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A Study to Evaluate Annual Rate of Exacerbations and Safety of 3 Dosage Strengths of Fluticasone Furoate (FF)/GW642444 Inhalation Powder in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01017952
First received: November 19, 2009
Last updated: June 29, 2016
Last verified: June 2016
Results First Received: May 30, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Condition: Pulmonary Disease, Chronic Obstructive
Interventions: Drug: FF/GW642444 Inhalation Powder
Drug: GW642444 Inhalation Powder

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

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
At Visit (V) 1, eligible participants (par.) entered a 4-week, open-label Run-in Period (RIP) to establish a stable Baseline. At V 2, eligible par. were randomized to a 52-week, double-blind Treatment Period. 2635 par. were screened, 2092 par. entered the RIP, and 1635 par. were randomized, out of which 1633 par. received >=1 study treatment dose.

Reporting Groups
  Description
FP/SAL 250/50 µg BID Participants (Par.) were instructed to take open label Fluticasone Propionate and Salmeterol (FP/SAL) 250/50 microgram (µg) twice daily (BID) from the ACCUHALER/DISKUS, one inhalation each morning and evening with approximately 12 hours between doses. In addition, all par. were provided supplemental albuterol/salbutamol (metered dose inhaler [MDI] and/or nebules) to be used as needed throughout the study.
VI 25 µg QD Participants received a Vilanterol (VI) 25 µg dry inhalation powder once daily (QD) in the morning from the Dry Powder Inhaler (DPI) for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 50/25 µg QD Participants received a Fluticasone Furoate/Vilanterol (FF/VI) 50/25 µg inhalation powder QD in the morning from the NDPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 100/25 µg QD Participants received a FF/VI 100/25 µg inhalation powder QD in the morning from the NDPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 200/25 µg QD Participants received a FF/VI 200/25 µg inhalation powder QD in the morning from the NDPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.

Participant Flow for 2 periods

Period 1:   4-week, Open-label Run-In Period
    FP/SAL 250/50 µg BID   VI 25 µg QD   FF/VI 50/25 µg QD   FF/VI 100/25 µg QD   FF/VI 200/25 µg QD
STARTED   2092   0   0   0   0 
COMPLETED   1633   0   0   0   0 
NOT COMPLETED   459   0   0   0   0 
Did Not Meet Continuation Criteria                356                0                0                0                0 
Adverse Event                23                0                0                0                0 
Study Closed/Tterminated                1                0                0                0                0 
Lost to Follow-up                6                0                0                0                0 
Physician Decision                10                0                0                0                0 
Withdrawal by Subject                63                0                0                0                0 

Period 2:   52-week, Double-blind Treatment Period
    FP/SAL 250/50 µg BID   VI 25 µg QD   FF/VI 50/25 µg QD   FF/VI 100/25 µg QD   FF/VI 200/25 µg QD
STARTED   0   409   412   403   409 
Completed the Treatment Period   0   285 [1]   305 [1]   293 [1]   307 [1] 
COMPLETED   0   284 [2]   303 [2]   291 [2]   306 [2] 
NOT COMPLETED   0   125   109   112   103 
Adverse Event                0                25                32                35                30 
Withdrawal by Subject                0                30                22                25                25 
Lack of Efficacy                0                35                14                16                14 
Protocol Violation                0                7                11                9                8 
Met Protocol-Defined Stopping Criteria                0                11                13                12                9 
Study Closed/Terminated                0                1                1                0                0 
Lost to Follow-up                0                6                8                6                10 
Physician Decision                0                10                8                9                7 
[1] Par. completed the treatment period if they attended the last treatment visit (Visit 11).
[2] Par. completed the study if they completed the treatment period and safety follow-up phone contact.



  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
VI 25 µg QD Participants received a Vilanterol (VI) 25 µg dry inhalation powder once daily (QD) in the morning from the Dry Powder Inhaler (DPI) for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 50/25 µg QD Participants received a Fluticasone Furoate/Vilanterol (FF/VI) 50/25 µg inhalation powder QD in the morning from the NDPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 100/25 µg QD Participants received a FF/VI 100/25 µg inhalation powder QD in the morning from the NDPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 200/25 µg QD Participants received a FF/VI 200/25 µg inhalation powder QD in the morning from the NDPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
Total Total of all reporting groups

Baseline Measures
   VI 25 µg QD   FF/VI 50/25 µg QD   FF/VI 100/25 µg QD   FF/VI 200/25 µg QD   Total 
Overall Participants Analyzed 
[Units: Participants]
 409   412   403   409   1633 
Age 
[Units: Years]
Mean (Standard Deviation)
 63.6  (9.29)   63.7  (9.56)   64.0  (9.28)   63.5  (8.84)   63.7  (9.24) 
Gender 
[Units: Participants]
         
Female   174   181   181   191   727 
Male   235   231   222   218   906 
Race/Ethnicity, Customized 
[Units: Participants]
         
