Trial Outcomes & Findings for A Study of Avastin (Bevacizumab) Plus Crossover Fluoropyrimidine-Based Chemotherapy in Patients With Metastatic Colorectal Cancer. (NCT NCT00700102)

NCT ID: NCT00700102

Last Updated: 2015-07-30

Results Overview

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 820 participants
• Primary outcome timeframe: within 6.5 years
• Results posted on: 2015-07-30

Participant Flow

This study enrolled 820 patients at 220 sites located in 15 countries in Europe and Saudi Arabia. Study AIO KRK 0504 enrolled 261 patients, and 559 patients subsequently enrolled in Study ML18147 when the study was transferred to Hoffmann LaRoche (in 2008).

Participant milestones

Measure	Chemotherapy Chemotherapy alone until disease progression, unacceptable toxicity, or patient refusal Chemotherapy: As prescribed	Chemotherapy + Bevacizumab Chemotherapy and Bevacizumab until disease progression, unacceptable toxicity, or patient refusal Chemotherapy: As prescribed Bevacizumab: Bevacizumab, 5 mg/kg intravenously (IV) on days 1 and 14 of each 4 week cycle, or 7.5 mg/kg IV on days 1 and 22 of each 6 week cycle.
Overall Study STARTED	411	409
Overall Study Intention to Treat	410	409
Overall Study Received at Least One Dose	407	403
Overall Study COMPLETED	9	14
Overall Study NOT COMPLETED	402	395

Reasons for withdrawal

Measure	Chemotherapy Chemotherapy alone until disease progression, unacceptable toxicity, or patient refusal Chemotherapy: As prescribed	Chemotherapy + Bevacizumab Chemotherapy and Bevacizumab until disease progression, unacceptable toxicity, or patient refusal Chemotherapy: As prescribed Bevacizumab: Bevacizumab, 5 mg/kg intravenously (IV) on days 1 and 14 of each 4 week cycle, or 7.5 mg/kg IV on days 1 and 22 of each 6 week cycle.
Overall Study Died	394	385
Overall Study Lost to Follow-up	8	10

Baseline Characteristics

A Study of Avastin (Bevacizumab) Plus Crossover Fluoropyrimidine-Based Chemotherapy in Patients With Metastatic Colorectal Cancer.

Baseline characteristics by cohort

Measure	Chemotherapy n=411 Participants Chemotherapy alone until disease progression, unacceptable toxicity, or patient refusal Chemotherapy: As prescribed	Chemotherapy + Bevacizumab n=409 Participants Chemotherapy and Bevacizumab until disease progression, unacceptable toxicity, or patient refusal Chemotherapy: As prescribed Bevacizumab: Bevacizumab, 5 mg/kg intravenously (IV) on days 1 and 14 of each 4 week cycle, or 7.5 mg/kg IV on days 1 and 22 of each 6 week cycle.	Total n=820 Participants Total of all reporting groups
Age, Continuous	61.9 years STANDARD_DEVIATION 9.55 • n=5 Participants	62.1 years STANDARD_DEVIATION 9.78 • n=7 Participants	62.0 years STANDARD_DEVIATION 9.66 • n=5 Participants
Sex: Female, Male Female	152 Participants n=5 Participants	142 Participants n=7 Participants	294 Participants n=5 Participants
Sex: Female, Male Male	259 Participants n=5 Participants	267 Participants n=7 Participants	526 Participants n=5 Participants

PRIMARY outcome

Timeframe: within 6.5 years

Population: Intention to treat

Outcome measures

Measure	Chemotherapy n=410 Participants Chemotherapy alone until disease progression, unacceptable toxicity, or patient refusal	Chemotherapy + Bevacizumab n=409 Participants Chemotherapy and Bevacizumab until disease progression, unacceptable toxicity, or patient refusal
Overall Survival: Time From Randomization to Death From Any Cause	9.8 months Interval 9.0 to 11.0	11.2 months Interval 10.0 to 12.0

