A Study of Imatinib Versus Nilotinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) (ENESTnd)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00471497
First received: May 7, 2007
Last updated: October 14, 2013
Last verified: October 2013
Results First Received: April 10, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Myelogenous Leukemia, Chronic
Interventions: Drug: nilotinib
Drug: imatinib

  Participant Flow
  Hide Participant Flow

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
Not Completed Study means that the patient discontinued from the study by study day 294 (data cut-off).

Reporting Groups
  Description
Imatinib 400 mg QD Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated.
Nilotinb 300 mg BID Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Nilotinib 400 mg BID Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.

Participant Flow:   Overall Study
    Imatinib 400 mg QD     Nilotinb 300 mg BID     Nilotinib 400 mg BID  
STARTED     283     282     281  
SAFETY ANALYSIS SET     280 [1]   279 [1]   277 [1]
COMPLETED     237 [2]   247 [2]   241 [2]
NOT COMPLETED     46     35     40  
Adverse Event                 19                 11                 22  
Abnormal Laboratory Value                 3                 6                 4  
Abnormal Test Procedure                 1                 0                 1  
Condition no longer requires study drug                 0                 1                 0  
Withdrawal by Subject                 3                 5                 5  
Lost to Follow-up                 1                 2                 1  
Death                 0                 2                 0  
Disease Progression                 8                 2                 2  
Protocol Violation                 3                 3                 5  
Sub optimal response or treat. failure                 8                 3                 0  
[1] Safety set contained patients who received at least one dose of study medication.
[2] Completed means patient is on treatment in core phase of the study (ongoing) by data cut-off.



  Baseline Characteristics
  Hide Baseline Characteristics

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.
Patients in the Full Analysis Set (FAS) were analyzed according to the treatment they were randomized to regardless of actual treatment received.

Reporting Groups
  Description
Imatinib 400 mg QD Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated.
Nilotinb 300 mg BID Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Nilotinib 400 mg BID Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Total Total of all reporting groups

Baseline Measures
    Imatinib 400 mg QD     Nilotinb 300 mg BID     Nilotinib 400 mg BID     Total  
Number of Participants  
[units: participants]
  283     282     281     846  
Age, Customized  
[units: Participants]
       
<35 years     63     67     65     195  
>= 35 - <45 years     67     50     59     176  
>=45 - <55 years     63     72     65     200  
>=55 - < 65 years     55     57     64     176  
>=65 years     35     36     28     99  
Gender  
[units: participants]
       
Female     125     124     106     355  
Male     158     158     175     491  



  Outcome Measures

1.  Primary:   Molecular Response Rate (MMR) at 12 Months   [ Time Frame: Baseline, 12 months ]

2.  Secondary:   Rate of Durable MMR at 24 Months.   [ Time Frame: Baseline, 24 months ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No

3.  Secondary:   Rate Reduction in BCR-ABL Transcript Levels in Nilotinib Treatment Arms With Imatinib at 12 Months   [ Time Frame: Baseline, 12 months ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No

4.  Secondary:   Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months   [ Time Frame: Baseline, 12 months ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No


  Serious Adverse Events
  Hide Serious Adverse Events

Time Frame No text entered.
Additional Description Safety set contained patients who received at least one dose of study medication. Patients were summarized according to the safety treatment allocation (the treatment they actually received first).

Reporting Groups
  Description
Imatinib 400 mg QD Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated.
Nilotinib 300 mg BID Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Nilotinib 400 mg BID Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.