White   360   359   353   359   1431 
African American/ African Heritage   9   14   7   9   39 
Asian   4   3   5   3   15 
African American/African Heritage & White   0   1   1   0   2 
American Indian or Alaska Native & White   20   19   21   20   80 
Asian & White   0   0   0   1   1 
Native Hawaiian or other Pacific Islander   0   0   0   1   1 
American Indian or Alaska Native   16   16   16   16   64 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Annual Rate of Moderate and Severe COPD Exacerbations Expressed as Least Square Mean   [ Time Frame: From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal ]

2.  Secondary:   Time to First Occurrence of Moderate or Severe COPD Exacerbation   [ Time Frame: From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal ]

3.  Secondary:   Annual Rate of Exacerbations Requiring Systemic/Oral Corticosteroids Expressed as Least Square Mean   [ Time Frame: From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal ]

4.  Secondary:   Change From Baseline in Trough FEV1 at Week 52 (Visit 11)   [ Time Frame: Baseline to Visit 11 (Week 52)/Early Withdrawal ]


  Serious Adverse Events
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Time Frame Serious adverse events (SAEs) and non-serious AEs will be collected from Baseline to the end of the treatment period (up to 52 weeks).
Additional Description SAEs and non-serious adverse events are reported for members of the Intent-to-Treat Population, comprised of all randomized participants who received at least one dose of study medication during the treatment period.

Reporting Groups
  Description
VI 25 µg QD Participants received a Vilanterol (VI) 25 µg dry inhalation powder once daily (QD) in the morning from the Dry Powder Inhaler (DPI) for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 50/25 µg QD Participants received a Fluticasone Furoate/Vilanterol (FF/VI) 50/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 100/25 µg QD Participants received a FF/VI 100/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 200/25 µg QD Participants received a FF/VI 200/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.

