Trial Outcomes & Findings for Sequential and Concurrent FOLFOXIRI/Bevacizumab Regimens Versus FOLFOX/Bevacizumab in First-Line Metastatic Colorectal Cancer (NCT NCT01765582)

NCT ID: NCT01765582

Last Updated: 2017-09-18

Results Overview

ORR1 was the percentage of participants with complete response (CR) or partial response (PR) during first-line therapy as assessed by investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1). CR was defined as disappearance of all extranodal target lesions and all pathological lymph nodes had to have decreased to \<10 millimeter (mm) in short axis. PR was defined as at least a 30% decrease in the sum of longest diameters of target lesions, taking as reference the baseline sum diameters. ORR1 = CR + PR

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 280 participants
• Primary outcome timeframe: Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years)
• Results posted on: 2017-09-18

Participant Flow

Participant milestones

Measure	Arm A: Concurrent FOLFOXIRI + Bevacizumab Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm B: Sequential FOLFOXIRI + Bevacizumab Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm C: FOLFOX + Bevacizumab Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Overall Study STARTED	93	92	95
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	93	92	95

Reasons for withdrawal

Measure	Arm A: Concurrent FOLFOXIRI + Bevacizumab Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm B: Sequential FOLFOXIRI + Bevacizumab Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm C: FOLFOX + Bevacizumab Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Overall Study Other	3	6	9
Overall Study Lost to Follow-up	2	2	1
Overall Study Death	31	36	33
Overall Study Sponsor Decision	46	42	42
Overall Study Withdrawal of Consent	11	6	10

Baseline Characteristics

Sequential and Concurrent FOLFOXIRI/Bevacizumab Regimens Versus FOLFOX/Bevacizumab in First-Line Metastatic Colorectal Cancer

Baseline characteristics by cohort

Measure	Arm A: Concurrent FOLFOXIRI + Bevacizumab n=93 Participants Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm B: Sequential FOLFOXIRI + Bevacizumab n=92 Participants Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm C: FOLFOX + Bevacizumab n=95 Participants Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Total n=280 Participants Total of all reporting groups
Age, Continuous	56.0 Years STANDARD_DEVIATION 11.53 • n=5 Participants	56.0 Years STANDARD_DEVIATION 10.46 • n=7 Participants	57.9 Years STANDARD_DEVIATION 9.86 • n=5 Participants	56.7 Years STANDARD_DEVIATION 10.63 • n=4 Participants
Sex: Female, Male Female	42 Participants n=5 Participants	40 Participants n=7 Participants	36 Participants n=5 Participants	118 Participants n=4 Participants
Sex: Female, Male Male	51 Participants n=5 Participants	52 Participants n=7 Participants	59 Participants n=5 Participants	162 Participants n=4 Participants

PRIMARY outcome

Timeframe: Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years)

Population: ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.

ORR1 was the percentage of participants with complete response (CR) or partial response (PR) during first-line therapy as assessed by investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1). CR was defined as disappearance of all extranodal target lesions and all pathological lymph nodes had to have decreased to <10 millimeter (mm) in short axis. PR was defined as at least a 30% decrease in the sum of longest diameters of target lesions, taking as reference the baseline sum diameters. ORR1 = CR + PR

Outcome measures

Measure	Arm A: Concurrent FOLFOXIRI + Bevacizumab n=93 Participants Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm B: Sequential FOLFOXIRI + Bevacizumab n=92 Participants Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm C: FOLFOX + Bevacizumab n=95 Participants Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arms A + B: Pooled FOLFOXIRI + Bevacizumab n=185 Participants This analysis set combines Arms A and B and represents participants who received either concurrent or sequential FOLFOXIRI with 5 mg/kg of bevacizumab during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Percentage of Participants With Overall Response During First-Line Therapy (ORR1)	72.0 Percentage of participants	72.8 Percentage of participants	62.1 Percentage of participants	72.4 Percentage of participants

PRIMARY outcome

Timeframe: Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years)

Population: ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.

