Trial Outcomes & Findings for The Effect of Liraglutide Versus Placebo When Added to Basal Insulin Analogues With or Without Metformin in Subjects With Type 2 Diabetes (NCT NCT01617434)

NCT ID: NCT01617434

Last Updated: 2017-03-08

Results Overview

The estimated mean change from baseline in HbA1c after 26 weeks of treatment.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 451 participants
• Primary outcome timeframe: Week 0 to Week 26
• Results posted on: 2017-03-08

Participant Flow

The trial was conducted at 76 sites in 9 countries i.e. 3 sites in Argentina; 9 sites in Canada; 5 sites in Finland; 9 sites in Germany; 9 sites in India; 2 sites in Mexico; 7 sites in Netherlands; 3 sites in Serbia; 29 sites in United States.

Participant milestones

Measure	Liraglutide Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Placebo Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.
Overall Study STARTED	226	225
Overall Study Exposed	225	225
Overall Study COMPLETED	191	174
Overall Study NOT COMPLETED	35	51

Reasons for withdrawal

Measure	Liraglutide Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Placebo Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.
Overall Study Adverse Event	12	3
Overall Study Protocol Violation	8	7
Overall Study Withdrawal Criteria	12	37
Overall Study Unclassified	3	4

Baseline Characteristics

The Effect of Liraglutide Versus Placebo When Added to Basal Insulin Analogues With or Without Metformin in Subjects With Type 2 Diabetes

Baseline characteristics by cohort

Measure	Liraglutide n=225 Participants Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Placebo n=225 Participants Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Total n=450 Participants Total of all reporting groups
Age, Continuous	59.3 years STANDARD_DEVIATION 9.2 • n=5 Participants	57.5 years STANDARD_DEVIATION 11.1 • n=7 Participants	58.4 years STANDARD_DEVIATION 10.2 • n=5 Participants
Sex: Female, Male Female	105 Participants n=5 Participants	89 Participants n=7 Participants	194 Participants n=5 Participants
Sex: Female, Male Male	120 Participants n=5 Participants	136 Participants n=7 Participants	256 Participants n=5 Participants
Body Weight	90.23 kg STANDARD_DEVIATION 19.98 • n=5 Participants	91.85 kg STANDARD_DEVIATION 21.33 • n=7 Participants	91.04 kg STANDARD_DEVIATION 20.66 • n=5 Participants
Fasting Plasma Glucose (FPG)	8.32 mmol/L STANDARD_DEVIATION 2.89 • n=5 Participants	8.21 mmol/L STANDARD_DEVIATION 2.90 • n=7 Participants	8.27 mmol/L STANDARD_DEVIATION 2.89 • n=5 Participants
Glycosylated Haemoglobin (HbA1c)	8.22 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.81 • n=5 Participants	8.28 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.90 • n=7 Participants	8.25 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.86 • n=5 Participants

PRIMARY outcome

Timeframe: Week 0 to Week 26

Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial product (liraglutide or placebo) and who provided at least one post-baseline efficacy value. 215 subjects in the liraglutide arm and 217 subjects in the placebo arm contributed to the statistical analysis.

The estimated mean change from baseline in HbA1c after 26 weeks of treatment.

Outcome measures

Measure	Liraglutide n=215 Participants Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Placebo n=217 Participants Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.
Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 26	-1.30 percentage of glycosylated haemoglobin Standard Deviation 1.015	-0.11 percentage of glycosylated haemoglobin Standard Deviation 1.088

SECONDARY outcome

Timeframe: Week 0 to Week 26

Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial product (liraglutide or placebo) and who provided at least one post-baseline efficacy value. 213 subjects in the liraglutide arm and 217 subjects in the placebo arm contributed to the statistical analysis.

The estimated mean change from baseline in FPG after 26 weeks of treatment.

Outcome measures

Measure	Liraglutide n=213 Participants Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Placebo n=217 Participants Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.
Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26	-1.44 mmol/L Standard Deviation 2.494	-0.16 mmol/L Standard Deviation 3.006

SECONDARY outcome

Timeframe: Week 0 to Week 26

Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial product (liraglutide or placebo) and who provided at least one post-baseline efficacy value. 191 subjects in the liraglutide arm and 196 subjects in the placebo arm contributed to the statistical analysis.

The estimated mean change from baseline in mean SMPG of 7-point profile (7-points were before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner and at bedtime) after 26 weeks of treatment.

