Exacerbation Study (INVIGORATE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00845728
First received: February 15, 2009
Last updated: September 16, 2013
Last verified: September 2013
Results First Received: July 3, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Chronic Obstructive Pulmonary Disease
Interventions: Drug: Indacaterol 150 µg
Drug: Tiotropium

  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
3,444 patients were randomized, but only 3,439 received treatment as 5 patients were mis-randomized.

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
Indacaterol

Indacaterol 150 μg o.d., delivered via SDDPI o.d. plus placebo to tiotropium o.d.

delivered via the manufacturer’s proprietary inhalation device (Handihaler®)

Tiotropium Tiotropium 18 μg o.d. delivered via the manufacturer’s proprietary inhalation device (Handihaler®) plus placebo to indacaterol o.d. delivered via SDDPI

Participant Flow:   Overall Study
    Indacaterol     Tiotropium  
STARTED     1723     1721  
Exposed     1721     1718  
COMPLETED     1337     1379  
NOT COMPLETED     386     342  
Abnormal laboratory value (s)                 2                 2  
Patient's inability to use the device                 4                 6  
Abnormal test procedure result (s)                 7                 2  
Lost to Follow-up                 22                 13  
Death                 24                 26  
Administrative Problems                 34                 26  
Protocol Violation                 36                 24  
Lack of Efficacy                 51                 39  
Adverse Event                 101                 96  
Withdrawal by Subject                 105                 108  



  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
Indacaterol

Indacaterol 150 μg o.d., delivered via SDDPI o.d. plus placebo to tiotropium o.d.

delivered via the manufacturer’s proprietary inhalation device (Handihaler®)

Tiotropium Tiotropium 18 μg o.d. delivered via the manufacturer’s proprietary inhalation device (Handihaler®) plus placebo to indacaterol o.d. delivered via SDDPI
Total Total of all reporting groups

Baseline Measures
    Indacaterol     Tiotropium     Total  
Number of Participants  
[units: participants]
  1721     1718     3439  
Age, Customized  
[units: Participants]
     
<65 years     929     909     1838  
≥ 65 years     792     809     1601  
Gender  
[units: Participants]
     
Female     377     405     782  
Male     1344     1313     2657  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Trough Forced Expiratory Volume in 1 Second (FEV1).   [ Time Frame: 12 weeks ]

2.  Secondary:   Rate of COPD Exacerbations   [ Time Frame: 52 weeks ]


  Serious Adverse Events
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Time Frame No text entered.
Additional Description No text entered.

Reporting Groups
  Description
IndIndacaterol Indacaterol 150 μg o.d., delivered via SDDPI o.d. plus placebo to tiotropium o.d. delivered via the manufacturer’s proprietary inhalation device (Handihaler®)
Tiotropium Tiotropium 18 μg o.d. delivered via the manufacturer’s proprietary inhalation device (Handihaler®) plus placebo to indacaterol o.d. delivered via SDDPI

