A Double-blinded Trial Comparing the Efficacy and Safety of Insulin Degludec/Liraglutide and Insulin Degludec Both in Combination With Metformin in Japanese Subjects With Type 2 Diabetes Mellitus Inadequately Controlled With Basal or Pre-mix/Combination Insulin Therapy and Oral Anti-diabetic Drugs

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02911948

Acronym

DUAL™ II Japan

Enrollment

210

Registered

2016-09-23

Start date

2016-09-21

Completion date

2017-11-22

Last updated

2021-04-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Diabetes, Diabetes Mellitus, Type 2

Brief summary

This trial is conducted in Asia. The aim of this trial is to compare the efficacy and safety of insulin degludec/liraglutide and insulin degludec both in combination with metformin in Japanese subjects with type 2 diabetes mellitus inadequately controlled with basal or pre-mix/combination insulin therapy and oral anti-diabetic drugs.

Interventions

DRUGInsulin degludec/liraglutide

Injected s.c. / subcutaneously (under the skin) once daily

DRUGInsulin degludec

Injected s.c. / subcutaneously (under the skin) once daily

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

20 Years to No maximum

Healthy volunteers

Inclusion criteria

* Male or female Japanese subjects, age at least 20 years at the time of signing informed consent * T2DM (type 2 diabetes mellitus) subjects (diagnosed clinically) for at least 6 months prior to screening * HbA1c (glycosylated haemoglobin) 7.5-11.0 per cent \[58 mmol/mol-97 mmol/mol\] (both inclusive) by central laboratory analysis * Subjects on stable daily insulin doses for at least 60 days prior to screening administered once or twice daily, either as basal insulin (e.g. IDeg, insulin glargine, insulin detemir, NPH insulin) or pre-mix/combination insulin (e.g. biphasic insulin aspart, insulin degludec/insulin aspart). Total daily insulin dose in the previous 60 days should be within 20-50 units, both inclusive, and on the day of screening, but fluctuations of plus/minus 20 per cent within the 60 days prior to screening are acceptable. The specified insulin treatment should be administered in combination with a stable daily dose of metformin within current approved Japanese label for at least 60 days prior to screening - additionally, the anti-diabetic treatment can be with or without a stable daily dose of one of the following other OADs (oral anti-diabetic drug): SU (sulfonylureas), glinides, alpha-glucosidase inhibitor, SGLT2i (sodium glucose co-transporter 2 inhibitor) or TZD (thiazolidinedione) within current approved Japanese label for at least 60 days prior to screening * Body Mass Index (BMI) equal or above 23 kg/m\^2

Exclusion criteria

* Receipt of any investigational medicinal product (IMP) within 30 days before screening * Use of any anti-diabetic drug in a period of 60 days before screening (except premix/ combination or basal insulin, metformin, SU, glinides, α-GI, SGLT2i, or TZD) or anticipated change in concomitant medication, which in the investigators opinion could interfere with glucose metabolism (e.g. systemic corticosteroids or bolus insulin) * Treatment with glucagon-like peptide-1 (GLP-1) receptor agonist during the last 60 days prior to screening and furthermore, the discontinuation of GLP-1 receptor agonist at any point in time must not have been due to safety concerns, tolerability issues or lack of efficacy, as judged by the investigator * Treatment with dipetidyl peptidase-4 (DPP-4) inhibitors during the last 60 days prior to screening - Impaired liver function, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) equal or above 2.5 times upper limit of normal * Renal impairment estimated Glomerular Filtration Rate (eGFR) below 60 mL/min/1.73m\^2 as per Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) * Screening calcitonin equal or above 50 ng/L * History of pancreatitis (acute or chronic) * Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN 2) * Subjects presently classified as being in New York Heart Association (NYHA) Class IV

Design outcomes

Primary

Measure	Time frame	Description
Change in Glycosylated Haemoglobin (HbA1c)	week 0, week 26	Change from baseline (week 0) in HbA1c after 26 weeks of treatment.

