Trial Outcomes & Findings for Comparison of the Efficacy and Safety of Two Intensification Strategies in Subjects With Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin (NCT NCT01388361)

NCT ID: NCT01388361

Last Updated: 2017-03-06

Results Overview

Values for change in HbA1c from baseline to 26 weeks of treatment period.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 413 participants
• Primary outcome timeframe: week 0, week 26
• Results posted on: 2017-03-06

Participant Flow

The trial was conducted at 119 sites in 12 countries: Austria (4), Belgium (4), Canada (15), Czech Republic (4), Denmark (6), Finland (6), France (4), Germany (12), Norway (6), Serbia (5), Spain (7) and United States (46). These sites enrolled subjects in the randomised or non-randomised arms of the trial.

Subjects treated with Insulin degludec (IDeg) once daily (OD) + metformin in trial NN1250-3643 (NCT01193309) were eligible for this trial. Eligible subjects with an HbA1c >/=7.0% at the end of 3643 trial were qualified to enter the extension trial 3948 and be randomised to add either liraglutide/insulin aspart to their prior IDeg + Met treatment.

Participant milestones

Measure	IDeg This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) \< 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	IDeg + Liraglutide All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	IDeg + IAsp OD Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.
Overall Study STARTED	236	88	89
Overall Study Exposed	234	87	86
Overall Study COMPLETED	224	76	75
Overall Study NOT COMPLETED	12	12	14

Reasons for withdrawal

Measure	IDeg This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) \< 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	IDeg + Liraglutide All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	IDeg + IAsp OD Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.
Overall Study Adverse Event	0	5	1
Overall Study Protocol Violation	0	0	2
Overall Study Withdrawal criteria	12	7	10
Overall Study Unclassified	0	0	1

Baseline Characteristics

Comparison of the Efficacy and Safety of Two Intensification Strategies in Subjects With Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin

Baseline characteristics by cohort

Measure	IDeg n=236 Participants This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) \< 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	IDeg + Liraglutide n=88 Participants All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	IDeg + IAsp OD n=89 Participants Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	Total n=413 Participants Total of all reporting groups
Age, Continuous	NA years STANDARD_DEVIATION NA • n=5 Participants	61.1 years STANDARD_DEVIATION 9.5 • n=7 Participants	60.9 years STANDARD_DEVIATION 8.8 • n=5 Participants	61.0 years STANDARD_DEVIATION 9.2 • n=4 Participants
Sex: Female, Male Female	NA Participants n=5 Participants	25 Participants n=7 Participants	36 Participants n=5 Participants	NA Participants n=4 Participants
Sex: Female, Male Male	NA Participants n=5 Participants	63 Participants n=7 Participants	53 Participants n=5 Participants	NA Participants n=4 Participants
Glycosylated haemoglobin (HbA1c)	NA percentage of glycosylated haemoglobin STANDARD_DEVIATION NA • n=5 Participants	7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 • n=7 Participants	7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 • n=5 Participants	7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.7 • n=4 Participants
Fasting plasma glucose (FPG)	NA mmol/L STANDARD_DEVIATION NA • n=5 Participants	6.4 mmol/L STANDARD_DEVIATION 2.4 • n=7 Participants	6.1 mmol/L STANDARD_DEVIATION 1.7 • n=5 Participants	6.3 mmol/L STANDARD_DEVIATION 2.1 • n=4 Participants

PRIMARY outcome

Timeframe: week 0, week 26

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

Values for change in HbA1c from baseline to 26 weeks of treatment period.

Outcome measures

Measure	IDeg n=236 Participants This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) \< 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	IDeg + Liraglutide n=88 Participants All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	IDeg + IAsp OD n=89 Participants Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.
Change From Baseline in HbA1c (%) (Glycosylated Haemoglobin)	0.10 percentage of glycosylated haemoglobin Standard Deviation 0.40	-0.74 percentage of glycosylated haemoglobin Standard Deviation 0.73	-0.39 percentage of glycosylated haemoglobin Standard Deviation 0.72

SECONDARY outcome

Timeframe: week 0, week 26

Population: Both sets of FAS and NAS included all randomised and non-randomised subjects in the treatment period. The FPG values were missing for 7 subjects in FAS (2 subjects with IDeg+ liraglutide; 5 subjects with IDeg+IAsp arm) and 10 subjects in NAS for IDeg arm at baseline. The missing data was imputed using LOCF.

Values for change in FPG in mmol/L from baseline to week 26 of randomised period.

Outcome measures

Measure	IDeg n=226 Participants This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) \< 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	IDeg + Liraglutide n=86 Participants All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	IDeg + IAsp OD n=84 Participants Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.
Change From Baseline in Fasting Plasma Glucose (FPG)	-1.23 mmol/L Standard Deviation 2.03	-0.14 mmol/L Standard Deviation 2.52	-0.04 mmol/L Standard Deviation 2.84

SECONDARY outcome

Timeframe: week 0, week 26

Population: Both sets of FAS and NAS included all randomised and non-randomised subjects in the treatment period and missing data was imputed using LOCF. At baseline, the body weight values were missing for 1 subject in IDeg + Liraglutide arm from FAS and 3 subjects in NAS for IDeg arm.

