Combination Chemotherapy With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for High Risk Stage II or Stage III Colon Cancer

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00112918
First received: June 2, 2005
Last updated: June 19, 2013
Last verified: June 2013
Results First Received: June 1, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Colorectal Cancer
Interventions: Biological: Bevacizumab
Drug: Capecitabine
Drug: 5-Fluorouracil (5-FU)
Drug: Leucovorin calcium
Drug: Oxaliplatin

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Randomization was stratified according to geographic region and disease stage (high-risk stage II or stage III N1 or stage III N2). The primary analysis population consisted of patients with Stage III disease.

Reporting Groups
  Description
FOLFOX4

Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-fluorouracil (5-FU), given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).

Weeks 25-48: Observation only.

FOLFOX4 + Bv

Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).

Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

XELOX+Bv

Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks).

Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).


Participant Flow:   Overall Study
    FOLFOX4     FOLFOX4 + Bv     XELOX+Bv  
STARTED     1151     1155     1145  
Received Treatment     1126     1145 [1]   1135  
Stage III Disease Population     955     960     952  
COMPLETED     854 [2]   810 [2]   846 [2]
NOT COMPLETED     297     345     299  
[1] Includes two patients from FOLFOX4 who received Bv and were assigned to FOLFOX4+Bv safety analysis
[2] Represents patients alive in follow-up at the time of final data cut-off (30 June 2012)



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Baseline Measures are based on the Intent-to-Treat - Stage III Disease Patient Population.

Reporting Groups
  Description
FOLFOX4

Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-fluorouracil (5-FU), given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).

Weeks 25-48: Observation only.

FOLFOX4 + Bv

Weeks 1–24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 – 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).

Weeks 25–48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

XELOX+Bv

Weeks 1–24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 – 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks).

Weeks 25–48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

Total Total of all reporting groups

Baseline Measures
    FOLFOX4     FOLFOX4 + Bv     XELOX+Bv     Total  
Number of Participants  
[units: participants]
  955     960     952     2867  
Age, Customized  
[units: participants]
       
<40     77     74     68     219  
40-65     603     625     588     1816  
>=65     275     261     296     832  
Gender  
[units: participants]
       
Female     425     473     432     1330  
Male     530     487     520     1537  
Race/Ethnicity, Customized  
[units: participants]
       
American Indian or Alaska Native     1     1     0     2  
Asian     139     115     123     377  
Black or African American     6     13     14     33  
White     791     813     795     2399  
Other     18     18     20     56  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Disease-free Survival in Stage III Cancer Patients - Time to Event   [ Time Frame: From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized). ]

2.  Primary:   Disease-free Survival in Stage III Cancer Patients - Number of Events   [ Time Frame: From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized). ]

3.  Secondary:   Overall Survival in Stage III Cancer Patients - Time to Event   [ Time Frame: From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized). ]

4.  Secondary:   Overall Survival in Stage III Cancer Patients - Number of Events   [ Time Frame: From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized). ]

5.  Secondary:   Overall Survival in Stage III Cancer Patients - Time to Event: Final Analysis   [ Time Frame: From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized). ]

6.  Secondary:   Overall Survival in Stage III Cancer Patients - Number of Events: Final Analysis   [ Time Frame: From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized). ]


  Serious Adverse Events
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Time Frame All adverse events occurring between the date of first drug intake and 28 days after last drug intake, regardless of which treatment group the patient was randomized to.
Additional Description No text entered.

Reporting Groups
  Description
FOLFOX4

Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with Leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).

Weeks 25-48: Observation only.

FOLFOX4 + Bv

Weeks 1–24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 – 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).

Weeks 25–48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

XELOX+Bv

Weeks 1–24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 – 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks).

Weeks 25–48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).