Serious Adverse Events
    IndIndacaterol     Tiotropium  
Total, serious adverse events      
# participants affected / at risk     263/1721 (15.28%)     255/1718 (14.84%)  
Blood and lymphatic system disorders      
Anaemia † 1    
# participants affected / at risk     0/1721 (0.00%)     3/1718 (0.17%)  
Iron deficiency anaemia † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Leukopenia † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Cardiac disorders      
Acute coronary syndrome † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Acute myocardial infarction † 1    
# participants affected / at risk     3/1721 (0.17%)     2/1718 (0.12%)  
Angina pectoris † 1    
# participants affected / at risk     5/1721 (0.29%)     5/1718 (0.29%)  
Angina unstable † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Aortic valve calcification † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Arrhythmia † 1    
# participants affected / at risk     3/1721 (0.17%)     1/1718 (0.06%)  
Arrhythmia supraventricular † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Arteriosclerosis coronary artery † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Atrial fibrillation † 1    
# participants affected / at risk     3/1721 (0.17%)     4/1718 (0.23%)  
Atrial flutter † 1    
# participants affected / at risk     2/1721 (0.12%)     1/1718 (0.06%)  
Atrioventricular block † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Atrioventricular block first degree † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Bradycardia † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Bundle branch block left † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Cardiac arrest † 1    
# participants affected / at risk     3/1721 (0.17%)     2/1718 (0.12%)  
Cardiac failure † 1    
# participants affected / at risk     3/1721 (0.17%)     5/1718 (0.29%)  
Cardiac failure chronic † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Cardiac failure congestive † 1    
# participants affected / at risk     3/1721 (0.17%)     1/1718 (0.06%)  
Cardio-respiratory arrest † 1    
# participants affected / at risk     3/1721 (0.17%)     2/1718 (0.12%)  
Cardiomegaly † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Cardiomyopathy † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Cardiopulmonary failure † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Congestive cardiomyopathy † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Cor pulmonale † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Coronary artery disease † 1    
# participants affected / at risk     1/1721 (0.06%)     3/1718 (0.17%)  
Cyanosis † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Diastolic dysfunction † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Ischaemic cardiomyopathy † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Left ventricular hypertrophy † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Mitral valve incompetence † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Myocardial infarction † 1    
# participants affected / at risk     4/1721 (0.23%)     8/1718 (0.47%)  
Myocardial ischaemia † 1    
# participants affected / at risk     6/1721 (0.35%)     4/1718 (0.23%)  
Palpitations † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Right ventricular failure † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Sinus bradycardia † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Supraventricular extrasystoles † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Tachyarrhythmia † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Ear and labyrinth disorders      
Hypoacusis † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Vertigo † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Endocrine disorders      
Goitre † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Eye disorders      
Angle closure glaucoma † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Cataract † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Maculopathy † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Retinal vein occlusion † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Gastrointestinal disorders      
Abdominal hernia † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Abdominal pain † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Abdominal pain upper † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Acute abdomen † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Ascites † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Colitis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Colitis ulcerative † 1    
# participants affected / at risk     0/1721 (0.00%)     3/1718 (0.17%)  
Colonic polyp † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Constipation † 1    
# participants affected / at risk     1/1721 (0.06%)     3/1718 (0.17%)  
Diarrhoea † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Diverticulum † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Duodenal fistula † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Duodenitis † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Enteritis † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Gastric ulcer † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Gastritis † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Gastrooesophageal reflux disease † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Haematemesis † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Ileus † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Inguinal hernia † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Intestinal ischaemia † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Intestinal obstruction † 1    
# participants affected / at risk     3/1721 (0.17%)     0/1718 (0.00%)  
Mallory-Weiss syndrome † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Melaena † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Nausea † 1    
# participants affected / at risk     2/1721 (0.12%)     0/1718 (0.00%)  
Oesophagitis † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Pancreatitis † 1    
# participants affected / at risk     0/1721 (0.00%)     3/1718 (0.17%)  
Pancreatitis acute † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Regurgitation † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Sigmoiditis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Small intestinal obstruction † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Thrombosis mesenteric vessel † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Umbilical hernia † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Upper gastrointestinal haemorrhage † 1    
# participants affected / at risk     2/1721 (0.12%)     1/1718 (0.06%)  
General disorders      
Chills † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Death † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Device dislocation † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Drug ineffective † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Malaise † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Multi-organ failure † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Non-cardiac chest pain † 1    
# participants affected / at risk     4/1721 (0.23%)     1/1718 (0.06%)  
Oedema due to cardiac disease † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Oedema peripheral † 1    
# participants affected / at risk     2/1721 (0.12%)     1/1718 (0.06%)  
Pyrexia † 1    
# participants affected / at risk     3/1721 (0.17%)     1/1718 (0.06%)  
Soft tissue inflammation † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Sudden cardiac death † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Sudden death † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Hepatobiliary disorders      
Bile duct stone † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Cholangitis acute † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Cholecystitis † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Cholelithiasis † 1    
