)  0/114 (0.00%) 
Lymphopenia  1  0/126 (0.00%)  0/538 (0.00%)  2/193 (1.04%)  0/114 (0.00%) 
Disseminated intravascular coagulation  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Bicytopenia  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Cardiac disorders         
Atrial fibrillation  1  1/126 (0.79%)  4/538 (0.74%)  0/193 (0.00%)  0/114 (0.00%) 
Cardiac failure  1  3/126 (2.38%)  4/538 (0.74%)  0/193 (0.00%)  0/114 (0.00%) 
Sinus bradycardia  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Acute myocardial infarction  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Aortic valve incompetence  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Arrhythmia  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Atrial flutter  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Atrioventricular block complete  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Cardiac failure acute  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  1/114 (0.88%) 
Mitral valve incompetence  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Myocardial ischaemia  1  0/126 (0.00%)  1/538 (0.19%)  1/193 (0.52%)  0/114 (0.00%) 
Myocardial infarction  1  0/126 (0.00%)  2/538 (0.37%)  1/193 (0.52%)  0/114 (0.00%) 
Ventricular arrhythmia  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Ventricular extrasystoles  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Ventricular tachycardia  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Angina unstable  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Cardiac arrest  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Cardiopulmonary failure  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Endocrine disorders         
Hypercalcaemia of malignancy  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Hyperparathyroidism  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Hyperthyroidism  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Eye disorders         
Retinal detachment  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Gastrointestinal disorders         
Lower gastrointestinal haemorrhage  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Stomatitis  1  1/126 (0.79%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Abdominal pain  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Abdominal pain upper  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Ascites  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Colitis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Diarrhoea  1  0/126 (0.00%)  1/538 (0.19%)  1/193 (0.52%)  0/114 (0.00%) 
Diverticular perforation  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Haematochezia  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Intestinal perforation  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Mouth haemorrhage  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Nausea  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  1/114 (0.88%) 
Peritoneal adhesions  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Vomiting  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Inguinal hernia  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Neutropenic colitis  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
General disorders         
Death  1  1/126 (0.79%)  1/538 (0.19%)  1/193 (0.52%)  1/114 (0.88%) 
Device related thrombosis  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
General physical health deterioration  1  1/126 (0.79%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Malaise  1  1/126 (0.79%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Pyrexia  1  3/126 (2.38%)  21/538 (3.90%)  11/193 (5.70%)  1/114 (0.88%) 
Asthenia  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Chest pain  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Chills  1  0/126 (0.00%)  4/538 (0.74%)  0/193 (0.00%)  0/114 (0.00%) 
Euthanasia  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Hyperthermia  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Multiple organ dysfunction syndrome  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Oedema peripheral  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Hepatobiliary disorders         
Cholangitis  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Cholecystitis  1  1/126 (0.79%)  0/538 (0.00%)  2/193 (1.04%)  1/114 (0.88%) 
Hepatic failure  1  2/126 (1.59%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Hepatocellular injury  1  2/126 (1.59%)  3/538 (0.56%)  0/193 (0.00%)  1/114 (0.88%) 
Acute hepatic failure  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Cholecystitis acute  1  0/126 (0.00%)  1/538 (0.19%)  1/193 (0.52%)  0/114 (0.00%) 
Hepatitis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Hepatitis toxic  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Liver disorder  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Drug-induced liver injury  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  1/114 (0.88%) 