Serious Adverse Events
    FOLFOX4     FOLFOX4 + Bv     XELOX+Bv  
Total, serious adverse events        
# participants affected / at risk     226/1126 (20.07%)     297/1145 (25.94%)     284/1135 (25.02%)  
Blood and lymphatic system disorders        
Neutropenia † 1      
# participants affected / at risk     18/1126 (1.60%)     18/1145 (1.57%)     0/1135 (0.00%)  
Febrile neutropenia † 1      
# participants affected / at risk     14/1126 (1.24%)     9/1145 (0.79%)     2/1135 (0.18%)  
Anaemia † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Idiopathic thrombocytopenia purpura † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Leukopenia † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Thrombocytopenia † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Cardiac disorders        
Myocardial infarction † 1      
# participants affected / at risk     1/1126 (0.09%)     5/1145 (0.44%)     1/1135 (0.09%)  
Angina pectoris † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     4/1135 (0.35%)  
Coronary artery disease † 1      
# participants affected / at risk     1/1126 (0.09%)     2/1145 (0.17%)     1/1135 (0.09%)  
Myocardial ischaemia † 1      
# participants affected / at risk     2/1126 (0.18%)     1/1145 (0.09%)     1/1135 (0.09%)  
Acute myocardial infarction † 1      
# participants affected / at risk     1/1126 (0.09%)     2/1145 (0.17%)     0/1135 (0.00%)  
Cardiac arrest † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     2/1135 (0.18%)  
Angina unstable † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     1/1135 (0.09%)  
Arteriospasm coronary † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     1/1135 (0.09%)  
Atrial fibrillation † 1      
# participants affected / at risk     2/1126 (0.18%)     0/1145 (0.00%)     0/1135 (0.00%)  
Acute coronary syndrome † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Cardiac asthma † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Cardiac failure † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Cardiac failure congestive † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Left ventricular dysfunction † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Mitral valve incompetence † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Palpitations † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Paroxysmal arrhythmia † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Pericardial haemorrhage † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Sinus arrest † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Ear and labyrinth disorders        
Vertigo † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     0/1135 (0.00%)  
Endocrine disorders        
Hypothyroidism † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     0/1135 (0.00%)  
Eye disorders        
Retinal detachment † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Retinal vein thrombosis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Uveitis † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Gastrointestinal disorders        
Diarrhoea † 1      
# participants affected / at risk     28/1126 (2.49%)     28/1145 (2.45%)     62/1135 (5.46%)  
Abdominal pain † 1      
# participants affected / at risk     11/1126 (0.98%)     14/1145 (1.22%)     18/1135 (1.59%)  
Vomiting † 1      
# participants affected / at risk     7/1126 (0.62%)     11/1145 (0.96%)     16/1135 (1.41%)  
Intestinal obstruction † 1      
# participants affected / at risk     6/1126 (0.53%)     9/1145 (0.79%)     7/1135 (0.62%)  
Nausea † 1      
# participants affected / at risk     0/1126 (0.00%)     4/1145 (0.35%)     7/1135 (0.62%)  
Rectal haemorrhage † 1      
# participants affected / at risk     1/1126 (0.09%)     7/1145 (0.61%)     3/1135 (0.26%)  
Enteritis † 1      
# participants affected / at risk     3/1126 (0.27%)     0/1145 (0.00%)     5/1135 (0.44%)  
Small intestinal obstruction † 1      
# participants affected / at risk     2/1126 (0.18%)     2/1145 (0.17%)     4/1135 (0.35%)  
Constipation † 1      
# participants affected / at risk     1/1126 (0.09%)     4/1145 (0.35%)     2/1135 (0.18%)  
Subileus † 1      
# participants affected / at risk     1/1126 (0.09%)     4/1145 (0.35%)     2/1135 (0.18%)  
Colitis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     5/1135 (0.44%)  
Abdominal adhesions † 1      
# participants affected / at risk     2/1126 (0.18%)     0/1145 (0.00%)     2/1135 (0.18%)  
Gastritis † 1      
# participants affected / at risk     3/1126 (0.27%)     1/1145 (0.09%)     0/1135 (0.00%)  
Gastrointestinal haemorrhage † 1      
# participants affected / at risk     0/1126 (0.00%)     2/1145 (0.17%)     2/1135 (0.18%)  
Gastrointestinal obstruction † 1      
# participants affected / at risk     0/1126 (0.00%)     3/1145 (0.26%)     1/1135 (0.09%)  
Haemorrhoids † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     2/1135 (0.18%)  
Oesophagitis † 1      
# participants affected / at risk     0/1126 (0.00%)     2/1145 (0.17%)     2/1135 (0.18%)  
Small intestinal perforation † 1      
# participants affected / at risk     0/1126 (0.00%)     4/1145 (0.35%)     0/1135 (0.00%)  
Enterocolitis † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     1/1135 (0.09%)  
Ileus paralytic † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     2/1135 (0.18%)  
Intestinal perforation † 1      
# participants affected / at risk     1/1126 (0.09%)     2/1145 (0.17%)     0/1135 (0.00%)  
Pancreatitis † 1      
# participants affected / at risk     2/1126 (0.18%)     1/1145 (0.09%)     0/1135 (0.00%)  
Pancreatitis acute † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     1/1135 (0.09%)  
Peritonitis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     2/1135 (0.18%)  
Stomatitis † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     2/1135 (0.18%)  
Abdominal distension † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     1/1135 (0.09%)  
Abdominal hernia † 1      
