Trial Outcomes & Findings for Effect of Liraglutide in Obese Subjects With Moderate or Severe Obstructive Sleep Apnoea: SCALE™ - Sleep Apnoea (NCT NCT01557166)

Last Updated: 2017-11-01

Results Overview

Observed mean change from baseline in AHI (events/hour) after 32 weeks of treatment. AHI (apnoea and hypopnoea events per hour of sleep) is a measure used for the diagnosis and severity classification of obstructive sleep apnoea. AHI severity category: none ≤4.9; mild 5.0-14.9; moderate 15.0-29.9; severe ≥30.0 events/hour.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

359 participants

Primary outcome timeframe

Week 0, Week 32

Results posted on

2017-11-01

Participant Flow

The trial was conducted at 40 sites in 2 countries, as follows: United States: 35 sites; Canada: 5 sites.

The trial consisted of a 2-week screening period before randomisation.

Participant milestones

Participant milestones
Measure	Liraglutide 3.0 mg Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Placebo Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.
Overall Study STARTED	180	179
Overall Study Exposed	176	179
Overall Study COMPLETED	134	142
Overall Study NOT COMPLETED	46	37

Reasons for withdrawal

Reasons for withdrawal
Measure	Liraglutide 3.0 mg Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Placebo Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.
Overall Study Adverse Event	20	6
Overall Study Lack of Efficacy	2	1
Overall Study Protocol Violation	8	5
Overall Study Withdrawn consent	12	20
Overall Study Target dose not tolerated	1	0
Overall Study Psychiatric disorder	1	0
Overall Study Unclassified	2	5

Baseline Characteristics

Effect of Liraglutide in Obese Subjects With Moderate or Severe Obstructive Sleep Apnoea: SCALE™ - Sleep Apnoea

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Liraglutide 3.0 mg n=180 Participants Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Placebo n=179 Participants Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Total n=359 Participants Total of all reporting groups
Age, Continuous	48.6 years STANDARD_DEVIATION 9.9 • n=93 Participants	48.4 years STANDARD_DEVIATION 9.5 • n=4 Participants	48.5 years STANDARD_DEVIATION 9.7 • n=27 Participants
Sex: Female, Male Female	51 Participants n=93 Participants	50 Participants n=4 Participants	101 Participants n=27 Participants
Sex: Female, Male Male	129 Participants n=93 Participants	129 Participants n=4 Participants	258 Participants n=27 Participants
Body weight	116.5 kg STANDARD_DEVIATION 23.0 • n=93 Participants	118.7 kg STANDARD_DEVIATION 25.4 • n=4 Participants	117.6 kg STANDARD_DEVIATION 24.2 • n=27 Participants
Body mass index (BMI)	38.9 kg/m^2 STANDARD_DEVIATION 6.4 • n=93 Participants	39.4 kg/m^2 STANDARD_DEVIATION 7.4 • n=4 Participants	39.1 kg/m^2 STANDARD_DEVIATION 6.9 • n=27 Participants
Apnoea-hypopnoea index (AHI)	49.0 events/hour STANDARD_DEVIATION 27.5 • n=93 Participants	49.3 events/hour STANDARD_DEVIATION 27.5 • n=4 Participants	49.2 events/hour STANDARD_DEVIATION 27.4 • n=27 Participants
Fasting plasma glucose (FPG)	5.4 mmol/L STANDARD_DEVIATION 0.6 • n=93 Participants	5.4 mmol/L STANDARD_DEVIATION 0.9 • n=4 Participants	5.4 mmol/L STANDARD_DEVIATION 0.8 • n=27 Participants
Glycosylated haemoglobin (HbA1c)	5.7 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.4 • n=93 Participants	5.6 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.4 • n=4 Participants	5.7 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.4 • n=27 Participants

PRIMARY outcome

Timeframe: Week 0, Week 32

Population: Full analysis set (FAS) - included all randomised subjects. 334 subjects contributed to the statistical analysis.

Outcome measures

Outcome measures
Measure	Liraglutide 3.0 mg n=168 Participants Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Placebo n=166 Participants Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.
Change From Baseline in Apnoea-hypopnoea Index (AHI)	-12.22 events/hour Standard Deviation 23.34	-6.08 events/hour Standard Deviation 25.90

SECONDARY outcome

Timeframe: Week 0, week 32

Population: Full analysis set (FAS) - included all randomised subjects. 353 subjects contributed to the statistical analysis.

Observed mean change from baseline in fasting body weight (kg) after 32 weeks of treatment.

Outcome measures

Outcome measures
Measure	Liraglutide 3.0 mg n=175 Participants Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Placebo n=178 Participants Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.
Change From Baseline in Body Weight (kg)	-6.73 kg Standard Deviation 6.59	-1.87 kg Standard Deviation 5.44

SECONDARY outcome

Timeframe: Week 0, week 32

Population: Full analysis set (FAS) - included all randomised subjects. 355 subjects contributed to the statistical analysis.

Observed mean change from baseline in fasting plasma glucose (mmol/L) after 32 weeks of treatment.

