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Trial record 5 of 159 for:    colon cancer AND Capecitabine AND Fluorouracil

A Study of Capecitabine (Xeloda) and Bevacizumab as a First-line Therapy in Patients With Metastatic Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT00069095
Recruitment Status : Completed
First Posted : September 18, 2003
Results First Posted : January 22, 2016
Last Update Posted : October 6, 2016
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Factorial Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Colorectal Cancer
Interventions Drug: Oxaliplatin 130 mg/m^2
Drug: Capecitabine 1000 mg/m^2
Drug: Bevacizumab 7.5 mg/kg
Drug: Placebo for bevacizumab 7.5 mg/kg
Drug: Oxaliplatin 85 mg/m^2
Drug: Leucovorin 200 mg/m^2
Drug: Fluorouracil 400 mg/m^2
Drug: Bevacizumab 5 mg/kg
Drug: Placebo for bevacizumab 5 mg/kg
Enrollment 2035
Recruitment Details This study was conducted in 32 countries - Australia, Austria, Brazil, Canada, China, Czech Republic, Denmark, Finland, France, Germany, Great Britain, Guatemala, Hong Kong, Hungary, Ireland, Israel, Italy, Korea, Mexico, New Zealand, Norway, Panama, Portugal, Russia, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey and USA.
Pre-assignment Details A total of 2035 participants were randomized to any one of the treatment groups in the study (634 participants in the initial 2-arm part and 1401 participants in the 2x2 factorial part of the study), but only 2034 received study treatment as 1 participant was enrolled twice in the study at 2 study centers.
Arm/Group Title Xelox Folfox-4 Xelox+P Folfox-4+P Xelox+BV Folfox-4+BV
Hide Arm/Group Description Participants in the 2-arm part of the study received intravenous infusion of oxaliplatin 130 mg/m^2 over 2 hours on Day 1 of every 3 weeks before the first dose of capecitabine. Capecitabine was administered orally within 30 minutes after the end of a meal (breakfast and dinner) at a dose of 1000 mg/m^2 twice-daily (equivalent to a total daily dose of 2000 mg/m^2), for the first 2 weeks of every 3-week cycle. Participants received up to 16 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2-arm part of the study received intravenous infusion of oxaliplatin 85 mg/m^2 on Day 1 of every 2-week cycle; concomitantly with leucovorin 200 mg/m^2 iv for 2 hours followed by fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2-week cycle. Participants received up to 24 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2x2 factorial part of the study received intravenous infusion of placebo control for bevacizumab (BV) [volume equivalent to 7.5 mg/kg BV] over 30 to 90 minutes followed by oxaliplatin 130 mg/m^2 over 2 hours on Day 1 of every 3 weeks in combination with capecitabine, administered orally at a dose of 1000 mg/m^2 twice-daily (equivalent to a total daily dose of 2000 mg/m^2), for the first 2 weeks of every 3-week cycle. Participants received up to 16 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2x2 factorial part of the study received intravenous infusion of placebo control for BV (volume equivalent to 5 mg/kg BV) over 30 to 90 minutes followed by oxaliplatin 85 mg/m^2 on Day 1 of every 2-week cycle; concomitantly with leucovorin 200 mg/m^2 iv for 2 hours followed by fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2-week cycle. Participants received up to 24 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2x2 factorial part of the study received intravenous infusion of bevacizumab 7.5 mg/kg over 30 to 90 minutes followed by oxaliplatin 130 mg/m^2 over 2 hours on Day 1 of every 3 weeks in combination with capecitabine, administered orally at a dose of 1000 mg/m^2 twice-daily (equivalent to a total daily dose of 2000 mg/m^2), for the first 2 weeks of every 3-week cycle. Participants received up to 16 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2x2 factorial part of the study received intravenous infusion of bevacizumab 5 mg/kg over 30 to 90 minutes followed by oxaliplatin 85 mg/m^2 on Day 1 of every 2-week cycle; concomitantly with leucovorin 200 mg/m^2 iv for 2 hours followed by fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2-week cycle. Participants received up to 24 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent.
Period Title: Primary Treatment Phase
Started 317 317 350 351 350 349
Completed 22 15 36 31 48 48
Not Completed 295 302 314 320 302 301
Reason Not Completed
Ongoing             0             0             5             7             7             4
Admin/Other             29             38             31             45             48             42
Adverse Event             99             92             71             72             109             101
Death             14             8             2             5             8             8
Failure to return             5             5             0             0             0             2
Insufficient Therapeutic Response             131             127             175             154             101             102
Refused treatment             15             26             17             31             24             27
Withdrew             2             3             8             2             4             9
Other Violation             0             1             1             1             0             1
Violation criteria             0             2             4             3             1             5
Period Title: Post-study Treatment Phase
Started 8 [1] 13 [1] 21 [1] 17 [1] 36 [1] 29 [1]
Completed 0 0 0 0 0 0
Not Completed 8 13 21 17 36 29
Reason Not Completed
Missing reason             1             3             12             8             18             17
Adverse Event             2             3             1             0             5             1
Eligible for surgery             2             0             0             0             0             0
Insufficient therapeutic response             1             4             5             6             7             9
Participant refusal/Admin reasons             1             0             0             0             0             1
Participant had complete response             1             1             0             0             0             0
More than 21 days delay between cycles             0             1             0             0             0             0
Investigator decision (enough treatment)             0             1             1             0             1             0
Participant withdrew consent             0             0             1             0             0             0
Participant will start new treatment             0             0             1             0             0             0
Participant wanted break from treatment             0             0             0             1             0             0
Participant completed treatment             0             0             0             1             0             0
Surgery             0             0             0             1             1             0
Death             0             0             0             0             1             0
Participant had progressive disease             0             0             0             0             1             0
Participant/Physician decision to stop             0             0             0             0             1             0
Preplanned 6 cycles after surgery             0             0             0             0             1             0
Investigator decision             0             0             0             0             0             1
[1]
Participants could enter the follow-up phase even without entering the post-study treatment phase.
Period Title: Follow-up Phase
Started 284 [1] 299 [1] 298 [1] 299 [1] 278 [1] 272 [1]
Completed 110 93 178 187 186 171
Not Completed 174 206 120 112 92 101
Reason Not Completed
Death             174             206             120             112             92             101
[1]
Participants could enter the follow-up phase even without entering the post-study treatment phase.
Arm/Group Title Xelox Folfox-4 Xelox+P Folfox-4+P Xelox+BV Folfox-4+BV Total
Hide Arm/Group Description Participants in the 2-arm part of the study received intravenous infusion of oxaliplatin 130 mg/m^2 over 2 hours on Day 1 of every 3 weeks before the first dose of capecitabine. Capecitabine was administered orally within 30 minutes after the end of a meal (breakfast and dinner) at a dose of 1000 mg/m^2 twice-daily (equivalent to a total daily dose of 2000 mg/m^2), for the first 2 weeks of every 3-week cycle. Participants received up to 16 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2-arm part of the study received intravenous infusion of oxaliplatin 85 mg/m^2 on Day 1 of every 2-week cycle; concomitantly with leucovorin 200 mg/m^2 iv for 2 hours followed by fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2-week cycle. Participants received up to 24 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2x2 factorial part of the study received intravenous infusion of placebo control for bevacizumab (BV) [volume equivalent to 7.5 mg/kg BV] over 30 to 90 minutes followed by oxaliplatin 130 mg/m^2 over 2 hours on Day 1 of every 3 weeks in combination with capecitabine, administered orally at a dose of 1000 mg/m^2 twice-daily (equivalent to a total daily dose of 2000 mg/m^2), for the first 2 weeks of every 3-week cycle. Participants received up to 16 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2x2 factorial part of the study received intravenous infusion of placebo control for BV (volume equivalent to 5 mg/kg BV) over 30 to 90 minutes followed by oxaliplatin 85 mg/m^2 on Day 1 of every 2-week cycle; concomitantly with leucovorin 200 mg/m^2 iv for 2 hours followed by fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2-week cycle. Participants received up to 24 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2x2 factorial part of the study received intravenous infusion of bevacizumab 7.5 mg/kg over 30 to 90 minutes followed by oxaliplatin 130 mg/m^2 over 2 hours on Day 1 of every 3 weeks in combination with capecitabine, administered orally at a dose of 1000 mg/m^2 twice-daily (equivalent to a total daily dose of 2000 mg/m^2), for the first 2 weeks of every 3-week cycle. Participants received up to 16 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2x2 factorial part of the study received intravenous infusion of bevacizumab 5 mg/kg over 30 to 90 minutes followed by oxaliplatin 85 mg/m^2 on Day 1 of every 2-week cycle; concomitantly with leucovorin 200 mg/m^2 iv for 2 hours followed by fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2-week cycle. Participants received up to 24 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Total of all reporting groups
Overall Number of Baseline Participants 317 317 350 351 350 349 2034
Hide Baseline Analysis Population Description
Baseline characteristics were described for the Intent-to-treat (ITT) population.This population included all randomized participants who provided written informed consent.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 317 participants 317 participants 350 participants 351 participants 350 participants 349 participants 2034 participants
60.3  (10.76) 60.6  (10.94) 59.1  (12.14) 58.8  (10.87) 59.7  (11.28) 59.7  (10.74) 59.7  (11.14)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 317 participants 317 participants 350 participants 351 participants 350 participants 349 participants 2034 participants
Female
123
  38.8%
113
  35.6%
145
  41.4%
165
  47.0%
137
  39.1%
144
  41.3%
827
  40.7%
Male
194
  61.2%
204
  64.4%
205
  58.6%
186
  53.0%
213
  60.9%
205
  58.7%
1207
  59.3%
1.Primary Outcome
Title Progression-free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored): Non-inferiority of XELOX Versus FOLFOX-4
Hide Description PFS was defined as the time from randomization to progressive disease or death. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participants with no tumor assessments after baseline who were alive at the time of clinical cutoff were censored at the date of randomization. Participants who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was based on tumor assessments made by the investigators according to the RECIST criteria. Non-inferiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4- containing arms was investigated.
Time Frame Baseline until disease progression or death, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The eligible patient population (EPP) excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
Arm/Group Title FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV XELOX/XELOX+P/XELOX+BV
Hide Arm/Group Description:

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Folfox-4: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin (given on day 1).
  2. Folfox-4+P: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  3. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Xelox: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin (given on day 1).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).
  3. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 937 967
Median (95% Confidence Interval)
Unit of Measure: days
259
(245 to 268)
241
(229 to 254)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV, XELOX/XELOX+P/XELOX+BV
Comments Equivalence of treatment arm A (‘XELOX’) to treatment arm B (‘FOLFOX-4’) was tested via the following hypotheses - H0: HRA/B >/= 1.23 versus H1: HRA/B < 1.23. HRA/B denotes the hazard of disease progression or death under treatment A (‘XELOX’) divided by the hazard of disease progression or death under treatment B (‘FOLFOX-4’).
Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority was demonstrated if the upper limit of the 2-sided 97.5% confidence interval (CI) for the hazard ratio (HR) was less than the predefined limit of 1.23 (the non-inferiority margin). A stratified Cox model was used. In order to retain an experiment-wise two-sided type I error of 5%, the non-inferiority analysis for PFS used a two-sided significance level of 2.5%.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.05
Confidence Interval (2-Sided) 97.5%
0.94 to 1.18
Estimation Comments [Not Specified]
2.Primary Outcome
Title PFS as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
Hide Description PFS was defined as the time from randomization to progressive disease or death. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participants with no tumor assessments after baseline who were alive at the time of clinical cutoff were censored at the date of randomization. Participants who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was based on tumor assessments made by the investigators according to the RECIST criteria. Superiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time Frame Baseline until disease progression or death, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included all randomized participants who provided written informed consent.
Arm/Group Title FOLFOX-4+P/XELOX+P FOLFOX-4+BV/XELOX+BV
Hide Arm/Group Description:

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+P: Participants received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 701 699
Median (95% Confidence Interval)
Unit of Measure: days
244.0
(230 to 257)
285.0
(271 to 297)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4+P/XELOX+P, FOLFOX-4+BV/XELOX+BV
Comments Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone [HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)] was presented.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0023
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 97.5%
0.72 to 0.95
Estimation Comments [Not Specified]
3.Secondary Outcome
Title PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Non-inferiority of XELOX Versus FOLFOX-4
Hide Description PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participants who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was analyzed on the basis of the tumor response assessments made by the IRC. Non-inferiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time Frame Baseline until disease progression or death, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
Arm/Group Title FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV XELOX/XELOX+P/XELOX+BV
Hide Arm/Group Description:

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Folfox-4: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin (given on day 1).
  2. Folfox-4+P: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  3. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Xelox: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin (given on day 1).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).
  3. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 937 967
Median (95% Confidence Interval)
Unit of Measure: days
304.0
(281 to 319)
261.0
(246 to 276)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV, XELOX/XELOX+P/XELOX+BV
Comments Equivalence of treatment arm A (‘XELOX’) to treatment arm B (‘FOLFOX-4’) was tested via the following hypotheses - H0: HRA/B >/= 1.23 versus H1: HRA/B < 1.23. HRA/B denotes the hazard of disease progression or death under treatment A (‘XELOX’) divided by the hazard of disease progression or death under treatment B (‘FOLFOX-4’).
Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority was demonstrated if the upper limit of the 2-sided 97.5% confidence interval (CI) for the hazard ratio (HR) was less than the predefined limit of 1.23 (the non-inferiority margin). A stratified Cox model was used. In order to retain an experiment-wise two-sided type I error of 5%, the non-inferiority analysis for PFS used a two-sided significance level of 2.5%.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.22
Confidence Interval (2-Sided) 97.5%
1.05 to 1.42
Estimation Comments [Not Specified]
4.Secondary Outcome
Title PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
Hide Description PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participants who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was analyzed on the basis of the tumor response assessments made by the IRC. Superiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Superiority of the bevacizumab-containing arms was compared with the placebo-containing arms.
Time Frame Baseline until disease progression or death, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included all randomized participants who provided written informed consent.
Arm/Group Title FOLFOX-4+P/XELOX+P FOLFOX-4+BV/XELOX+BV
Hide Arm/Group Description:

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+P: Participants received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 701 699
Median (95% Confidence Interval)
Unit of Measure: days
259.0
(244 to 278)
335.0
(310 to 363)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4+P/XELOX+P, FOLFOX-4+BV/XELOX+BV
Comments Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone [HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)] was presented.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.70
Confidence Interval (2-Sided) 97.5%
0.58 to 0.83
Estimation Comments [Not Specified]
5.Secondary Outcome
Title PFS (On-treatment Approach): Non-inferiority of XELOX Versus FOLFOX-4
Hide Description PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. The on-treatment analysis included only tumor assessments and death events that occurred no later than 28 days after the last confirmed intake of any study medication in the primary study treatment phase. Participants who did not have an event during this interval were censored at the date of the last tumor assessment within this time window, or on day 1 if no tumor assessment was available after baseline. Participants who underwent surgical resection with curative intent without prior progression within 28 days after the last confirmed intake of any study medication in the primary study treatment phase were censored at the date of surgery. The on-treatment approach excluded the possible impact of other treatments that might have been started before disease progression. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time Frame Baseline until disease progression or death, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
Arm/Group Title FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV XELOX/XELOX+P/XELOX+BV
Hide Arm/Group Description:

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Folfox-4: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin (given on day 1).
  2. Folfox-4+P: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  3. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Xelox: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin (given on day 1).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).
  3. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 937 967
Median (95% Confidence Interval)
Unit of Measure: days
268.0
(252 to 290)
234.0
(221 to 251)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV, XELOX/XELOX+P/XELOX+BV
Comments HRs and 97.5% confidence interval were reported for treatment arm A (XELOX/XELOX+P/XELOX+BV) versus treatment arm B (FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV).
Type of Statistical Test Non-Inferiority or Equivalence
Comments Fewer events were expected in the ‘on-treatment analysis’, thus leading to reduced power. No formal statistical testing was therefore applied.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.24
Confidence Interval (2-Sided) 97.5%
1.07 to 1.44
Estimation Comments [Not Specified]
6.Secondary Outcome
Title PFS (On-treatment Approach): Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
Hide Description PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. The on-treatment analysis included only tumor assessments and death events that occurred no later than 28 days after the last confirmed intake of any study medication in the primary study treatment phase. Participants who did not have an event during this interval were censored at the date of the last tumor assessment within this time window, or on day 1 if no tumor assessment was available after baseline. Participants who underwent surgical resection with curative intent without prior progression within 28 days after the last confirmed intake of any study medication in the primary study treatment phase were censored at the date of surgery. The on-treatment approach excluded the possible impact of other treatments that might have been started before disease progression. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time Frame Baseline until disease progression or death, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included all randomized participants who provided written informed consent.
Arm/Group Title FOLFOX-4+P/XELOX+P FOLFOX-4+BV/XELOX+BV
Hide Arm/Group Description:

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+P: Participants received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 701 699
Median (95% Confidence Interval)
Unit of Measure: days
241.0
(227 to 254)
316.0
(294 to 338)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4+P/XELOX+P, FOLFOX-4+BV/XELOX+BV
Comments Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone [HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)] was presented.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.63
Confidence Interval (2-Sided) 97.5%
0.52 to 0.75
Estimation Comments [Not Specified]
7.Secondary Outcome
Title PFS by General Approach, Participants With Curative Surgery Not Censored: Non-inferiority of XELOX Versus FOLFOX-4
Hide Description PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. Participants who underwent curative surgery after experiencing a sufficient shrinkage of their tumor were not censored at the date of surgery, but any relapse, new occurrence of colorectal cancer, or death was considered as an event. Non-inferiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time Frame Baseline until disease progression or death, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
Arm/Group Title FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV XELOX/XELOX+P/XELOX+BV
Hide Arm/Group Description:

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Folfox-4: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin (given on day 1).
  2. Folfox-4+P: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  3. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Xelox: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin (given on day 1).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).
  3. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 937 967
Median (95% Confidence Interval)
Unit of Measure: days
260.0
(247 to 270)
244.0
(230 to 255)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV, XELOX/XELOX+P/XELOX+BV
Comments Equivalence of treatment arm A (‘XELOX’) to treatment arm B (‘FOLFOX-4’) was tested via the following hypotheses - H0: HRA/B >/= 1.23 versus H1: HRA/B < 1.23. HRA/B denotes the hazard of disease progression or death under treatment A (‘XELOX’) divided by the hazard of disease progression or death under treatment B (‘FOLFOX-4’).
Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority was demonstrated if the upper limit of the 2-sided 97.5% confidence interval (CI) for the hazard ratio (HR) was less than the predefined limit of 1.23 (the non-inferiority margin). A stratified Cox model was used. In order to retain an experiment-wise two-sided type I error of 5%, the non-inferiority analysis for PFS used a two-sided significance level of 2.5%.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.03
Confidence Interval (2-Sided) 97.5%
0.92 to 1.15
Estimation Comments [Not Specified]
8.Secondary Outcome
Title PFS by General Approach, Participants With Curative Surgery Not Censored: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
Hide Description PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. Participants who underwent curative surgery after experiencing a sufficient shrinkage of their tumor were not censored at the date of surgery, but any relapse, new occurrence of colorectal cancer, or death was considered as an event. Superiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time Frame Baseline until disease progression or death, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included all randomized participants who provided written informed consent.
Arm/Group Title FOLFOX-4+P/XELOX+P FOLFOX-4+BV/XELOX+BV
Hide Arm/Group Description:

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+P: Participants received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 701 699
Median (95% Confidence Interval)
Unit of Measure: days
245.0
(230 to 258)
287.0
(276 to 300)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4+P/XELOX+P, FOLFOX-4+BV/XELOX+BV
Comments Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone [HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)] was presented.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0015
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 97.5%
0.72 to 0.95
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Overall Survival: Non-inferiority of XELOX Versus FOLFOX-4
Hide Description Overall survival was defined as the time from the date of randomization to the date of death. Participants who were not reported to have died at the time of the clinical cut-off date for the analysis were censored using the date they were last known to be alive. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time Frame Baseline until disease progression or death, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
Arm/Group Title FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV XELOX/XELOX+P/XELOX+BV
Hide Arm/Group Description:

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Folfox-4: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin (given on day 1).
  2. Folfox-4+P: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  3. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Xelox: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin (given on day 1).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).
  3. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 937 967
Median (95% Confidence Interval)
Unit of Measure: days
549.0
(528 to 576)
577.0
(535 to 615)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV, XELOX/XELOX+P/XELOX+BV
Comments HRs and 97.5% confidence interval were reported for treatment arm A (XELOX/XELOX+P/XELOX+BV) versus treatment arm B (FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV).
Type of Statistical Test Non-Inferiority or Equivalence
Comments This study was not powered for testing non-inferiority of XELOX vs FOLFOX-4 with respect to overall survival and no margin could be derived following the effect retention concept. The same margins used for the PFS analysis [Non-inferiority was demonstrated if the upper limit of the 2-sided 97.5% confidence interval (CI) for the hazard ratio (HR) was less than the predefined limit of 1.23 (the non-inferiority margin)] were therefore applied to OS as well.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.97
Confidence Interval (2-Sided) 97.5%
0.84 to 1.14
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Overall Survival: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
Hide Description Overall survival was defined as the time from the date of randomization to the date of death. Participants who were not reported to have died at the time of the clinical cut-off date for the analysis were censored using the date they were last known to be alive. Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time Frame Baseline until disease progression or death, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included all randomized participants who provided written informed consent.
Arm/Group Title FOLFOX-4+P/XELOX+P FOLFOX-4+BV/XELOX+BV
Hide Arm/Group Description:

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+P: Participants received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 701 699
Median (95% Confidence Interval)
Unit of Measure: days
574.0
(537 to 592)
551.0
(528 to 635)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4+P/XELOX+P, FOLFOX-4+BV/XELOX+BV
Comments Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone [HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)] was presented together with the 97.5% confidence interval.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1921
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.89
Confidence Interval (2-Sided) 97.5%
0.72 to 1.09
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Best Overall Response (BOR) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST): Non-inferiority of XELOX Versus FOLFOX-4
Hide Description According to the RECIST criteria, BOR in an individual participant was defined as the best response recorded from the start of the treatment until disease progression or recurrence. Only tumor assessments as assessed by the investigator and made up to and including 28 days after last intake of study medication in the primary study treatment phase not later than date of first curative surgery were included in these analyses. Responders were defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR). Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time Frame From baseline until disease progression/recurrence, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
Arm/Group Title FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV XELOX/XELOX+P/XELOX+BV
Hide Arm/Group Description:

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Folfox-4: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin (given on day 1).
  2. Folfox-4+P: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  3. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Xelox: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin (given on day 1).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).
  3. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 937 967
Measure Type: Number
Unit of Measure: Percentage of responders
49.4 46.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV, XELOX/XELOX+P/XELOX+BV
Comments Non-inferiority of XELOX with/without bevacizumab to FOLFOX-4 with/without bevacizumab was tested by the pair of hypotheses - H0: OR(XELOX/XELOX+P/XELOX+BV)/(FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV) </= 0.66 versus H1: OR(XELOX/XELOX+P/XELOX+BV)/(FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV) > 0.66, where OR denotes Odds ratio.
Type of Statistical Test Non-Inferiority or Equivalence
Comments The analysis was based on the two-sided 97.5% confidence interval for OR(XELOX/XELOX+P/XELOX+BV)/(FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV). Non-inferiority of XELOX with/without bevacizumab to FOLFOX-4 with/without bevacizumab was concluded if the lower limit of this confidence interval is above 0.66.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.89
Confidence Interval (2-Sided) 97.5%
0.72 to 1.09
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Best Overall Response (BOR) as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
Hide Description According to the RECIST criteria, BOR in an individual participant was defined as the best response recorded from the start of the treatment until disease progression or recurrence. Only tumor assessments as assessed by the investigator and made up to and including 28 days after last intake of study medication in the primary study treatment phase not later than date of first curative surgery were included in these analyses. Responders were defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR). Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time Frame From baseline until disease progression/recurrence, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included all randomized participants who provided written informed consent.
Arm/Group Title FOLFOX-4+P/XELOX+P FOLFOX-4+BV/XELOX+BV
Hide Arm/Group Description:

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+P: Participants received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 701 699
Measure Type: Number
Unit of Measure: Percentage of responders
49.2 46.5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4+P/XELOX+P, FOLFOX-4+BV/XELOX+BV
Comments Superiority of adding bevacizumab to chemotherapy was tested as follows - H0: OR(FOLFOX-4+BV/XELOX+BV)/(FOLFOX-4+P/XELOX+P) </= 1.0 versus H1: OR(FOLFOX-4+BV/XELOX+BV)/(FOLFOX-4+P/XELOX+P) > 1.0. The test used a two-sided significance level of 2.5%.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3091
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.90
Confidence Interval (2-Sided) 97.5%
0.71 to 1.14
Estimation Comments [Not Specified]
13.Secondary Outcome
Title BOR as Assessed by the IRC According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
Hide Description According to the RECIST criteria, the BOR in an individual participant was the best response recorded from the start of the treatment until disease progression/recurrence (taking the smallest measurements recorded since the baseline assessment as a reference for PD). The BOR as assessed by the IRC was determined based on tumor assessments that were made up to and including 28 days after last intake of study medication in the primary study treatment phase. Responders were defined as the percentage of participants with a complete response (CR) or partial response (PR). Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time Frame From baseline until disease progression/recurrence, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
Arm/Group Title FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV XELOX/XELOX+P/XELOX+BV
Hide Arm/Group Description:

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Folfox-4: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin (given on day 1).
  2. Folfox-4+P: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  3. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Xelox: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin (given on day 1).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).
  3. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 937 967
Measure Type: Number
Unit of Measure: Percentage of responders
38.6 37.1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV, XELOX/XELOX+P/XELOX+BV
Comments Non-inferiority of XELOX with/without bevacizumab to FOLFOX-4 with/without bevacizumab was tested by the pair of hypotheses - H0: OR(XELOX/XELOX+P/XELOX+BV)/(FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV) </= 0.66 versus H1: OR(XELOX/XELOX+P/XELOX+BV)/(FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV) > 0.66
Type of Statistical Test Non-Inferiority or Equivalence
Comments The analysis was based on the two-sided 97.5% confidence interval for OR(XELOX/XELOX+P/XELOX+BV)/(FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV). Non-inferiority of XELOX with/without bevacizumab to FOLFOX-4 with/without bevacizumab shall be concluded if the lower limit of this confidence interval is above 0.66.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.94
Confidence Interval (2-Sided) 97.5%
0.76 to 1.16
Estimation Comments [Not Specified]
14.Secondary Outcome
Title BOR as Assessed by the IRC According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
Hide Description According to the RECIST criteria, the BOR in an individual participant was the best response recorded from the start of the treatment until disease progression/recurrence (taking the smallest measurements recorded since the baseline assessment as a reference for PD). The BOR as assessed by the IRC was determined based on tumor assessments that were made up to and including 28 days after last intake of study medication in the primary study treatment phase. Responders were defined as the percentage of participants with a complete response (CR) or partial response (PR). Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time Frame From baseline until disease progression/recurrence, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included all randomized participants who provided written informed consent.
Arm/Group Title FOLFOX-4+P/XELOX+P FOLFOX-4+BV/XELOX+BV
Hide Arm/Group Description:

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+P: Participants received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 701 699
Measure Type: Number
Unit of Measure: Percentage of responders
37.5 37.5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4+P/XELOX+P, FOLFOX-4+BV/XELOX+BV
Comments Superiority of adding bevacizumab to chemotherapy was tested as follows - H0: OR(FOLFOX-4+BV/XELOX+BV)/(FOLFOX 4+P/XELOX+P) </= 1.0 versus H1: OR(FOLFOX-4+BV/XELOX+BV)/(FOLFOX-4+P/XELOX+P) > 1.0. The test used a two-sided significance level of 2.5%
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9887
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.00
Confidence Interval (2-Sided) 97.5%
0.78 to 1.28
Estimation Comments [Not Specified]
15.Secondary Outcome
Title Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
Hide Description Time to treatment failure was defined as the time from the date of randomization to the date of discontinuation of the primary study treatment phase due to adverse event/intercurrent illness, insufficient therapeutic response, death, failure to return, refusing treatment/being unwilling to cooperate, or withdrawing consent; discontinuation of the post study treatment phase due to adverse event, progressive disease, death, participant refusal/administrative reasons, or withdrawing consent; documented disease progression; or death due to any cause, whichever occurred first. The general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase.The on-treatment approach included only tumor assessments and deaths that occurred no later than 28 days after the last confirmed intake of any study medication in the primary study treatment phase only.
Time Frame From baseline until disease progression/recurrence, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The safety population included all participants who were randomized and received at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
Arm/Group Title FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV XELOX/XELOX+P/XELOX+BV
Hide Arm/Group Description:

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Folfox-4: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin (given on day 1).
  2. Folfox-4+P: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  3. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Xelox: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin (given on day 1).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).
  3. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 990 1008
Median (95% Confidence Interval)
Unit of Measure: days
General Approach
191.0
(183 to 202)
179.0
(171 to 187)
On-treatment Approach
190.0
(182 to 200)
176.0
(170 to 185)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV, XELOX/XELOX+P/XELOX+BV
Comments General approach: HRs and 97.5% confidence interval were reported for treatment arm A (XELOX/XELOX+P/XELOX+BV) versus treatment arm B (FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV)
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal statistical testing was done.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.08
Confidence Interval (2-Sided) 97.5%
0.97 to 1.20
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV, XELOX/XELOX+P/XELOX+BV
Comments On-treatment Approach: HRs and 97.5% confidence interval were reported for treatment arm A (XELOX/XELOX+P/XELOX+BV) versus treatment arm B (FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV).
Type of Statistical Test Non-Inferiority or Equivalence
Comments Fewer events were expected in analyses using the on-treatment approach than in the analyses using the general approach, thus leading to reduced power.Therefore, no formal statistical testing was performed.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.10
Confidence Interval (2-Sided) 97.5%
0.98 to 1.23
Estimation Comments [Not Specified]
16.Secondary Outcome
Title Time to Treatment Failure as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
Hide Description Time to treatment failure was defined as the time from the date of randomization to the date of discontinuation of the primary study treatment phase due to adverse event/intercurrent illness, insufficient therapeutic response, death, failure to return, refusing treatment/being unwilling to cooperate, or withdrawing consent; discontinuation of the post study treatment phase due to adverse event, progressive disease, death, participant refusal/administrative reasons, or withdrawing consent; documented disease progression; or death due to any cause, whichever occurred first. The general approach included all tumor assessments or deaths that occurred during the primary study treatment phase, the post-study treatment phase, or the follow-up phase. The on-treatment approach included only tumor assessments and deaths that occurred no later than 28 days after the last confirmed intake of any study medication in the primary study treatment phase only.
Time Frame From baseline until disease progression/recurrence, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The safety population included all participants who were randomized and received at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
Arm/Group Title FOLFOX-4+P/XELOX+P FOLFOX-4+BV/XELOX+BV
Hide Arm/Group Description:

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+P: Participants received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 675 694
Median (95% Confidence Interval)
Unit of Measure: days
General Approach
183.0
(176 to 198)
209.0
(199 to 220)
On-treatment Approach
182.0
(175 to 196)
208.0
(198 to 220)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4+P/XELOX+P, FOLFOX-4+BV/XELOX+BV
Comments General approach: Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone [HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)] was presented.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0030
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.84
Confidence Interval (2-Sided) 97.5%
0.74 to 0.96
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection FOLFOX-4+P/XELOX+P, FOLFOX-4+BV/XELOX+BV
Comments On treatment approach: Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone [HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)] was presented.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.81
Confidence Interval (2-Sided) 97.5%
0.70 to 0.92
Estimation Comments [Not Specified]
17.Secondary Outcome
Title Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
Hide Description For participants whose BOR was CR or PR, time to response was measured as the time from randomization to the first time when the measurement criteria for CR or PR (whichever status was recorded first) was met. It was based on tumor assessments made by the investigators according to the RECIST criteria. Results were reported as the number of participants achieving a response in 8 time categories from Week 1 to Week 54. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time Frame Week 1 to Week 54
Hide Outcome Measure Data
Hide Analysis Population Description
The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
Arm/Group Title FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV XELOX/XELOX+P/XELOX+BV
Hide Arm/Group Description:

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Folfox-4: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin (given on day 1).
  2. Folfox-4+P: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  3. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Xelox: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin (given on day 1).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).
  3. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 937 967
Measure Type: Number
Unit of Measure: Participants
Week 1-6 67 93
Week 7-12 190 191
Week 13-18 155 110
Week 19-24 25 38
Week 25-30 14 13
Week 31-36 7 3
Week 37-42 3 1
Week 49-54 2 0
18.Secondary Outcome
Title Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
Hide Description For participants whose BOR was CR or PR, time to response was measured as the time from randomization to the first time when the measurement criteria for CR or PR (whichever status was recorded first) was met. It was based on tumor assessments made by the investigators according to the RECIST criteria. Results were reported as the number of participants achieving a response in 8 time categories from Week 1 to Week 54. Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time Frame Week 1 to Week 54
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included all randomized participants who provided written informed consent.
Arm/Group Title FOLFOX-4+P/XELOX+P XELOX/XELOX+P/XELOX+BV
Hide Arm/Group Description:

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+P: Participants received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Xelox: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin (given on day 1).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).
  3. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 701 699
Measure Type: Number
Unit of Measure: Participants
Week 1-6 58 48
Week 7-12 146 138
Week 13-18 105 87
Week 19-24 26 29
Week 25-30 7 12
Week 31-36 2 8
Week 37-42 1 2
Week 49-54 0 1
19.Secondary Outcome
Title Duration of Overall Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
Hide Description Duration of overall response was measured from the time that measurement criteria were first met for CR or PR (whichever status was recorded first) until the first date when progressive disease or death was documented. It was based on tumor assessments made by the investigators according to the RECIST criteria. Participants who neither progressed nor died were censored at the date of the last tumor assessment. Participants undergoing surgical resection with curative intent were censored at the date of surgery. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time Frame From baseline until disease progression/recurrence, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
Arm/Group Title FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV XELOX/XELOX+P/XELOX+BV
Hide Arm/Group Description:

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Folfox-4: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin (given on day 1).
  2. Folfox-4+P: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  3. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Xelox: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin (given on day 1).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).
  3. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 937 967
Median (95% Confidence Interval)
Unit of Measure: days
239.0
(225 to 256)
226.0
(211 to 246)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV, XELOX/XELOX+P/XELOX+BV
Comments HRs and 97.5% confidence interval were reported for treatment arm A (XELOX/XELOX+P/XELOX+BV) versus treatment arm B (FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV)
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal statistical testing was performed for duration of overall response.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.02
Confidence Interval (2-Sided) 97.5%
0.86 to 1.22
Estimation Comments [Not Specified]
20.Secondary Outcome
Title Duration of Overall Response as Assessed by the Investigator According to RECIST: Superiority Analysis of Chemotherapy Plus Bevacizumab Versus Chemotherapy Alone
Hide Description Duration of overall response was measured from the time that measurement criteria were first met for CR or PR (whichever status was recorded first) until the first date when progressive disease or death was documented. It was based on tumor assessments made by the investigators according to the RECIST criteria. Participants who neither progressed nor died were censored at the date of the last tumor assessment. Participants undergoing surgical resection with curative intent were censored at the date of surgery. Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time Frame From baseline until disease progression/recurrence, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included all randomized participants who provided written informed consent.
Arm/Group Title FOLFOX-4+P/XELOX+P FOLFOX-4+BV/XELOX+BV
Hide Arm/Group Description:

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+P: Participants received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 701 699
Median (95% Confidence Interval)
Unit of Measure: days
225.0
(217 to 240)
257.0
(241 to 278)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4+P/XELOX+P, FOLFOX-4+BV/XELOX+BV
Comments Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone [HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)] was presented.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0307
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.82
Confidence Interval (2-Sided) 97.5%
0.66 to 1.01
Estimation Comments [Not Specified]
21.Secondary Outcome
Title Duration of Complete Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
Hide Description For complete responders, the duration of complete response was measured from the time measurement criteria were first met for complete response until the date that progressive disease (or death) was documented. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time Frame From baseline until disease progression/recurrence, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
Arm/Group Title FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV XELOX/XELOX+P/XELOX+BV
Hide Arm/Group Description:

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Folfox-4: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin (given on day 1).
  2. Folfox-4+P: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  3. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).

Participants from the initial 2-arm part and the 2x2 factorial part of the study including the following groups -

  1. Xelox: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin (given on day 1).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).
  3. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 937 967
Median (95% Confidence Interval)
Unit of Measure: days
347.0
(196 to 403)
589.0 [1] 
(270 to NA)
[1]
The estimate is Not Available due to insufficient follow-up time to estimate the missing parameter.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV, XELOX/XELOX+P/XELOX+BV
Comments HRs and 97.5% confidence interval were reported for treatment arm A (XELOX/XELOX+P/XELOX+BV) versus treatment arm B (FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV).
Type of Statistical Test Non-Inferiority or Equivalence
Comments No formal statistical testing was done.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.35
Confidence Interval (2-Sided) 97.5%
0.09 to 1.39
Estimation Comments [Not Specified]
22.Secondary Outcome
Title Duration of Complete Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
Hide Description For complete responders, the duration of complete response was measured from the time measurement criteria were first met for complete response until the date that progressive disease (or death) was documented. Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time Frame From baseline until disease progression/recurrence, approximately 2 years 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included all randomized participants who provided written informed consent.
Arm/Group Title FOLFOX-4+P/XELOX+P FOLFOX-4+BV/XELOX+BV
Hide Arm/Group Description:

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+P: Participants received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and placebo control for bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+P: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and placebo (P) control for bevacizumab (both given on day 1 every 3 weeks).