# participants affected / at risk     2/1126 (0.18%)     0/1145 (0.00%)     0/1135 (0.00%)  
Anal fissure † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     0/1135 (0.00%)  
Anal fistula † 1      
# participants affected / at risk     0/1126 (0.00%)     2/1145 (0.17%)     0/1135 (0.00%)  
Gastrointestinal necrosis † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     0/1135 (0.00%)  
Haematemesis † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     0/1135 (0.00%)  
Haematochezia † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     2/1135 (0.18%)  
Ileus † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     0/1135 (0.00%)  
Mechanical ileus † 1      
# participants affected / at risk     2/1126 (0.18%)     0/1145 (0.00%)     0/1135 (0.00%)  
Abdominal discomfort † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Abdominal pain lower † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Abdominal pain upper † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Abdominal rigidity † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Acute abdomen † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Caecitis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Colitis ulcerative † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Crohn's disease † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Duodenitis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Dyspepsia † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Enterocolitis haemorrhagic † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Erosive oesophagitis † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Faecaloma † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Food poisoning † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Gastric ulcer † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Gastric volvulus † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Gastrointestinal perforation † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Gastrooesophageal reflux disease † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Hiatus hernia, obstructive † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Ileal perforation † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Intestinal angina † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Intestinal dilatation † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Intestinal fistula † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Intestinal ischaemia † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Intestinal prolapse † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Intestinal strangulation † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Large intestine perforation † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Lower gastrointestinal haemorrhage † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Mallory-Weiss syndrome † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Melaena † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Mesenteric vein thrombosis † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Neutropenic colitis † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Rectal perforation † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Umbilical hernia † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Upper gastrointestinal haemorrhage † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Volvulus of small bowel † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
General disorders        
Pyrexia † 1      
# participants affected / at risk     20/1126 (1.78%)     10/1145 (0.87%)     16/1135 (1.41%)  
Non-cardiac chest pain † 1      
# participants affected / at risk     1/1126 (0.09%)     2/1145 (0.17%)     5/1135 (0.44%)  
Sudden death † 1      
# participants affected / at risk     0/1126 (0.00%)     2/1145 (0.17%)     3/1135 (0.26%)  
Asthenia † 1      
# participants affected / at risk     0/1126 (0.00%)     3/1145 (0.26%)     1/1135 (0.09%)  
Chest pain † 1      
# participants affected / at risk     1/1126 (0.09%)     2/1145 (0.17%)     1/1135 (0.09%)  
Extravasation † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     2/1135 (0.18%)  
Medical device complication † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     0/1135 (0.00%)  
Multi-organ failure † 1      
# participants affected / at risk     2/1126 (0.18%)     0/1145 (0.00%)     0/1135 (0.00%)  
Thrombosis in device † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     1/1135 (0.09%)  
Adhesion † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Catheter site pain † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Chills † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Device leakage † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Device malfunction † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
General physical health deterioration † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Hernia obstructive † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Hyperpyrexia † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Infusion site thrombosis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Malaise † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Pain † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Performance status decreased † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Sudden cardiac death † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Visceral pain † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Hepatobiliary disorders        
Cholecystitis † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     2/1135 (0.18%)  
Portal vein thrombosis † 1      
# participants affected / at risk     1/1126 (0.09%)     2/1145 (0.17%)     1/1135 (0.09%)  
Cholangitis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Cholecystitis acute † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Cholelithiasis † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Cytolytic hepatitis † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Hepatic function abnormal † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Hepatitis toxic † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Hepatotoxicity † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Hyperbilirubinaemia † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Immune system disorders        