PFS1 was defined as time from randomization to the first occurrence of disease progression during first-line therapy, as assessed by the Investigator using RECIST v1.1, or death from any cause, whichever occurs first. Disease progression was defined as sum of longest diameters increased by at least 20% from the smallest value on study. The sum of longest diameters must also demonstrate an absolute increase of at least 5 mm.

Outcome measures

Measure	Arm A: Concurrent FOLFOXIRI + Bevacizumab n=93 Participants Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm B: Sequential FOLFOXIRI + Bevacizumab n=92 Participants Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm C: FOLFOX + Bevacizumab n=95 Participants Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arms A + B: Pooled FOLFOXIRI + Bevacizumab n=185 Participants This analysis set combines Arms A and B and represents participants who received either concurrent or sequential FOLFOXIRI with 5 mg/kg of bevacizumab during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Progression-Free Survival During First-Line Therapy (PFS1)	11.86 months Interval 9.95 to 16.62	11.37 months Interval 9.2 to 13.34	9.46 months Interval 8.08 to 11.2	11.70 months Interval 10.35 to 13.34

SECONDARY outcome

Timeframe: Randomization up to disease progression during second-line therapy or death, whichever occurs first (up to approximately 3 years)

Population: ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.

Time to PFS2 was defined as time from randomization to the first occurrence of disease progression after reinduction of second-line therapy, as assessed by the Investigator using RECIST v1.1, or death from any cause, whichever occurs first. Disease progression was defined as sum of longest diameters increased by at least 20% from the smallest value on study. The sum of longest diameters must also demonstrate an absolute increase of at least 5mm.

Outcome measures

Measure	Arm A: Concurrent FOLFOXIRI + Bevacizumab n=24 Participants Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm B: Sequential FOLFOXIRI + Bevacizumab n=30 Participants Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm C: FOLFOX + Bevacizumab n=29 Participants Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arms A + B: Pooled FOLFOXIRI + Bevacizumab n=54 Participants This analysis set combines Arms A and B and represents participants who received either concurrent or sequential FOLFOXIRI with 5 mg/kg of bevacizumab during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Time to PFS2	18.76 months Interval 13.63 to 24.31	13.17 months Interval 10.61 to 16.82	14.75 months Interval 11.01 to 16.13	15.08 months Interval 13.17 to 18.53

SECONDARY outcome

Timeframe: Randomization until death due to any cause (up to approximately 3 years)

Population: ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.

OS was defined as the time from the date of randomization to the date of death from any cause.

Outcome measures

Measure	Arm A: Concurrent FOLFOXIRI + Bevacizumab n=93 Participants Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm B: Sequential FOLFOXIRI + Bevacizumab n=92 Participants Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm C: FOLFOX + Bevacizumab n=95 Participants Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arms A + B: Pooled FOLFOXIRI + Bevacizumab n=185 Participants This analysis set combines Arms A and B and represents participants who received either concurrent or sequential FOLFOXIRI with 5 mg/kg of bevacizumab during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Overall Survival (OS)	33.97 months Interval 23.69 to 33.97	28.32 months Interval 22.21 to N/A = NE = not evaluable: The value cannot be estimated because the curve representing the upper confidence limits for the survivor function lies above 0.5.	30.65 months Interval 25.17 to 30.65	28.32 months Interval 23.75 to N/A = NE = not evaluable:The value cannot be estimated because the curve representing the upper confidence limits for the survivor function lies above 0.5.

SECONDARY outcome

Timeframe: Randomization up to approximately 3 years

Population: ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.

Reported here is the proportion of participants who underwent liver metastases resections calculated as follows: number of participants who underwent liver metastases resections divided by total number of participants in each arm.

Outcome measures

Measure	Arm A: Concurrent FOLFOXIRI + Bevacizumab n=93 Participants Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm B: Sequential FOLFOXIRI + Bevacizumab n=92 Participants Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm C: FOLFOX + Bevacizumab n=95 Participants Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arms A + B: Pooled FOLFOXIRI + Bevacizumab n=185 Participants This analysis set combines Arms A and B and represents participants who received either concurrent or sequential FOLFOXIRI with 5 mg/kg of bevacizumab during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Proportion of Participants Who Underwent Liver Metastases Resections	0.17 Proportion of participants Interval 0.11 to 0.24	0.10 Proportion of participants Interval 0.05 to 0.15	0.08 Proportion of participants Interval 0.04 to 0.13	0.14 Proportion of participants Interval 0.09 to 0.18

SECONDARY outcome

Timeframe: Randomization up to approximately 3 years

Population: ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.

