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Aflibercept Versus Placebo in Combination With Irinotecan and 5-FU in the Treatment of Patients With Metastatic Colorectal Cancer After Failure of an Oxaliplatin Based Regimen (VELOUR)

This study has been completed.
Sponsor:
Collaborators:
Regeneron Pharmaceuticals
NSABP Foundation Inc
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00561470
First received: November 20, 2007
Last updated: September 27, 2012
Last verified: March 2012
Results First Received: August 17, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator);   Primary Purpose: Treatment
Conditions: Colorectal Neoplasms
Neoplasm Metastasis
Interventions: Drug: Placebo
Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
Drug: FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)

  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
Between 19 November 2007 and 16 March 2010, 614 participants were randomized to the placebo arm and 612 participants were randomized to the aflibercept arm.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Placebo/FOLFIRI Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Aflibercept/FOLFIRI Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks

Participant Flow:   Overall Study
    Placebo/FOLFIRI     Aflibercept/FOLFIRI  
STARTED     614     612  
TREATED     609     607  
SAFETY POPULATION     605 [1]   611 [2]
ONGOING TREATMENT     11 [3]   14 [3]
COMPLETED     0 [4]   0 [4]
NOT COMPLETED     614     612  
Adverse Event                 74                 163  
Disease progression                 437                 305  
poor compliance to protocol                 4                 4  
Lost to Follow-up                 2                 0  
Physician Decision                 21                 20  
Consent Withdrawn                 2                 6  
Subject request                 43                 77  
Metastatic surgery                 10                 12  
Unauthorized procedure                 3                 1  
Randomized but not treated                 5                 5  
Missed visit window                 1                 4  
Planning surgery                 1                 1  
Ongoing Treatment                 11                 14  
[1] Treated participants excluding 4 who received at least 1 dose of Aflibercept
[2] Treated participants including 4 from Placebo/FOLFIRI who received at least 1 dose of Aflibercept
[3] Participants continuing treatment on the cutoff date of the final analysis
[4] Participants met treatment discontinuation criteria or were ongoing treatment on the cutoff date



  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.
No text entered.

Reporting Groups
  Description
Placebo/Folfiri Participants with Metastatic Colorectal Cancer administered Placebo and FOLFIRI (Irinotecan, 5- Fluorouracil, and Leucovorin)
Aflibercept/Folfiri Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept and FOLFIRI (Irinotecan, 5- Fluorouracil, and Leucovorin)
Total Total of all reporting groups

Baseline Measures
    Placebo/Folfiri     Aflibercept/Folfiri     Total  
Number of Participants  
[units: participants]
  614     612     1226  
Age  
[units: years]
Mean ± Standard Deviation
  60.2  ± 10.8     59.5  ± 10.5     59.8  ± 10.7  
Age, Customized  
[units: participants]
     
<65 years     376     407     783  
>=65 but <75 years     199     172     371  
>=75 years     39     33     72  
Gender, Customized  
[units: participants]
     
Male     353     365     718  
Female     261     247     508  
Race/Ethnicity, Customized  
[units: participants]
     
Caucasian/White     523     548     1071  
Black     27     16     43  
Asian/Oriental     51     35     86  
Other     13     13     26  
Region of Enrollment  
[units: participants]
     
ARGENTINA     4     2     6  
AUSTRALIA     42     54     96  
AUSTRIA     3     4     7  
BELGIUM     37     45     82  
BRAZIL     21     27     48  
CHILE     31     33     64  
CZECH REPUBLIC     30     47     77  
DENMARK     9     6     15  
ESTONIA     7     3     10  
FRANCE     1     1     2  
GERMANY     23     12     35  
GREECE     9     10     19  
ITALY     26     23     49  
KOREA, REPUBLIC OF     39     26     65  
NETHERLANDS     20     14     34  
NEW ZEALAND     13     7     20  
NORWAY     14     19     33  
POLAND     24     32     56  
PUERTO RICO     4     2     6  
ROMANIA     16     16     32  
RUSSIAN FEDERATION     35     40     75  
SOUTH AFRICA     36     31     67  
SPAIN     27     28     55  
SWEDEN     10     4     14  
TURKEY     4     2     6  
UKRAINE     11     11     22  
UNITED KINGDOM     47     52     99  
UNITED STATES     71     61     132  
Eastern Cooperative Oncology Group (ECOG) performance status score [1]
[units: participants]
     