Corresponds to the values of change in body weight in kilograms from baseline to week 26.

Outcome measures

Measure	IDeg n=233 Participants This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) \< 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	IDeg + Liraglutide n=87 Participants All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	IDeg + IAsp OD n=89 Participants Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.
Change From Baseline in Body Weight	0.1 kg Standard Deviation 2.7	-1.0 kg Standard Deviation 1.3	0.3 kg Standard Deviation 0.9

SECONDARY outcome

Timeframe: Onset on or after the first day of exposure to investigational product for 26 weeks of treatment period and no later than 7 days after last exposure to investigational product.

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

Corresponds to number of treatment emergent hypoglycaemic events from onset on or after the first day of exposure to investigational product and no later than 7 days after last exposure to investigational product. Confirmed hypoglycaemia was defined as the pool of severe hypoglycaemic episodes and minor episodes with a plasma glucose (PG) value < 3.1 mmol/L (56 mg/dL).

Outcome measures

Measure	IDeg n=236 Participants This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) \< 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	IDeg + Liraglutide n=87 Participants All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	IDeg + IAsp OD n=86 Participants Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.
Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes Confirmed(severe+minor)	313 events	40 events	330 events
Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes Severe	1 events	0 events	0 events

Adverse Events

IDeg

Serious events: 11 serious events

Other events: 64 other events

Deaths: 0 deaths

IDeg + Liraglutide

Serious events: 4 serious events

Other events: 40 other events

Deaths: 0 deaths

IDeg + IAsp OD

Serious events: 5 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Measure	IDeg n=236 participants at risk This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) \< 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	IDeg + Liraglutide n=87 participants at risk All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	IDeg + IAsp OD n=86 participants at risk Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.
Cardiac disorders Acute myocardial infarction	0.42% 1/236 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Cardiac disorders Angina pectoris	0.42% 1/236 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Cardiac disorders Coronary artery disease	0.00% 0/236 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	1.1% 1/87 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Eye disorders Vitreous detachment	0.00% 0/236 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	1.2% 1/86 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/236 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	1.1% 1/87 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Pancreatitis	0.00% 0/236 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	1.2% 1/86 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
General disorders Chest pain	0.42% 1/236 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
General disorders Non-cardiac chest pain	0.85% 2/236 • Number of events 2 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Hepatobiliary disorders Cholelithiasis	0.42% 1/236 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Cellulitis	0.42% 1/236 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. 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% 0/236 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	1.2% 1/86 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Metabolism and nutrition disorders Diabetes mellitus inadequate control	0.00% 0/236 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	1.2% 1/86 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Metabolism and nutrition disorders Hypoglycaemia	0.42% 1/236 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.42% 1/236 • Number of events 2 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. 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) Bladder cancer	0.00% 0/236 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	1.1% 1/87 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Nervous system disorders Cerebrovascular accident	0.00% 0/236 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	1.2% 1/86 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Nervous system disorders Syncope	0.42% 1/236 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Renal and urinary disorders Calculus ureteric	0.42% 1/236 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Renal and urinary disorders Glomerulonephritis	0.42% 1/236 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.42% 1/236 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Vascular disorders Hypertensive crisis	0.42% 1/236 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/87 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Vascular disorders Peripheral vascular disorder	0.00% 0/236 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	1.1% 1/87 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.

Other adverse events

Measure	IDeg n=236 participants at risk This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) \< 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms.	IDeg + Liraglutide n=87 participants at risk All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.	IDeg + IAsp OD n=86 participants at risk Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period.
Gastrointestinal disorders Diarrhoea	3.4% 8/236 • Number of events 10 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	10.3% 9/87 • Number of events 12 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	1.2% 1/86 • Number of events 2 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Nausea	1.3% 3/236 • Number of events 3 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	20.7% 18/87 • Number of events 25 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	1.2% 1/86 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Gastrointestinal disorders Vomiting	1.7% 4/236 • Number of events 4 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	5.7% 5/87 • Number of events 5 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Bronchitis	5.5% 13/236 • Number of events 14 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	1.1% 1/87 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	2.3% 2/86 • Number of events 2 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Infections and infestations Nasopharyngitis	18.2% 43/236 • Number of events 54 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	10.3% 9/87 • Number of events 11 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	12.8% 11/86 • Number of events 12 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. 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	5.1% 12/236 • Number of events 15 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	4.6% 4/87 • Number of events 5 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	3.5% 3/86 • Number of events 3 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Investigations Lipase increased	0.00% 0/236 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	6.9% 6/87 • Number of events 7 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	0.00% 0/86 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.
Musculoskeletal and connective tissue disorders Pain in extremity	0.85% 2/236 • Number of events 2 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	5.7% 5/87 • Number of events 5 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.	1.2% 1/86 • Number of events 1 • Treatment emergent adverse events were collected during 26 week treatment period + 7 days follow up. The SAS included all subjects who received at least one dose of the investigational product or its comparator.

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