The proportion of participants considered by the investigator to be unresectable at study enrollment who subsequently underwent attempted curative resections of metastases was calculated as follows: number of participants considered by the investigator to be unresectable at study enrollment who subsequently underwent attempted curative resections of metastases divided by total number of participants in each arm. This outcome represents a measure of the rate of conversion from unresectable to resectable disease.

Outcome measures

Measure	Arm A: Concurrent FOLFOXIRI + Bevacizumab n=93 Participants Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm B: Sequential FOLFOXIRI + Bevacizumab n=92 Participants Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm C: FOLFOX + Bevacizumab n=95 Participants Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arms A + B: Pooled FOLFOXIRI + Bevacizumab n=185 Participants This analysis set combines Arms A and B and represents participants who received either concurrent or sequential FOLFOXIRI with 5 mg/kg of bevacizumab during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Proportion of Participants Considered by the Investigator to be Unresectable on Study Enrollment Who Subsequently Underwent Attempted Curative Resections of Metastases	0.24 Proportion of participants Interval 0.16 to 0.31	0.17 Proportion of participants Interval 0.11 to 0.24	0.14 Proportion of participants Interval 0.08 to 0.19	0.21 Proportion of participants Interval 0.16 to 0.25

SECONDARY outcome

Timeframe: Randomization up to approximately 3 years

Population: Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.

An adverse event is any untoward medical occurrence in a subject 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.

Outcome measures

Measure	Arm A: Concurrent FOLFOXIRI + Bevacizumab n=91 Participants Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm B: Sequential FOLFOXIRI + Bevacizumab n=90 Participants Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm C: FOLFOX + Bevacizumab n=90 Participants Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arms A + B: Pooled FOLFOXIRI + Bevacizumab n=181 Participants This analysis set combines Arms A and B and represents participants who received either concurrent or sequential FOLFOXIRI with 5 mg/kg of bevacizumab during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Percentage of Participants With Adverse Events	100 Percentage of participants	98.9 Percentage of participants	100 Percentage of participants	99.4 Percentage of participants

