Trial Outcomes & Findings for Effect of Liraglutide on Blood Glucose Control in Subjects With Type 2 Diabetes (NCT NCT00393718)

NCT ID: NCT00393718

Last Updated: 2017-03-08

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

400 participants

Primary outcome timeframe

after 24 weeks of treatment

Results posted on

2017-03-08

Participant Flow

75 sites in Japan.

Subjects included in the study were patients with type 2 diabetes treated with diet therapy only or diet therapy and one OAD (Oral Anti-Diabetic Drug). Subjects on OAD therapy discontinued their current treatment during the run-in period (Weeks 4-6 before dosing). A total of 411 subjects were randomised, 11 subjects were not exposed to study drug.

Participant milestones

Participant milestones
Measure	Liraglutide Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide Glibenclamide 1.25-2.5 mg + liraglutide placebo
Overall Study STARTED	268	132
Overall Study COMPLETED	225	110
Overall Study NOT COMPLETED	43	22

Reasons for withdrawal

Reasons for withdrawal
Measure	Liraglutide Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide Glibenclamide 1.25-2.5 mg + liraglutide placebo
Overall Study Adverse Event	20	8
Overall Study Protocol Violation	1	2
Overall Study Lack of Efficacy	10	9
Overall Study Hypoglycaemia	3	2
Overall Study Subject decision	5	0
Overall Study Withdrawal of consent	2	1
Overall Study Missed measurement	1	0
Overall Study Move	1	0

Baseline Characteristics

Effect of Liraglutide on Blood Glucose Control in Subjects With Type 2 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Liraglutide n=268 Participants Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=132 Participants Glibenclamide 1.25-2.5 mg + liraglutide placebo	Total n=400 Participants Total of all reporting groups
Age, Customized 20-29 years	4 participants n=93 Participants	0 participants n=4 Participants	4 participants n=27 Participants
Age, Customized 30-39 years	11 participants n=93 Participants	6 participants n=4 Participants	17 participants n=27 Participants
Age, Customized 40-49 years	43 participants n=93 Participants	20 participants n=4 Participants	63 participants n=27 Participants
Age, Customized 50-59 years	77 participants n=93 Participants	46 participants n=4 Participants	123 participants n=27 Participants
Age, Customized 60-69 years	98 participants n=93 Participants	40 participants n=4 Participants	138 participants n=27 Participants
Age, Customized 70- years	35 participants n=93 Participants	20 participants n=4 Participants	55 participants n=27 Participants
Age, Continuous	58.2 years STANDARD_DEVIATION 10.4 • n=93 Participants	58.5 years STANDARD_DEVIATION 10.4 • n=4 Participants	58.3 years STANDARD_DEVIATION 10.4 • n=27 Participants
Sex: Female, Male Female	85 Participants n=93 Participants	46 Participants n=4 Participants	131 Participants n=27 Participants
Sex: Female, Male Male	183 Participants n=93 Participants	86 Participants n=4 Participants	269 Participants n=27 Participants
BMI	24.90 kg/m2 STANDARD_DEVIATION 3.69 • n=93 Participants	24.62 kg/m2 STANDARD_DEVIATION 3.84 • n=4 Participants	24.81 kg/m2 STANDARD_DEVIATION 3.74 • n=27 Participants
Body Weight	66.19 kg STANDARD_DEVIATION 12.61 • n=93 Participants	65.43 kg STANDARD_DEVIATION 12.89 • n=4 Participants	65.94 kg STANDARD_DEVIATION 12.69 • n=27 Participants
Duration of diabetes	8.13 years STANDARD_DEVIATION 6.68 • n=93 Participants	8.48 years STANDARD_DEVIATION 6.84 • n=4 Participants	8.25 years STANDARD_DEVIATION 6.73 • n=27 Participants
HbA1c	8.27 percentage of total haemoglobin STANDARD_DEVIATION 0.75 • n=93 Participants	8.28 percentage of total haemoglobin STANDARD_DEVIATION 0.78 • n=4 Participants	8.28 percentage of total haemoglobin STANDARD_DEVIATION 0.76 • n=27 Participants

PRIMARY outcome

Timeframe: after 24 weeks of treatment

Population: Full Analysis Set (FAS) using LOCF (Last Observation Carried Forward) is all subjects who received at least one dose of study drug and have valid measurements both at baseline and at least one time point after baseline.

