Trial Outcomes & Findings for Roflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Fixed Dose Combinations of Long-acting β2-agonist (LABA) and Inhaled Corticosteroid (ICS) (NCT NCT01443845)

NCT ID: NCT01443845

Last Updated: 2017-04-13

Results Overview

Rate of moderate or severe COPD exacerbations, defined as requiring oral or parenteral glucocorticosteroids (moderate) or requiring hospitalization and/or leading to death (severe), during the double-blind treatment period.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 2354 participants
• Primary outcome timeframe: Baseline to Week 52
• Results posted on: 2017-04-13

Participant Flow

Recruitment occurred from September 2011 to October 2014 for a total of 380 study centers screened patients for the study: Italy, Spain, United States, Ukraine, Argentina, Russia, Philippines, Romania, Serbia, Canada, Malaysia, Thailand, Mexico, Peru and Taiwan.

The study consisted of 2 weeks of single-blind placebo lead-in with fixed-dose combination (FDC) long-acting β2-agonist(s) (LABA)/inhaled corticosteroid(s) (ICS) treatment followed by 52 weeks of double-blind treatment in addition to maintenance FDC LABA/ICS.

Participant milestones

Measure	Placebo Dose-matched placebo, oral administration, once per day.	Roflumilast Roflumilast 500 µg, oral administration, once per day
Overall Study STARTED	1176	1178
Overall Study COMPLETED	922	841
Overall Study NOT COMPLETED	254	337

Reasons for withdrawal

Measure	Placebo Dose-matched placebo, oral administration, once per day.	Roflumilast Roflumilast 500 µg, oral administration, once per day
Overall Study Protocol Violation	43	45
Overall Study Other reasons, such as COPD exacerbation	44	44
Overall Study Deterioration in pulmonary function	1	4
Overall Study Lack of Efficacy	10	5
Overall Study Adverse Event	64	138
Overall Study Withdrawal by Subject	63	67
Overall Study Military Conflict - Site Terminated	20	21
Overall Study Lost to Follow-up	9	13

Baseline Characteristics

Roflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Fixed Dose Combinations of Long-acting β2-agonist (LABA) and Inhaled Corticosteroid (ICS)