Outcome measures

Measure	Liraglutide n=191 Participants Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Placebo n=196 Participants Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.
Change in Mean Self-Measured Plasma Glucose (SMPG) of 7-Point Profile From Baseline to Week 26	-2.61 mmol/L Standard Deviation 2.248	-1.02 mmol/L Standard Deviation 3.061

SECONDARY outcome

Timeframe: Week 0 to Week 26

Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial product (liraglutide or placebo) and who provided at least one post-baseline efficacy value. 215 subjects in the liraglutide arm and 216 subjects in the placebo arm contributed to the statistical analysis.

The estimated mean change in body weight after 26 weeks of treatment.

Outcome measures

Measure	Liraglutide n=215 Participants Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Placebo n=216 Participants Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.
Change in Body Weight From Baseline to Week 26	-3.54 kg Standard Deviation 3.669	-0.42 kg Standard Deviation 3.909

SECONDARY outcome

Timeframe: At Week 26

Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial product (liraglutide or placebo) and who provided at least one post-baseline efficacy value. 211 subjects in the liraglutide arm and 217 subjects in the placebo arm contributed to the statistical analysis.

Number of subjects achieving HbA1c below 7.0% (American Diabetes Association [ADA] target) after 26 weeks of treatment

Outcome measures

Measure	Liraglutide n=211 Participants Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Placebo n=217 Participants Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.
Number of Subjects Achieving HbA1c Below 7.0% (American Diabetes Association [ADA] Target)	59.24 percentage of subjects	14.02 percentage of subjects

SECONDARY outcome

Timeframe: At Week 26

Population: Full analysis set (FAS) included all randomised subjects who received at least one dose of trial product and who provided at least one post-baseline efficacy value. 211 subjects in the liraglutide arm and 217 subjects in the placebo arm contributed to the statistical analysis.

Number of subjects achieving HbA1c below or equal to 6.5% (American Association of Clinical Endocrinologists [AACE] target) after 26 weeks of treatment.

Outcome measures

Measure	Liraglutide n=211 Participants Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Placebo n=217 Participants Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.
Number of Subjects Achieving HbA1c Below or Equal to 6.5% (American Association of Clinical Endocrinologists [AACE] Target)	42.91 percentage of subjects	3.60 percentage of subjects

SECONDARY outcome

Timeframe: Week 0 to Week 26 + 7 days follow up

Population: Safety analysis set includes all subjects who received at least one dose of the trial product.

An AE was defined as treatment emergent if the onset date (or increase in severity) was on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. The adverse events were categorised as 'serious' and 'non-serious' adverse events. Adverse events were also categorised according to the severity as 'mild', 'moderate' and 'severe' adverse events.

Outcome measures

Measure	Liraglutide n=225 Participants Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Placebo n=225 Participants Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.
Number of Adverse Events (AEs) During The Randomised Treatment Period Adverse Events	4918 Events/1000 years of patient exposure	3737 Events/1000 years of patient exposure
Number of Adverse Events (AEs) During The Randomised Treatment Period Serious Adverse Events	149 Events/1000 years of patient exposure	101 Events/1000 years of patient exposure
Number of Adverse Events (AEs) During The Randomised Treatment Period Severe Adverse Events	169 Events/1000 years of patient exposure	101 Events/1000 years of patient exposure
Number of Adverse Events (AEs) During The Randomised Treatment Period Moderate Adverse Events	1274 Events/1000 years of patient exposure	1060 Events/1000 years of patient exposure
Number of Adverse Events (AEs) During The Randomised Treatment Period Mild Adverse Events	3474 Events/1000 years of patient exposure	2575 Events/1000 years of patient exposure

SECONDARY outcome

Timeframe: Week 0 to Week 26 + 7 days follow up

Population: Safety analysis set includes all subjects who received at least one dose of the trial products.

A minor hypoglycaemic episode was defined as either, (a) an episode with symptoms consistent with hypoglycaemia with confirmation by blood glucose <2.8 mmol/L (50 mg/dL) or plasma glucose <3.1 mmol/L (56 mg/dL) that was handled by the subject him/herself or (b) any asymptomatic blood glucose value <2.8 mmol/L (50 mg/dL) or plasma glucose value <3.1 mmol/L (56 mg/dL).

Outcome measures

Measure	Liraglutide n=225 Participants Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Placebo n=225 Participants Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.
Number of Minor Hypoglycaemic Episodes During The Randomised Treatment Period	126 Events/100 years of patient exposure	83 Events/100 years of patient exposure

SECONDARY outcome

Timeframe: Week 0 to Week 26 + 7 days follow up

Population: Safety analysis set includes all subjects who received at least one dose of the trial products.