Serious Adverse Events
    Imatinib 400 mg QD     Nilotinib 300 mg BID     Nilotinib 400 mg BID  
Total, serious adverse events        
# participants affected / at risk     66/280 (23.57%)     64/279 (22.94%)     76/277 (27.44%)  
Blood and lymphatic system disorders        
Anaemia † 1      
# participants affected / at risk     1/280 (0.36%)     2/279 (0.72%)     5/277 (1.81%)  
Bone marrow failure † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Febrile neutropenia † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     2/277 (0.72%)  
Iron deficiency anaemia † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Leukocytosis † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Leukopenia † 1      
# participants affected / at risk     2/280 (0.71%)     1/279 (0.36%)     0/277 (0.00%)  
Neutropenia † 1      
# participants affected / at risk     1/280 (0.36%)     3/279 (1.08%)     4/277 (1.44%)  
Pancytopenia † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     1/277 (0.36%)  
Splenomegaly † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Thrombocytopenia † 1      
# participants affected / at risk     2/280 (0.71%)     5/279 (1.79%)     4/277 (1.44%)  
Cardiac disorders        
Acute myocardial infarction † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     3/277 (1.08%)  
Angina pectoris † 1      
# participants affected / at risk     1/280 (0.36%)     2/279 (0.72%)     7/277 (2.53%)  
Angina unstable † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Atrial fibrillation † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     2/277 (0.72%)  
Atrial thrombosis † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Brugada syndrome † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Cardiac arrest † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Cardiac failure congestive † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     1/277 (0.36%)  
Cardio-respiratory arrest † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Cardiogenic shock † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Coronary artery disease † 1      
# participants affected / at risk     0/280 (0.00%)     3/279 (1.08%)     4/277 (1.44%)  
Coronary artery stenosis † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     3/277 (1.08%)  
Myocardial infarction † 1      
# participants affected / at risk     1/280 (0.36%)     2/279 (0.72%)     2/277 (0.72%)  
Myocardial ischaemia † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     0/277 (0.00%)  
Palpitations † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     0/277 (0.00%)  
Pericardial effusion † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     1/277 (0.36%)  
Pericarditis † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Tachyarrhythmia † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Tachycardia † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Ventricular arrhythmia † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Congenital, familial and genetic disorders        
Trisomy 8 † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Ear and labyrinth disorders        
Vertigo † 1      
# participants affected / at risk     0/280 (0.00%)     2/279 (0.72%)     1/277 (0.36%)  
Endocrine disorders        
Hyperthyroidism † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Hypothyroidism † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     1/277 (0.36%)  
Eye disorders        
Amaurosis fugax † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Cataract † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Photophobia † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Retinopathy † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Visual impairment † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Gastrointestinal disorders        
Abdominal pain † 1      
# participants affected / at risk     2/280 (0.71%)     4/279 (1.43%)     5/277 (1.81%)  
Abdominal pain lower † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Abdominal pain upper † 1      
# participants affected / at risk     2/280 (0.71%)     0/279 (0.00%)     4/277 (1.44%)  
Anal inflammation † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Ascites † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Constipation † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Diarrhoea † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Duodenal ulcer † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Dyspepsia † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Enteritis † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Faecal vomiting † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Food poisoning † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Gastritis † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     2/277 (0.72%)  
Gastrointestinal disorder † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Gastrointestinal haemorrhage † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     2/277 (0.72%)  
Gastrooesophageal reflux disease † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Haemorrhoids † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     1/277 (0.36%)  
Ileus paralytic † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Intestinal obstruction † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     2/277 (0.72%)  
Intestinal stenosis † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Nausea † 1      
# participants affected / at risk     2/280 (0.71%)     1/279 (0.36%)     2/277 (0.72%)  
Oesophageal ulcer † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Pancreatic fistula † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Pancreatitis † 1      
# participants affected / at risk     0/280 (0.00%)     2/279 (0.72%)     1/277 (0.36%)  
Pancreatitis acute † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Peptic ulcer † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Peritoneal haemorrhage † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Rectal haemorrhage † 1      
# participants affected / at risk     0/280 (0.00%)     3/279 (1.08%)     0/277 (0.00%)  
Retroperitoneal haematoma † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Small intestinal obstruction † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Subileus † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Toothache † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Vomiting † 1      
# participants affected / at risk     3/280 (1.07%)     2/279 (0.72%)     4/277 (1.44%)  
General disorders        
Asthenia † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Chest pain † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     0/277 (0.00%)  
Death † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     1/277 (0.36%)  
Drug interaction † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Fatigue † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     1/277 (0.36%)  
Generalised oedema † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Hernia † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Inflammation † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Non-cardiac chest pain † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     2/277 (0.72%)  
Oedema peripheral † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     1/277 (0.36%)  
Performance status decreased † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Pyrexia † 1      
# participants affected / at risk     2/280 (0.71%)     3/279 (1.08%)     3/277 (1.08%)  
Spinal pain † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Thrombosis in device † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Hepatobiliary disorders        
Biliary colic † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     1/277 (0.36%)  
Cholelithiasis † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Drug-induced liver injury † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Hepatic function abnormal † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     3/277 (1.08%)  
Hepatic necrosis † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Hepatitis † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Hyperbilirubinaemia † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Infections and infestations        
Anal infection † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Appendicitis † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     0/277 (0.00%)  
Bronchitis † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Bronchopneumonia † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Campylobacter gastroenteritis † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Cellulitis † 1      