Participants from the 2x2 factorial part of the study including the following groups -

  1. Folfox-4+BV: Participants who received 2-week cycles of infused leucovorin, bolus injection fluorouracil and continuous infusion fluorouracil (given on days 1 and 2), combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 2 weeks).
  2. Xelox+BV: Capecitabine was administered as an oral twice-daily outpatient intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment) combined with intravenous oxaliplatin and intravenous bevacizumab (both given on day 1 every 3 weeks).
Overall Number of Participants Analyzed 701 699
Median (95% Confidence Interval)
Unit of Measure: days
403.0 [1] 
(228 to NA)
386.0
(133 to 386)
[1]
The estimate is Not Available due to insufficient follow-up time to estimate the missing parameter.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FOLFOX-4+P/XELOX+P, FOLFOX-4+BV/XELOX+BV
Comments Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone [HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)] was presented.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8207
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.20
Confidence Interval (2-Sided) 97.5%
0.20 to 7.05
Estimation Comments [Not Specified]
Time Frame Approximately 2 years 6 months
Adverse Event Reporting Description Serious adverse events (SAEs) and non-serious adverse events were reported for members of the safety population, which included all participants were randomized and received at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
 
Arm/Group Title Xelox Folfox-4 Xelox+P Folfox-4+P Xelox+BV Folfox-4+BV
Hide Arm/Group Description Participants in the 2-arm part of the study received intravenous infusion of oxaliplatin 130 mg/m^2 over 2 hours on Day 1 of every 3 weeks before the first dose of capecitabine. Capecitabine was administered orally within 30 minutes after the end of a meal (breakfast and dinner) at a dose of 1000 mg/m^2 twice-daily (equivalent to a total daily dose of 2000 mg/m^2), for the first 2 weeks of every 3-week cycle. Participants received up to 16 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2-arm part of the study received intravenous infusion of oxaliplatin 85 mg/m^2 on Day 1 of every 2-week cycle; concomitantly with leucovorin 200 mg/m^2 iv for 2 hours followed by fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2-week cycle. Participants received up to 24 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2x2 factorial part of the study received intravenous infusion of placebo control for bevacizumab (BV) [volume equivalent to 7.5 mg/kg BV] over 30 to 90 minutes followed by oxaliplatin 130 mg/m^2 over 2 hours on Day 1 of every 3 weeks in combination with capecitabine, administered orally at a dose of 1000 mg/m^2 twice-daily (equivalent to a total daily dose of 2000 mg/m^2), for the first 2 weeks of every 3-week cycle. Participants received up to 16 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2x2 factorial part of the study received intravenous infusion of placebo control for BV (volume equivalent to 5 mg/kg BV) over 30 to 90 minutes followed by oxaliplatin 85 mg/m^2 on Day 1 of every 2-week cycle; concomitantly with leucovorin 200 mg/m^2 iv for 2 hours followed by fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2-week cycle. Participants received up to 24 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2x2 factorial part of the study received intravenous infusion of bevacizumab 7.5 mg/kg over 30 to 90 minutes followed by oxaliplatin 130 mg/m^2 over 2 hours on Day 1 of every 3 weeks in combination with capecitabine, administered orally at a dose of 1000 mg/m^2 twice-daily (equivalent to a total daily dose of 2000 mg/m^2), for the first 2 weeks of every 3-week cycle. Participants received up to 16 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. Participants in the 2x2 factorial part of the study received intravenous infusion of bevacizumab 5 mg/kg over 30 to 90 minutes followed by oxaliplatin 85 mg/m^2 on Day 1 of every 2-week cycle; concomitantly with leucovorin 200 mg/m^2 iv for 2 hours followed by fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2-week cycle. Participants received up to 24 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent.
All-Cause Mortality
Xelox Folfox-4 Xelox+P Folfox-4+P Xelox+BV Folfox-4+BV
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Xelox Folfox-4 Xelox+P Folfox-4+P Xelox+BV Folfox-4+BV
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   117/316 (37.03%)   120/313 (38.34%)   121/339 (35.69%)   128/336 (38.10%)   131/353 (37.11%)   146/341 (42.82%) 
Blood and lymphatic system disorders             
Febrile neutropenia  1  3/316 (0.95%)  14/313 (4.47%)  1/339 (0.29%)  15/336 (4.46%)  2/353 (0.57%)  14/341 (4.11%) 
Neutropenia  1  2/316 (0.63%)  9/313 (2.88%)  1/339 (0.29%)  6/336 (1.79%)  0/353 (0.00%)  5/341 (1.47%) 
Thrombocytopenia  1  0/316 (0.00%)  2/313 (0.64%)  2/339 (0.59%)  1/336 (0.30%)  0/353 (0.00%)  1/341 (0.29%) 
Anaemia  1  1/316 (0.32%)  2/313 (0.64%)  1/339 (0.29%)  3/336 (0.89%)  0/353 (0.00%)  1/341 (0.29%) 
Blood disorder  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Coagulopathy  1  1/316 (0.32%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Leukopenia  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  2/341 (0.59%) 
Agranulocytosis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Haemolytic anaemia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Pancytopenia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Thrombotic thrombocytopenic purpura  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Cardiac disorders             
Atrial fibrillation  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  1/336 (0.30%)  4/353 (1.13%)  2/341 (0.59%) 
Myocardial infarction  1  0/316 (0.00%)  3/313 (0.96%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  3/341 (0.88%) 
Pericardial effusion  1  2/316 (0.63%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Cardiac arrest  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  1/336 (0.30%)  2/353 (0.57%)  0/341 (0.00%) 
Angina pectoris  1  1/316 (0.32%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Cardiomyopathy  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Myocardial ischaemia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  2/353 (0.57%)  1/341 (0.29%) 
Arrhythmia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  1/341 (0.29%) 
Acute left ventricular failure  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Acute myocardial infarction  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Atrial thrombosis  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Bradycardia  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Cardiac failure congestive  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Cardio-respiratory arrest  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Cardiogenic shock  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Cardiopulmonary failure  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Sick sinus syndrome  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Supraventricular tachycardia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Ventricular fibrillation  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Ear and labyrinth disorders             
Vertigo  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Eye disorders             
Retinal vascular thrombosis  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Amaurosis  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Gastrointestinal disorders             
Diarrhoea  1  27/316 (8.54%)  13/313 (4.15%)  25/339 (7.37%)  7/336 (2.08%)  26/353 (7.37%)  8/341 (2.35%) 
Vomiting  1  7/316 (2.22%)  7/313 (2.24%)  16/339 (4.72%)  2/336 (0.60%)  14/353 (3.97%)  7/341 (2.05%) 
Abdominal pain  1  4/316 (1.27%)  7/313 (2.24%)  7/339 (2.06%)  6/336 (1.79%)  5/353 (1.42%)  7/341 (2.05%) 
Intestinal obstruction  1  4/316 (1.27%)  6/313 (1.92%)  6/339 (1.77%)  9/336 (2.68%)  4/353 (1.13%)  6/341 (1.76%) 
Small intestinal obstruction  1  5/316 (1.58%)  3/313 (0.96%)  3/339 (0.88%)  2/336 (0.60%)  4/353 (1.13%)  7/341 (2.05%) 
Nausea  1  1/316 (0.32%)  6/313 (1.92%)  4/339 (1.18%)  0/336 (0.00%)  5/353 (1.42%)  2/341 (0.59%) 
Constipation  1  1/316 (0.32%)  5/313 (1.60%)  1/339 (0.29%)  3/336 (0.89%)  3/353 (0.85%)  0/341 (0.00%) 
Gastrointestinal haemorrhage  1  1/316 (0.32%)  2/313 (0.64%)  3/339 (0.88%)  1/336 (0.30%)  0/353 (0.00%)  3/341 (0.88%) 
Ascites  1  3/316 (0.95%)  0/313 (0.00%)  1/339 (0.29%)  1/336 (0.30%)  0/353 (0.00%)  1/341 (0.29%) 
Rectal haemorrhage  1  1/316 (0.32%)  2/313 (0.64%)  2/339 (0.59%)  0/336 (0.00%)  4/353 (1.13%)  1/341 (0.29%) 
Stomatitis all  1  2/316 (0.63%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  1/353 (0.28%)  2/341 (0.59%) 
Enteritis  1  3/316 (0.95%)  0/313 (0.00%)  1/339 (0.29%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Intestinal perforation  1  1/316 (0.32%)  1/313 (0.32%)  1/339 (0.29%)  0/336 (0.00%)  2/353 (0.57%)  1/341 (0.29%) 
Abdominal pain upper  1  1/316 (0.32%)  1/313 (0.32%)  1/339 (0.29%)  1/336 (0.30%)  0/353 (0.00%)  1/341 (0.29%) 
Ileus  1  0/316 (0.00%)  1/313 (0.32%)  2/339 (0.59%)  0/336 (0.00%)  2/353 (0.57%)  0/341 (0.00%) 
Colitis  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  2/336 (0.60%)  1/353 (0.28%)  0/341 (0.00%) 
Haematemesis  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  2/336 (0.60%)  0/353 (0.00%)  0/341 (0.00%) 
Large intestinal obstruction  1  1/316 (0.32%)  1/313 (0.32%)  1/339 (0.29%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Mechanical ileus  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Pancreatitis  1  1/316 (0.32%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Gastrointestinal toxicity  1  0/316 (0.00%)  0/313 (0.00%)  2/339 (0.59%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Intestinal functional disorder  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Melaena  1  0/316 (0.00%)  1/313 (0.32%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Abdominal adhesions  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Abdominal distension  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Caecitis  1  0/316 (0.00%)  2/313 (0.64%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Enterocolitis  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Enterovesical fistula  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Gastritis  1  1/316 (0.32%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Gastrointestinal disorder  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  2/353 (0.57%)  0/341 (0.00%) 