Outcome measures

Outcome measures
Measure	Liraglutide 3.0 mg n=178 Participants Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Placebo n=177 Participants Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.
Change From Baseline in Fasting Plasma Glucose	-0.15 mmol/L Standard Deviation 0.69	0.17 mmol/L Standard Deviation 0.96

SECONDARY outcome

Timeframe: Week 0, week 32

Population: Full analysis set (FAS) - included all randomised subjects. 345 subjects contributed to the statistical analysis

Observed mean change from baseline in glycosylated haemoglobin (HbA1c) (%) after 32 weeks of treatment.

Outcome measures

Outcome measures
Measure	Liraglutide 3.0 mg n=174 Participants Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Placebo n=171 Participants Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.
Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%)	-0.36 percentage of glycosylated haemoglobin Standard Deviation 0.30	-0.17 percentage of glycosylated haemoglobin Standard Deviation 0.29

Adverse Events

Liraglutide 3.0 mg

Serious events: 6 serious events

Other events: 117 other events

Deaths: 0 deaths

Placebo

Serious events: 6 serious events

Other events: 84 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Liraglutide 3.0 mg n=176 participants at risk Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Placebo n=179 participants at risk Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.
Gastrointestinal disorders Constipation	11.9% 21/176 • Number of events 26 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	3.4% 6/179 • Number of events 7 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Gastrointestinal disorders Diarrhoea	16.5% 29/176 • Number of events 38 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	7.8% 14/179 • Number of events 17 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Gastrointestinal disorders Dyspepsia	8.5% 15/176 • Number of events 20 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	1.1% 2/179 • Number of events 2 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Gastrointestinal disorders Gastrooesophageal reflux disease	5.7% 10/176 • Number of events 11 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.00% 0/179 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Gastrointestinal disorders Nausea	26.7% 47/176 • Number of events 59 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	6.7% 12/179 • Number of events 14 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Gastrointestinal disorders Vomiting	7.4% 13/176 • Number of events 16 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	2.8% 5/179 • Number of events 5 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
General disorders Injection site haematoma	4.0% 7/176 • Number of events 8 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	7.3% 13/179 • Number of events 14 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Infections and infestations Influenza	5.1% 9/176 • Number of events 12 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	5.0% 9/179 • Number of events 9 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Infections and infestations Nasopharyngitis	8.5% 15/176 • Number of events 19 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	10.1% 18/179 • Number of events 20 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Infections and infestations Upper respiratory tract infection	10.2% 18/176 • Number of events 25 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	10.6% 19/179 • Number of events 25 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Investigations Lipase increased	5.1% 9/176 • Number of events 11 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	2.8% 5/179 • Number of events 6 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Musculoskeletal and connective tissue disorders Arthralgia	4.0% 7/176 • Number of events 7 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	5.0% 9/179 • Number of events 9 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Nervous system disorders Headache	14.2% 25/176 • Number of events 26 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	11.2% 20/179 • Number of events 23 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.

Additional Information

Public Access to Clinical Trials

Novo Nordisk A/S

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to review any scientific paper, presentation, communication or other information concerning the investigation described in the protocol. Novo Nordisk reserves the right to prior review of such publications and to ask for deferment of publication of individual site results until after the primary manuscript is accepted for publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	Liraglutide 3.0 mg n=176 participants at risk Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Placebo n=179 participants at risk Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.
Cardiac disorders Angina pectoris	1.1% 2/176 • Number of events 3 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.00% 0/179 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Cardiac disorders Angina unstable	0.00% 0/176 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.56% 1/179 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Cardiac disorders Myocardial infarction	0.00% 0/176 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.56% 1/179 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Cardiac disorders Sinus arrest	0.57% 1/176 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.00% 0/179 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/176 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.56% 1/179 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Gastrointestinal disorders Obstruction gastric	0.00% 0/176 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.56% 1/179 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Hepatobiliary disorders Cholecystitis	0.00% 0/176 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.56% 1/179 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Hepatobiliary disorders Cholelithiasis	0.57% 1/176 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.00% 0/179 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Infections and infestations Pneumonia	0.57% 1/176 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.00% 0/179 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Injury, poisoning and procedural complications Procedural pain	0.57% 1/176 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.00% 0/179 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Injury, poisoning and procedural complications Spinal fracture	0.57% 1/176 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.00% 0/179 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Metabolism and nutrition disorders Dehydration	0.57% 1/176 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.00% 0/179 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Musculoskeletal and connective tissue disorders Bone lesion	0.00% 0/176 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.56% 1/179 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/176 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.56% 1/179 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Psychiatric disorders Anxiety	0.57% 1/176 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.00% 0/179 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Psychiatric disorders Depression suicidal	0.57% 1/176 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.00% 0/179 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Psychiatric disorders Nightmare	0.00% 0/176 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.56% 1/179 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal swelling	0.57% 1/176 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.00% 0/179 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Respiratory, thoracic and mediastinal disorders Sleep apnoea syndrome	0.57% 1/176 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.00% 0/179 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.
Surgical and medical procedures Coronary revascularisation	0.57% 1/176 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.	0.56% 1/179 • Number of events 1 • Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment. Safety analysis set - included all randomised subjects exposed to trial drug.