Secondary

Measure	Time frame	Description
Change in Fasting Plasma Glucose (FPG)	week 0, week 26	Change from baseline (week 0) in FPG after 26 weeks of treatment.
Responder (Yes/no): HbA1c Less Than or Equal to 6.5%	After 26 weeks	Number of subjects with HbA1c less than or equal to 6.5% after 26 weeks.
Responder (Yes/no): HbA1c Less Than or Equal to 6.5% and Without Weight Gain	After 26 weeks	Number of subjects with HbA1c less than or equal to 6.5% and without weight gain
Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes	During 26 weeks of treatment	Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product. Severe or BG confirmed hypoglycaemic episodes were defined as episodes that were severe according to the American Diabetes Association (ADA) classification or BG confirmed by a plasma glucose value \< 3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. Severe hypoglycaemia according to the ADA definition: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration.
Daily Insulin Dose	After 26 weeks	Actual daily total insulin dose after 26 weeks.
Responder (Yes/no): HbA1c Less Than 7.0%	After 26 weeks	Number of subjects with HbA1c less than 7.0% after 26 weeks.
Responder (Yes/no): HbA1c Less Than 7.0% and Without Weight Gain	After 26 weeks	Number of subjects with HbA1c less than 7.0% and without weight gain after 26 weeks.
Responder (Yes/no): HbA1c Less Than 7.0% Without Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment	After 26 weeks	Number of subjects with HbA1c less than 7.0% after 26 weeks, who did not experience treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the last 12 weeks of treatment. Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product. Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification or BG confirmed by a plasma glucose value \< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
Responder (Yes/no): HbA1c Less Than 7.0% and Without Weight Gain and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment	After 26 weeks	Number of subjects with HbA1c less than 7.0% and no weight gain after 26 weeks, who did not experience treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the last 12 weeks of treatment. Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product. Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification or BG confirmed by a plasma glucose value \< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
Responder (Yes/no): HbA1c Less Than or Equal to 6.5% Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment	After 26 weeks	Number of subjects with HbA1c less than or equal to 6.5% after 26 weeks, who did not experience treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the last 12 weeks of treatment. Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product. Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification or BG confirmed by a plasma glucose value \< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
Responder (Yes/no): HbA1c Less Than or Equal to 6.5% and Without Weight Gain and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment	After 26 weeks	Number of subjects with HbA1c less than or equal to 6.5% and no weight gain after 26 weeks, who did not experience treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the last 12 weeks of treatment. Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product. Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification or BG confirmed by a plasma glucose value \< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
Change in Waist Circumference	week 0, week 26	Change from baseline (week 0) in waist circumference after 26 weeks of treatment.
Change in Blood Pressure (Systolic and Diastolic)	week 0, week 26	Change from baseline in blood pressure (systolic and diastolic) after 26 weeks of treatment.
Change in Body Weight	week 0, week 26	Change from baseline (week 0) in body weight after 26 weeks of treatment.
Change in SMBG 9-point Profile: Mean of the 9-point Profile	Week 0, week 26	Subjects were instructed to measure their plasma glucose at following timepoints: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, at bedtime, at 4:00 a.m. and before breakfast the following day. Mean of the 9-point profile was defined as the area under the profile (calculated using the trapezoidal method) divided by the measurement time.
Change in SMBG 9-point Profile: Mean of Postprandial Plasma Glucose Increments (From Before Meal to 90 Minutes After Breakfast, Lunch and Dinner)	Week 0, week 26	Subjects were instructed to measure their plasma glucose at following timepoints: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, at bedtime, at 4:00 a.m. and before breakfast the following day. The mean increment over all meals was derived as the mean of all available meal increments.
Fasting Lipid Profile	Week 0, week 26	Lipid profile includes total cholesterol, low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein cholesterol (HDL cholesterol), very low density lipoprotein cholesterol (VLDL cholesterol), triglycerides and free fatty acids. Lipid profile parameters are represented as ratio to baseline values.
Number of Treatment Emergent Adverse Events (TEAE)	During 26 weeks of treatment	Treatment emergent adverse event is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product. If the event had onset date before the first day of exposure on randomised treatment and increased in severity during the treatment period and until 7 days after the last drug date, then this event was considered as a TEAE.
Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes	During 26 weeks of treatment	Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product. Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the American Diabetes Association (ADA) classification or BG confirmed by a plasma glucose value \< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Severe hypoglycaemia according to the ADA definition: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration.
Number of Treatment Emergent Hypoglycaemic Episodes According to American Diabetes Association (ADA) Definition	During 26 weeks of treatment	Results represent total number of treatment emergent hypoglycaemic episodes that fall under ADA's definition of hypoglycaemia. ADA's definition of hypoglycaemia includes following categories: 1. Severe hypoglycaemia 2. Documented symptomatic hypoglycaemia 3. Asymptomatic hypoglycaemia 4. Probable symptomatic hypoglycaemia 5. Pseudo-hypoglycaemia. Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product.
Number of Treatment Emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes	During 26 weeks of treatment	Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product. Nocturnal period: The period between 00:01 and 05:59 a.m. (both inclusive). Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the American Diabetes Association (ADA) classification or BG confirmed by a plasma glucose value \< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Severe hypoglycaemia according to the ADA definition: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration.
Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Screening (week -2 to week 0), week 26	The result of the fundus photography/dilated fundoscopy was interpreted by the investigator into following categories: Normal; Abnormal (Abn), Not Clinically significant (NCS); Abnormal, Clinically significant (CS). Reported results are number of subjects with 'normal'; 'Abn, NCS' and 'Abn, CS' fundoscopy/fundus photography results at screening (week -2 to week 0) and week 26.
Change in Clinical Evaluation: Electrocardiogram (ECG)	Screening (week -2 to week 0), week 26	The result of the ECG was interpreted by the investigator into following categories: Normal; Abnormal (Abn), Not Clinically significant (NCS); Abnormal, Clinically significant (CS). Reported results are number of subjects with 'normal'; 'Abn, NCS' and 'Abn, CS' ECG results at screening (week -2 to week 0) and week 26.
Change in Pulse	Week 0, week 26	Change in pulse after 26 weeks of treatment.
Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire	week 0, week 26	For the DTR-QOL questionnaire, change from baseline in the 'Total score' and the following four 'Domain scores' were analysed: 1. Burden on social activities and daily activities 2. Anxiety and dissatisfaction with treatment 3. Hypoglycaemia 4. Satisfaction with treatment. The scoring range of 'Total score' was converted to 0-100 (best case response = 100; worst case response = 0). The scoring range for each of four domains was converted to 0-100 (best case response = 100; worst case response = 0).
Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: EuroQol-5D (EQ-5D-5L) Questionnaire	week 0, week 26	Overall health state was rated by patients using the EQ-5D-5L visual analogue scale (VAS) and the EQ-5D-5L index score. The EQ-5D-5L VAS is a vertical scale where patients can rank their health from 0 (worst health imaginable) to 100 (best health imaginable). The EQ-5D-5L index score was calculated based on the 5 dimensions, i.e., mobility, self-care, usual activities (e.g., work, study), pain/discomfort and anxiety/depression with five response levels for each dimension, i.e., no problems, slight problems, moderate problems, severe problems and extreme problems. The scores from 5 dimensions are then converted to the EQ-5D-5L index score scale: 0 - 1 (full health/best-case response = 1; death/worst-case response = 0).
Self-measured Blood Glucose (SMBG) 9-point Profile (Individual Points in the Profile)	After 26 weeks	Subjects were instructed to measure their plasma glucose at following timepoints: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, at bedtime, at 4:00 a.m. and before breakfast the following day.