Outcome measures

Outcome measures
Measure	Liraglutide n=263 Participants Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=130 Participants Glibenclamide 1.25-2.5 mg + liraglutide placebo
Glycosylated Haemoglobin A1c (HbA1c) After 24 Weeks of Treatment	6.99 percentage of total haemoglobin Standard Error 0.07	7.50 percentage of total haemoglobin Standard Error 0.09

SECONDARY outcome

Timeframe: after 52 weeks of treatment

Outcome measures

Outcome measures
Measure	Liraglutide n=263 Participants Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=130 Participants Glibenclamide 1.25-2.5 mg + liraglutide placebo
Glycosylated Haemoglobin A1c (HbA1c) After 52 Weeks of Treatment	7.31 percentage of total haemoglobin Standard Error 0.08	7.80 percentage of total haemoglobin Standard Error 0.10

SECONDARY outcome

Timeframe: after 24 weeks of treatment

Outcome measures

Outcome measures
Measure	Liraglutide n=261 Participants Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=130 Participants Glibenclamide 1.25-2.5 mg + liraglutide placebo
Fasting Plasma Glucose After 24 Weeks of Treatment	137.2 mg/dL Standard Error 1.9	150.1 mg/dL Standard Error 2.5

SECONDARY outcome

Timeframe: after 52 weeks of treatment

Outcome measures

Outcome measures
Measure	Liraglutide n=261 Participants Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=130 Participants Glibenclamide 1.25-2.5 mg + liraglutide placebo
Fasting Plasma Glucose After 52 Weeks of Treatment	145.8 mg/dL Standard Error 2.4	157.5 mg/dL Standard Error 3.2

SECONDARY outcome

Timeframe: after 24 weeks of treatment

Postprandial glucose AUC measured 0-3 hours after a meal after 24 weeks of treatment

Outcome measures

Outcome measures
Measure	Liraglutide n=243 Participants Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=119 Participants Glibenclamide 1.25-2.5 mg + liraglutide placebo
Postprandial Glucose AUC After 24 Weeks of Treatment	557.54 mg/dL *h Standard Error 9.53	670.60 mg/dL *h Standard Error 12.69

SECONDARY outcome

Timeframe: after 52 weeks of treatment

Postprandial glucose AUC measured 0-3 hours after a meal after 52 weeks of treatment

Outcome measures

Outcome measures
Measure	Liraglutide n=228 Participants Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=112 Participants Glibenclamide 1.25-2.5 mg + liraglutide placebo
Postprandial Glucose AUC After 52 Weeks of Treatment	608.66 mg/dL *h Standard Error 11.18	683.17 mg/dL *h Standard Error 14.96

SECONDARY outcome

Timeframe: after 24 weeks of treatment

Plasma glucose (PG) profile measured after 24 weeks of treatment. The time points during the day were: Before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner, and at bedtime.

Outcome measures

Outcome measures
Measure	Liraglutide n=237 Participants Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=120 Participants Glibenclamide 1.25-2.5 mg + liraglutide placebo
Mean PG in 7-point Plasma Glucose Profile After 24 Weeks of Treatment	155.98 mg/dL Standard Error 2.61	173.61 mg/dL Standard Error 3.51

SECONDARY outcome

Timeframe: after 52 weeks of treatment

Mean plasma glucose(PG) in 7-point plasma glucose profile measured after 52 weeks of treatment. The 7 time points during the day were: Before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner, and at bedtime.

Outcome measures

Outcome measures
Measure	Liraglutide n=237 Participants Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=119 Participants Glibenclamide 1.25-2.5 mg + liraglutide placebo
Mean PG in 7-point Plasma Glucose Profile After 52 Weeks of Treatment	167.39 mg/dL Standard Error 3.22	184.60 mg/dL Standard Error 4.34

SECONDARY outcome

Timeframe: after 24 weeks of treatment

Mean postprandial plasma glucose (PG) increment in 7-point plasma glucose profile, ie the mean of the difference of plasma glucose measured before and after a meal, after 24 weeks of treatment. The 7 time points during the day were: Before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner, and at bedtime.