Adverse Events

Arm A: Concurrent FOLFOXIRI + Bevacizumab

Serious events: 39 serious events

Other events: 91 other events

Deaths: 0 deaths

Arm B: Sequential FOLFOXIRI + Bevacizumab

Serious events: 42 serious events

Other events: 89 other events

Deaths: 0 deaths

Arm C: FOLFOX + Bevacizumab

Serious events: 43 serious events

Other events: 89 other events

Deaths: 0 deaths

Serious adverse events

Measure	Arm A: Concurrent FOLFOXIRI + Bevacizumab n=91 participants at risk Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm B: Sequential FOLFOXIRI + Bevacizumab n=90 participants at risk Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm C: FOLFOX + Bevacizumab n=90 participants at risk Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
General disorders Non-cardiac chest pain	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Hepatobiliary disorders Cholelithiasis	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Hepatobiliary disorders Hepatic failure	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Hepatobiliary disorders Hepatic haemorrhage	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Hepatobiliary disorders Jaundice cholestatic	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Blood and lymphatic system disorders Febrile neutropenia	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Blood and lymphatic system disorders Neutropenia	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Blood and lymphatic system disorders Leukopenia	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Cardiac disorders Acute myocardial infarction	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Cardiac disorders Myocardial infarction	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Cardiac disorders Arteriospasm coronary	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Cardiac disorders Cardiac arrest	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Cardiac disorders Supraventricular tachycardia	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Diarrhoea	5.5% 5/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Abdominal pain	3.3% 3/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Constipation	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Gastrointestinal haemorrhage	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	3.3% 3/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Anal fistula	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Ascites	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Colitis	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Abdominal pain upper	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Anal fissure	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Duodenal ulcer	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Small intestinal obstruction	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	3.3% 3/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Vomiting	3.3% 3/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Large intestine perforation	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	3.3% 3/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Nausea	3.3% 3/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Large intestinal obstruction	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Rectal perforation	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Rectal Haemorrhage	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Gastrointestinal perforation	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Ileus	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Intestinal perforation	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Large intestinal stenosis	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Obstruction gastric	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Rectal obstruction	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Death	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Pyrexia	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Asthenia	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Chest pain	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Fatigue	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders General physical health deterioration	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Medical device pain	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Mucosal inflammation	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Pneumonia	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Sepsis	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Abdominal abscess	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	3.3% 3/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Urinary tract infection	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Clostridium difficile colitis	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Gastroenteritis	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Subcutaneous abscess	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Appendicitis	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Bacterial infection	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Carbuncle	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Device related infection	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Diverticulitis	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Enterocolitis infectious	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Gastroenteritis viral	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Liver abscess	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Necrotising fasciitis	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Neutropenic sepsis	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Pelvic abscess	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Pneumococcal sepsis	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Rectal abscess	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Septic shock	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Stoma site infection	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Urinary tract infection bacterial	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Urosepsis	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Wound infection	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Injury, poisoning and procedural complications Accidental overdose	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Injury, poisoning and procedural complications Cystitis radiation	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Injury, poisoning and procedural complications Fall	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Injury, poisoning and procedural complications Femoral neck fracture	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Injury, poisoning and procedural complications Infusion related reaction	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Injury, poisoning and procedural complications Postoperative respiratory failure	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Injury, poisoning and procedural complications Procedural complication	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Injury, poisoning and procedural complications Stoma obstruction	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Injury, poisoning and procedural complications Stoma site pain	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Injury, poisoning and procedural complications Thoracic vertebral fracture	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Investigations Neutrophil count decreased	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Investigations Blood bilirubin increased	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Metabolism and nutrition disorders Dehydration	6.6% 6/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	3.3% 3/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Metabolism and nutrition disorders Hypokalaemia	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Metabolism and nutrition disorders Electrolyte imbalance	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Metabolism and nutrition disorders Failure to thrive	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Metabolism and nutrition disorders Lactic acidosis	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Back pain	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Pathological fracture	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Soft tissue necrosis	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Synovitis	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour compression	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Syncope	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Central nervous system lesion	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Cerebrovascular accident	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Embolic stroke	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Encephalopathy	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Headache	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Metabolic encephalopathy	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Spinal cord compression	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Subarachnoid haemorrhage	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Psychiatric disorders Mental status changes	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Renal and urinary disorders Acute kidney injury	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Renal and urinary disorders Acute prerenal failure	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Renal and urinary disorders Nephrolithiasis	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Renal and urinary disorders Urinary bladder rupture	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	3.3% 3/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Respiratory, thoracic and mediastinal disorders Laryngeal oedema	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Skin and subcutaneous tissue disorders Skin ulcer	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Surgical and medical procedures Wound drainage	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Vascular disorders Deep vein thrombosis	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Vascular disorders Air embolism	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Vascular disorders Hypotension	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Intestinal obstruction	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.