Countries

Japan

Participant flow

Recruitment details

The trial was conducted at 38 sites in Japan as follows: 38 sites screened and 37 sites randomised subjects.

Participants by arm

Arm	Count
Insulin Degludec/Liraglutide Eligible subjects were treated with insulin degludec/liraglutide (IDegLira) in combination with metformin (at stable pre-trial dose and frequency level) for 26 weeks. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36 mg liraglutide), with the option of choosing up to 16 dose steps (16 units IDeg/0.6 mg liraglutide) at the investigator's discretion. IDegLira was titrated twice weekly according to a predefined titration algorithm to a maximum of 50 dose steps (50 units IDeg/1.8 mg liraglutide), aiming to reach a fasting plasma glucose target between 72 mg/dL (4.0 mmol/L) and 90 mg/dL (5.0 mmol/L). IDegLira was injected subcutaneously (s.c.), once daily (OD) in the thigh, upper arm (deltoid region) or abdomen. One follow-up contact was scheduled at least 7 to 10 days after end of treatment.	105
Insulin Degludec Eligible subjects were treated with insulin degludec (IDeg) in combination with metformin (at stable pre-trial dose and frequency level) for 26 weeks. The starting dose of IDeg was 10 units IDeg, with the option of choosing up to 16 units IDeg at the investigator's discretion. IDeg was titrated twice weekly according to a predefined titration algorithm to a maximum of 50 units IDeg, aiming to reach a fasting plasma glucose target between 72 mg/dL (4.0 mmol/L) and 90 mg/dL (5.0 mmol/L). IDeg was injected subcutaneously (s.c.), once daily (OD) in the thigh, upper arm (deltoid region) or abdomen. One follow-up contact was scheduled at least 7 to 10 days after end of treatment.	105
Total	210

Withdrawals & dropouts

Period	Reason	FG001
Overall Study	Lack of Efficacy	1
Overall Study	Protocol Violation	1
Overall Study	Unclassified	3
Overall Study	Withdrawal by Subject	2