SECONDARY outcome

Timeframe: within approximately 9.6 years

Outcome measures

Measure	Chemotherapy n=410 Participants Chemotherapy alone until disease progression, unacceptable toxicity, or patient refusal	Chemotherapy + Bevacizumab n=409 Participants Chemotherapy and Bevacizumab until disease progression, unacceptable toxicity, or patient refusal
Overall Survival: Months From Time of First Line Therapy	22.5 months Interval 21.0 to 25.0	23.9 months Interval 22.0 to 26.0

SECONDARY outcome

Timeframe: within 6.5 years

Population: Unstratified intention to treat population

Outcome measures

Measure	Chemotherapy n=410 Participants Chemotherapy alone until disease progression, unacceptable toxicity, or patient refusal	Chemotherapy + Bevacizumab n=409 Participants Chemotherapy and Bevacizumab until disease progression, unacceptable toxicity, or patient refusal
Participants With Progression Free Survival Event	394 participants	386 participants

SECONDARY outcome

Timeframe: within 6.5 years

Population: Unstratified intention to treat population

Outcome measures

Measure	Chemotherapy n=410 Participants Chemotherapy alone until disease progression, unacceptable toxicity, or patient refusal	Chemotherapy + Bevacizumab n=409 Participants Chemotherapy and Bevacizumab until disease progression, unacceptable toxicity, or patient refusal
Progression Free Survival: Time to Event	4.1 Months Interval 0.0 to 27.0	5.7 Months Interval 0.0 to 38.0

SECONDARY outcome

Timeframe: within 6.5 years

Population: Participants with measurable disease

Outcome measures

Measure	Chemotherapy n=406 Participants Chemotherapy alone until disease progression, unacceptable toxicity, or patient refusal	Chemotherapy + Bevacizumab n=404 Participants Chemotherapy and Bevacizumab until disease progression, unacceptable toxicity, or patient refusal
Response Rate: Percentage of Participants With Best Overall Response, Defined as Confirmed Complete Response (CR) or Partial Response (PR) According to RECIST Criteria	3.9 percentage of participants Interval 2.3 to 6.3	5.4 percentage of participants Interval 3.4 to 8.1

SECONDARY outcome

Timeframe: within 6.5 years

Population: Participants with measurable disease

Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment.

Outcome measures

Measure	Chemotherapy n=406 Participants Chemotherapy alone until disease progression, unacceptable toxicity, or patient refusal	Chemotherapy + Bevacizumab n=404 Participants Chemotherapy and Bevacizumab until disease progression, unacceptable toxicity, or patient refusal
Response Rate: Participants With Response Status Based on RECIST Criteria Complete response	0.5 percentage of participants Interval 0.1 to 1.8	0.2 percentage of participants Interval 0.0 to 1.4
Response Rate: Participants With Response Status Based on RECIST Criteria Partial response	3.4 percentage of participants Interval 1.9 to 5.7	5.2 percentage of participants Interval 3.2 to 7.8
Response Rate: Participants With Response Status Based on RECIST Criteria Stable Disease	50.2 percentage of participants Interval 45.3 to 55.2	62.6 percentage of participants Interval 57.7 to 67.4
Response Rate: Participants With Response Status Based on RECIST Criteria Progressive Disease	35.0 percentage of participants Interval 30.3 to 39.8	21.5 percentage of participants Interval 17.6 to 25.9
Response Rate: Participants With Response Status Based on RECIST Criteria Missing (No Response Assessment)	10.8 percentage of participants Missing data not analyzable	10.4 percentage of participants Missing data not analyzable