Drug hypersensitivity † 1      
# participants affected / at risk     5/1126 (0.44%)     3/1145 (0.26%)     1/1135 (0.09%)  
Hypersensitivity † 1      
# participants affected / at risk     3/1126 (0.27%)     1/1145 (0.09%)     1/1135 (0.09%)  
Anaphylactic reaction † 1      
# participants affected / at risk     0/1126 (0.00%)     3/1145 (0.26%)     0/1135 (0.00%)  
Anaphylactic shock † 1      
# participants affected / at risk     2/1126 (0.18%)     0/1145 (0.00%)     1/1135 (0.09%)  
Anaphylactiod reaction † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Infections and infestations        
Device related infection † 1      
# participants affected / at risk     8/1126 (0.71%)     12/1145 (1.05%)     4/1135 (0.35%)  
Pneumonia † 1      
# participants affected / at risk     3/1126 (0.27%)     4/1145 (0.35%)     5/1135 (0.44%)  
Urinary tract infection † 1      
# participants affected / at risk     2/1126 (0.18%)     5/1145 (0.44%)     4/1135 (0.35%)  
Sepsis † 1      
# participants affected / at risk     4/1126 (0.36%)     3/1145 (0.26%)     3/1135 (0.26%)  
Gastroenteritis † 1      
# participants affected / at risk     1/1126 (0.09%)     5/1145 (0.44%)     3/1135 (0.26%)  
Infection † 1      
# participants affected / at risk     5/1126 (0.44%)     3/1145 (0.26%)     1/1135 (0.09%)  
Abdominal abscess † 1      
# participants affected / at risk     2/1126 (0.18%)     4/1145 (0.35%)     2/1135 (0.18%)  
Catheter site infection † 1      
# participants affected / at risk     4/1126 (0.36%)     4/1145 (0.35%)     0/1135 (0.00%)  
Neutropenic sepsis † 1      
# participants affected / at risk     4/1126 (0.36%)     1/1145 (0.09%)     1/1135 (0.09%)  
Lower respiratory tract infection † 1      
# participants affected / at risk     3/1126 (0.27%)     2/1145 (0.17%)     0/1135 (0.00%)  
Anal abscess † 1      
# participants affected / at risk     0/1126 (0.00%)     3/1145 (0.26%)     1/1135 (0.09%)  
Cellulitis † 1      
# participants affected / at risk     3/1126 (0.27%)     0/1145 (0.00%)     1/1135 (0.09%)  
Abdominal wall abscess † 1      
# participants affected / at risk     0/1126 (0.00%)     2/1145 (0.17%)     1/1135 (0.09%)  
Device related sepsis † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     1/1135 (0.09%)  
Staphylococcal sepsis † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     2/1135 (0.18%)  
Abscess † 1      
# participants affected / at risk     0/1126 (0.00%)     2/1145 (0.17%)     0/1135 (0.00%)  
Erysipelas † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     1/1135 (0.09%)  
Herpes zoster † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     1/1135 (0.09%)  
Neutropenic infection † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     0/1135 (0.00%)  
Pelvic abscess † 1      
# participants affected / at risk     0/1126 (0.00%)     2/1145 (0.17%)     0/1135 (0.00%)  
Septic shock † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     1/1135 (0.09%)  
Upper respiratory tract infection † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     1/1135 (0.09%)  
Viral infection † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     1/1135 (0.09%)  
Abdominal infection † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Appendicitis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Appendicitis perforated † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Aspergillosis † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Bacteraemia † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Bronchopneumonia † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Bronchopulmonary aspergillosis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Campylobacter infection † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Candida sepsis † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Catheter site cellulitis † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Cholecystitis infective † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Clostridial infection † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Clostridium difficile colitis † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Diverticulitis † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Enteritis infection † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Gastroenteritis norovirus † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Gastroenteritis viral † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Hepatitis viral † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Herpes zoster ophthalmic † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Incision site cellulitis † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Intervertebral discitis † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Intestinal fistual infection † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Klebsiella bacteraemia † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Klebsiella infection † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Lower respiratory tract infection viral † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Oral candidiasis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Orchitis † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Overgrowth bacterial † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Perineal abscess † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Pharyngitis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Post procedural infection † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Postoperative abscess † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Psoas abscess † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Puncture site infection † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Respiratory tract infection † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Skin infection † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Staphylococcal bacteraemia † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Subcutaneous abscess † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Tooth abscess † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Tuberculosis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Wound abscess † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Wound infection † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Injury, poisoning and procedural complications        