Immune system disorders         
Anaphylactic reaction  1  3/126 (2.38%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Cytokine release syndrome  1  5/126 (3.97%)  1/538 (0.19%)  2/193 (1.04%)  0/114 (0.00%) 
Allergy to immunoglobulin therapy  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Drug hypersensitivity  1  0/126 (0.00%)  4/538 (0.74%)  0/193 (0.00%)  0/114 (0.00%) 
Hypersensitivity  1  0/126 (0.00%)  2/538 (0.37%)  3/193 (1.55%)  1/114 (0.88%) 
Autoimmune disorder  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Infections and infestations         
Appendicitis  1  1/126 (0.79%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Bacterial sepsis  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Bronchitis  1  2/126 (1.59%)  2/538 (0.37%)  1/193 (0.52%)  0/114 (0.00%) 
Clostridium difficile colitis  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Enterococcal sepsis  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Erysipelas  1  1/126 (0.79%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Fungal infection  1  1/126 (0.79%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Herpes simplex  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Herpes zoster  1  1/126 (0.79%)  4/538 (0.74%)  2/193 (1.04%)  0/114 (0.00%) 
Infection  1  1/126 (0.79%)  4/538 (0.74%)  1/193 (0.52%)  0/114 (0.00%) 
Influenza  1  1/126 (0.79%)  0/538 (0.00%)  2/193 (1.04%)  0/114 (0.00%) 
Lower respiratory tract infection  1  1/126 (0.79%)  2/538 (0.37%)  0/193 (0.00%)  3/114 (2.63%) 
Oropharyngeal candidiasis  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Pneumonia  1  11/126 (8.73%)  52/538 (9.67%)  13/193 (6.74%)  16/114 (14.04%) 
Pneumonia viral  1  1/126 (0.79%)  1/538 (0.19%)  1/193 (0.52%)  0/114 (0.00%) 
Progressive multifocal leukoencephalopathy  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Sepsis  1  1/126 (0.79%)  5/538 (0.93%)  4/193 (2.07%)  1/114 (0.88%) 
Septic shock  1  1/126 (0.79%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Sinusitis  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Staphylococcal sepsis  1  1/126 (0.79%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Subcutaneous abscess  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Tracheobronchitis  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Urinary tract infection  1  1/126 (0.79%)  6/538 (1.12%)  0/193 (0.00%)  2/114 (1.75%) 
Urosepsis  1  1/126 (0.79%)  1/538 (0.19%)  0/193 (0.00%)  1/114 (0.88%) 
Abdominal sepsis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Abscess limb  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Acute hepatitis B  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Arthritis infective  1  0/126 (0.00%)  1/538 (0.19%)  1/193 (0.52%)  0/114 (0.00%) 
Aspergillus infection  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Atypical pneumonia  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Brain abscess  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Bronchitis bacterial  1  0/126 (0.00%)  1/538 (0.19%)  1/193 (0.52%)  0/114 (0.00%) 
Bronchopulmonary aspergillosis  1  0/126 (0.00%)  3/538 (0.56%)  0/193 (0.00%)  0/114 (0.00%) 
Campylobacter gastroenteritis  1  0/126 (0.00%)  2/538 (0.37%)  1/193 (0.52%)  0/114 (0.00%) 
Campylobacter infection  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Cellulitis  1  0/126 (0.00%)  3/538 (0.56%)  1/193 (0.52%)  1/114 (0.88%) 
Clostridium colitis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Clostridium difficile infection  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Cryptosporidiosis infection  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Cytomegalovirus infection  1  0/126 (0.00%)  4/538 (0.74%)  0/193 (0.00%)  0/114 (0.00%) 
Device related infection  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Diverticulitis  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Ear infection  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Eczema infected  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Encephalitis viral  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Endocarditis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Escherichia bacteraemia  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  1/114 (0.88%) 
Gastroenteritis  1  0/126 (0.00%)  2/538 (0.37%)  1/193 (0.52%)  0/114 (0.00%) 
Giardiasis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
H1N1 influenza  1  0/126 (0.00%)  1/538 (0.19%)  1/193 (0.52%)  0/114 (0.00%) 
Herpes zoster oticus  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Infected skin ulcer  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Hepatitis B  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Infective exacerbation chronic obstructive airways disease  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Lung infection  1  0/126 (0.00%)  4/538 (0.74%)  3/193 (1.55%)  0/114 (0.00%) 