Adverse Events

Chemotherapy

Serious events: 137 serious events

Other events: 379 other events

Deaths: 0 deaths

Chemotherapy + Bevacizumab

Serious events: 130 serious events

Other events: 382 other events

Deaths: 0 deaths

Serious adverse events

Measure	Chemotherapy n=409 participants at risk Chemotherapy alone until disease progression, unacceptable toxicity, or patient refusal	Chemotherapy + Bevacizumab n=401 participants at risk Chemotherapy and Bevacizumab until disease progression, unacceptable toxicity, or patient refusal
Gastrointestinal disorders Abdominal hernia	0.73% 3/409 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Abdominal pain	2.2% 9/409 • Number of events 9 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	1.5% 6/401 • Number of events 6 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Abdominal pain lower	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Abdominal pain upper	0.49% 2/409 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Ascites	0.49% 2/409 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Colonic obstruction	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Constipation	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Diarrhoea	3.9% 16/409 • Number of events 16 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	3.2% 13/401 • Number of events 13 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Enteritis	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.75% 3/401 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Enterovesical fistula	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.50% 2/401 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Gastritis	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Gastrointestinal disorder	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Gastrointestinal hopomotility	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.50% 2/401 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Gastrointestinal inflammation	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Gastrointestinal obstruction	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Gastrointestinal toxicity	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Haematochezia	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Ileus	0.98% 4/409 • Number of events 4 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Inguinal hernia	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Inguinal hernia, obstructive	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Intestinal obstruction	0.98% 4/409 • Number of events 4 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.50% 2/401 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Intestinal perforation	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	1.00% 4/401 • Number of events 4 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Large intestine perforation	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Nausea	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.75% 3/401 • Number of events 4 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Oesophagitis	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Pancreatitis	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Proctalgia	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Rectal haemorrhage	0.49% 2/409 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Vomiting	0.98% 4/409 • Number of events 4 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	1.7% 7/401 • Number of events 7 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Subileus	0.49% 2/409 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	1.7% 7/401 • Number of events 8 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Sepsis	1.2% 5/409 • Number of events 6 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.50% 2/401 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Infection	0.73% 3/409 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.75% 3/401 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Pneumonia	0.49% 2/409 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.75% 3/401 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Device related infection	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.75% 3/401 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Febrile infection	0.49% 2/409 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Urosepsis	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.50% 2/401 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Anal abscess	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.50% 2/401 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Gastroenteritis	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.50% 2/401 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Lung infection	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Sinusitis	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Abdominal abscess	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Abdominal infection	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Appendicitis	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Atypical pneumonia	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Bronchitis	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Cellulitis	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Cholecystitis infective	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Clostridium difficile infection	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Device related sepsis	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Enterococcal sepsis	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Gastroenteritis clostridial	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Gastrointestinal infection	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Peritonitis	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Respiratory tract infection	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Septic shock	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Staphylococcal infection	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Staphylococcal sepsis	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Systemic candida	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Urinary tract infection	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Viral infection	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Pyrexia	2.7% 11/409 • Number of events 13 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	1.7% 7/401 • Number of events 10 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Disease progression	0.98% 4/409 • Number of events 4 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.75% 3/401 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders General physical health deterioration	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.75% 3/401 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Chest pain	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.50% 2/401 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Fatigue	0.49% 2/409 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Mucosal inflammation	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.50% 2/401 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Asthenia	0.49% 2/409 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Obstruction	0.49% 2/409 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Device breakage	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Drug withdrawal syndrome	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Extravasation	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Multi-organ failure	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Stent malfunction	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Sudden cardiac death	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Sudden death	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Blood and lymphatic system disorders Neutropenia	1.7% 7/409 • Number of events 8 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	2.0% 8/401 • Number of events 8 