Baseline characteristics by cohort

Measure	Placebo n=1174 Participants Dose-matched placebo, oral administration, once per day.	Roflumilast n=1178 Participants Roflumilast 500 µg, oral administration, once per day	Total n=2352 Participants Total of all reporting groups
Age, Continuous	64.5 years STANDARD_DEVIATION 8.4 • n=5 Participants	64.4 years STANDARD_DEVIATION 8.8 • n=7 Participants	64.5 years STANDARD_DEVIATION 8.6 • n=5 Participants
Age, Customized Adults 40-65 years	634 Participants n=5 Participants	640 Participants n=7 Participants	1274 Participants n=5 Participants
Age, Customized Adults over 65 years	540 Participants n=5 Participants	538 Participants n=7 Participants	1078 Participants n=5 Participants
Sex/Gender, Customized Male	794 Participants n=5 Participants	821 Participants n=7 Participants	1615 Participants n=5 Participants
Sex/Gender, Customized Female	380 Participants n=5 Participants	357 Participants n=7 Participants	737 Participants n=5 Participants
Race/Ethnicity, Customized White	944 Participants n=5 Participants	935 Participants n=7 Participants	1879 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	27 Participants n=5 Participants	35 Participants n=7 Participants	62 Participants n=5 Participants
Race/Ethnicity, Customized Asian	170 Participants n=5 Participants	167 Participants n=7 Participants	337 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	6 Participants n=5 Participants	16 Participants n=7 Participants	22 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Other	27 Participants n=5 Participants	23 Participants n=7 Participants	50 Participants n=5 Participants
Region of Enrollment Colombia	7 participants n=5 Participants	10 participants n=7 Participants	17 participants n=5 Participants
Region of Enrollment Argentina	197 participants n=5 Participants	198 participants n=7 Participants	395 participants n=5 Participants
Region of Enrollment Russian Federation	77 participants n=5 Participants	77 participants n=7 Participants	154 participants n=5 Participants
Region of Enrollment Romania	55 participants n=5 Participants	54 participants n=7 Participants	109 participants n=5 Participants
Region of Enrollment United States	458 participants n=5 Participants	457 participants n=7 Participants	915 participants n=5 Participants
Region of Enrollment Philippines	130 participants n=5 Participants	131 participants n=7 Participants	261 participants n=5 Participants
Region of Enrollment Ukraine	95 participants n=5 Participants	95 participants n=7 Participants	190 participants n=5 Participants
Region of Enrollment Malaysia	6 participants n=5 Participants	7 participants n=7 Participants	13 participants n=5 Participants
Region of Enrollment Thailand	18 participants n=5 Participants	16 participants n=7 Participants	34 participants n=5 Participants
Region of Enrollment Spain	6 participants n=5 Participants	6 participants n=7 Participants	12 participants n=5 Participants
Region of Enrollment Canada	14 participants n=5 Participants	15 participants n=7 Participants	29 participants n=5 Participants
Region of Enrollment Taiwan	7 participants n=5 Participants	6 participants n=7 Participants	13 participants n=5 Participants
Region of Enrollment Italy	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Region of Enrollment Mexico	22 participants n=5 Participants	22 participants n=7 Participants	44 participants n=5 Participants
Region of Enrollment Serbia	47 participants n=5 Participants	47 participants n=7 Participants	94 participants n=5 Participants
Region of Enrollment Peru	35 participants n=5 Participants	36 participants n=7 Participants	71 participants n=5 Participants
Ethnicity Hispanic or Latino	272 Participants n=5 Participants	268 Participants n=7 Participants	540 Participants n=5 Participants
Ethnicity Not Hispanic or Latino	902 Participants n=5 Participants	910 Participants n=7 Participants	1812 Participants n=5 Participants
ICS/LABA Therapy Advair	766 Participants n=5 Participants	768 Participants n=7 Participants	1534 Participants n=5 Participants
ICS/LABA Therapy Symbicort	408 Participants n=5 Participants	410 Participants n=7 Participants	818 Participants n=5 Participants
Long-acting muscarinic antagonist(s) (LAMA) use LAMA	546 Participants n=5 Participants	548 Participants n=7 Participants	1094 Participants n=5 Participants
Long-acting muscarinic antagonist(s) (LAMA) use No-LAMA	628 Participants n=5 Participants	630 Participants n=7 Participants	1258 Participants n=5 Participants
BMI Category Under weight: < 18.5	95 Participants n=5 Participants	100 Participants n=7 Participants	195 Participants n=5 Participants
BMI Category Normal weight: >= 18.5 to < 25	480 Participants n=5 Participants	468 Participants n=7 Participants	948 Participants n=5 Participants
BMI Category Over weight: >= 25 to < 30	347 Participants n=5 Participants	342 Participants n=7 Participants	689 Participants n=5 Participants
BMI Category Obese: >= 30	252 Participants n=5 Participants	268 Participants n=7 Participants	520 Participants n=5 Participants
Weight	72.57 kg STANDARD_DEVIATION 18.67 • n=5 Participants	73.63 kg STANDARD_DEVIATION 19.57 • n=7 Participants	73.10 kg STANDARD_DEVIATION 19.13 • n=5 Participants
Height	167.53 cm STANDARD_DEVIATION 9.39 • n=5 Participants	167.80 cm STANDARD_DEVIATION 9.35 • n=7 Participants	167.67 cm STANDARD_DEVIATION 9.37 • n=5 Participants
Body-Mass Index (BMI)	25.72 kg/m2 STANDARD_DEVIATION 5.72 • n=5 Participants	25.99 kg/m2 STANDARD_DEVIATION 5.91 • n=7 Participants	25.86 kg/m2 STANDARD_DEVIATION 5.82 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline to Week 52

Population: Intent-to-Treat Study Population

Rate of moderate or severe COPD exacerbations, defined as requiring oral or parenteral glucocorticosteroids (moderate) or requiring hospitalization and/or leading to death (severe), during the double-blind treatment period.

Outcome measures

Measure	Placebo n=1174 Participants Dose-matched placebo, oral administration, once per day.	Roflumilast n=1178 Participants Roflumilast 500 µg, oral administration, once per day
Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year.	1.27 COPD exacerbations per patient per year Interval 1.17 to 1.39	1.17 COPD exacerbations per patient per year Interval 1.06 to 1.28

SECONDARY outcome

Timeframe: Week 0 (Visit 2) to Week 52

Population: Intent-to-Treat Study Population

Rate of moderate or severe COPD exacerbations, defined as requiring hospitalization and/or leading to death (severe), during the double-blind treatment period.