Incisional hernia † 1      
# participants affected / at risk     1/1126 (0.09%)     2/1145 (0.17%)     2/1135 (0.18%)  
Procedural site reaction † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     2/1135 (0.18%)  
Accident at work † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Anastomotic stenosis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Brachial plexus injury † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Cervical vertebral fracture † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Drug toxicity † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Fall † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Foot fracture † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Femur fracture † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Head injury † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Joint dislocation † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Multiple fractures † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Post procedural fistula † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Post procedural haemorrhage † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Road traffic accident † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Subdural haematoma † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Thoracic vertebral fracture † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Tibia fracture † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Investigations        
Blood lactate dehydrogenase increased † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     1/1135 (0.09%)  
Blood creatinine increased † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Blood glucose fluctuation † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Weight increased † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Metabolism and nutrition disorders        
Dehydration † 1      
# participants affected / at risk     7/1126 (0.62%)     10/1145 (0.87%)     17/1135 (1.50%)  
Hyperglycaemia † 1      
# participants affected / at risk     3/1126 (0.27%)     4/1145 (0.35%)     2/1135 (0.18%)  
Hypokalaemia † 1      
# participants affected / at risk     2/1126 (0.18%)     3/1145 (0.26%)     2/1135 (0.18%)  
Decreased appetite † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     2/1135 (0.18%)  
Hypertriglyceridaemia † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     1/1135 (0.09%)  
Hypocalcaemia † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     1/1135 (0.09%)  
Hyponatraemia † 1      
# participants affected / at risk     0/1126 (0.00%)     2/1145 (0.17%)     0/1135 (0.00%)  
Diabetes mellitus † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Diabetic ketoacidosis † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Gout † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Hypercholesterolaemia † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Hypomagnesaemia † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Musculoskeletal and connective tissue disorders        
Musculoskeletal pain † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     1/1135 (0.09%)  
Intervertebral disc protusion † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Muscle spasms † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Muscular weakness † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Musculoskeletal chest pain † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Musculoskeletal disorder † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Myalgia † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Pain in extremity † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)        
Breast cancer † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     1/1135 (0.09%)  
Benign lung neoplasm † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Nervous system disorders        
Syncope † 1      
# participants affected / at risk     2/1126 (0.18%)     5/1145 (0.44%)     1/1135 (0.09%)  
Transient ischaemic attack † 1      
# participants affected / at risk     1/1126 (0.09%)     3/1145 (0.26%)     2/1135 (0.18%)  
Cerebrovascular accident † 1      
# participants affected / at risk     0/1126 (0.00%)     2/1145 (0.17%)     1/1135 (0.09%)  
Neuropathy peripheral † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     1/1135 (0.09%)  
Convulsion † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     0/1135 (0.00%)  
Dizziness † 1      
# participants affected / at risk     2/1126 (0.18%)     0/1145 (0.00%)     0/1135 (0.00%)  
Epilepsy † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     2/1135 (0.18%)  
Headache † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     1/1135 (0.09%)  
Ischaemic stroke † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     2/1135 (0.18%)  
Peripheral sensory neuropathy † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     1/1135 (0.09%)  