Participants with ECOG Score = 0     350     349     699  
Participants with ECOG Score = 1     250     250     500  
Participants with ECOG Score = 2     14     13     27  
Prior Bevacizumab [2]
[units: participants]
     
Yes     187     186     373  
No     427     426     853  
[1] The ECOG score assesses how the disease affects a participant's daily living abilities. It ranges from 0-5, with 0 being the best and 5 being the worst outcome. "0" reflects a fully active participant, able to carry on all pre-disease performance without restriction. "1" reflects a participant restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. "2" reflects an ambulatory participant, who is up and about more than 50% of waking hours, and capable of all self-care but unable to carry out any work activities.
[2] Number of participants randomized in the prior bevacizumab stratum as per the interactive voice response system (IVRS).



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Overall Survival (OS)   [ Time Frame: From the date of the first randomization until the study data cut-off date, 07 February 2011 (approximately three years) ]

2.  Secondary:   Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC)   [ Time Frame: From the date of the first randomization until the occurrence of 561 OS events, 06 May 2010 (approximately 30 months) ]

3.  Secondary:   Overall Objective Response Rate (ORR) Based on the Tumor Assessment by the Independent Review Committee (IRC) as Per Response Evaluation Criteria in Solid Tumours (RECIST) Criteria   [ Time Frame: From the date of the first randomization until the study data cut-off date, 06 May 2010 (approximately 30 months) ]

4.  Secondary:   Number of Participants With Adverse Events (AE)   [ Time Frame: From the date of the first randomization up to 30 days after the treatment discontinuation or until TEAE was resolved or stabilized ]

5.  Secondary:   Immunogenicity Assessment: Number of Participants With Positive Sample(s) in the Anti-drug Antibodies (ADA) Assay and in the Neutralizing Anti-drug Antibodies (NAb) Assay   [ Time Frame: Baseline, every other treatment cycle, 30 days and 90 days after the last infusion of aflibercept/placebo ]


  Serious Adverse Events
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Time Frame From treatment initiation to 7 February, 2011
Additional Description No text entered.

Reporting Groups
  Description
Placebo/FOLFIRI Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Aflibercept/FOLFIRI Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks

Serious Adverse Events
    Placebo/FOLFIRI     Aflibercept/FOLFIRI  
Total, serious adverse events      
# participants affected / at risk     198/605 (32.73%)     294/611 (48.12%)  
Blood and lymphatic system disorders      
Neutropenia * 1    
# participants affected / at risk     4/605 (0.66%)     11/611 (1.80%)  
Thrombocytopenia * 1    
# participants affected / at risk     3/605 (0.50%)     2/611 (0.33%)  
Anaemia * 1    
# participants affected / at risk     3/605 (0.50%)     7/611 (1.15%)  
Febrile neutropenia * 1    
# participants affected / at risk     6/605 (0.99%)     19/611 (3.11%)  
Coagulopathy * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
Pancytopenia * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
Thrombotic microangiopathy * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Cardiac disorders      
Angina pectoris * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Atrial fibrillation * 1    
# participants affected / at risk     2/605 (0.33%)     3/611 (0.49%)  
Sinus bradycardia * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Acute myocardial infarction * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
Myocardial ischaemia * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Cardiac failure congestive * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Intracardiac thrombus * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Myocardial infarction * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Pericarditis * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Endocrine disorders      
Hypercalcaemia of malignancy * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Eye disorders      
Periorbital oedema * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Gastrointestinal disorders      
Diarrhoea * 1    
# participants affected / at risk     14/605 (2.31%)     44/611 (7.20%)  
Nausea * 1    
# participants affected / at risk     3/605 (0.50%)     4/611 (0.65%)  
Stomatitis * 1    
# participants affected / at risk     0/605 (0.00%)     8/611 (1.31%)  
Vomiting * 1    
# participants affected / at risk     7/605 (1.16%)     10/611 (1.64%)  
Abdominal pain * 1    
# participants affected / at risk     7/605 (1.16%)     12/611 (1.96%)  
Constipation * 1    
# participants affected / at risk     4/605 (0.66%)     6/611 (0.98%)  
Abdominal pain upper * 1    
# participants affected / at risk     3/605 (0.50%)     4/611 (0.65%)  
Haemorrhoids * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
Rectal haemorrhage * 1    
# participants affected / at risk     4/605 (0.66%)     6/611 (0.98%)  
Aphthous stomatitis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Proctalgia * 1    
# participants affected / at risk     0/605 (0.00%)     3/611 (0.49%)  
Ascites * 1    
# participants affected / at risk     4/605 (0.66%)     3/611 (0.49%)  
Gastrooesophageal reflux disease * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Intestinal obstruction * 1    
# participants affected / at risk     11/605 (1.82%)     10/611 (1.64%)  
Abdominal pain lower * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Gastritis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Enteritis * 1    
# participants affected / at risk     1/605 (0.17%)     2/611 (0.33%)  
Gingivitis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Ileus * 1    
# participants affected / at risk     5/605 (0.83%)     4/611 (0.65%)  
Colitis * 1    
# participants affected / at risk     1/605 (0.17%)     4/611 (0.65%)  
Small intestinal obstruction * 1    
# participants affected / at risk     2/605 (0.33%)     5/611 (0.82%)  
Anal haemorrhage * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Faecal incontinence * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Gastrointestinal haemorrhage * 1    
# participants affected / at risk     0/605 (0.00%)     3/611 (0.49%)  
Gastrointestinal inflammation * 1    
# participants affected / at risk     0/605 (0.00%)     3/611 (0.49%)  
Periodontitis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Gastrointestinal obstruction * 1    
# participants affected / at risk     2/605 (0.33%)     1/611 (0.16%)  
Haematemesis * 1    
# participants affected / at risk     2/605 (0.33%)     0/611 (0.00%)  
Mechanical ileus * 1    
# participants affected / at risk     2/605 (0.33%)     1/611 (0.16%)  
Colitis ischaemic * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Colonic obstruction * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
Duodenal ulcer perforation * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Peritonitis * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Small intestinal perforation * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Subileus * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
Colonic fistula * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Duodenal obstruction * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Duodenal ulcer haemorrhage * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Enterocolitis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Enterocutaneous fistula * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Gastrointestinal hypomotility * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Gastrointestinal perforation * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Ileal perforation * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Ileitis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Large intestinal haemorrhage * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Large intestinal obstruction * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Lower gastrointestinal haemorrhage * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Mallory-weiss syndrome * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Mesenteric vein thrombosis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Neutropenic colitis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Pancreatitis * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Rectal obstruction * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Rectal stenosis * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
General disorders      
Fatigue * 1    
# participants affected / at risk     3/605 (0.50%)     2/611 (0.33%)  
Asthenia * 1    
# participants affected / at risk     4/605 (0.66%)     5/611 (0.82%)  
Pyrexia * 1    
# participants affected / at risk     15/605 (2.48%)     10/611 (1.64%)  
Oedema peripheral * 1    
# participants affected / at risk     3/605 (0.50%)     0/611 (0.00%)  
Disease progression * 1    
# participants affected / at risk     14/605 (2.31%)     16/611 (2.62%)  
Pain * 1    
# participants affected / at risk     1/605 (0.17%)     2/611 (0.33%)  
Non-cardiac chest pain * 1    
# participants affected / at risk     1/605 (0.17%)     2/611 (0.33%)  
Malaise * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Thrombosis in device * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
General physical health deterioration * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Medical device complication * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Death * 1    