Lymphangitis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Meningitis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Meningitis cryptococcal  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Myringitis bullous  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Nasopharyngitis  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Neutropenic sepsis  1  0/126 (0.00%)  1/538 (0.19%)  2/193 (1.04%)  0/114 (0.00%) 
Oral candidiasis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Perirectal abscess  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Pneumonia cytomegaloviral  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Pneumonia pseudomonal  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Pseudomembranous colitis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Pseudomonal sepsis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Pyelonephritis  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Splenic abscess  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Upper respiratory tract infection  1  0/126 (0.00%)  2/538 (0.37%)  1/193 (0.52%)  0/114 (0.00%) 
Viral infection  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Visceral leishmaniasis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
West nile viral infection  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Wound infection  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Escherichia infection  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Fungal oesophagitis  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Cerebral toxoplasmosis  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Herpes virus infection  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Laryngitis viral  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Listeriosis  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Peritonitis  1  0/126 (0.00%)  1/538 (0.19%)  1/193 (0.52%)  0/114 (0.00%) 
Pneumococcal sepsis  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Pneumonia fungal  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Pneumonia pneumococcal  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Retinitis viral  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Varicella zoster virus infection  1  0/126 (0.00%)  0/538 (0.00%)  2/193 (1.04%)  0/114 (0.00%) 
Lung infection pseudomonal  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Pneumonia bacterial  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Respiratory tract infection  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  2/114 (1.75%) 
Skin infection  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Urinary tract infection enterococcal  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Injury, poisoning and procedural complications         
Femoral neck fracture  1  1/126 (0.79%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Thoracic vertebral fracture  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Ankle fracture  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Cervical vertebral fracture  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Craniocerebral injury  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Femur fracture  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  2/114 (1.75%) 
Foot fracture  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Hip fracture  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  1/114 (0.88%) 
Radiation skin injury  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Rib fracture  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Road traffic accident  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Spinal compression fracture  1  0/126 (0.00%)  1/538 (0.19%)  1/193 (0.52%)  1/114 (0.88%) 
Toxicity to various agents  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Wrist fracture  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Fall  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Head injury  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Radiation mucositis  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Investigations         
Hepatic enzyme increased  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Oxygen saturation decreased  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Weight decreased  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Alanine aminotransferase increased  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Aspartate aminotransferase increased  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Blood creatinine increased  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Blood pressure increased  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Gamma-glutamyltransferase increased  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Neutrophil count decreased  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Transaminases increased  1  0/126 (0.00%)  0/538 (0.00%)  2/193 (1.04%)  0/114 (0.00%) 