Serious Adverse Events
    VI 25 µg QD   FF/VI 50/25 µg QD   FF/VI 100/25 µg QD   FF/VI 200/25 µg QD
Total, serious adverse events         
# participants affected / at risk   66/409 (16.14%)   71/412 (17.23%)   67/403 (16.63%)   61/409 (14.91%) 
Blood and lymphatic system disorders         
Anaemia † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   2/403 (0.50%)   0/409 (0.00%) 
Cardiac disorders         
Atrial fibrillation † 1         
# participants affected / at risk   1/409 (0.24%)   1/412 (0.24%)   2/403 (0.50%)   0/409 (0.00%) 
Acute myocardial infarction † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   2/403 (0.50%)   0/409 (0.00%) 
Angina pectoris † 1         
# participants affected / at risk   1/409 (0.24%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Bradycardia † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   2/409 (0.49%) 
Cardiac arrest † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   1/403 (0.25%)   0/409 (0.00%) 
Cardiac failure † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Myocardial infarction † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   1/409 (0.24%) 
Supraventricular tachycardia † 1         
# participants affected / at risk   2/409 (0.49%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Tachycardia † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   2/403 (0.50%)   0/409 (0.00%) 
Angina unstable † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Atrial flutter † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Cardiac failure congestive † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Cardiomyopathy † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Coronary artery disease † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Coronary artery stenosis † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Myocardial ischaemia † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Tachyarrhythmia † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Ventricular tachycardia † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Ear and labyrinth disorders         
Vertigo † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Endocrine disorders         
Hyperthyroidism † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   1/409 (0.24%) 
Eye disorders         
Eye haemorrhage † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Gastrointestinal disorders         
Abdominal hernia † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   1/409 (0.24%) 
Abdominal pain † 1         
# participants affected / at risk   0/409 (0.00%)   2/412 (0.49%)   0/403 (0.00%)   0/409 (0.00%) 
Constipation † 1         
# participants affected / at risk   0/409 (0.00%)   2/412 (0.49%)   0/403 (0.00%)   0/409 (0.00%) 
Small intestinal obstruction † 1         
# participants affected / at risk   1/409 (0.24%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Abdominal adhesions † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Diverticulum intestinal † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Duodenal ulcer † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Gastric ulcer † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Gastrooesophageal reflux disease † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Ileus † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Inguinal hernia † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Intestinal obstruction † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Intestinal perforation † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Megacolon † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Oesophageal achalasia † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Oesophageal stenosis † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Pancreatitis acute † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
General disorders         
Non-cardiac chest pain † 1         
# participants affected / at risk   2/409 (0.49%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Chest pain † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   1/409 (0.24%) 
Fatigue † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Hepatobiliary disorders         
Cholelithiasis † 1         
# participants affected / at risk   1/409 (0.24%)   1/412 (0.24%)   2/403 (0.50%)   0/409 (0.00%) 
Cholecystitis † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Cholecystitis acute † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Immune system disorders         
Anaphylactic shock † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Infections and infestations         
Pneumonia † 1         
# participants affected / at risk   6/409 (1.47%)   10/412 (2.43%)   12/403 (2.98%)   9/409 (2.20%) 
Infective exacerbation of chronic obstructive airways diseas † 1         
# participants affected / at risk   0/409 (0.00%)   2/412 (0.49%)   2/403 (0.50%)   3/409 (0.73%) 
Bronchitis † 1         
# participants affected / at risk   2/409 (0.49%)   2/412 (0.49%)   1/403 (0.25%)   0/409 (0.00%) 
Cellulitis † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   2/403 (0.50%)   1/409 (0.24%) 
Lower respiratory tract infection † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   2/409 (0.49%) 
Diverticulitis † 1         
# participants affected / at risk   1/409 (0.24%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Lobar pneumonia † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   2/403 (0.50%)   0/409 (0.00%) 
Urinary tract infection † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   1/409 (0.24%) 
Abscess limb † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Bacteraemia † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Gastroenteritis † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Lung abscess † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Pelvic inflammatory disease † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Pneumonia primary atypical † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Postoperative wound infection † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Pyelonephritis † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Tracheobronchitis † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Injury, poisoning and procedural complications         
Hip fracture † 1         
# participants affected / at risk   1/409 (0.24%)   2/412 (0.49%)   0/403 (0.00%)   0/409 (0.00%) 
Acetabulum fracture † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Concussion † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Contusion † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Fall † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Femur fracture † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Humerus fracture † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Muscle strain † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Pelvic fracture † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Rib fracture † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Road traffic accident † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Spinal compression fracture † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Traumatic haematoma † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Investigations         
Blood pressure increased † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Electrocardiogram abnormal † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Metabolism and nutrition disorders         
Hyponatraemia † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Gout † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Musculoskeletal and connective tissue disorders         
Arthralgia † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Musculoskeletal chest pain † 1         
# participants affected / at risk   2/409 (0.49%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Arthropathy † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Osteoarthritis † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Lung squamous cell carcinoma stage unspecified † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   1/403 (0.25%)   1/409 (0.24%) 
Prostate cancer † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   1/409 (0.24%) 
Small cell lung cancer stage unspecified † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   1/409 (0.24%) 
Thyroid cancer † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   2/409 (0.49%) 
B-cell lymphoma † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Basal cell carcinoma † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Bladder cancer † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Bladder neoplasm † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Bone neoplasm † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Breast cancer † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Bronchial neoplasm † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Laryngeal cancer † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Leukaemia † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Lung neoplasm † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Lung neoplasm malignant † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Malignant melanoma † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Metastases to bone † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Metastases to gastrointestinal tract † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Metastatic squamous cell carcinoma † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Neoplasm malignant † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Neoplasm recurrence † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Neuroendocrine tumour † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Pelvic neoplasm † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Pituitary tumour benign † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Renal cancer † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Renal cell carcinoma † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Skin cancer † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Squamous cell carcinoma † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Uterine leiomyoma † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Nervous system disorders         
Cerebrovascular accident † 1         
# participants affected / at risk   2/409 (0.49%)   1/412 (0.24%)   0/403 (0.00%)   1/409 (0.24%) 
Syncope † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   2/403 (0.50%)   0/409 (0.00%) 
Cerebral ischaemia † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Convulsion † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Ischaemic stroke † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Presyncope † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Subarachnoid haemorrhage † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Transient ischaemic attack † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Psychiatric disorders         
Major depression † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   1/409 (0.24%) 
Suicidal ideation † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Renal and urinary disorders         
Renal failure acute † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Calculus ureteric † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Haematuria † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Urinary bladder polyp † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Reproductive system and breast disorders         
Benign prostatic hyperplasia † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Cervical dysplasia † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Chronic obstructive pulmonary disease † 1         
# participants affected / at risk   25/409 (6.11%)   26/412 (6.31%)   29/403 (7.20%)   23/409 (5.62%) 
Pneumothorax † 1         
# participants affected / at risk   0/409 (0.00%)   2/412 (0.49%)   1/403 (0.25%)   1/409 (0.24%) 
Respiratory failure † 1         
# participants affected / at risk   0/409 (0.00%)   2/412 (0.49%)   0/403 (0.00%)   2/409 (0.49%) 
Dyspnoea † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   1/403 (0.25%)   1/409 (0.24%) 
Pleural effusion † 1         
# participants affected / at risk   1/409 (0.24%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Acute respiratory failure † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Chronic respiratory failure † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Haemoptysis † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Hypoxia † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Pulmonary bulla † 1         
# participants affected / at risk   0/409 (0.00%)   1/412 (0.24%)   0/403 (0.00%)   0/409 (0.00%) 
Pulmonary hypertension † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Pulmonary oedema † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Respiratory distress † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Skin and subcutaneous tissue disorders         
Angioedema † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Urticaria † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Vascular disorders         
Aortic aneurysm † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Arteriosclerosis † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Circulatory collapse † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Deep vein thrombosis † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   0/403 (0.00%)   1/409 (0.24%) 
Haemorrhage † 1         
# participants affected / at risk   0/409 (0.00%)   0/412 (0.00%)   1/403 (0.25%)   0/409 (0.00%) 
Labile blood pressure † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Peripheral arterial occlusive disease † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
Thrombophlebitis † 1         
# participants affected / at risk   1/409 (0.24%)   0/412 (0.00%)   0/403 (0.00%)   0/409 (0.00%) 
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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