Trial Outcomes & Findings for The Effect of Insulin Degludec in Combination With Liraglutide and Metformin in Subjects With Type 2 Diabetes Qualifying for Treatment Intensification (NCT NCT01664247)

NCT ID: NCT01664247

Last Updated: 2017-09-25

Results Overview

Change from baseline in HbA1c after 26 weeks of treatment

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 346 participants
• Primary outcome timeframe: Week 0, week 26
• Results posted on: 2017-09-25

Participant Flow

The trial was conducted at 129 sites in 11 countries randomised subjects: Canada (7), France (10), Germany (8), Israel (6), Italy (7), Serbia (7), South Africa (6), Ukraine (4), United Arab Emirates (3), United Kingdom (6), and United States (65).

Participant milestones

Measure	IDeg Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Overall Study STARTED	174	172
Overall Study Exposed	173	170
Overall Study COMPLETED	160	131
Overall Study NOT COMPLETED	14	41

Reasons for withdrawal

Measure	IDeg Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Overall Study Adverse Event	5	3
Overall Study Protocol Violation	3	5
Overall Study Withdrawal Criteria	1	4
Overall Study Unclassified	5	29

Baseline Characteristics

The Effect of Insulin Degludec in Combination With Liraglutide and Metformin in Subjects With Type 2 Diabetes Qualifying for Treatment Intensification

Baseline characteristics by cohort

Measure	IDeg n=174 Participants Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo n=172 Participants Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Total n=346 Participants Total of all reporting groups
Age, Continuous	57.0 years STANDARD_DEVIATION 10.0 • n=5 Participants	57.3 years STANDARD_DEVIATION 9.4 • n=7 Participants	57.2 years STANDARD_DEVIATION 9.7 • n=5 Participants
Sex: Female, Male Female	76 Participants n=5 Participants	68 Participants n=7 Participants	144 Participants n=5 Participants
Sex: Female, Male Male	98 Participants n=5 Participants	104 Participants n=7 Participants	202 Participants n=5 Participants
Glycosylated haemoglobin (HbA1c)	7.5 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 • n=5 Participants	7.6 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 • n=7 Participants	7.6 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 • n=5 Participants
Fasting plasma glucose (FPG)	8.7 mmol/L STANDARD_DEVIATION 2.1 • n=5 Participants	9.1 mmol/L STANDARD_DEVIATION 2.2 • n=7 Participants	8.9 mmol/L STANDARD_DEVIATION 2.2 • n=5 Participants

PRIMARY outcome

Timeframe: Week 0, week 26

Population: The FAS included all randomised subjects and missing data was imputed using last observation carried forward (LOCF).

Change from baseline in HbA1c after 26 weeks of treatment

Outcome measures

Measure	IDeg n=174 Participants Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo n=172 Participants Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%)	-0.99 percentage of glycosylated haemoglobin Standard Error 0.08	-0.07 percentage of glycosylated haemoglobin Standard Error 0.08

SECONDARY outcome

Timeframe: Week 0, week 26

Population: The FAS included all randomised subjects and missing data was imputed using LOCF. For 6 subjects FPG values were missing.

Change from baseline in FPG after 26 weeks of treatment

Outcome measures

Measure	IDeg n=172 Participants Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo n=168 Participants Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Change From Baseline in Fasting Plasma Glucose (FPG)	-2.60 mmol/L Standard Deviation 2.91	-0.28 mmol/L Standard Deviation 2.44

SECONDARY outcome

Timeframe: After 26 weeks of randomised treatment.

Population: The FAS included all randomised subjects and missing data was imputed using LOCF.

Number of responders for HbA1c below 7.0%, after 26 weeks of randomised treatment.

Outcome measures

Measure	IDeg n=174 Participants Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo n=172 Participants Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Number of Responders for HbA1c (Below 7.0 %)	77.6 percentage (%) of subjects	35.5 percentage (%) of subjects

SECONDARY outcome

Timeframe: Week 0, week 26

Population: The FAS included all randomised subjects and missing data was imputed using LOCF. For 8 subjects the baseline values were missing

Change from baseline after 26 weeks of treatment in the average of the pre-breakfast self measured plasma glucose (SMPG) measured on the day of the contact and the two days immediately prior to the contact. The least squares means presented are the estimated values after 26 weeks of treatment and the statistical analysis presents the treatment difference of the change from baseline values as the model is adjusted for baseline.