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Blood and lymphatic system disorders Febrile neutropenia	0.98% 4/409 • Number of events 4 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.75% 3/401 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Blood and lymphatic system disorders Anaemia	0.49% 2/409 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Blood and lymphatic system disorders Idiopathic thrombocytopenic purpura	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Blood and lymphatic system disorders Leukopenia	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Blood and lymphatic system disorders Pancytopenia	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.98% 4/409 • Number of events 4 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	1.7% 7/401 • Number of events 7 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.50% 2/401 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.49% 2/409 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Lung disorder	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Lung infiltration	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Renal and urinary disorders Acute prerenal failure	0.49% 2/409 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Renal and urinary disorders Renal failure	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Renal and urinary disorders Ureteric obstruction	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Renal and urinary disorders Haematuria	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Renal and urinary disorders Pyelocaliectasis	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Renal and urinary disorders Renal colic	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Renal and urinary disorders Renal failure acute	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Renal and urinary disorders Ureteric stenosis	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Renal and urinary disorders Urinary incontinence	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Renal and urinary disorders Urinary retention	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Hepatobiliary disorders Cholestasis	0.98% 4/409 • Number of events 4 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.50% 2/401 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Hepatobiliary disorders Biliary fistula	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Hepatobiliary disorders Cholangitis	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Hepatobiliary disorders Cholecystitis	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Hepatobiliary disorders Cholelithiasis	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Hepatobiliary disorders Hyperbilirubinaemia	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Hepatobiliary disorders Jaundice cholestatic	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Immune system disorders Drug hypersensitivity	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	1.5% 6/401 • Number of events 7 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Immune system disorders Anaphylactic shock	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Immune system disorders Hypersensitivity	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Vascular disorders Deep vein thrombosis	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.75% 3/401 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Vascular disorders Hypertensive emergency	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Vascular disorders Aortic stenosis	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Vascular disorders Circulatory collapse	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Vascular disorders Hypertension	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Vascular disorders Hypertensive crisis	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Vascular disorders Pelvic venous thrombosis	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Vascular disorders Venous thrombosis	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Injury, poisoning and procedural complications Post procedural haemorrhage	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.50% 2/401 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Injury, poisoning and procedural complications Anastomotic complication	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Injury, poisoning and procedural complications Fall	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Injury, poisoning and procedural complications Femur fracture	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Injury, poisoning and procedural complications Humerus fracture	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Injury, poisoning and procedural complications Radius fracture	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Injury, poisoning and procedural complications Spinal fracture	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Cardiac disorders Myocardial infarction	0.49% 2/409 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Cardiac disorders Atrial fibrillation	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Cardiac disorders Acute myocardial infarction	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Cardiac disorders Cardiac arrest	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Cardiac disorders Cardiopulmonary failure	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Cardiac disorders Tachycardia	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Nervous system disorders Cerebral atrophy	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Nervous system disorders Cerebral infarction	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Nervous system disorders Cerebrovascular accident	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Nervous system disorders Headache	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Nervous system disorders Phrenic nerve paralysis	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Nervous system disorders Polyneuropathy	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Nervous system disorders Sciatica	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Nervous system disorders Syncope	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Metabolism and nutrition disorders Dehydration	0.73% 3/409 • Number of events 3 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Metabolism and nutrition disorders Decreased appetite	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Metabolism and nutrition disorders Malnutrition	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Musculoskeletal and connective tissue disorders Arthralgia	0.49% 2/409 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Musculoskeletal and connective tissue disorders Groin pain	0.49% 2/409 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oncologic complication	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour compression	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Psychiatric disorders Suicide attempt	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.50% 2/401 • Number of events 2 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Psychiatric disorders Disorientation	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Psychiatric disorders Drug dependence	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Investigations Volume blood decreased	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Investigations Weight decreased	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Surgical and medical procedures Intestinal operation	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Surgical and medical procedures Ureteral stent insertion	0.24% 1/409 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.00% 0/401 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Reproductive system and breast disorders Epididymitis	0.00% 0/409 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	0.25% 1/401 • Number of events 1 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.