Cerebral ischaemia † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Dysaesthesia † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Encephalopathy † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Leukoaraiosis † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Loss of consciousness † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Migraine † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Monoparesis † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Neurotoxicity † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Orthostatic intolerance † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Paraesthesia † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Post herpetic neuralgia † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Reversible ischaemic neurological deficit † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Reversible posterior leukoencephalopathy syndrome † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Sensory disturbance † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Somnolence † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Speech disorder † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Psychiatric disorders        
Depression † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     1/1135 (0.09%)  
Alcoholism † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Anxiety † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Renal and urinary disorders        
Hydronephrosis † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     1/1135 (0.09%)  
Renal failure acute † 1      
# participants affected / at risk     2/1126 (0.18%)     1/1145 (0.09%)     0/1135 (0.00%)  
Renal failure † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     1/1135 (0.09%)  
Renal impairment † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     1/1135 (0.09%)  
Ureteric stenosis † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     0/1135 (0.00%)  
Acute prerenal failure † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Calculus ureteric † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Calculus urinary † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Nephrogenic diabetes insipidus † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Nephrotic syndrome † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Reproductive system and breast disorders        
Female genital tract fistula † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Prostatitis † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Vaginal haemorrhage † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Respiratory, thoracic and mediastinal disorders        
Pulmonary embolism † 1      
# participants affected / at risk     11/1126 (0.98%)     15/1145 (1.31%)     10/1135 (0.88%)  
Dyspnoea † 1      
# participants affected / at risk     2/1126 (0.18%)     3/1145 (0.26%)     2/1135 (0.18%)  
Epistaxis † 1      
# participants affected / at risk     0/1126 (0.00%)     3/1145 (0.26%)     1/1135 (0.09%)  
Bronchospasm † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     2/1135 (0.18%)  
Dysaesthesia pharynx † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     3/1135 (0.26%)  
Laryngospasm † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     3/1135 (0.26%)  
Pneumothorax † 1      
# participants affected / at risk     1/1126 (0.09%)     2/1145 (0.17%)     0/1135 (0.00%)  
Respiratory failure † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     2/1135 (0.18%)  
Acute respiratory distress syndrome † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Interstitial lung disease † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Organising pneumonia † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Pneumonia aspiration † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Pulmonary artery thrombosis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Pulmonary oedema † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Skin and subcutaneous tissue disorders        
Angioedema † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Drug eruption † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Palmar-Plantar † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Swelling face † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Urticaria † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Social circumstances        
Pregnancy of partner † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Surgical and medical procedures        
Central venous catheter removal † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Vascular disorders        
Deep vein thrombosis † 1      
# participants affected / at risk     9/1126 (0.80%)     16/1145 (1.40%)     12/1135 (1.06%)  
Hypertension † 1      
# participants affected / at risk     1/1126 (0.09%)     2/1145 (0.17%)     13/1135 (1.15%)  
Venous thrombosis † 1      
# participants affected / at risk     3/1126 (0.27%)     5/1145 (0.44%)     1/1135 (0.09%)  
Jugular vein thrombosis † 1      
# participants affected / at risk     2/1126 (0.18%)     3/1145 (0.26%)     0/1135 (0.00%)  
Subclavian vein thrombosis † 1      
# participants affected / at risk     1/1126 (0.09%)     2/1145 (0.17%)     2/1135 (0.18%)  
Venous thrombosis limb † 1      
# participants affected / at risk     0/1126 (0.00%)     3/1145 (0.26%)     2/1135 (0.18%)  
Hypertensive crisis † 1      
# participants affected / at risk     0/1126 (0.00%)     3/1145 (0.26%)     1/1135 (0.09%)  
Hypotension † 1      
# participants affected / at risk     0/1126 (0.00%)     2/1145 (0.17%)     1/1135 (0.09%)  
Thrombophlebitis † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     0/1135 (0.00%)  
Thrombosis † 1      
# participants affected / at risk     1/1126 (0.09%)     1/1145 (0.09%)     0/1135 (0.00%)  
Arterial stenosis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Arterial thrombosis † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Arterial thrombosis limb † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Axillary vein thrombosis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Pelvic venous thrombosis † 1      
# participants affected / at risk     0/1126 (0.00%)     0/1145 (0.00%)     1/1135 (0.09%)  
Peripheral ischaemia † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Phlebitis † 1      
# participants affected / at risk     0/1126 (0.00%)     1/1145 (0.09%)     0/1135 (0.00%)  
Thrombophlebitis superficial † 1      
# participants affected / at risk     1/1126 (0.09%)     0/1145 (0.00%)     0/1135 (0.00%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA (13.0)




