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Study of Cisplatin/Vinorelbine +/- Cetuximab as First-line Treatment of Advanced Non Small Cell Lung Cancer (FLEX) (FLEX)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT00148798
First received: September 7, 2005
Last updated: June 13, 2014
Last verified: June 2014
Results First Received: August 24, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Non Small Cell Lung Cancer (NSCLC)
Interventions: Drug: cetuximab + cisplatin + vinorelbine
Drug: cisplatin + vinorelbine

  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
First/last subject (informed consent): October 2004/January 2006. Clinical data cut-off: 18 July 2007. Last subject completed 16 May 2012. Subjects randomized at 155 centers; Asia/Australia: 21; Europe: 120; South America: 14.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Enrolled: 1,861 after consent to epidermal growth factor receptor (EGFR) assessment; 603 excluded (mainly non-fulfillment of inclusion or exclusion criteria). 1,258 screened for eligibility after consent for study procedures; 143 excluded (mainly non-fulfillment of inclusion or exclusion criteria). 1,125 subjects randomized.

Reporting Groups
  Description
Cetuximab Plus Chemotherapy

cetuximab given as an intravenous (i.v.) infusion every week (400mg/m^2 initial dose and 250mg/m^2 subsequent doses) until progressive disease (PD) + cisplatin 80mg/m^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m^2 i.v. infusion on days 1 and 8 of each 3-week cycle.

Safety population: includes all treated subjects.

Chemotherapy Alone

cisplatin 80mg/m^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m^2 i.v. infusion on days 1 and 8 of each 3-week cycle.

Safety population: includes all treated subjects.


Participant Flow:   Overall Study
    Cetuximab Plus Chemotherapy   Chemotherapy Alone
STARTED   557 [1]   568 [2] 
COMPLETED   557   568 
NOT COMPLETED   0   0 
[1] Intent To Treat (ITT) Population
[2] ITT Population



  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
Cetuximab Plus Chemotherapy

cetuximab given as an intravenous (i.v.) infusion every week (400mg/m^2 initial dose and 250mg/m^2 subsequent doses) until progressive disease (PD) + cisplatin 80mg/m^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m^2 i.v. infusion on days 1 and 8 of each 3-week cycle.

Safety population: includes all treated subjects.

Chemotherapy Alone

cisplatin 80mg/m^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m^2 i.v. infusion on days 1 and 8 of each 3-week cycle.

Safety population: includes all treated subjects.

Total Total of all reporting groups

Baseline Measures
   Cetuximab Plus Chemotherapy   Chemotherapy Alone   Total 
Overall Participants Analyzed 
[Units: Participants]
 557   568   1125 
Age 
[Units: Years]
Median (Full Range)
 59 
 (18 to 78) 
 60 
 (20 to 83) 
 59 
 (18 to 83) 
Age, Customized 
[Units: Participants]
     
<18 years   0   0   0 
Between 18 and 65 years   385   389   774 
>=65 years   172   179   351 
Gender 
[Units: Participants]
     
Female   172   163   335 
Male   385   405   790 
Region of Enrollment 
[Units: Participants]
     
Australia   20   23   43 
Hong Kong   2   2   4 
Singapore   5   5   10 
Korea, Republic of   28   26   54 
Taiwan   21   22   43 
Austria   9   7   16 
Belgium   3   10   13 
Bulgaria   12   12   24 
Czech Republic   12   17   29 
France   25   25   50 
Germany   91   88   179 
Hungary   21   23   44 
Ireland   3   4   7 
Netherlands   10   10   20 
Poland   59   50   109 
Portugal   3   0   3 
Russian Federation   23   16   39 
Slovakia   8   12   20 
Spain   16   13   29 
Sweden   6   3   9 
Switzerland   10   6   16 
Turkey   1   2   3 
United Kingdom   23   21   44 
Ukraine   56   71   127 
Chile   10   16   26 
Italy   18   23   41 
Argentina   5   2   7 
Mexico   9   8   17 
Brazil   48   51   99 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Overall Survival Time (OS)   [ Time Frame: Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 ]