Other adverse events

Measure	Chemotherapy n=409 participants at risk Chemotherapy alone until disease progression, unacceptable toxicity, or patient refusal	Chemotherapy + Bevacizumab n=401 participants at risk Chemotherapy and Bevacizumab until disease progression, unacceptable toxicity, or patient refusal
Gastrointestinal disorders Diarrhoea	43.3% 177/409 • Number of events 333 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	58.1% 233/401 • Number of events 471 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Nausea	41.6% 170/409 • Number of events 294 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	44.4% 178/401 • Number of events 340 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Vomiting	25.4% 104/409 • Number of events 162 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	29.7% 119/401 • Number of events 188 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Abdominal pain	18.6% 76/409 • Number of events 91 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	22.2% 89/401 • Number of events 126 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Constipation	18.1% 74/409 • Number of events 96 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	20.4% 82/401 • Number of events 120 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Stomatitis	7.8% 32/409 • Number of events 47 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	10.0% 40/401 • Number of events 69 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Gastrointestinal disorders Abdominal pain upper	5.4% 22/409 • Number of events 31 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	9.2% 37/401 • Number of events 44 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Asthenia	25.9% 106/409 • Number of events 263 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	26.4% 106/401 • Number of events 246 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Fatigue	19.6% 80/409 • Number of events 126 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	23.4% 94/401 • Number of events 154 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Mucosal inflammation	10.5% 43/409 • Number of events 72 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	19.0% 76/401 • Number of events 136 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Pyrexia	10.8% 44/409 • Number of events 61 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	16.5% 66/401 • Number of events 92 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
General disorders Oedema peripheral	6.4% 26/409 • Number of events 30 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	5.0% 20/401 • Number of events 23 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Blood and lymphatic system disorders Neutropenia	21.0% 86/409 • Number of events 159 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	27.9% 112/401 • Number of events 246 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Blood and lymphatic system disorders Thrombocytopenia	12.5% 51/409 • Number of events 102 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	17.2% 69/401 • Number of events 124 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Blood and lymphatic system disorders Leukopenia	8.6% 35/409 • Number of events 62 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	13.2% 53/401 • Number of events 110 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Blood and lymphatic system disorders Anaemia	14.2% 58/409 • Number of events 93 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	10.2% 41/401 • Number of events 58 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Nervous system disorders Paraesthesia	16.4% 67/409 • Number of events 139 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	19.5% 78/401 • Number of events 179 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Nervous system disorders Neuropathy peripheral	12.7% 52/409 • Number of events 99 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	11.5% 46/401 • Number of events 94 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Nervous system disorders Polyneuropathy	10.5% 43/409 • Number of events 67 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	12.7% 51/401 • Number of events 98 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Nervous system disorders Peripheral sensory neuropathy	5.1% 21/409 • Number of events 47 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	8.0% 32/401 • Number of events 58 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Nervous system disorders Neurotoxicity	3.2% 13/409 • Number of events 29 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	6.7% 27/401 • Number of events 53 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Nervous system disorders Headache	3.7% 15/409 • Number of events 20 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	7.2% 29/401 • Number of events 40 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Skin and subcutaneous tissue disorders Alopecia	16.6% 68/409 • Number of events 85 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	17.7% 71/401 • Number of events 92 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	8.8% 36/409 • Number of events 68 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	12.5% 50/401 • Number of events 96 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Epistaxis	4.6% 19/409 • Number of events 21 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	17.5% 70/401 • Number of events 88 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Dyspnoea	9.3% 38/409 • Number of events 48 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	9.0% 36/401 • Number of events 40 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Cough	7.6% 31/409 • Number of events 35 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	8.7% 35/401 • Number of events 42 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Metabolism and nutrition disorders Decreased appetite	18.8% 77/409 • Number of events 99 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	19.7% 79/401 • Number of events 105 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Metabolism and nutrition disorders Hypokalaemia	4.6% 19/409 • Number of events 32 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	6.5% 26/401 • Number of events 34 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Nasopharyngitis	4.4% 18/409 • Number of events 20 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	7.0% 28/401 • Number of events 33 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Infections and infestations Urinary tract infection	5.1% 21/409 • Number of events 28 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	5.2% 21/401 • Number of events 24 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Vascular disorders Hypertension	5.9% 24/409 • Number of events 29 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	11.7% 47/401 • Number of events 72 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Musculoskeletal and connective tissue disorders Back pain	4.9% 20/409 • Number of events 29 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	7.5% 30/401 • Number of events 39 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.
Investigations Weight decreased	5.9% 24/409 • Number of events 26 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.	9.2% 37/401 • Number of events 38 • First subject first visit to end of trial within 7.25 years Safety Analysis Set was defined as all randomized patients who received any amount of study treatment, and were analyzed according to actual treatment received.

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