Baseline characteristics

Characteristic	Insulin Degludec/Liraglutide	Insulin Degludec	Total
Age, Continuous	56.6 Years STANDARD_DEVIATION 10.4	55.5 Years STANDARD_DEVIATION 10	56.0 Years STANDARD_DEVIATION 10.2
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	105 Participants	105 Participants	210 Participants
Glycosylated Haemoglobin (HbA1c)	8.61 Percentage of HbA1c STANDARD_DEVIATION 0.88	8.56 Percentage of HbA1c STANDARD_DEVIATION 0.8	8.58 Percentage of HbA1c STANDARD_DEVIATION 0.84
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	105 Participants	105 Participants	210 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	0 Participants	0 Participants	0 Participants
Sex: Female, Male Female	35 Participants	42 Participants	77 Participants
Sex: Female, Male Male	70 Participants	63 Participants	133 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 105	0 / 105
other Total, other adverse events	54 / 105	48 / 105
serious Total, serious adverse events	3 / 105	4 / 105

Outcome results

Primary

Change in Glycosylated Haemoglobin (HbA1c)

Change from baseline (week 0) in HbA1c after 26 weeks of treatment.

Time frame: week 0, week 26

Population: Full Analysis Set (FAS) included all randomised subjects (210 subjects). The statistical evaluation of the FAS followed the intention-to-treat (ITT) principle and subjects contributed to the evaluation as randomised. Missing data were imputed using last observation carried forward (LOCF) method.

Arm	Measure	Value (MEAN)	Dispersion
Insulin Degludec/Liraglutide	Change in Glycosylated Haemoglobin (HbA1c)	-1.95 Percentage of HbA1c	Standard Deviation 1.01
Insulin Degludec	Change in Glycosylated Haemoglobin (HbA1c)	-0.65 Percentage of HbA1c	Standard Deviation 0.98

Comparison: The response and change from baseline in response after 26 weeks are analysed using an ANCOVA model with treatment and pre-trial anti-diabetic treatment as fixed factors and corresponding baseline HbA1c value as covariate.p-value: <0.000195% CI: [-1.5, -1.06]ANCOVA

Secondary

Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire

For the DTR-QOL questionnaire, change from baseline in the 'Total score' and the following four 'Domain scores' were analysed: 1. Burden on social activities and daily activities 2. Anxiety and dissatisfaction with treatment 3. Hypoglycaemia 4. Satisfaction with treatment. The scoring range of 'Total score' was converted to 0-100 (best case response = 100; worst case response = 0). The scoring range for each of four domains was converted to 0-100 (best case response = 100; worst case response = 0).

Time frame: week 0, week 26

Arm	Measure	Group	Value (MEAN)	Dispersion
Insulin Degludec/Liraglutide	Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire	Burden on social activities and daily activities	5.7 Score on a scale	Standard Deviation 17.3
Insulin Degludec/Liraglutide	Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire	Hypoglycaemia	-2.6 Score on a scale	Standard Deviation 25.5
Insulin Degludec/Liraglutide	Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire	Anxiety and dissatisfaction with treatment	12.9 Score on a scale	Standard Deviation 20.8
Insulin Degludec/Liraglutide	Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire	Satisfaction with treatment	15.8 Score on a scale	Standard Deviation 22.5
Insulin Degludec/Liraglutide	Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire	Total score	7.9 Score on a scale	Standard Deviation 14.8
Insulin Degludec	Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire	Satisfaction with treatment	-0.4 Score on a scale	Standard Deviation 24.7
Insulin Degludec	Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire	Total score	0.1 Score on a scale	Standard Deviation 13.4
Insulin Degludec	Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire	Burden on social activities and daily activities	0.6 Score on a scale	Standard Deviation 17.1
Insulin Degludec	Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire	Anxiety and dissatisfaction with treatment	0.4 Score on a scale	Standard Deviation 17.2
Insulin Degludec	Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire	Hypoglycaemia	-1.6 Score on a scale	Standard Deviation 25.9

Secondary

Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: EuroQol-5D (EQ-5D-5L) Questionnaire

Overall health state was rated by patients using the EQ-5D-5L visual analogue scale (VAS) and the EQ-5D-5L index score. The EQ-5D-5L VAS is a vertical scale where patients can rank their health from 0 (worst health imaginable) to 100 (best health imaginable). The EQ-5D-5L index score was calculated based on the 5 dimensions, i.e., mobility, self-care, usual activities (e.g., work, study), pain/discomfort and anxiety/depression with five response levels for each dimension, i.e., no problems, slight problems, moderate problems, severe problems and extreme problems. The scores from 5 dimensions are then converted to the EQ-5D-5L index score scale: 0 - 1 (full health/best-case response = 1; death/worst-case response = 0).