2.  Secondary:   Progression-free Survival Time   [ Time Frame: Time from randomization to disease progression, death or last tumor assessment, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 ]

3.  Secondary:   Best Overall Response Rate   [ Time Frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 ]

4.  Secondary:   Disease Control Rate   [ Time Frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 ]

5.  Secondary:   Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status   [ Time Frame: at baseline, at cycle 3, at month 6, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 ]

6.  Secondary:   Quality of Life Assessment (EORTC QLQ-C30) Social Functioning   [ Time Frame: at baseline, at cycle 3, at month 6, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 ]

7.  Secondary:   A Population Pharmacokinetic (PK) Analysis for Cetuximab in Non-Small Cell Lung Cancer (NSCLC) - Serum Cetuximab Concentrations   [ Time Frame: Week 1, Day 1: baseline and end of infusion; Week 7, Day 43: within 12 h after cetuximab administration. ]

8.  Secondary:   Safety - Number of Patients Experiencing Any Adverse Event   [ Time Frame: time from first dose up to 30 after last dose of study treatment, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 ]


  Serious Adverse Events
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Time Frame Time from first dose up to 30 days after the last dose of study treatment.
Additional Description Treatment-emergent adverse events were defined as those with onset occurring at or after the first dosing day of study medication and up to 30 days after the last administration of any study drug or the clinical cut-off date.

Reporting Groups
  Description
Cetuximab Plus Chemotherapy

cetuximab given as an intravenous (i.v.) infusion every week (400mg/m^2 initial dose and 250mg/m^2 subsequent doses) until progressive disease (PD) + cisplatin 80mg/m^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m^2 i.v. infusion on days 1 and 8 of each 3-week cycle.

Safety population: includes all treated subjects.

Chemotherapy Alone

cisplatin 80mg/m^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m^2 i.v. infusion on days 1 and 8 of each 3-week cycle.

Safety population: includes all treated subjects.