Outcome measures

Measure	IDeg n=171 Participants Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo n=167 Participants Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Change From Baseline in Mean Pre-breakfast Measurements Used for Titration	5.88 mmol/L Standard Error 0.14	8.23 mmol/L Standard Error 0.15

SECONDARY outcome

Timeframe: Week 0, week 26

Population: The FAS included all randomised subjects. The subjects not analysed were 12, 45, 46, 44, 44, 54, 56 and 21 subjects for before breakfast, 90 mins after breakfast, before lunch, 90 mins after start of lunch, before main evening meal, 90 mins after main evening meal, before bedtime and before breakfast the following day time points respectively.

The change from baseline in the 8-point SMPG profile after 26 weeks of randomised treatment. The least squares means presented are the estimated values after 26 weeks of treatment and the statistical analysis presents the treatment difference of the change from baseline values as the model is adjusted for baseline.

Outcome measures

Measure	IDeg n=172 Participants Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo n=169 Participants Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Change From Baseline in 8-point Profile Before breakfast, N=170, 164	5.85 mmol/L Standard Error 0.15	8.54 mmol/L Standard Error 0.16
Change From Baseline in 8-point Profile 90 min after breakfast, N=153, 148	7.65 mmol/L Standard Error 0.24	9.75 mmol/L Standard Error 0.25
Change From Baseline in 8-point Profile Before lunch, N=151,149	6.33 mmol/L Standard Error 0.18	8.34 mmol/L Standard Error 0.19
Change From Baseline in 8-point Profile 90 min after lunch, N=152,150	7.73 mmol/L Standard Error 0.21	9.67 mmol/L Standard Error 0.21
Change From Baseline in 8-point Profile Before evening meal, N=154,148	6.77 mmol/L Standard Error 0.20	9.51 mmol/L Standard Error 0.21
Change From Baseline in 8-point Profile 90 mins after evening meal, N=147,145	7.93 mmol/L Standard Error 0.21	9.65 mmol/L Standard Error 0.22
Change From Baseline in 8-point Profile Before bedtime, N=148, 142	7.21 mmol/L Standard Error 0.20	8.95 mmol/L Standard Error 0.21
Change From Baseline in 8-point Profile Before breakfast the next day, N=164,161	6.05 mmol/L Standard Error 0.17	8.55 mmol/L Standard Error 0.18

SECONDARY outcome

Timeframe: Week 0, week 26

Population: The FAS included all randomised subjects and missing data is imputed using LOCF. Mean values were missing for 11 subjects.

Change from baseline in mean of the 8-point profile after 26 weeks of randomised treatment.

Outcome measures

Measure	IDeg n=169 Participants Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo n=166 Participants Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Change From Baseline in Mean of the 8-point Profile	-2.3 mmol/L Standard Deviation 1.8	-0.5 mmol/L Standard Deviation 1.7

SECONDARY outcome

Timeframe: Weeks 0 - 26

Population: The safety analysis set (SAS) included all subjects who received at least one dose of the investigational product or its comparator.

Number of confirmed hypoglycaemic episodes from week 0 to 26 weeks of randomised treatment. A hypoglycaemic episode was defined as treatment emergent if the onset of the episode occurred after the first administration of investigational medicinal product and no later than 7 days after the last day on trial product. Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia or minor hypoglycaemic episodes.

Outcome measures

Measure	IDeg n=173 Participants Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo n=170 Participants Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Number of Hypoglycaemic Episodes	47 events	9 events

SECONDARY outcome

Timeframe: Weeks 0 - 26

Population: The SAS included all subjects who received at least one dose of the investigational product or its comparator.

Number of treatment emergent AEs (TEAEs) from week 0 to week 26 of the randomised treatment. A TEAE was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment.