Other adverse events

Measure	Arm A: Concurrent FOLFOXIRI + Bevacizumab n=91 participants at risk Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm B: Sequential FOLFOXIRI + Bevacizumab n=90 participants at risk Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.	Arm C: FOLFOX + Bevacizumab n=90 participants at risk Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Blood and lymphatic system disorders Neutropenia	46.2% 42/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	47.8% 43/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	32.2% 29/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Blood and lymphatic system disorders Anaemia	17.6% 16/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	18.9% 17/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	26.7% 24/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Blood and lymphatic system disorders Thrombocytopenia	9.9% 9/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	13.3% 12/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	10.0% 9/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Ear and labyrinth disorders Ear pain	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Eye disorders Vision blurred	18.7% 17/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	10.0% 9/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	7.8% 7/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Eye disorders Lacrimation increased	4.4% 4/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	8.9% 8/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	7.8% 7/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Diarrhoea	80.2% 73/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	72.2% 65/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	54.4% 49/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Constipation	30.8% 28/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	50.0% 45/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	45.6% 41/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Abdominal pain	38.5% 35/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	33.3% 30/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	31.1% 28/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Dyspepsia	8.8% 8/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	16.7% 15/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	11.1% 10/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Abdominal pain upper	9.9% 9/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	15.6% 14/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	3.3% 3/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Flatulence	13.2% 12/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	7.8% 7/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Gastrooesophageal reflux disease	5.5% 5/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	12.2% 11/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	10.0% 9/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Abdominal distention	5.5% 5/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	10.0% 9/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Haematochezia	8.8% 8/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	3.3% 3/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Ascites	3.3% 3/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Dry mouth	6.6% 6/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Dysphagia	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Nausea	64.8% 59/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	71.1% 64/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	58.9% 53/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Vomiting	36.3% 33/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	40.0% 36/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	26.7% 24/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Stomatitis	34.1% 31/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	40.0% 36/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	27.8% 25/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Haemorrhoids	7.7% 7/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	12.2% 11/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	13.3% 12/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Rectal haemorrhage	12.1% 11/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	10.0% 9/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Oral pain	11.0% 10/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	8.9% 8/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Gastrointestinal disorders Proctalgia	8.8% 8/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Fatigue	74.7% 68/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	75.6% 68/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	66.7% 60/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Temperature intolerance	28.6% 26/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	26.7% 24/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	27.8% 25/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Mucosal inflammation	17.6% 16/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	17.8% 16/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	15.6% 14/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Pyrexia	17.6% 16/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	11.1% 10/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	16.7% 15/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Oedema peripheral	11.0% 10/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	12.2% 11/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Chills	7.7% 7/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	7.8% 7/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	11.1% 10/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Pain	4.4% 4/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	12.2% 11/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	10.0% 9/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Asthenia	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	7.8% 7/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	10.0% 9/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Chest pain	6.6% 6/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Peripheral swelling	6.6% 6/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	3.3% 3/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Influenza like illness	3.3% 3/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
General disorders Oedema	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Immune system disorders Hypersensitivity	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Urinary tract infection	14.3% 13/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	17.8% 16/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	18.9% 17/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Upper respiratory tract infection	13.2% 12/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	12.2% 11/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	7.8% 7/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Sinusitis	6.6% 6/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	12.2% 11/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Nasopharyngitis	4.4% 4/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	3.3% 3/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Infections and infestations Oral herpes	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Injury, poisoning and procedural complications Infusion related reaction	14.3% 13/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Injury, poisoning and procedural complications Fall	5.5% 5/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Injury, poisoning and procedural complications Contusion	5.5% 5/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	3.3% 3/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Investigations Weight decreased	18.7% 17/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	12.2% 11/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	22.2% 20/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Investigations Neutrophil count decreased	15.4% 14/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	13.3% 12/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	12.2% 11/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Investigations Aspartate aminotransferase increased	6.6% 6/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	7.8% 7/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Investigations White blood cell count decreased	3.3% 3/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	8.9% 8/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Investigations Blood alkaline phosphatase increased	6.6% 6/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	3.3% 3/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Investigations Blood bilirubin increased	3.3% 3/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	7.8% 7/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Investigations Platelet count decreased	4.4% 4/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Metabolism and nutrition disorders Deceased appetite	41.8% 38/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	42.2% 38/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	37.8% 34/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Metabolism and nutrition disorders Hypokalaemia	26.4% 