# participants affected / at risk     1/1721 (0.06%)     2/1718 (0.12%)  
Gallbladder fistula † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Hepatic function abnormal † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Hyperbilirubinaemia † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Jaundice † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Immune system disorders      
Drug hypersensitivity † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Infections and infestations      
Anal abscess † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Appendicitis perforated † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Bronchitis † 1    
# participants affected / at risk     3/1721 (0.17%)     2/1718 (0.12%)  
Bronchitis bacterial † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Bronchopneumonia † 1    
# participants affected / at risk     2/1721 (0.12%)     3/1718 (0.17%)  
Clostridial infection † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Diverticulitis † 1    
# participants affected / at risk     1/1721 (0.06%)     2/1718 (0.12%)  
Gastroenteritis † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
H1N1 influenza † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Helicobacter infection † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Herpes zoster † 1    
# participants affected / at risk     1/1721 (0.06%)     4/1718 (0.23%)  
Influenza † 1    
# participants affected / at risk     4/1721 (0.23%)     2/1718 (0.12%)  
Intervertebral discitis † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Lobar pneumonia † 1    
# participants affected / at risk     4/1721 (0.23%)     4/1718 (0.23%)  
Lower respiratory tract infection † 1    
# participants affected / at risk     28/1721 (1.63%)     18/1718 (1.05%)  
Lower respiratory tract infection bacterial † 1    
# participants affected / at risk     4/1721 (0.23%)     2/1718 (0.12%)  
Lower respiratory tract infection viral † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Lung abscess † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Lung infection † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Meningitis † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Meningitis viral † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Nasopharyngitis † 1    
# participants affected / at risk     3/1721 (0.17%)     3/1718 (0.17%)  
Oral candidiasis † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Pneumococcal sepsis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Pneumonia † 1    
# participants affected / at risk     29/1721 (1.69%)     24/1718 (1.40%)  
Pneumonia bacterial † 1    
# participants affected / at risk     1/1721 (0.06%)     2/1718 (0.12%)  
Pneumonia pneumococcal † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Pneumonia staphylococcal † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Pseudomonas infection † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Pulmonary tuberculosis † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Respiratory tract infection bacterial † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Respiratory tract infection viral † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Sepsis † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Septic shock † 1    
# participants affected / at risk     1/1721 (0.06%)     3/1718 (0.17%)  
Sinusitis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Testicular abscess † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Tracheobronchitis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Upper respiratory tract infection † 1    
# participants affected / at risk     3/1721 (0.17%)     2/1718 (0.12%)  
Upper respiratory tract infection bacterial † 1    
# participants affected / at risk     18/1721 (1.05%)     16/1718 (0.93%)  
Urinary tract infection † 1    
# participants affected / at risk     1/1721 (0.06%)     2/1718 (0.12%)  
Urosepsis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Viral sepsis † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Viral upper respiratory tract infection † 1    
# participants affected / at risk     12/1721 (0.70%)     11/1718 (0.64%)  
Injury, poisoning and procedural complications      
Ankle fracture † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Concussion † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Contusion † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Fall † 1    
# participants affected / at risk     2/1721 (0.12%)     1/1718 (0.06%)  
Femoral neck fracture † 1    
# participants affected / at risk     1/1721 (0.06%)     2/1718 (0.12%)  
Femur fracture † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Hip fracture † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Penetrating abdominal trauma † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Post procedural fistula † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Rib fracture † 1    
# participants affected / at risk     2/1721 (0.12%)     1/1718 (0.06%)  
Tibia fracture † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Traumatic shock † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Investigations      
Arteriogram coronary † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
C-reactive protein increased † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Prostatic specific antigen increased † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Metabolism and nutrition disorders      
Decreased appetite † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Diabetes mellitus † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Diabetes mellitus inadequate control † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Hyperkalaemia † 1    
# participants affected / at risk     2/1721 (0.12%)     0/1718 (0.00%)  
Hyponatraemia † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Musculoskeletal and connective tissue disorders      
Axillary mass † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Back pain † 1    
# participants affected / at risk     4/1721 (0.23%)     0/1718 (0.00%)  
Cervical spinal stenosis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Exostosis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Intervertebral disc degeneration † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Intervertebral disc disorder † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Intervertebral disc protrusion † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Musculoskeletal chest pain † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Musculoskeletal pain † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Myalgia † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Neck pain † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Osteonecrosis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Rotator cuff syndrome † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Spinal column stenosis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Spinal osteoarthritis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
Benign neoplasm of prostate † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Bladder cancer † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Bladder papilloma † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Breast cancer † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Bronchial carcinoma † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Colon adenoma † 1    
# participants affected / at risk     2/1721 (0.12%)     0/1718 (0.00%)  
Colon cancer † 1    
# participants affected / at risk     2/1721 (0.12%)     1/1718 (0.06%)  
Colon neoplasm † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Gallbladder cancer † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Gastric cancer † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Glioblastoma † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Lung adenocarcinoma † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Lung cancer metastatic † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Lung neoplasm † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Lung neoplasm malignant † 1    