Gastrointestinal hypomotility  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Gastrointestinal obstruction  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Gastrooesophageal reflux disease  1  1/316 (0.32%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Ileus paralytic  1  1/316 (0.32%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Intestinal haemorrhage  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Pericoronitis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Peritonitis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  1/341 (0.29%) 
Abdominal pain lower  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Anal fissure  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Anal stenosis  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Colonic obstruction  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Crohn's disease  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Duodenal ulcer  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Dyspepsia  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Enterocolonic fistula  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Faecaloma  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Gastrointestinal necrosis  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Gastrointestinal perforation  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Haematochezia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Inguinal hernia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Intestinal ischemia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Lower gastrointestinal haemorrhage  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Oesophagitis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Proctalgia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Rectal perforation  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Subileus  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Toxic dilatation of intestine  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Upper gastrointestinal haemorrhage  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
General disorders             
Pyrexia  1  16/316 (5.06%)  16/313 (5.11%)  6/339 (1.77%)  16/336 (4.76%)  7/353 (1.98%)  15/341 (4.40%) 
Asthenia  1  1/316 (0.32%)  1/313 (0.32%)  2/339 (0.59%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Chest pain  1  2/316 (0.63%)  1/313 (0.32%)  1/339 (0.29%)  0/336 (0.00%)  1/353 (0.28%)  2/341 (0.59%) 
Catheter related complication  1  1/316 (0.32%)  2/313 (0.64%)  1/339 (0.29%)  2/336 (0.60%)  0/353 (0.00%)  2/341 (0.59%) 
Fatigue  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  1/341 (0.29%) 
General physical health deterioration  1  2/316 (0.63%)  0/313 (0.00%)  1/339 (0.29%)  1/336 (0.30%)  1/353 (0.28%)  1/341 (0.29%) 
Oedema peripheral  1  0/316 (0.00%)  2/313 (0.64%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Multi-organ failure  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  2/353 (0.57%)  2/341 (0.59%) 
Performance status decreased  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Extravasation  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  1/341 (0.29%) 
Non-cardiac chest pain  1  1/316 (0.32%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Pain  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Infusion related reaction  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  1/341 (0.29%) 
Sudden death  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  2/353 (0.57%)  0/341 (0.00%) 
Wound necrosis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Chills  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Impaired healing  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Oedema  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Hepatobiliary disorders             
Hepatic failure  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  1/353 (0.28%)  0/341 (0.00%) 
Bile duct obstruction  1  1/316 (0.32%)  1/313 (0.32%)  0/339 (0.00%)  2/336 (0.60%)  0/353 (0.00%)  0/341 (0.00%) 
Hyperbilirubinaemia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Portal vein thrombosis  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  1/353 (0.28%)  1/341 (0.29%) 
Cholangitis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Cholecystitis  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Hepatic function abnormal  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Hepatitis  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Hepatitis Cholestatic  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Immune system disorders             
Hypersensitivity  1  0/316 (0.00%)  0/313 (0.00%)  2/339 (0.59%)  2/336 (0.60%)  2/353 (0.57%)  2/341 (0.59%) 
Drug hypersensitivity  1  0/316 (0.00%)  0/313 (0.00%)  2/339 (0.59%)  3/336 (0.89%)  0/353 (0.00%)  0/341 (0.00%) 
Anaphylactic reaction  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Anaphylactic shock  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Infections and infestations             
Central line infection  1  1/316 (0.32%)  4/313 (1.28%)  1/339 (0.29%)  9/336 (2.68%)  0/353 (0.00%)  4/341 (1.17%) 
Pneumonia  1  2/316 (0.63%)  5/313 (1.60%)  4/339 (1.18%)  3/336 (0.89%)  4/353 (1.13%)  3/341 (0.88%) 
Infection  1  0/316 (0.00%)  1/313 (0.32%)  1/339 (0.29%)  4/336 (1.19%)  0/353 (0.00%)  5/341 (1.47%) 
Sepsis  1  4/316 (1.27%)  4/313 (1.28%)  1/339 (0.29%)  2/336 (0.60%)  4/353 (1.13%)  4/341 (1.17%) 
Urinary tract infection  1  1/316 (0.32%)  1/313 (0.32%)  3/339 (0.88%)  5/336 (1.49%)  1/353 (0.28%)  1/341 (0.29%) 
Septic shock  1  1/316 (0.32%)  2/313 (0.64%)  1/339 (0.29%)  1/336 (0.30%)  2/353 (0.57%)  2/341 (0.59%) 
Cellulitis  1  2/316 (0.63%)  1/313 (0.32%)  2/339 (0.59%)  0/336 (0.00%)  0/353 (0.00%)  2/341 (0.59%) 
Catheter site infection  1  0/316 (0.00%)  2/313 (0.64%)  0/339 (0.00%)  2/336 (0.60%)  0/353 (0.00%)  0/341 (0.00%) 
Lower respiratory tract infection  1  1/316 (0.32%)  1/313 (0.32%)  1/339 (0.29%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Neutropenic sepsis  1  0/316 (0.00%)  2/313 (0.64%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  2/341 (0.59%) 
Diverticulitis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Abdominal abscess  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  2/341 (0.59%) 
Bacteraemia  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  2/353 (0.57%)  0/341 (0.00%) 
Respiratory tract infection  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  2/341 (0.59%) 
Bacterial sepsis  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Clostridium difficile colitis  1  1/316 (0.32%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Postoperative wound infection  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Abdominal infection  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Abdominal wall infection  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Abscess  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  2/341 (0.59%) 
Diarrhoea infectious  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Gastroenteritis  1  1/316 (0.32%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Gastrointestinal infection  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Hepatitis B  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Pneumonia pneumococcal  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Pyelonephritis  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Urosepsis  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Viral pharyngitis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Abdominal wall abscess  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Acinetobacter bacteraemia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Anal fistula infection  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Bacterial infection  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Bronchitis  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Bronchopneumonia  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Catheter related infection  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Catheter sepsis  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Fungaemia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Neutropenic infection  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Peritoneal infection  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Pseudomonas infection  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Pyonephrosis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Rectal abscess  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Staphylococcal infection  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Staphylococcal sepsis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Upper respiratory tract infection  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Injury, poisoning and procedural complications             
Post procedural haemorrhage  1  1/316 (0.32%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Gastrointestinal stoma complication  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  2/336 (0.60%)  0/353 (0.00%)  0/341 (0.00%) 
Lumbar vertebral fracture  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Stent occlussion  1  1/316 (0.32%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Fall  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Femur fracture  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  1/341 (0.29%) 
Head injury  1  1/316 (0.32%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Radius fracture  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Device migration  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Failure to anastomose  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Femoral neck fracture  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Hip fracture  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Overdose  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Skull fracture  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Tendon rupture  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Thoracic vertebral fracture  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Ulna fracture  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Vascular graft occlussion  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Investigations             
Blood creatinine increased  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Transaminases increased  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