Metabolism and nutrition disorders         
Tumour lysis syndrome  1  1/126 (0.79%)  29/538 (5.39%)  3/193 (1.55%)  3/114 (2.63%) 
Diabetes mellitus  1  0/126 (0.00%)  3/538 (0.56%)  0/193 (0.00%)  0/114 (0.00%) 
Diabetes mellitus inadequate control  1  0/126 (0.00%)  2/538 (0.37%)  1/193 (0.52%)  0/114 (0.00%) 
Hypercalcaemia  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  1/114 (0.88%) 
Hyperglycaemia  1  0/126 (0.00%)  2/538 (0.37%)  1/193 (0.52%)  1/114 (0.88%) 
Hyperuricaemia  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Malnutrition  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Type 2 diabetes mellitus  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  1/114 (0.88%) 
Fluid overload  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Hypoglycaemia  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Musculoskeletal and connective tissue disorders         
Back pain  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Fistula inflammation  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Musculoskeletal chest pain  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Osteoarthritis  1  0/126 (0.00%)  4/538 (0.74%)  0/193 (0.00%)  0/114 (0.00%) 
Rheumatoid arthritis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Spinal column stenosis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Spinal pain  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Arthritis  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Adenocarcinoma of colon  1  1/126 (0.79%)  2/538 (0.37%)  1/193 (0.52%)  0/114 (0.00%) 
Bladder transitional cell carcinoma  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Cholangiocarcinoma  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Clear cell renal cell carcinoma  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Metastatic carcinoma of the bladder  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Richter's syndrome  1  1/126 (0.79%)  2/538 (0.37%)  1/193 (0.52%)  0/114 (0.00%) 
Spinal meningioma benign  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Squamous cell carcinoma  1  1/126 (0.79%)  6/538 (1.12%)  0/193 (0.00%)  1/114 (0.88%) 
Squamous cell carcinoma of skin  1  1/126 (0.79%)  4/538 (0.74%)  0/193 (0.00%)  1/114 (0.88%) 
Adenocarcinoma  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Adenocarcinoma gastric  1  0/126 (0.00%)  3/538 (0.56%)  0/193 (0.00%)  1/114 (0.88%) 
Adenosquamous cell lung cancer  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Basal cell carcinoma  1  0/126 (0.00%)  7/538 (1.30%)  0/193 (0.00%)  2/114 (1.75%) 
Bladder cancer stage 0, with cancer in situ  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Bowen's disease  1  1/126 (0.79%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Acute myeloid leukaemia  1  0/126 (0.00%)  0/538 (0.00%)  2/193 (1.04%)  1/114 (0.88%) 
Breast cancer  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Metastatic renal cell carcinoma  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Myelodysplastic syndrome  1  0/126 (0.00%)  2/538 (0.37%)  1/193 (0.52%)  0/114 (0.00%) 
Prostate cancer  1  0/126 (0.00%)  3/538 (0.56%)  1/193 (0.52%)  0/114 (0.00%) 
Colon cancer  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Malignant melanoma  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  2/114 (1.75%) 
Nasal cavity cancer  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Primary myelofibrosis  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Rectal adenocarcinoma  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Bronchial carcinoma  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Chronic myeloid leukaemia  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Endometrial cancer  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Hepatocellular carcinoma  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Intraductal proliferative breast lesion  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Laryngeal cancer  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Lung adenocarcinoma  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Lung adenocarcinoma metastatic  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Lung cancer metastatic  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Lung neoplasm malignant  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Metastatic bronchial carcinoma  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Metastatic malignant melanoma  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Metastatic squamous cell carcinoma  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Myelofibrosis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Neoplasm malignant  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Pancreatic carcinoma metastatic  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Prostatic adenoma  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Skin cancer  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Small cell lung cancer metastatic  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Nervous system disorders         