# participants affected / at risk     4/1721 (0.23%)     5/1718 (0.29%)  
Metastases to central nervous system † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Metastases to peritoneum † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Myelofibrosis † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Neoplasm malignant † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Neoplasm prostate † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Ovarian cancer † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Pancreatic carcinoma † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Prostate cancer † 1    
# participants affected / at risk     3/1721 (0.17%)     1/1718 (0.06%)  
Prostatic adenoma † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Rectal cancer † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Rectal neoplasm † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Renal cancer † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Salivary gland adenoma † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Squamous cell carcinoma of skin † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Nervous system disorders      
Amyotrophic lateral sclerosis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Brain injury † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Cerebral haemorrhage † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Cerebral infarction † 1    
# participants affected / at risk     2/1721 (0.12%)     1/1718 (0.06%)  
Cerebral ischaemia † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Cerebral thrombosis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Cerebrovascular accident † 1    
# participants affected / at risk     2/1721 (0.12%)     1/1718 (0.06%)  
Coma † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Depressed level of consciousness † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Dizziness † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Grand mal convulsion † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Haemorrhage intracranial † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Headache † 1    
# participants affected / at risk     2/1721 (0.12%)     0/1718 (0.00%)  
Hypoglycaemic coma † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Hypoxic-ischaemic encephalopathy † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Intracranial aneurysm † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Ischaemic stroke † 1    
# participants affected / at risk     2/1721 (0.12%)     0/1718 (0.00%)  
Lacunar infarction † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Memory impairment † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Peripheral sensorimotor neuropathy † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Peripheral sensory neuropathy † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Presyncope † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Sensory loss † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Spinal cord compression † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Syncope † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Transient ischaemic attack † 1    
# participants affected / at risk     2/1721 (0.12%)     4/1718 (0.23%)  
Vascular encephalopathy † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Psychiatric disorders      
Anxiety † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Completed suicide † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Confusional state † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Depression † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Renal and urinary disorders      
Bladder neck obstruction † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Haematuria † 1    
# participants affected / at risk     2/1721 (0.12%)     0/1718 (0.00%)  
Nephrotic syndrome † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Renal failure † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Renal failure acute † 1    
# participants affected / at risk     3/1721 (0.17%)     0/1718 (0.00%)  
Urethral stenosis † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Urinary retention † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Reproductive system and breast disorders      
Benign prostatic hyperplasia † 1    
# participants affected / at risk     2/1721 (0.12%)     3/1718 (0.17%)  
Respiratory, thoracic and mediastinal disorders      
Acute respiratory distress syndrome † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Acute respiratory failure † 1    
# participants affected / at risk     4/1721 (0.23%)     2/1718 (0.12%)  
Apnoea † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Chronic obstructive pulmonary disease † 1    
# participants affected / at risk     147/1721 (8.54%)     121/1718 (7.04%)  
Cough † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Dyspnoea † 1    
# participants affected / at risk     12/1721 (0.70%)     4/1718 (0.23%)  
Haemoptysis † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Hydrothorax † 1    
# participants affected / at risk     0/1721 (0.00%)     2/1718 (0.12%)  
Hypercapnia † 1    
# participants affected / at risk     2/1721 (0.12%)     1/1718 (0.06%)  
Hypoxia † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Interstitial lung disease † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Laryngeal oedema † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Lung disorder † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Lung infiltration † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Oropharyngeal pain † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Pleural effusion † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Pleurisy † 1    
# participants affected / at risk     2/1721 (0.12%)     2/1718 (0.12%)  
Pneumonia aspiration † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Pneumothorax † 1    
# participants affected / at risk     4/1721 (0.23%)     2/1718 (0.12%)  
Productive cough † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Pulmonary embolism † 1    
# participants affected / at risk     1/1721 (0.06%)     3/1718 (0.17%)  
Pulmonary oedema † 1    
# participants affected / at risk     2/1721 (0.12%)     0/1718 (0.00%)  
Respiratory acidosis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Respiratory failure † 1    
# participants affected / at risk     4/1721 (0.23%)     6/1718 (0.35%)  
Sleep apnoea syndrome † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Sputum increased † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Skin and subcutaneous tissue disorders      
Angioedema † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Vascular disorders      
Aortic aneurysm † 1    
# participants affected / at risk     2/1721 (0.12%)     0/1718 (0.00%)  
Aortic stenosis † 1    
# participants affected / at risk     2/1721 (0.12%)     0/1718 (0.00%)  
Circulatory collapse † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Deep vein thrombosis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Hypertension † 1    
# participants affected / at risk     2/1721 (0.12%)     1/1718 (0.06%)  
Hypertensive crisis † 1    
# participants affected / at risk     1/1721 (0.06%)     1/1718 (0.06%)  
Hypertensive emergency † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Hypotension † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Peripheral arterial occlusive disease † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Peripheral artery stenosis † 1    
# participants affected / at risk     1/1721 (0.06%)     0/1718 (0.00%)  
Peripheral ischaemia † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Phlebitis † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Varicose vein † 1    
# participants affected / at risk     0/1721 (0.00%)     1/1718 (0.06%)  
Events were collected by systematic assessment
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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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