Severe hypoglycaemia episode was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions.

Outcome measures

Measure	Liraglutide n=225 Participants Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Placebo n=225 Participants Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.
Number of Severe Hypoglycaemic Episodes During The Randomised Treatment Period	0 Events/100 years of patient exposure	0 Events/100 years of patient exposure

Adverse Events

Placebo

Serious events: 7 serious events

Other events: 46 other events

Deaths: 0 deaths

Liraglutide

Serious events: 11 serious events

Other events: 103 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=225 participants at risk Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Liraglutide n=225 participants at risk Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.
Cardiac disorders Acute myocardial infarction	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Cardiac disorders Coronary artery disease	0.89% 2/225 • Number of events 2 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Gastrointestinal disorders Ileus	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Infections and infestations Arthritis bacterial	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Infections and infestations Cellulitis staphylococcal	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Infections and infestations Ear infection	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Infections and infestations Gastroenteritis	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Infections and infestations Genital herpes	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Infections and infestations Osteomyelitis	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Infections and infestations Pneumonia	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Infections and infestations Pyelonephritis	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Injury, poisoning and procedural complications Fall	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Injury, poisoning and procedural complications Incisional hernia	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Injury, poisoning and procedural complications Rib fracture	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Injury, poisoning and procedural complications Road traffic accident	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Injury, poisoning and procedural complications Tendon rupture	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Injury, poisoning and procedural complications Thoracic vertebral fracture	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Injury, poisoning and procedural complications Wound	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Investigations Electrocardiogram change	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Metabolism and nutrition disorders Hyperglycaemia	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of the tongue	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Nervous system disorders Intercostal neuralgia	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Psychiatric disorders Post-traumatic stress disorder	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Surgical and medical procedures Percutaneous coronary intervention	0.00% 0/225 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	0.44% 1/225 • Number of events 1 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.

Other adverse events

Measure	Placebo n=225 participants at risk Placebo was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the placebo was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.	Liraglutide n=225 participants at risk Liraglutide was administered subcutaneously (s.c. injection, under the skin) once daily (OD) for 26 weeks in combination with pre-trial basal insulin analogue regimen ± metformin. The starting dose of the liraglutide was 0.6 mg/day; dose was escalated to 1.2 mg/day after one week and 1.8 mg/day after 2 weeks; dose was maintained at 1.8 mg day for subsequent weeks until the end of the trial. All subjects continued their pre-trial insulin therapy of insulin glargine (100 U/mL, s.c. injection) or insulin detemir (100 U/mL, s.c. injection). Oral anti diabetic drug metformin was administered as a tablet with a total daily dose of ≥1500 mg, divided into one to three doses per day.
Gastrointestinal disorders Diarrhoea	4.9% 11/225 • Number of events 14 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	10.7% 24/225 • Number of events 29 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Gastrointestinal disorders Dyspepsia	0.89% 2/225 • Number of events 2 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	7.1% 16/225 • Number of events 20 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Gastrointestinal disorders Nausea	3.1% 7/225 • Number of events 8 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	22.2% 50/225 • Number of events 62 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Gastrointestinal disorders Vomiting	0.89% 2/225 • Number of events 3 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	8.9% 20/225 • Number of events 28 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Infections and infestations Influenza	7.1% 16/225 • Number of events 21 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	3.6% 8/225 • Number of events 11 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Infections and infestations Nasopharyngitis	6.2% 14/225 • Number of events 16 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	5.8% 13/225 • Number of events 19 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Investigations Lipase increased	2.2% 5/225 • Number of events 5 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	7.1% 16/225 • Number of events 16 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Metabolism and nutrition disorders Decreased appetite	2.2% 5/225 • Number of events 5 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	9.8% 22/225 • Number of events 22 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Musculoskeletal and connective tissue disorders Back pain	5.3% 12/225 • Number of events 13 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	5.3% 12/225 • Number of events 13 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.
Nervous system disorders Headache	7.1% 16/225 • Number of events 20 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.	3.6% 8/225 • Number of events 9 • Week 0 to Week 26 + 7 days follow up Safety analysis set includes all subjects who received at least one dose of the trial product.

Additional Information

Public Access to Clinical Trials

Novo Nordisk A/S

Email: clinicaltrials@novonordisk.com

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 this protocol. Any such communication must be submitted in writing to the Novo Nordisk trial manager before submission for comments. Comments will be given within four weeks from receipt of the planned communication.
• Publication restrictions are in place

Restriction type: OTHER