International normalized ratio increased  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  1/353 (0.28%)  0/341 (0.00%) 
Blood bilirubin abnormal  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Endoscopic retrograde cholangiopancreatography  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Metabolism and nutrition disorders             
Dehydration  1  4/316 (1.27%)  9/313 (2.88%)  10/339 (2.95%)  2/336 (0.60%)  10/353 (2.83%)  4/341 (1.17%) 
Hypokalaemia`  1  2/316 (0.63%)  0/313 (0.00%)  1/339 (0.29%)  1/336 (0.30%)  2/353 (0.57%)  0/341 (0.00%) 
Hyperglycaemia  1  1/316 (0.32%)  0/313 (0.00%)  2/339 (0.59%)  0/336 (0.00%)  2/353 (0.57%)  1/341 (0.29%) 
Anorexia  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Hypernatraemia  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Hyponatraemia  1  1/316 (0.32%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Hypocalcaemia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Hypoalbuminaemia  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Hypomagnesaemia  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Malnutrition  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Cachexia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Diabetic ketoacidosis  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Hypercalcaemia  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Hypovolaemia  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Musculoskeletal and connective tissue disorders             
Pain in extremity  1  2/316 (0.63%)  2/313 (0.64%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Musculoskeletal chest pain  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  1/341 (0.29%) 
Muscular weakness  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Muscle contracture  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Myalgia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Neck pain  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  1/341 (0.29%) 
Shoulder pain  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Arthralgia  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Flank pain  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Cancer pain  1  0/316 (0.00%)  0/313 (0.00%)  2/339 (0.59%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Tumor haemorrhage  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  1/341 (0.29%) 
Colon neoplasm  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Breast cancer  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Gastric neoplasm  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Malignant pleural effusion  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Metastases to ovary  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Neoplasm  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Tumour associated fever  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Nervous system disorders             
Dizziness  1  2/316 (0.63%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Neuropathy peripheral  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Convulsion  1  1/316 (0.32%)  1/313 (0.32%)  0/339 (0.00%)  1/336 (0.30%)  1/353 (0.28%)  0/341 (0.00%) 
Syncope  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  1/353 (0.28%)  1/341 (0.29%) 
Cerebrovascular accident  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  1/353 (0.28%)  1/341 (0.29%) 
Headache  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Transient ischaemic attack  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  1/336 (0.30%)  1/353 (0.28%)  0/341 (0.00%) 
Cerebral infarction  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Coordination abnormal  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Dementia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Loss of consciousness  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Neuralgia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Spinal cord compression  1  1/316 (0.32%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Cerebral haemorrhage  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Cerebral ischaemia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Depressed level of consciousness  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Encephalophathy  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Hepatic encephalopathy  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Hypoaesthesia  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Paraesthesia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Psychiatric disorders             
Confusional state  1  1/316 (0.32%)  1/313 (0.32%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Anxiety  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Depression  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Renal and urinary disorders             
Renal failure acute  1  1/316 (0.32%)  0/313 (0.00%)  3/339 (0.88%)  0/336 (0.00%)  3/353 (0.85%)  2/341 (0.59%) 
Renal failure  1  1/316 (0.32%)  0/313 (0.00%)  1/339 (0.29%)  1/336 (0.30%)  2/353 (0.57%)  0/341 (0.00%) 
Haematuria  1  3/316 (0.95%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Hydronephrosis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Renal colic  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Urinary bladder haemmorhage  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Urinary retention  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  1/353 (0.28%)  0/341 (0.00%) 
Obstructive uropathy  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Renal impairment  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Renal tubular disorder  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Renal tubular necrosis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Ureteric obstruction  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Reproductive system and breast disorders             
Vaginal fistula  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Vaginal haemorrhage  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Pulmonary embolism  1  9/316 (2.85%)  3/313 (0.96%)  3/339 (0.88%)  5/336 (1.49%)  9/353 (2.55%)  8/341 (2.35%) 
Dyspnoea  1  1/316 (0.32%)  1/313 (0.32%)  2/339 (0.59%)  3/336 (0.89%)  4/353 (1.13%)  3/341 (0.88%) 
Pneumothorax  1  0/316 (0.00%)  2/313 (0.64%)  0/339 (0.00%)  1/336 (0.30%)  3/353 (0.85%)  2/341 (0.59%) 
Dysaesthesia pharynx  1  0/316 (0.00%)  0/313 (0.00%)  4/339 (1.18%)  0/336 (0.00%)  2/353 (0.57%)  0/341 (0.00%) 
Respiratory failure  1  1/316 (0.32%)  1/313 (0.32%)  0/339 (0.00%)  1/336 (0.30%)  1/353 (0.28%)  3/341 (0.88%) 
Acute respiratory distress syndrome  1  0/316 (0.00%)  1/313 (0.32%)  1/339 (0.29%)  0/336 (0.00%)  1/353 (0.28%)  1/341 (0.29%) 
Alveolitis fibrosing  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Bronchospasm  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  1/341 (0.29%) 
Pneumonia aspiration  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Atelectasis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Chronic obstructive pulmonary disease  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Dyspnoea exertional  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Epistaxis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  1/353 (0.28%)  0/341 (0.00%) 
Lung disorder  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Pleural effusion  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Acute respiratory failure  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Haemoptysis  1  0/316 (0.00%)  1/313 (0.32%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Hypoxia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Interstitial lung disease  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Laryngospasm  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Pulmonary fibrosis  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Skin and subcutaneous tissue disorders             
Palmar-plantar erythrodysaesthesia syndrome  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Rash maculo-papular  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Angioneurotic oedema  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Skin toxicity  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Skin ulcer  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Urticaria  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Vascular purpura  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Surgical and medical procedures             
Catheter placement  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Colostomy closure  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Ileostomy closure  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Vascular disorders             
Deep vein thrombosis  1  6/316 (1.90%)  6/313 (1.92%)  1/339 (0.29%)  7/336 (2.08%)  7/353 (1.98%)  6/341 (1.76%) 
Thrombosis  1  2/316 (0.63%)  0/313 (0.00%)  1/339 (0.29%)  2/336 (0.60%)  2/353 (0.57%)  1/341 (0.29%) 
Hypertension  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  2/353 (0.57%)  1/341 (0.29%) 
Jugular vein thrombosis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  2/336 (0.60%)  0/353 (0.00%)  0/341 (0.00%) 
Hypotension  1  0/316 (0.00%)  0/313 (0.00%)  1/339 (0.29%)  1/336 (0.30%)  0/353 (0.00%)  1/341 (0.29%) 
Thrombophlebitis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  1/353 (0.28%)  1/341 (0.29%) 
Embolism  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  2/341 (0.59%) 
Peripheral ischaemia  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  1/341 (0.29%) 
Hypertensive crisis  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  2/353 (0.57%)  0/341 (0.00%) 
Pelvic venous thrombosis  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Venous thrombosis limb  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Circulatory collapse  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Embolism venous  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Haematoma  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Haemorrhage  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  1/353 (0.28%)  0/341 (0.00%) 
Hypovolaemic shock  1  1/316 (0.32%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  0/341 (0.00%) 
Poor venous access  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  1/336 (0.30%)  0/353 (0.00%)  0/341 (0.00%) 
Shock  1  0/316 (0.00%)  0/313 (0.00%)  0/339 (0.00%)  0/336 (0.00%)  0/353 (0.00%)  1/341 (0.29%) 
Shock haemorrhagic  1  0/316 (0.00%)  0/313 (0.00%)