Haemorrhage intracranial  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Paraparesis  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Presyncope  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Tremor  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Balance disorder  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Cerebral haematoma  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Cerebral haemorrhage  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Cerebral ischaemia  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Epilepsy  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Ischaemic stroke  1  0/126 (0.00%)  3/538 (0.56%)  0/193 (0.00%)  0/114 (0.00%) 
Seizure  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  1/114 (0.88%) 
Syncope  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Transient ischaemic attack  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Central nervous system lesion  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Muscle spasticity  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Psychiatric disorders         
Completed suicide  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Alcohol withdrawal syndrome  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Depression  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Renal and urinary disorders         
Chronic kidney disease  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Acute kidney injury  1  0/126 (0.00%)  4/538 (0.74%)  1/193 (0.52%)  0/114 (0.00%) 
Haematuria  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Hypertensive nephropathy  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Nephrolithiasis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Renal failure  1  0/126 (0.00%)  1/538 (0.19%)  1/193 (0.52%)  0/114 (0.00%) 
Renal impairment  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Urethral prolapse  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Urinary tract obstruction  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Respiratory, thoracic and mediastinal disorders         
Dyspnoea  1  2/126 (1.59%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Pulmonary oedema  1  1/126 (0.79%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Bronchiectasis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Chylothorax  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Cough  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Hypoxia  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Interstitial lung disease  1  0/126 (0.00%)  2/538 (0.37%)  1/193 (0.52%)  0/114 (0.00%) 
Lung disorder  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Obliterative bronchiolitis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Pharyngeal inflammation  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Pleural effusion  1  0/126 (0.00%)  3/538 (0.56%)  0/193 (0.00%)  0/114 (0.00%) 
Pleurisy  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Pneumonia aspiration  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Pneumonitis  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Pneumothorax  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  1/114 (0.88%) 
Pulmonary embolism  1  0/126 (0.00%)  4/538 (0.74%)  1/193 (0.52%)  1/114 (0.88%) 
Pulmonary necrosis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Respiratory alkalosis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Aspiration  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Organising pneumonia  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Oropharyngeal pain  1  0/126 (0.00%)  0/538 (0.00%)  1/193 (0.52%)  0/114 (0.00%) 
Acute respiratory distress syndrome  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Skin and subcutaneous tissue disorders         
Decubitus ulcer  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Dermatitis allergic  1  0/126 (0.00%)  1/538 (0.19%)  1/193 (0.52%)  0/114 (0.00%) 
Purpura  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Diabetic foot  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Rash maculo-papular  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Drug eruption  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Urticaria  1  0/126 (0.00%)  0/538 (0.00%)  0/193 (0.00%)  1/114 (0.88%) 
Vascular disorders         
Hypertension  1  2/126 (1.59%)  2/538 (0.37%)  1/193 (0.52%)  0/114 (0.00%) 
Hypotension  1  4/126 (3.17%)  4/538 (0.74%)  1/193 (0.52%)  1/114 (0.88%) 
Peripheral arterial occlusive disease  1  1/126 (0.79%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Peripheral artery thrombosis  1  1/126 (0.79%)  0/538 (0.00%)  0/193 (0.00%)  0/114 (0.00%) 