Outcome measures

Measure	Placebo n=1174 Participants Dose-matched placebo, oral administration, once per day.	Roflumilast n=1178 Participants Roflumilast 500 µg, oral administration, once per day
Rate of COPD Exacerbations That Led to Hospitalization or Death (ie, Severe COPD Exacerbations)	0.29 COPD exacerbations per patient per year Interval 0.25 to 0.34	0.28 COPD exacerbations per patient per year Interval 0.23 to 0.33

SECONDARY outcome

Timeframe: Week 0 (Visit 2) to Week 52

Rate of moderate or severe COPD exacerbations treated with antibiotics during the double-blind treatment period.

Outcome measures

Measure	Placebo n=1174 Participants Dose-matched placebo, oral administration, once per day.	Roflumilast n=1178 Participants Roflumilast 500 µg, oral administration, once per day
Rate of Moderate or Severe COPD Exacerbations or COPD Exacerbations Treated With Antibiotics	1.45 COPD Exacerbations per Patient per Year Interval 1.34 to 1.57	1.31 COPD Exacerbations per Patient per Year Interval 1.2 to 1.43

SECONDARY outcome

Timeframe: Week 0 (Visit 2) to Week 52

Population: Intent-to-Treat Population who the completed 52-week treatment period

Mean change from randomization (Visit 2) over 52 weeks of treatment in predose forced expiratory volume in 1 second (FEV1)

Outcome measures

Measure	Placebo n=1105 Participants Dose-matched placebo, oral administration, once per day.	Roflumilast n=1054 Participants Roflumilast 500 µg, oral administration, once per day
Mean Change in Predose Forced Expiratory Volume in 1 Second (FEV1)	-0.0091 Liters Standard Error 0.0047	0.0441 Liters Standard Error 0.0048