Outcome measures

Outcome measures
Measure	Liraglutide n=238 Participants Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=120 Participants Glibenclamide 1.25-2.5 mg + liraglutide placebo
Mean Postprandial PG Increment in 7-point Plasma Glucose Profile After 24 Weeks of Treatment	59.69 mg/dL Standard Error 2.83	79.66 mg/dL Standard Error 3.75

SECONDARY outcome

Timeframe: after 52 weeks of treatment

Mean postprandial plasma glucose (PG) increment in 7-point plasma glucose profile, ie the mean of the difference of plasma glucose measured before and after a meal, after 52 weeks of treatment. The 7 time points during the day were: Before breakfast, 120 minutes after start of breakfast, before lunch, 120 minutes after start of lunch, before dinner, 120 minutes after start of dinner, and at bedtime.

Outcome measures

Outcome measures
Measure	Liraglutide n=238 Participants Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=119 Participants Glibenclamide 1.25-2.5 mg + liraglutide placebo
Mean Postprandial PG Increment in 7-point Plasma Glucose Profile After 52 Weeks of Treatment	63.56 mg/dL Standard Error 2.96	76.59 mg/dL Standard Error 3.94

SECONDARY outcome

Timeframe: after 24 weeks of treatment

Outcome measures

Outcome measures
Measure	Liraglutide n=265 Participants Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=130 Participants Glibenclamide 1.25-2.5 mg + liraglutide placebo
Body Weight After 24 Weeks of Treatment	64.06 kg Standard Error 0.15	65.97 kg Standard Error 0.20

SECONDARY outcome

Timeframe: after 52 weeks of treatment

Outcome measures

Outcome measures
Measure	Liraglutide n=265 Participants Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=130 Participants Glibenclamide 1.25-2.5 mg + liraglutide placebo
Body Weight After 52 Weeks of Treatment	64.30 kg Standard Error 0.19	66.01 kg Standard Error 0.25

SECONDARY outcome

Timeframe: over 52 weeks of treatment

Population: Full Analysis Set (FAS) consists of all subjects who received at least one dose of study drug.

Hypoglycaemic episodes measured over 52 weeks of treatment. Hypoglycaemic episodes were defined as major, minor, or symptoms only. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L. Symptoms only if subject was able to treat her/himself and with no plasma glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L.

Outcome measures

Outcome measures
Measure	Liraglutide n=268 Participants Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=132 Participants Glibenclamide 1.25-2.5 mg + liraglutide placebo
Hypoglycaemic Episodes All hypoglycaemic episodes	0.694 number of events per year of exposure	3.843 number of events per year of exposure
Hypoglycaemic Episodes Major	0.000 number of events per year of exposure	0.000 number of events per year of exposure
Hypoglycaemic Episodes Minor	0.187 number of events per year of exposure	1.103 number of events per year of exposure
Hypoglycaemic Episodes Symptoms only	0.507 number of events per year of exposure	2.740 number of events per year of exposure