Serious Adverse Events
    Cetuximab Plus Chemotherapy   Chemotherapy Alone
Total, serious adverse events     
# participants affected / at risk   325/548 (59.31%)   244/562 (43.42%) 
Blood and lymphatic system disorders     
Anaemia † 1     
# participants affected / at risk   11/548 (2.01%)   12/562 (2.14%) 
Febrile bone marrow aplasia † 1     
# participants affected / at risk   4/548 (0.73%)   0/562 (0.00%) 
Febrile neutropenia † 1     
# participants affected / at risk   96/548 (17.52%)   67/562 (11.92%) 
Granulocytopenia † 1     
# participants affected / at risk   2/548 (0.36%)   1/562 (0.18%) 
Leukopenia † 1     
# participants affected / at risk   15/548 (2.74%)   8/562 (1.42%) 
Neutropenia † 1     
# participants affected / at risk   47/548 (8.58%)   33/562 (5.87%) 
Pancytopenia † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Cardiac disorders     
Acute myocardial infarction † 1     
# participants affected / at risk   4/548 (0.73%)   0/562 (0.00%) 
Angina pectoris † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Arrhythmia supraventricular † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Atrial fibrillation † 1     
# participants affected / at risk   0/548 (0.00%)   4/562 (0.71%) 
Cardiac arrest † 1     
# participants affected / at risk   0/548 (0.00%)   2/562 (0.36%) 
Cardiac failure † 1     
# participants affected / at risk   1/548 (0.18%)   2/562 (0.36%) 
Cardiac failure acute † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Cardiac tamponade † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Cardio-respiratory arrest † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Cardiogenic shock † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Cardiopulmonary failure † 1     
# participants affected / at risk   3/548 (0.55%)   3/562 (0.53%) 
Left ventricular failure † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Microvascular angina † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Myocardial infarction † 1     
# participants affected / at risk   2/548 (0.36%)   1/562 (0.18%) 
Myocardial ischaemia † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Palpitations † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Pericardial effusion † 1     
# participants affected / at risk   2/548 (0.36%)   2/562 (0.36%) 
Right ventricular failure † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Supraventricular tachycardia † 1     
# participants affected / at risk   0/548 (0.00%)   2/562 (0.36%) 
Tachycardia † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Tricuspid valve incompetence † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Ventricular fibrillation † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Congenital, familial and genetic disorders     
Tracheo-oesophageal fistula † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Ear and labyrinth disorders     
Deafness † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Vertigo † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Eye disorders     
Retinal detachment † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Gastrointestinal disorders     
Abdominal distension † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Abdominal pain † 1     
# participants affected / at risk   6/548 (1.09%)   8/562 (1.42%) 
Abdominal pain upper † 1     
# participants affected / at risk   2/548 (0.36%)   1/562 (0.18%) 
Anal ulcer † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Colitis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Constipation † 1     
# participants affected / at risk   5/548 (0.91%)   6/562 (1.07%) 
Diarrhoea † 1     
# participants affected / at risk   8/548 (1.46%)   5/562 (0.89%) 
Dyspepsia † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Dysphagia † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Enteritis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Faecaloma † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Gastric ulcer † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Gastrointestinal haemorrhage † 1     
# participants affected / at risk   0/548 (0.00%)   2/562 (0.36%) 
Haematemesis † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Ileus paralytic † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Intestinal obstruction † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Intestinal perforation † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Melaena † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Nausea † 1     
# participants affected / at risk   6/548 (1.09%)   5/562 (0.89%) 
Odynophagia † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Oesophagitis † 1     
# participants affected / at risk   3/548 (0.55%)   1/562 (0.18%) 
Vomiting † 1     
# participants affected / at risk   16/548 (2.92%)   14/562 (2.49%) 
General disorders     
Asthenia † 1     
# participants affected / at risk   4/548 (0.73%)   2/562 (0.36%) 
Chest discomfort † 1     
# participants affected / at risk   0/548 (0.00%)   2/562 (0.36%) 
Chest pain † 1     
# participants affected / at risk   7/548 (1.28%)   6/562 (1.07%) 
Death † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Drug interaction † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Fatigue † 1     
# participants affected / at risk   5/548 (0.91%)   2/562 (0.36%) 
Gait disturbance † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
General physical health deterioration † 1     
# participants affected / at risk   22/548 (4.01%)   4/562 (0.71%) 
Injection site reaction † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Malaise † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Mucosal inflammation † 1     
# participants affected / at risk   2/548 (0.36%)   1/562 (0.18%) 
Multi-organ failure † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Oedema † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Pain † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Performance status decreased † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Pyrexia † 1     
# participants affected / at risk   16/548 (2.92%)   6/562 (1.07%) 
Sudden death † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Hepatobiliary disorders     
Hepatic pain † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Hyperbilirubinaemia † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Immune system disorders     
Anaphylactic reaction † 1     
# participants affected / at risk   3/548 (0.55%)   0/562 (0.00%) 
Anaphylactic shock † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Drug hypersensitivity † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Hypersensitivity † 1     
# participants affected / at risk   5/548 (0.91%)   1/562 (0.18%) 
Serum sickness † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Infections and infestations     