Adverse Events

Placebo

Serious events: 162 serious events

Other events: 188 other events

Deaths: 0 deaths

Roflumilast

Serious events: 180 serious events

Other events: 317 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=1174 participants at risk Dose-matched placebo, oral administration, once per day.	Roflumilast n=1178 participants at risk Roflumilast 500 µg, oral administration, once per day
Blood and lymphatic system disorders Leukocytosis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Blood and lymphatic system disorders Anaemia macrocytic	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Syncope	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Pancreatitis acute	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Constipation	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.25% 3/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Cerebrovascular accident	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Cervical radiculopathy	0.00% 0/380 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.28% 1/357 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Haemorrhagic transformation stroke	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Ischaemic stroke	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Seizure	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Transient ischaemic attack	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Cerebral haemorrhage	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Cerebral ventricle dilatation	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Faeces soft	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Haemorrhoidal haemorrhage	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Dizziness	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Hydrocephalus	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Lumbar radiculopathy	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Presyncope	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Subarachnoid haemorrhage	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Headache	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.25% 3/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Vascular encephalopathy	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Drooling	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Hemiparesis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Eye disorders Glaucoma	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Eye disorders Cataract	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Eye disorders Hyphaema	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Eye disorders Keratitis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Eye disorders Mydriasis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Ear and labyrinth disorders Vertigo	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Ear and labyrinth disorders Vertigo positional	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.42% 5/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Nausea	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.25% 3/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Colitis ischaemic	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Intestinal obstruction	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Vomiting	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Abdominal hernia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Abdominal pain	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Abdominal strangulated hernia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Food poisoning	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Gastrointestinal angiodysplasia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Inguinal hernia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Peptic ulcer	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Portal hypertensive gastropathy	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Varices oesophageal	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Colitis	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Diarrhoea	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Dyspepsia	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Erosive duodenitis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Gastritis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Gastritis erosive	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Nasal polyps	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Obliterative bronchiolitis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Gastrointestinal ulcer haemorrhage	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary mass	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Bullous lung disease	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Hydrothorax	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Hyperventilation	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Sinus congestion	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Sputum retention	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Cough	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Lung infiltration	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Blood and lymphatic system disorders Anaemia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.34% 4/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Blood and lymphatic system disorders Iron deficiency anaemia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Haemorrhoids	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Periarthritis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Osteopenia	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Endocrine disorders Adrenal insufficiency	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Metabolism and nutrition disorders Hypokalaemia	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.25% 3/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Metabolism and nutrition disorders Cachexia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Metabolism and nutrition disorders Decreased appetite	0.26% 3/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Metabolism and nutrition disorders Dehydration	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Metabolism and nutrition disorders Malnutrition	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Metabolism and nutrition disorders Hypoglycaemia	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Metabolism and nutrition disorders Fluid imbalance	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Metabolism and nutrition disorders Gout	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Metabolism and nutrition disorders Hypercholesterolaemia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Metabolism and nutrition disorders Hypoalbuminaemia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Metabolism and nutrition disorders Dyslipidaemia	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Pneumonia	3.8% 45/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	4.0% 47/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Sepsis	0.34% 4/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.25% 3/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Gastroenteritis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.25% 3/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Pneumonia bacterial	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Septic shock	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Amoebic dysentery	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Atypical pneumonia	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Bronchitis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Cellulitis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Cholecystitis infective	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Clostridium difficile colitis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Endocarditis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Epididymitis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Escherichia urinary tract infection	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Infectious colitis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Infective exacerbation of bronchiectasis	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Influenza	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Lobar pneumonia	0.60% 7/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Localised infection	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Lower respiratory tract infection	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Mycobacterium avium complex infection	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Orchitis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Pneumonia staphylococcal	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Soft tissue infection	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Subcutaneous abscess	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Abdominal discomfort	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Dysphagia	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Salivary hypersecretion	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Renal and urinary disorders Acute kidney injury	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Renal and urinary disorders Haematuria	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Renal and urinary disorders Calculus ureteric	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Renal and urinary disorders Pollakiuria	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Renal and urinary disorders Urinary retention	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Renal and urinary disorders Azotaemia	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Hepatobiliary disorders Cholelithiasis	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Hepatobiliary disorders Cholecystitis acute	0.26% 3/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Hepatobiliary disorders Cholecystitis chronic	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Hepatobiliary disorders Cholecystitis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Hepatobiliary disorders Hepatic cirrhosis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Skin and subcutaneous tissue disorders Skin ulcer	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Skin and subcutaneous tissue disorders Decubitus ulcer	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Skin and subcutaneous tissue disorders Erythema	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Skin and subcutaneous tissue disorders Night sweats	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Skin and subcutaneous tissue disorders Pruritus	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Tooth infection	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Urinary tract infection	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Cervical spinal stenosis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Intervertebral disc degeneration	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Urosepsis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Patellofemoral pain syndrome	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Viral infection	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Polymyalgia rheumatica	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Bursitis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Mobility decreased	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Bronchopneumonia	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Osteochondrosis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Chronic hepatitis C	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Colonic abscess	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Device related sepsis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Diverticulitis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Gastroenteritis viral	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Lung infection	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Oesophageal candidiasis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Oral candidiasis	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Pneumonia pneumococcal	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Pneumonia pseudomonal	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Pulmonary tuberculosis	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Pyelonephritis acute	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Respiratory tract infection	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Systemic candida	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Tracheobronchitis viral	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Abdominal sepsis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Bronchitis bacterial	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Candida infection	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Fungal infection	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Furuncle	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Nasopharyngitis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Onychomycosis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Skin infection	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Tracheitis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Pharyngitis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Respiratory tract infection bacterial	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.26% 3/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Chronic respiratory failure	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Laryngeal granuloma	