Adverse Events

Liraglutide

Serious events: 20 serious events

Other events: 172 other events

Deaths: 0 deaths

Glibenclamide

Serious events: 14 serious events

Other events: 91 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Liraglutide n=268 participants at risk Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=132 participants at risk Glibenclamide 1.25-2.5 mg + liraglutide placebo
Infections and infestations Nasopharyngitis	37.3% 100/268 • Number of events 183 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	43.2% 57/132 • Number of events 94 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Infections and infestations Bronchitis	4.1% 11/268 • Number of events 13 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	6.1% 8/132 • Number of events 11 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Gastrointestinal disorders Diarrhoea	9.7% 26/268 • Number of events 31 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	6.8% 9/132 • Number of events 12 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Gastrointestinal disorders Constipation	7.8% 21/268 • Number of events 23 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	5.3% 7/132 • Number of events 8 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Gastrointestinal disorders Stomach discomfort	5.2% 14/268 • Number of events 21 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	2.3% 3/132 • Number of events 5 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Gastrointestinal disorders Nausea	5.2% 14/268 • Number of events 24 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	1.5% 2/132 • Number of events 3 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Musculoskeletal and connective tissue disorders Back pain	6.3% 17/268 • Number of events 17 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	6.8% 9/132 • Number of events 9 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Musculoskeletal and connective tissue disorders Arthralgia	3.0% 8/268 • Number of events 9 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	8.3% 11/132 • Number of events 11 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Respiratory, thoracic and mediastinal disorders Upper respiratory tract inflammation	9.3% 25/268 • Number of events 48 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	6.8% 9/132 • Number of events 10 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain	0.75% 2/268 • Number of events 2 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	5.3% 7/132 • Number of events 7 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Eye disorders Diabetic retinopathy	6.0% 16/268 • Number of events 16 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	6.8% 9/132 • Number of events 10 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Nervous system disorders Headache	5.6% 15/268 • Number of events 22 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	4.5% 6/132 • Number of events 11 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Vascular disorders Hypertension	4.1% 11/268 • Number of events 11 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	5.3% 7/132 • Number of events 7 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).

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 acknowledges the Investigator's right to publish the entire results of the trial. Any such scientific paper, presentation, communication or other information concerning the investigation described in this protocol, must be submitted in writing to Novo Nordisk Trial Manager prior to submission for publication/presentation for comments. Comments will be given within four weeks from receipt of the manuscript.
Publication restrictions are in place

Restriction type: OTHER

Measure	Liraglutide n=268 participants at risk Liraglutide 0.9 mg + glibenclamide placebo	Glibenclamide n=132 participants at risk Glibenclamide 1.25-2.5 mg + liraglutide placebo
Cardiac disorders Acute myocardial infarction	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Cardiac disorders Myocardial infarction	0.75% 2/268 • Number of events 2 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.76% 1/132 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Gastrointestinal disorders Colonic polyp	0.00% 0/268 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.76% 1/132 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Gastrointestinal disorders Constipation	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Gastrointestinal disorders Inguinal hernia	0.00% 0/268 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.76% 1/132 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Gastrointestinal disorders Vomiting	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.76% 1/132 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Hepatobiliary disorders Cholelithiasis	0.00% 0/268 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.76% 1/132 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Infections and infestations Gangrene	0.00% 0/268 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.76% 1/132 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Infections and infestations Gastroenteritis	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Infections and infestations Pneumonia	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Injury, poisoning and procedural complications Arthropod sting	0.00% 0/268 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.76% 1/132 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/268 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.76% 1/132 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Injury, poisoning and procedural complications Ventriculoperitoneal shunt malfunction	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Investigations Aspartate aminotransferase increased	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Investigations Blood creatine phosphokinase MB	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Investigations Blood creatine phosphokinase increased	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Investigations Blood lactate dehydrogenase increased	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Musculoskeletal and connective tissue disorders Arthritis	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Musculoskeletal and connective tissue disorders Spinal ligament ossification	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bowen's disease	0.00% 0/268 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.76% 1/132 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastric cancer	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Laryngeal cancer	0.00% 0/268 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.76% 1/132 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic neoplasm	0.00% 0/268 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.76% 1/132 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Multiple myeloma	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal cancer	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cell carcinoma	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid neoplasm	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Nervous system disorders Cerebral infarction	0.00% 0/268 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	1.5% 2/132 • Number of events 2 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Nervous system disorders Dizziness	0.00% 0/268 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.76% 1/132 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Psychiatric disorders Suicide attempt	0.00% 0/268 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.76% 1/132 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Renal and urinary disorders Neurogenic bladder	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Reproductive system and breast disorders Endometriosis	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Respiratory, thoracic and mediastinal disorders Sleep apnoea syndrome	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).
Surgical and medical procedures Colon polypectomy	0.37% 1/268 • Number of events 1 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).	0.00% 0/132 • Adverse events were collected in a time span over 52 weeks. The safety analysis population consists of all subjects exposed to study drug (Full Analysis Set, FAS).