Anal abscess † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Bacteraemia † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Bacterial sepsis † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Brain abscess † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Bronchitis † 1     
# participants affected / at risk   2/548 (0.36%)   2/562 (0.36%) 
Bronchitis bacterial † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Bronchopneumonia † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Catheter related infection † 1     
# participants affected / at risk   3/548 (0.55%)   0/562 (0.00%) 
Cellulitis † 1     
# participants affected / at risk   4/548 (0.73%)   0/562 (0.00%) 
Central line infection † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Clostridial infection † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Clostridium difficile colitis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Dengue fever † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Diverticulitis † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Febrile infection † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Gangrene † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Gastroenteritis † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Infection † 1     
# participants affected / at risk   3/548 (0.55%)   1/562 (0.18%) 
Laryngitis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Laryngotracheo bronchitis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Lobar pneumonia † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Lower respiratory tract infection † 1     
# participants affected / at risk   4/548 (0.73%)   2/562 (0.36%) 
Lung abscess † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Lung infection † 1     
# participants affected / at risk   2/548 (0.36%)   1/562 (0.18%) 
Nasopharyngitis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Neutropenic infection † 1     
# participants affected / at risk   9/548 (1.64%)   5/562 (0.89%) 
Neutropenic sepsis † 1     
# participants affected / at risk   9/548 (1.64%)   5/562 (0.89%) 
Parotitis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Peritonsillar abscess † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Pharyngitis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Pharyngotonsillitis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Pneumonia † 1     
# participants affected / at risk   19/548 (3.47%)   13/562 (2.31%) 
Pneumonia necrotising † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Pneumonia streptococcal † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Postoperative wound infection † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Pulmonary tuberculosis † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Pyothorax † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Respiratory tract infection † 1     
# participants affected / at risk   2/548 (0.36%)   2/562 (0.36%) 
Sepsis † 1     
# participants affected / at risk   9/548 (1.64%)   3/562 (0.53%) 
Septic shock † 1     
# participants affected / at risk   6/548 (1.09%)   0/562 (0.00%) 
Staphylococcal infection † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Staphylococcal sepsis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Urinary tract infection † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Wound infection † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Injury, poisoning and procedural complications     
Femoral neck fracture † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Femur fracture † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Lumbar vertebral fracture † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Overdose † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Investigations     
Aspiration bronchial † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Blood creatinine increased † 1     
# participants affected / at risk   5/548 (0.91%)   4/562 (0.71%) 
Blood glucose abnormal † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Blood potassium decreased † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Blood urea increased † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
C-reactive protein increased † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Karnofsky scale worsened † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Neutrophil count decreased † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Pulmonary arterial pressure increased † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Weight decreased † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
White blood cell count decreased † 1     
# participants affected / at risk   2/548 (0.36%)   1/562 (0.18%) 
Metabolism and nutrition disorders     
Anorexia † 1     
# participants affected / at risk   4/548 (0.73%)   2/562 (0.36%) 
Dehydration † 1     
# participants affected / at risk   12/548 (2.19%)   9/562 (1.60%) 
Diabetes mellitus † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Fluid overload † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Hypercreatininaemia † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Hyperglycaemia † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Hyperkalaemia † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Hypocalcaemia † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Hypoglycaemia † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Hypokalaemia † 1     
# participants affected / at risk   4/548 (0.73%)   0/562 (0.00%) 
Hypomagnesaemia † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Hyponatraemia † 1     
# participants affected / at risk   2/548 (0.36%)   1/562 (0.18%) 
Metabolic acidosis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthralgia † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Back pain † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Bone pain † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Muscular weakness † 1     
# participants affected / at risk   0/548 (0.00%)   2/562 (0.36%) 
Musculoskeletal pain † 1     
# participants affected / at risk   2/548 (0.36%)   1/562 (0.18%) 
Neck pain † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Pathological fracture † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Malignant neoplasm progression † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Metastases to heart † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Metastases to meninges † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Neoplasm progression † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Testis cancer † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Tumour pain † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Nervous system disorders     