  Other Adverse Events
  Hide Other Adverse Events

Time Frame All adverse events occurring between the date of first drug intake and 28 days after last drug intake, regardless of which treatment group the patient was randomized to.
Additional Description No text entered.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
FOLFOX4

Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with Leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).

Weeks 25-48: Observation only.

FOLFOX4 + Bv

Weeks 1–24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 – 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).

Weeks 25–48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

XELOX+Bv

Weeks 1–24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 – 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks).

Weeks 25–48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).


Other Adverse Events
    FOLFOX4     FOLFOX4 + Bv     XELOX+Bv  
Total, other (not including serious) adverse events        
# participants affected / at risk     1112/1126     1127/1145     1117/1135  
Blood and lymphatic system disorders        
Neutropenia † 1      
# participants affected / at risk     660/1126 (58.61%)     567/1145 (49.52%)     273/1135 (24.05%)  
Thrombocytopenia † 1      
# participants affected / at risk     331/1126 (29.40%)     115/1145 (10.04%)     99/1135 (8.72%)  
Anaemia † 1      
# participants affected / at risk     116/1126 (10.30%)     89/1145 (7.77%)     74/1135 (6.52%)  
Leukopenia † 1      
# participants affected / at risk     79/1126 (7.02%)     55/1145 (4.80%)     34/1135 (3.00%)  
Eye disorders        
Lacrimation increased † 1      
# participants affected / at risk     70/1126 (6.22%)     69/1145 (6.03%)     35/1135 (3.08%)  
Gastrointestinal disorders        
Nausea † 1      
# participants affected / at risk     725/1126 (64.39%)     761/1145 (66.46%)     720/1135 (63.44%)  
Diarrhoea † 1      
# participants affected / at risk     620/1126 (55.06%)     699/1145 (61.05%)     699/1135 (61.59%)  
Vomiting † 1      
# participants affected / at risk     385/1126 (34.19%)     394/1145 (34.41%)     460/1135 (40.53%)  
Stomatitis † 1      
# participants affected / at risk     310/1126 (27.53%)     360/1145 (31.44%)     246/1135 (21.67%)  
Constipation † 1      
# participants affected / at risk     308/1126 (27.35%)     324/1145 (28.30%)     219/1135 (19.30%)  
Abdominal pain † 1      
# participants affected / at risk     220/1126 (19.54%)     227/1145 (19.83%)     214/1135 (18.85%)  
Dyspepsia † 1      
# participants affected / at risk     126/1126 (11.19%)     162/1145 (14.15%)     84/1135 (7.40%)  
Abdominal pain upper † 1      
# participants affected / at risk     86/1126 (7.64%)     118/1145 (10.31%)     113/1135 (9.96%)  
Haemorrhoids † 1      
# participants affected / at risk     29/1126 (2.58%)     68/1145 (5.94%)     41/1135 (3.61%)  
General disorders        
Fatigue † 1      
# participants affected / at risk     404/1126 (35.88%)     425/1145 (37.12%)     355/1135 (31.28%)  
Asthenia † 1      
# participants affected / at risk     241/1126 (21.40%)     251/1145 (21.92%)     250/1135 (22.03%)  
Pyrexia † 1      
# participants affected / at risk     186/1126 (16.52%)     185/1145 (16.16%)     106/1135 (9.34%)  
Mucosal inflammation † 1      
# participants affected / at risk     85/1126 (7.55%)     85/1145 (7.42%)     57/1135 (5.02%)  
Temperature intolerance † 1      
# participants affected / at risk     61/1126 (5.42%)     61/1145 (5.33%)     50/1135 (4.41%)  
Oedema peripheral † 1      
# participants affected / at risk     54/1126 (4.80%)     62/1145 (5.41%)     45/1135 (3.96%)  
Immune system disorders        
Drug hypersensitivity † 1      
# participants affected / at risk     66/1126 (5.86%)     72/1145 (6.29%)     32/1135 (2.82%)  
Infections and infestations        
Nasopharyngitis † 1      
# participants affected / at risk     76/1126 (6.75%)     92/1145 (8.03%)     70/1135 (6.17%)  
Upper respiratory tract infection † 1      
# participants affected / at risk     52/1126 (4.62%)     87/1145 (7.60%)     55/1135 (4.85%)  
Investigations        
Weight increased † 1      
# participants affected / at risk     58/1126 (5.15%)     81/1145 (7.07%)     68/1135 (5.99%)  
Weight decreased † 1      
# participants affected / at risk     26/1126 (2.31%)     56/1145 (4.89%)     61/1135 (5.37%)  
Metabolism and nutrition disorders        
Decreased appetite † 1      
# participants affected / at risk     268/1126 (23.80%)     324/1145 (28.30%)     295/1135 (25.99%)  
Musculoskeletal and connective tissue disorders        