Flushing  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Haematoma  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Hypertensive crisis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Orthostatic hypotension  1  0/126 (0.00%)  2/538 (0.37%)  0/193 (0.00%)  0/114 (0.00%) 
Peripheral vascular disorder  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Shock haemorrhagic  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Vena cava thrombosis  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Thrombophlebitis superficial  1  0/126 (0.00%)  1/538 (0.19%)  0/193 (0.00%)  0/114 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
G-Mono G-Benda G-FC G-Clb
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   103/126 (81.75%)   495/538 (92.01%)   183/193 (94.82%)   105/114 (92.11%) 
Blood and lymphatic system disorders         
Anaemia  1  19/126 (15.08%)  131/538 (24.35%)  50/193 (25.91%)  26/114 (22.81%) 
Leukopenia  1  5/126 (3.97%)  69/538 (12.83%)  23/193 (11.92%)  8/114 (7.02%) 
Neutropenia  1  45/126 (35.71%)  283/538 (52.60%)  136/193 (70.47%)  58/114 (50.88%) 
Thrombocytopenia  1  27/126 (21.43%)  161/538 (29.93%)  66/193 (34.20%)  35/114 (30.70%) 
Lymphopenia  1  2/126 (1.59%)  53/538 (9.85%)  11/193 (5.70%)  2/114 (1.75%) 
Gastrointestinal disorders         
Constipation  1  6/126 (4.76%)  71/538 (13.20%)  24/193 (12.44%)  14/114 (12.28%) 
Diarrhoea  1  6/126 (4.76%)  80/538 (14.87%)  38/193 (19.69%)  10/114 (8.77%) 
Nausea  1  22/126 (17.46%)  145/538 (26.95%)  76/193 (39.38%)  25/114 (21.93%) 
Vomiting  1  8/126 (6.35%)  69/538 (12.83%)  44/193 (22.80%)  14/114 (12.28%) 
Abdominal pain  1  3/126 (2.38%)  23/538 (4.28%)  10/193 (5.18%)  4/114 (3.51%) 
General disorders         
Asthenia  1  6/126 (4.76%)  44/538 (8.18%)  30/193 (15.54%)  13/114 (11.40%) 
Chest discomfort  1  7/126 (5.56%)  15/538 (2.79%)  7/193 (3.63%)  3/114 (2.63%) 
Chills  1  17/126 (13.49%)  89/538 (16.54%)  30/193 (15.54%)  17/114 (14.91%) 
Fatigue  1  7/126 (5.56%)  70/538 (13.01%)  19/193 (9.84%)  22/114 (19.30%) 
Pyrexia  1  26/126 (20.63%)  172/538 (31.97%)  58/193 (30.05%)  27/114 (23.68%) 
Oedema peripheral  1  3/126 (2.38%)  31/538 (5.76%)  3/193 (1.55%)  9/114 (7.89%) 
Infections and infestations         
Bronchitis  1  8/126 (6.35%)  35/538 (6.51%)  15/193 (7.77%)  5/114 (4.39%) 
Influenza  1  5/126 (3.97%)  11/538 (2.04%)  11/193 (5.70%)  4/114 (3.51%) 
Nasopharyngitis  1  8/126 (6.35%)  23/538 (4.28%)  16/193 (8.29%)  3/114 (2.63%) 
Upper respiratory tract infection  1  5/126 (3.97%)  43/538 (7.99%)  12/193 (6.22%)  5/114 (4.39%) 
Urinary tract infection  1  5/126 (3.97%)  26/538 (4.83%)  6/193 (3.11%)  8/114 (7.02%) 
Sinusitis  1  2/126 (1.59%)  16/538 (2.97%)  13/193 (6.74%)  5/114 (4.39%) 
Respiratory tract infection  1  4/126 (3.17%)  10/538 (1.86%)  4/193 (2.07%)  6/114 (5.26%) 
Investigations         
Alanine aminotransferase increased  1  4/126 (3.17%)  12/538 (2.23%)  11/193 (5.70%)  2/114 (1.75%) 
Aspartate aminotransferase increased  1  4/126 (3.17%)  15/538 (2.79%)  10/193 (5.18%)  5/114 (4.39%) 
Metabolism and nutrition disorders         
Decreased appetite  1  3/126 (2.38%)  43/538 (7.99%)  11/193 (5.70%)  10/114 (8.77%) 
Hyperuricaemia  1  0/126 (0.00%)  32/538 (5.95%)  6/193 (3.11%)  10/114 (8.77%) 
Musculoskeletal and connective tissue disorders         
Arthralgia  1  7/126 (5.56%)  20/538 (3.72%)  7/193 (3.63%)  8/114 (7.02%) 
Back pain  1  6/126 (4.76%)  35/538 (6.51%)  13/193 (6.74%)  10/114 (8.77%) 
Nervous system disorders         
Headache  1  8/126 (6.35%)  44/538 (8.18%)  22/193 (11.40%)  10/114 (8.77%) 
Tremor  1  6/126 (4.76%)  11/538 (2.04%)  2/193 (1.04%)  6/114 (5.26%) 
Dizziness  1  2/126 (1.59%)  22/538 (4.09%)  3/193 (1.55%)  8/114 (7.02%) 
Respiratory, thoracic and mediastinal disorders         
Cough  1  15/126 (11.90%)  55/538 (10.22%)  28/193 (14.51%)  15/114 (13.16%) 
Dyspnoea  1  9/126 (7.14%)  53/538 (9.85%)  24/193 (12.44%)  11/114 (9.65%) 
Skin and subcutaneous tissue disorders         
Hyperhidrosis  1  5/126 (3.97%)  20/538 (3.72%)  8/193 (4.15%)  7/114 (6.14%) 
Pruritus  1  4/126 (3.17%)  23/538 (4.28%)  10/193 (5.18%)  2/114 (1.75%) 
Rash  1  4/126 (3.17%)  44/538 (8.18%)  24/193 (12.44%)  11/114 (9.65%) 
Vascular disorders         
Hypertension  1  5/126 (3.97%)  44/538 (8.18%)  16/193 (8.29%)  5/114 (4.39%) 
Hypotension  1  10/126 (7.94%)  53/538 (9.85%)  17/193 (8.81%)  16/114 (14.04%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.1
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
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01905943     History of Changes
Other Study ID Numbers: MO28543
2013-000087-29 ( EudraCT Number )
First Submitted: July 19, 2013
First Posted: July 23, 2013
Results First Submitted: December 21, 2017
Results First Posted: October 29, 2018
Last Update Posted: December 11, 2018