Altered state of consciousness † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Cerebellar syndrome † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Cerebral artery embolism † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Cerebral haemorrhage † 1     
# participants affected / at risk   0/548 (0.00%)   2/562 (0.36%) 
Cerebral infarction † 1     
# participants affected / at risk   0/548 (0.00%)   2/562 (0.36%) 
Cerebral ischaemia † 1     
# participants affected / at risk   3/548 (0.55%)   0/562 (0.00%) 
Cerebrovascular accident † 1     
# participants affected / at risk   2/548 (0.36%)   5/562 (0.89%) 
Cognitive disorder † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Coma † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Convulsion † 1     
# participants affected / at risk   3/548 (0.55%)   0/562 (0.00%) 
Coordination abnormal † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Depressed level of consciousness † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Dizziness † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Dysarthria † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Embolic cerebral infarction † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Epilepsy † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Headache † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Hemiparesis † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Hemiplegia † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Horner's syndrome † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Monoparesis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Nervous system disorder † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Neuralgia † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Paraparesis † 1     
# participants affected / at risk   0/548 (0.00%)   2/562 (0.36%) 
Paraplegia † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Somnolence † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Speech disorder † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Spinal cord compression † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Syncope † 1     
# participants affected / at risk   1/548 (0.18%)   2/562 (0.36%) 
Syncope vasovagal † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Transverse sinus thrombosis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Psychiatric disorders     
Agitation † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Confusional state † 1     
# participants affected / at risk   5/548 (0.91%)   4/562 (0.71%) 
Depression † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Hallucination † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Mental disorder † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Renal and urinary disorders     
Renal colic † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Renal failure † 1     
# participants affected / at risk   6/548 (1.09%)   6/562 (1.07%) 
Renal failure acute † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Renal impairment † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Acute respiratory distress syndrome † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Acute respiratory failure † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Apnoea † 1     
# participants affected / at risk   2/548 (0.36%)   0/562 (0.00%) 
Cough † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Dyspnoea † 1     
# participants affected / at risk   18/548 (3.28%)   13/562 (2.31%) 
Haemoptysis † 1     
# participants affected / at risk   3/548 (0.55%)   6/562 (1.07%) 
Hypoxia † 1     
# participants affected / at risk   0/548 (0.00%)   2/562 (0.36%) 
Lung infiltration † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Pleural effusion † 1     
# participants affected / at risk   2/548 (0.36%)   4/562 (0.71%) 
Pneumonitis † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Pneumothorax † 1     
# participants affected / at risk   1/548 (0.18%)   3/562 (0.53%) 
Pulmonary embolism † 1     
# participants affected / at risk   20/548 (3.65%)   13/562 (2.31%) 
Pulmonary haemorrhage † 1     
# participants affected / at risk   1/548 (0.18%)   2/562 (0.36%) 
Pulmonary oedema † 1     
# participants affected / at risk   1/548 (0.18%)   2/562 (0.36%) 
Respiratory distress † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Respiratory failure † 1     
# participants affected / at risk   14/548 (2.55%)   9/562 (1.60%) 
Respiratory tract haemorrhage † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Skin and subcutaneous tissue disorders     
Erythema † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Rash † 1     
# participants affected / at risk   4/548 (0.73%)   0/562 (0.00%) 
Rash maculo-papular † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Vascular disorders     
Arterial occlusive disease † 1     
# participants affected / at risk   0/548 (0.00%)   2/562 (0.36%) 
Arterial thrombosis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Axillary vein thrombosis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Deep vein thrombosis † 1     
# participants affected / at risk   9/548 (1.64%)   3/562 (0.53%) 
Embolism † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Haematoma † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Hypertension † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Hypertensive crisis † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Hypotension † 1     
# participants affected / at risk   5/548 (0.91%)   0/562 (0.00%) 
Iliac artery occlusion † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Jugular vein thrombosis † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Pelvic venous thrombosis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Peripheral ischaemia † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Phlebitis † 1     
# participants affected / at risk   0/548 (0.00%)   2/562 (0.36%) 
Shock † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Superior vena caval occlusion † 1     
# participants affected / at risk   1/548 (0.18%)   2/562 (0.36%) 
Thrombosis † 1     
# participants affected / at risk   2/548 (0.36%)   2/562 (0.36%) 
Varicose vein † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Vascular fragility † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Vasculitis † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Vena cava thrombosis † 1     
# participants affected / at risk   0/548 (0.00%)   1/562 (0.18%) 
Venous thrombosis † 1     
# participants affected / at risk   1/548 (0.18%)   1/562 (0.18%) 
Visceral arterial ischaemia † 1     
# participants affected / at risk   1/548 (0.18%)   0/562 (0.00%) 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA (Unspecified)




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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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