24/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	18.9% 17/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	16.7% 15/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Metabolism and nutrition disorders Dehydration	24.2% 22/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	14.4% 13/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	14.4% 13/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Metabolism and nutrition disorders Hyperglycaemia	4.4% 4/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Metabolism and nutrition disorders Hyponatraemia	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	7.8% 7/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Metabolism and nutrition disorders Hypomagnesaemia	5.5% 5/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Back pain	13.2% 12/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	24.4% 22/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	22.2% 20/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Arthralgia	13.2% 12/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	20.0% 18/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	13.3% 12/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Pain in extremity	14.3% 13/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	16.7% 15/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	8.9% 8/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	5.5% 5/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	14.4% 13/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	10.0% 9/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Muscle spasms	4.4% 4/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	8.9% 8/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Myalgia	8.8% 8/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Muscular weakness	4.4% 4/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Pain in jaw	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	7.8% 7/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Bone pain	5.5% 5/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Musculoskeletal and connective tissue disorders Neck pain	3.3% 3/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	7.8% 7/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Neuropathy peripheral	36.3% 33/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	35.6% 32/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	35.6% 32/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Peripheral sensory neuropathy	29.7% 27/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	33.3% 30/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	40.0% 36/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Dysgeusia	29.7% 27/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	24.4% 22/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	25.6% 23/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Headache	28.6% 26/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	32.2% 29/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	18.9% 17/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Dizziness	19.8% 18/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	24.4% 22/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	18.9% 17/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Paraesthesia	9.9% 9/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	13.3% 12/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	15.6% 14/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Nervous system disorders Hypoaesthesia	4.4% 4/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Psychiatric disorders Insomnia	20.9% 19/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	25.6% 23/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	30.0% 27/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Psychiatric disorders Anxiety	14.3% 13/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	13.3% 12/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	8.9% 8/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Psychiatric disorders Depression	9.9% 9/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	13.3% 12/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	12.2% 11/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Renal and urinary disorders Proteinuria	16.5% 15/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	16.7% 15/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	16.7% 15/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Renal and urinary disorders Dysuria	3.3% 3/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Respiratory, thoracic and mediastinal disorders Epistaxis	35.2% 32/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	33.3% 30/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	24.4% 22/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Respiratory, thoracic and mediastinal disorders Cough	16.5% 15/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	33.3% 30/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	18.9% 17/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	13.2% 12/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	14.4% 13/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	8.9% 8/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	7.7% 7/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	18.9% 17/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	7.8% 7/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Respiratory, thoracic and mediastinal disorders Dysphonia	7.7% 7/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	3.3% 3/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	11.1% 10/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Respiratory, thoracic and mediastinal disorders Nasal congestion	7.7% 7/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Respiratory, thoracic and mediastinal disorders Hiccups	6.6% 6/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	6.6% 6/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	24.2% 22/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	31.1% 28/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	25.6% 23/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Skin and subcutaneous tissue disorders Alopecia	26.4% 24/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	25.6% 23/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	15.6% 14/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Skin and subcutaneous tissue disorders Rash	9.9% 9/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	18.9% 17/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	10.0% 9/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Skin and subcutaneous tissue disorders Dry skin	7.7% 7/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	12.2% 11/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	13.3% 12/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Skin and subcutaneous tissue disorders Pruritus	6.6% 6/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	10.0% 9/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Skin and subcutaneous tissue disorders Hyperhidrosis	7.7% 7/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Skin and subcutaneous tissue disorders Skin hyperpigmentation	7.7% 7/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	4.4% 4/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Skin and subcutaneous tissue disorders Skin discolouration	3.3% 3/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Skin and subcutaneous tissue disorders Rash maculo-papular	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Skin and subcutaneous tissue disorders Nail discolouration	0.00% 0/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Surgical and medical procedures Sinus operation	2.2% 2/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	1.1% 1/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Vascular disorders Hypertension	38.5% 35/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	40.0% 36/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	26.7% 24/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Vascular disorders Hot flush	11.0% 10/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	3.3% 3/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Vascular disorders Hypotension	7.7% 7/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	2.2% 2/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	11.1% 10/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Vascular disorders Deep vein thrombosis	4.4% 4/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	7.8% 7/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	6.7% 6/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Vascular disorders Embolism	1.1% 1/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	0.00% 0/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Investigations Alanine aminotransferase increased	6.6% 6/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	5.6% 5/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Respiratory, thoracic and mediastinal disorders Dyspnoea	15.4% 14/91 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	16.7% 15/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.	7.8% 7/90 • From baseline up to approximately 3 years. Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: genentech@druginfo.com

Results disclosure agreements

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

Restriction type: OTHER