Outcome measures

Measure	IDeg n=173 Participants Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo n=170 Participants Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Number of Adverse Events	285 events	252 events

SECONDARY outcome

Timeframe: Week 0, week 26

Population: The FAS included all randomised subjects and missing data was imputed using LOCF. For 3 subjects PRO scores were missing at the baseline and did not contribute to the analysis.

Change in subject's quality of life was evaluated using the Short-Form 36 Health Survey version 2 (SF-36®v2). Evaluations were performed at baseline and at the last treatment visit (week 26). SF-36 was assessed on a scale range of 0.65 to 80.73 for physical health and -8.81 to 81.65 for mental health respectively, where higher scores indicated a better quality of life. 0-100 scores from the SF-36 were converted to a norm-based score using a T-score transformation in order to obtain a direct interpretation in relation to the distribution of the scores in the 1998 U.S. general population.

Outcome measures

Measure	IDeg n=174 Participants Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo n=169 Participants Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Change From Baseline in Patient Reported Health-related Quality of Life Using the Short-Form 36 Health Survey Version 2 (SF-36®v2) Physical health	0.5 T-scores Standard Deviation 6.3	0.0 T-scores Standard Deviation 6.2
Change From Baseline in Patient Reported Health-related Quality of Life Using the Short-Form 36 Health Survey Version 2 (SF-36®v2) Mental health	0.6 T-scores Standard Deviation 8.1	-0.7 T-scores Standard Deviation 8.8

Adverse Events

IDeg

Serious events: 6 serious events

Other events: 33 other events

Deaths: 0 deaths

Placebo

Serious events: 9 serious events

Other events: 32 other events

Deaths: 0 deaths

Serious adverse events

Measure	IDeg n=173 participants at risk Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo n=170 participants at risk Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Cardiac disorders Atrial fibrillation	0.00% 0/173 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.59% 1/170 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Cardiac disorders Cardiac failure	0.00% 0/173 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.59% 1/170 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Cardiac disorders Cardiac failure congestive	0.00% 0/173 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.59% 1/170 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Cardiac disorders Tachycardia	0.00% 0/173 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.59% 1/170 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Cardiac disorders Ventricular tachycardia	0.00% 0/173 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.59% 1/170 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Abdominal hernia	0.58% 1/173 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/170 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Gastritis erosive	0.58% 1/173 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/170 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Upper respiratory tract infection	0.00% 0/173 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.59% 1/170 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Urosepsis	0.00% 0/173 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.59% 1/170 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/173 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.59% 1/170 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lentigo maligna stage II	0.58% 1/173 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/170 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	0.00% 0/173 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.59% 1/170 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Transitional cell carcinoma	0.00% 0/173 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.59% 1/170 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/173 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.59% 1/170 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Surgical and medical procedures Cholecystectomy	0.58% 1/173 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/170 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Surgical and medical procedures Diabetes mellitus management	0.58% 1/173 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/170 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Surgical and medical procedures Medical device removal	0.58% 1/173 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/170 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Vascular disorders Aortic stenosis	0.58% 1/173 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/170 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Vascular disorders Femoral artery occlusion	0.58% 1/173 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/170 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Vascular disorders Peripheral artery stenosis	0.58% 1/173 • Number of events 1 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/170 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.

Other adverse events

Measure	IDeg n=173 participants at risk Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.	Placebo n=170 participants at risk Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period.
Gastrointestinal disorders Diarrhoea	5.8% 10/173 • Number of events 10 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	7.6% 13/170 • Number of events 17 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Nasopharyngitis	8.1% 14/173 • Number of events 15 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	6.5% 11/170 • Number of events 12 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.
Investigations Lipase increased	5.8% 10/173 • Number of events 11 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.	7.6% 13/170 • Number of events 15 • The adverse events were collected in a time frame of 26 weeks + 7 days follow up. Adverse event with an onset date 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 SAS included all subjects who received at least one dose of the investigational product or its comparator.

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 any Investigator plans for publication 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 prior to submission for comments. Comments will be given within four weeks from receipt of the planned communication.
• Publication restrictions are in place

Restriction type: OTHER