# participants affected / at risk     1/605 (0.17%)     2/611 (0.33%)  
Suprapubic pain * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Mucosal inflammation * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Sudden death * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Hepatobiliary disorders      
Hyperbilirubinaemia * 1    
# participants affected / at risk     4/605 (0.66%)     2/611 (0.33%)  
Cholecystitis * 1    
# participants affected / at risk     1/605 (0.17%)     4/611 (0.65%)  
Biliary colic * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Cholangitis * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Hepatic function abnormal * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Jaundice cholestatic * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Bile duct obstruction * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Hepatic haemorrhage * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Hepatitis * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Hepatotoxicity * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Immune system disorders      
Hypersensitivity * 1    
# participants affected / at risk     2/605 (0.33%)     0/611 (0.00%)  
Infections and infestations      
Urinary tract infection * 1    
# participants affected / at risk     3/605 (0.50%)     8/611 (1.31%)  
Upper respiratory tract infection * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Pneumonia * 1    
# participants affected / at risk     5/605 (0.83%)     11/611 (1.80%)  
Lower respiratory tract infection * 1    
# participants affected / at risk     2/605 (0.33%)     1/611 (0.16%)  
Device related infection * 1    
# participants affected / at risk     6/605 (0.99%)     5/611 (0.82%)  
Bronchitis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Cystitis * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Oral candidiasis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Neutropenic infection * 1    
# participants affected / at risk     5/605 (0.83%)     4/611 (0.65%)  
Sinusitis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Viral infection * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Pharyngitis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Respiratory tract infection * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Sepsis * 1    
# participants affected / at risk     5/605 (0.83%)     8/611 (1.31%)  
Gastroenteritis * 1    
# participants affected / at risk     2/605 (0.33%)     1/611 (0.16%)  
Catheter site infection * 1    
# participants affected / at risk     0/605 (0.00%)     3/611 (0.49%)  
Infection * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Lobar pneumonia * 1    
# participants affected / at risk     5/605 (0.83%)     0/611 (0.00%)  
Lung infection * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Anal abscess * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Diverticulitis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Neutropenic sepsis * 1    
# participants affected / at risk     0/605 (0.00%)     3/611 (0.49%)  
Perirectal abscess * 1    
# participants affected / at risk     0/605 (0.00%)     3/611 (0.49%)  
Subcutaneous abscess * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Abscess jaw * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Clostridial infection * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Oesophageal candidiasis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Septic shock * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
Appendicitis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Bacterial sepsis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Beta haemolytic streptococcal infection * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Bronchopneumonia * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Device related sepsis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Emphysematous cystitis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Enterocolitis infectious * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Escherichia infection * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Pelvic abscess * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Perinephric abscess * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Peritonitis bacterial * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Pneumonia streptococcal * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Rectal abscess * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Staphylococcal sepsis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Viral diarrhoea * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Injury, poisoning and procedural complications      
Fall * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Post procedural haemorrhage * 1    
# participants affected / at risk     1/605 (0.17%)     2/611 (0.33%)  
Skin laceration * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Gastrointestinal stoma complication * 1    
# participants affected / at risk     0/605 (0.00%)     3/611 (0.49%)  
Head injury * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Incisional hernia * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Wound dehiscence * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Ankle fracture * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Femoral neck fracture * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Femur fracture * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Limb traumatic amputation * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Pneumothorax traumatic * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Subdural haematoma * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Investigations      
Neutrophil count decreased * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Blood creatinine increased * 1    
# participants affected / at risk     2/605 (0.33%)     2/611 (0.33%)  
Blood bilirubin increased * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Haemoglobin decreased * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
International normalised ratio increased * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Blood creatine increased * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
C-reactive protein increased * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Hepatic enzyme increased * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Metabolism and nutrition disorders      
Decreased appetite * 1    
# participants affected / at risk     2/605 (0.33%)     3/611 (0.49%)  
Dehydration * 1    
# participants affected / at risk     7/605 (1.16%)     24/611 (3.93%)  
Diabetes mellitus * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Hypoglycaemia * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
Hyponatraemia * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
Failure to thrive * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Hypoproteinaemia * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Musculoskeletal and connective tissue disorders      
Back pain * 1    