# participants affected / at risk     2/280 (0.71%)     1/279 (0.36%)     2/277 (0.72%)  
Escherichia urinary tract infection † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Gastroenteritis † 1      
# participants affected / at risk     2/280 (0.71%)     0/279 (0.00%)     1/277 (0.36%)  
Gastrointestinal infection † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
H1N1 influenza † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Haematoma infection † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Herpes zoster † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Infected skin ulcer † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Lower respiratory tract infection † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Oral infection † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Peritonitis † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Peritonitis bacterial † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Pneumonia † 1      
# participants affected / at risk     1/280 (0.36%)     2/279 (0.72%)     3/277 (1.08%)  
Pneumonia legionella † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Postoperative wound infection † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Pseudomonal sepsis † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Pulpitis dental † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Salpingitis † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Sepsis † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Sinusitis † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     1/277 (0.36%)  
Tracheobronchitis † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Upper respiratory tract infection † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Urinary tract infection † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Viral infection † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Viral rash † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Wound infection † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Injury, poisoning and procedural complications        
Abdominal injury † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Alcohol poisoning † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Brain contusion † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Cardiac valve replacement complication † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Chest injury † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Contusion † 1      
# participants affected / at risk     2/280 (0.71%)     0/279 (0.00%)     0/277 (0.00%)  
Coronary artery restenosis † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Facial bones fracture † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Fall † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Femoral neck fracture † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Femur fracture † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     1/277 (0.36%)  
Foot fracture † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Gun shot wound † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Hand fracture † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Head injury † 1      
# participants affected / at risk     2/280 (0.71%)     0/279 (0.00%)     0/277 (0.00%)  
Incorrect dose administered † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Intentional overdose † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Jaw fracture † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Joint injury † 1      
# participants affected / at risk     2/280 (0.71%)     0/279 (0.00%)     0/277 (0.00%)  
Laceration † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Ligament injury † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Ligament sprain † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Muscle rupture † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Pneumothorax traumatic † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Procedural pain † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Rib fracture † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Road traffic accident † 1      
# participants affected / at risk     3/280 (1.07%)     0/279 (0.00%)     2/277 (0.72%)  
Skeletal injury † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Spinal fracture † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Sternal fracture † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Subdural haematoma † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Subdural haemorrhage † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     0/277 (0.00%)  
Traumatic renal injury † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Upper limb fracture † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Vascular graft occlusion † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Wrist fracture † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Investigations        
Alanine aminotransferase increased † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Amylase increased † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Aspartate aminotransferase increased † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Blast cell count increased † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Blood alkaline phosphatase increased † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Blood creatine phosphokinase MB increased † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Blood creatinine increased † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Cardioactive drug level increased † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Electrocardiogram QT prolonged † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Gamma-glutamyltransferase increased † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Lipase increased † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     2/277 (0.72%)  
Troponin I increased † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     1/277 (0.36%)  
Troponin T increased † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Urine output decreased † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Metabolism and nutrition disorders        
Dehydration † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Diabetes mellitus † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Diabetes mellitus inadequate control † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Fluid overload † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Hyperkalaemia † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Hypoglycaemia † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Hyponatraemia † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Hypophosphataemia † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Musculoskeletal and connective tissue disorders        
Arthralgia † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Back pain † 1      
# participants affected / at risk     2/280 (0.71%)     2/279 (0.72%)     5/277 (1.81%)  
Foot deformity † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Intervertebral disc disorder † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     0/277 (0.00%)  
Intervertebral disc protrusion † 1      
# participants affected / at risk     3/280 (1.07%)     3/279 (1.08%)     0/277 (0.00%)  
Muscle haemorrhage † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Muscle spasms † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Muscular weakness † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Musculoskeletal pain † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Myalgia † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Osteoarthritis † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     1/277 (0.36%)  
Pain in extremity † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     1/277 (0.36%)  
Rheumatoid arthritis † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Spondyloarthropathy † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)        
Acute leukaemia † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
B-cell lymphoma † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Benign uterine neoplasm † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Blast crisis in myelogenous leukaemia † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Chloroma † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Colon cancer stage I † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Gastric cancer † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     1/277 (0.36%)  