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Pregnancy, puerperium and perinatal conditions Pneumothorax spontaneous	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary congestion	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Respiratory muscle weakness	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Bronchiectasis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Bronchitis chronic	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Aortic aneurysm	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.25% 3/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Hypertension	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.25% 3/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Angiodysplasia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Hypovolaemic shock	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Deep vein thrombosis	0.26% 3/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Hypertensive crisis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Intermittent claudication	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Peripheral ischaemia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Phlebitis	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Superior vena cava syndrome	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Varicose vein	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Femoral artery occlusion	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Intra-abdominal haematoma	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Peripheral arterial occlusive disease	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Thrombophlebitis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Hypotension	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Vascular disorders Accelerated hypertension	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastric cancer	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.26% 3/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to liver	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma gastric	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenosquamous cell lung cancern	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer stage 0	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Epithelioid mesothelioma	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic cancer	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Invasive ductal breast carcinoma	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Laryngeal squamous cell carcinoma	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung squamous cell carcinoma metastatic	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to bone	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to lung	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to lymph nodes	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to spine	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to spleen	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neuroendocrine carcinoma	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic carcinoma	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Polycythaemia vera	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small cell lung cancer limited stage	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Brain neoplasm	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung carcinoma cell type unspecified stage IV	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung squamous cell carcinoma stage III	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer stage III	0.26% 1/380 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/357 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.25% 2/794 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/821 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectosigmoid cancer	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cell carcinoma	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of the cervix	0.26% 1/380 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/357 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Transitional cell carcinoma	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Immune system disorders Anaphylactic reaction	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Immune system disorders Seasonal allergy	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
General disorders Non-cardiac chest pain	0.26% 3/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.51% 6/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
General disorders Incarcerated hernia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
General disorders Multi-organ failure	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
General disorders Sudden cardiac death	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
General disorders Death	0.26% 3/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
General disorders Fatigue	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
General disorders Generalised oedema	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
General disorders Asthenia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
General disorders Discomfort	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
General disorders Oedema peripheral	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
General disorders Peripheral swelling	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
General disorders Pyrexia	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
General disorders Chest pain	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Psychiatric disorders Anxiety	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Psychiatric disorders Completed suicide	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Psychiatric disorders Confusional state	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Psychiatric disorders Depression	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Psychiatric disorders Major depression	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Psychiatric disorders Schizophrenia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Psychiatric disorders Suicidal ideation	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Psychiatric disorders Mental status changes	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Psychiatric disorders Insomnia	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Reproductive system and breast disorders Adnexa uteri mass	0.26% 1/380 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/357 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Reproductive system and breast disorders Adnexal torsion	0.26% 1/380 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/357 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.13% 1/794 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/821 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Fall	0.34% 4/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.25% 3/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Femur fracture	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Heat stroke	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Hip fracture	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Ligament sprain	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Post procedural haematoma	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Pulmonary contusion	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Rib fracture	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Road traffic accident	0.26% 3/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Clavicle fracture	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Contusion	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Eye injury	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Hand fracture	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Lower limb fracture	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Procedural pain	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Radius fracture	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Tibia fracture	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Toxicity to various agents	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Ulna fracture	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Injury, poisoning and procedural complications Upper limb fracture	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Investigations Oxygen saturation decreased	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Investigations Weight decreased	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Investigations Tinea pedis	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Investigations Nutritional condition abnormal	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Investigations Weight increased	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Acute myocardial infarction	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.59% 7/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Cardiac arrest	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.42% 5/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Atrial fibrillation	0.43% 5/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.34% 4/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Angina pectoris	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.25% 3/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Cardio-respiratory arrest	0.26% 3/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.25% 3/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Cardiogenic shock	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.25% 3/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Supraventricular tachycardia	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.25% 3/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Angina unstable	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Cardiac failure	0.26% 3/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Myocardial infarction	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.17% 2/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Acute coronary syndrome	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Arrhythmia	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Arrhythmia supraventricular	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Arteriosclerosis coronary artery	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Atrial flutter	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Atrioventricular block complete	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Cardiac failure congestive	0.34% 4/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Cardiomyopathy	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Cardiopulmonary failure	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Cor pulmonale acute	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Coronary artery disease	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Coronary artery insufficiency	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Left ventricular failure	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Stress cardiomyopathy	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Coronary artery occlusion	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Cardiac failure chronic	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Myocardial rupture	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Tachycardia	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Cardiac disorders Cardiomegaly	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Congenital, familial and genetic disorders Hydrocele	0.00% 0/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.08% 1/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Congenital, familial and genetic disorders Choledochal cyst	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Congenital, familial and genetic disorders Hypertrophic cardiomyopathy	0.09% 1/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.00% 0/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.51% 6/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.59% 7/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.43% 5/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.59% 7/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.17% 2/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	0.34% 4/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.

Other adverse events

Measure	Placebo n=1174 participants at risk Dose-matched placebo, oral administration, once per day.	Roflumilast n=1178 participants at risk Roflumilast 500 µg, oral administration, once per day
Investigations Weight decreased	2.3% 27/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	7.7% 91/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Nervous system disorders Headache	4.1% 48/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	6.8% 80/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Diarrhoea	3.1% 36/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	10.1% 119/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Gastrointestinal disorders Nausea	2.6% 30/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	5.3% 62/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.
Infections and infestations Upper respiratory tract infection	5.6% 66/1174 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.	5.1% 60/1178 • Adverse event data was collected from the start of the 52-week double-blind treatment period, to 30 days after the end of treatment.

Additional Information

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AstraZeneca

Phone: 1-877-240-9479

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Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: OTHER