Arthralgia † 1      
# participants affected / at risk     63/1126 (5.60%)     140/1145 (12.23%)     122/1135 (10.75%)  
Pain in extremity † 1      
# participants affected / at risk     63/1126 (5.60%)     78/1145 (6.81%)     116/1135 (10.22%)  
Back pain † 1      
# participants affected / at risk     79/1126 (7.02%)     87/1145 (7.60%)     66/1135 (5.81%)  
Musculoskeletal pain † 1      
# participants affected / at risk     35/1126 (3.11%)     86/1145 (7.51%)     46/1135 (4.05%)  
Myalgia † 1      
# participants affected / at risk     39/1126 (3.46%)     70/1145 (6.11%)     56/1135 (4.93%)  
Nervous system disorders        
Peripheral sensory neuropathy † 1      
# participants affected / at risk     430/1126 (38.19%)     430/1145 (37.55%)     436/1135 (38.41%)  
Paraesthesia † 1      
# participants affected / at risk     310/1126 (27.53%)     328/1145 (28.65%)     314/1135 (27.67%)  
Neuropathy peripheral † 1      
# participants affected / at risk     252/1126 (22.38%)     234/1145 (20.44%)     204/1135 (17.97%)  
Headache † 1      
# participants affected / at risk     169/1126 (15.01%)     284/1145 (24.80%)     219/1135 (19.30%)  
Dysgeusia † 1      
# participants affected / at risk     237/1126 (21.05%)     222/1145 (19.39%)     152/1135 (13.39%)  
Dysaesthesia † 1      
# participants affected / at risk     128/1126 (11.37%)     106/1145 (9.26%)     128/1135 (11.28%)  
Dizziness † 1      
# participants affected / at risk     102/1126 (9.06%)     117/1145 (10.22%)     79/1135 (6.96%)  
Neurotoxicity † 1      
# participants affected / at risk     60/1126 (5.33%)     69/1145 (6.03%)     50/1135 (4.41%)  
Lethargy † 1      
# participants affected / at risk     44/1126 (3.91%)     50/1145 (4.37%)     59/1135 (5.20%)  
Psychiatric disorders        
Insomnia † 1      
# participants affected / at risk     135/1126 (11.99%)     132/1145 (11.53%)     91/1135 (8.02%)  
Anxiety † 1      
# participants affected / at risk     45/1126 (4.00%)     60/1145 (5.24%)     61/1135 (5.37%)  
Renal and urinary disorders        
Proteinuria † 1      
# participants affected / at risk     19/1126 (1.69%)     73/1145 (6.38%)     69/1135 (6.08%)  
Respiratory, thoracic and mediastinal disorders        
Epistaxis † 1      
# participants affected / at risk     228/1126 (20.25%)     424/1145 (37.03%)     216/1135 (19.03%)  
Cough † 1      
# participants affected / at risk     86/1126 (7.64%)     120/1145 (10.48%)     41/1135 (3.61%)  
Dyspnoea † 1      
# participants affected / at risk     57/1126 (5.06%)     74/1145 (6.46%)     73/1135 (6.43%)  
Dysphonia † 1      
# participants affected / at risk     17/1126 (1.51%)     91/1145 (7.95%)     74/1135 (6.52%)  
Dysaesthesia pharynx † 1      
# participants affected / at risk     37/1126 (3.29%)     28/1145 (2.45%)     79/1135 (6.96%)  
Oropharyngeal pain † 1      
# participants affected / at risk     52/1126 (4.62%)     59/1145 (5.15%)     33/1135 (2.91%)  
Skin and subcutaneous tissue disorders        
Palmar-Plantar Erythrodysaesthesia Syndrome † 1      
# participants affected / at risk     98/1126 (8.70%)     119/1145 (10.39%)     435/1135 (38.33%)  
Alopecia † 1      
# participants affected / at risk     231/1126 (20.52%)     241/1145 (21.05%)     73/1135 (6.43%)  
Rash † 1      
# participants affected / at risk     114/1126 (10.12%)     112/1145 (9.78%)     110/1135 (9.69%)  
Dry skin † 1      
# participants affected / at risk     52/1126 (4.62%)     66/1145 (5.76%)     50/1135 (4.41%)  
Pruritus † 1      
# participants affected / at risk     36/1126 (3.20%)     65/1145 (5.68%)     28/1135 (2.47%)  
Vascular disorders        
Hypertension † 1      
# participants affected / at risk     196/1126 (17.41%)     472/1145 (41.22%)     468/1135 (41.23%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA (13.0)



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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Limitations and Caveats
Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:  
Name/Title: Medical Communications
Organization: Hoffman-LaRoche
phone: 800-821-8590


No publications provided by Hoffmann-La Roche

Publications automatically indexed to this study:

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00112918     History of Changes
Other Study ID Numbers: CDR0000427299, P30CA016042, UCLA-0412086-01, ROCHE-BO17920A
Study First Received: June 2, 2005
Results First Received: June 1, 2012
Last Updated: June 19, 2013
Health Authority: United States: Food and Drug Administration