Gastrointestinal stromal tumour † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Hepatic neoplasm malignant recurrent † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Leiomyoma † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Leukaemic retinopathy † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Liposarcoma † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Meningioma † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Metastases to liver † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Metastases to lung † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Metastases to lymph nodes † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Metastatic neoplasm † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Ovarian epithelial cancer † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Pancreatic neuroendocrine tumour † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Paraproteinaemia † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Prostate cancer † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     1/277 (0.36%)  
Skin cancer † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Squamous cell carcinoma of skin † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Nervous system disorders        
Basilar artery stenosis † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Brain oedema † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Central nervous system lesion † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Cerebral haemorrhage † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     2/277 (0.72%)  
Cerebral infarction † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     0/277 (0.00%)  
Cerebrovascular accident † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     1/277 (0.36%)  
Cerebrovascular disorder † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Cervicobrachial syndrome † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Complicated migraine † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Depressed level of consciousness † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Dizziness † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     0/277 (0.00%)  
Epilepsy † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Headache † 1      
# participants affected / at risk     1/280 (0.36%)     3/279 (1.08%)     1/277 (0.36%)  
Hemiparesis † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Hypoaesthesia † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Ischaemic stroke † 1      
# participants affected / at risk     0/280 (0.00%)     2/279 (0.72%)     2/277 (0.72%)  
Migraine † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Multiple sclerosis † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Neuralgia † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Polyneuropathy † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Sciatica † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Speech disorder † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Syncope † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Transient ischaemic attack † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Pregnancy, puerperium and perinatal conditions        
Retained products of conception † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Psychiatric disorders        
Alcohol abuse † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Alcohol withdrawal syndrome † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Anxiety † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Completed suicide † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Confusional state † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Depression † 1      
# participants affected / at risk     1/280 (0.36%)     2/279 (0.72%)     2/277 (0.72%)  
Mental status changes † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Somatisation disorder † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Suicidal ideation † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Suicide attempt † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     1/277 (0.36%)  
Renal and urinary disorders        
Azotaemia † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Calculus ureteric † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Pelvi-ureteric obstruction † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Renal colic † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Renal failure † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Renal failure acute † 1      
# participants affected / at risk     2/280 (0.71%)     0/279 (0.00%)     1/277 (0.36%)  
Renal failure chronic † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Renal impairment † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Reproductive system and breast disorders        
Adnexa uteri pain † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Benign prostatic hyperplasia † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Breast swelling † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Endometrial hyperplasia † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Menstruation irregular † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Metrorrhagia † 1      
# participants affected / at risk     0/280 (0.00%)     2/279 (0.72%)     0/277 (0.00%)  
Ovarian cyst † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Ovarian cyst ruptured † 1      
# participants affected / at risk     2/280 (0.71%)     0/279 (0.00%)     0/277 (0.00%)  
Scrotal swelling † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Respiratory, thoracic and mediastinal disorders        
Aspiration † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Atelectasis † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Bronchial obstruction † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Dyspnoea † 1      
# participants affected / at risk     0/280 (0.00%)     3/279 (1.08%)     2/277 (0.72%)  
Haemothorax † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Interstitial lung disease † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Obstructive airways disorder † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Painful respiration † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Pharyngeal oedema † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Pleural effusion † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     1/277 (0.36%)  
Pneumothorax † 1      
# participants affected / at risk     1/280 (0.36%)     1/279 (0.36%)     0/277 (0.00%)  
Pulmonary haemorrhage † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Pulmonary oedema † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Respiratory failure † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Skin and subcutaneous tissue disorders        
Angioedema † 1      
# participants affected / at risk     1/280 (0.36%)     0/279 (0.00%)     0/277 (0.00%)  
Urticaria † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Vascular disorders        
Aortic aneurysm † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Aortic stenosis † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     1/277 (0.36%)  
Arterial occlusive disease † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Arterial stenosis limb † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Arteriosclerosis † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Femoral arterial stenosis † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     1/277 (0.36%)  
Hypertension † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Hypertensive crisis † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Hypotension † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Iliac artery stenosis † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Intermittent claudication † 1      
# participants affected / at risk     0/280 (0.00%)     2/279 (0.72%)     0/277 (0.00%)  
Peripheral arterial occlusive disease † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     1/277 (0.36%)  
Thrombophlebitis † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Varicose vein † 1      
# participants affected / at risk     0/280 (0.00%)     1/279 (0.36%)     0/277 (0.00%)  
Vena cava thrombosis † 1      
# participants affected / at risk     0/280 (0.00%)     0/279 (0.00%)     1/277 (0.36%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA




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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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