# participants affected / at risk     4/605 (0.66%)     3/611 (0.49%)  
Bone pain * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Musculoskeletal chest pain * 1    
# participants affected / at risk     2/605 (0.33%)     0/611 (0.00%)  
Bursitis * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Osteonecrosis of jaw * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Pathological fracture * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Fistula * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
Metastatic pain * 1    
# participants affected / at risk     3/605 (0.50%)     2/611 (0.33%)  
Cancer pain * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Tumour pain * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Metastases to central nervous system * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Benign neoplasm of cervix uteri * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Bladder cancer * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Tumour associated fever * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Nervous system disorders      
Headache * 1    
# participants affected / at risk     1/605 (0.17%)     3/611 (0.49%)  
Peripheral sensory neuropathy * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Syncope * 1    
# participants affected / at risk     3/605 (0.50%)     1/611 (0.16%)  
Presyncope * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Transient ischaemic attack * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
Migraine * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Spinal cord compression * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Aphasia * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Brachial plexopathy * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Cerebrovascular accident * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Coma * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Convulsion * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Disturbance in attention * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Haemorrhage intracranial * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Metabolic encephalopathy * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Psychiatric disorders      
Anxiety * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Depression * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Confusional state * 1    
# participants affected / at risk     2/605 (0.33%)     2/611 (0.33%)  
Hallucination * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Mental status changes * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Renal and urinary disorders      
Proteinuria * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Haematuria * 1    
# participants affected / at risk     2/605 (0.33%)     1/611 (0.16%)  
Urinary retention * 1    
# participants affected / at risk     1/605 (0.17%)     4/611 (0.65%)  
Urinary incontinence * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Hydronephrosis * 1    
# participants affected / at risk     3/605 (0.50%)     1/611 (0.16%)  
Renal failure acute * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
Renal impairment * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
Renal vein thrombosis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Bladder neck obstruction * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Nephrotic syndrome * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Renal failure * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Cystitis haemorrhagic * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Nephrolithiasis * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Obstructive uropathy * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Urinary tract obstruction * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Reproductive system and breast disorders      
Pelvic pain * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Balanitis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Respiratory, thoracic and mediastinal disorders      
Epistaxis * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
Cough * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Dyspnoea * 1    
# participants affected / at risk     3/605 (0.50%)     3/611 (0.49%)  
Oropharyngeal pain * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Pulmonary embolism * 1    
# participants affected / at risk     12/605 (1.98%)     19/611 (3.11%)  
Pleural effusion * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Pleuritic pain * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Atelectasis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Interstitial lung disease * 1    
# participants affected / at risk     2/605 (0.33%)     0/611 (0.00%)  
Pneumonitis * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Pneumothorax * 1    
# participants affected / at risk     0/605 (0.00%)     2/611 (0.33%)  
Acute pulmonary oedema * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Acute respiratory distress syndrome * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Acute respiratory failure * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Pneumomediastinum * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Pneumonia aspiration * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Pulmonary artery thrombosis * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Pulmonary hypertension * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Skin and subcutaneous tissue disorders      
Rash maculo-papular * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Vascular disorders      
Hypertension * 1    
# participants affected / at risk     0/605 (0.00%)     10/611 (1.64%)  
Deep vein thrombosis * 1    
# participants affected / at risk     7/605 (1.16%)     7/611 (1.15%)  
Hypotension * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Jugular vein thrombosis * 1    
# participants affected / at risk     2/605 (0.33%)     0/611 (0.00%)  
Vena cava thrombosis * 1    
# participants affected / at risk     2/605 (0.33%)     2/611 (0.33%)  
Pelvic venous thrombosis * 1    
# participants affected / at risk     2/605 (0.33%)     0/611 (0.00%)  
Orthostatic hypotension * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Subclavian vein thrombosis * 1    
# participants affected / at risk     2/605 (0.33%)     1/611 (0.16%)  
Circulatory collapse * 1    
# participants affected / at risk     1/605 (0.17%)     1/611 (0.16%)  
Thrombophlebitis * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Arterial thrombosis limb * 1    
# participants affected / at risk     1/605 (0.17%)     0/611 (0.00%)  
Embolism arterial * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Hypovolaemic shock * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
Superior vena caval occlusion * 1    
# participants affected / at risk     0/605 (0.00%)     1/611 (0.16%)  
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA 13.1




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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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