Time frame: week 0, week 26

Arm	Measure	Group	Value (MEAN)	Dispersion
Insulin Degludec/Liraglutide	Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: EuroQol-5D (EQ-5D-5L) Questionnaire	Change in VAS score	6.3 Score on a scale	Standard Deviation 17.8
Insulin Degludec/Liraglutide	Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: EuroQol-5D (EQ-5D-5L) Questionnaire	Index score	0.02 Score on a scale	Standard Deviation 0.08
Insulin Degludec	Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: EuroQol-5D (EQ-5D-5L) Questionnaire	Change in VAS score	-1.0 Score on a scale	Standard Deviation 15.5
Insulin Degludec	Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: EuroQol-5D (EQ-5D-5L) Questionnaire	Index score	-0.01 Score on a scale	Standard Deviation 0.11

Secondary

Change in Blood Pressure (Systolic and Diastolic)

Change from baseline in blood pressure (systolic and diastolic) after 26 weeks of treatment.

Time frame: week 0, week 26

Arm	Measure	Group	Value (MEAN)	Dispersion
Insulin Degludec/Liraglutide	Change in Blood Pressure (Systolic and Diastolic)	Systolic blood pressure	-0.6 mmHg	Standard Deviation 14.7
Insulin Degludec/Liraglutide	Change in Blood Pressure (Systolic and Diastolic)	Diastolic blood pressure	0.9 mmHg	Standard Deviation 9
Insulin Degludec	Change in Blood Pressure (Systolic and Diastolic)	Systolic blood pressure	0.9 mmHg	Standard Deviation 13.6
Insulin Degludec	Change in Blood Pressure (Systolic and Diastolic)	Diastolic blood pressure	1.2 mmHg	Standard Deviation 9

Secondary

Change in Body Weight

Change from baseline (week 0) in body weight after 26 weeks of treatment.

Time frame: week 0, week 26

Arm	Measure	Value (MEAN)	Dispersion
Insulin Degludec/Liraglutide	Change in Body Weight	-0.7 Kg	Standard Deviation 3.5
Insulin Degludec	Change in Body Weight	0.7 Kg	Standard Deviation 2.7

Secondary

Change in Clinical Evaluation: Electrocardiogram (ECG)

The result of the ECG was interpreted by the investigator into following categories: Normal; Abnormal (Abn), Not Clinically significant (NCS); Abnormal, Clinically significant (CS). Reported results are number of subjects with 'normal'; 'Abn, NCS' and 'Abn, CS' ECG results at screening (week -2 to week 0) and week 26.

Time frame: Screening (week -2 to week 0), week 26

Population: Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (210 subjects). Subjects in the safety set contributed to the evaluation as treated. Missing data were imputed using last observation carried forward (LOCF) method.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Electrocardiogram (ECG)	At screening visit - normal	80 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Electrocardiogram (ECG)	At screening visit - Abn, NCS	20 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Electrocardiogram (ECG)	At screening visit - Abn, CS	5 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Electrocardiogram (ECG)	Week 26 -normal	82 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Electrocardiogram (ECG)	Week 26 - Abn, NCS	17 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Electrocardiogram (ECG)	Week 26 - Abn, CS	6 Participants
Insulin Degludec	Change in Clinical Evaluation: Electrocardiogram (ECG)	Week 26 - Abn, NCS	20 Participants
Insulin Degludec	Change in Clinical Evaluation: Electrocardiogram (ECG)	At screening visit - normal	82 Participants
Insulin Degludec	Change in Clinical Evaluation: Electrocardiogram (ECG)	Week 26 -normal	82 Participants
Insulin Degludec	Change in Clinical Evaluation: Electrocardiogram (ECG)	At screening visit - Abn, NCS	18 Participants
Insulin Degludec	Change in Clinical Evaluation: Electrocardiogram (ECG)	Week 26 - Abn, CS	3 Participants
Insulin Degludec	Change in Clinical Evaluation: Electrocardiogram (ECG)	At screening visit - Abn, CS	5 Participants

Secondary

Change in Clinical Evaluation: Fundoscopy or Fundus Photography

The result of the fundus photography/dilated fundoscopy was interpreted by the investigator into following categories: Normal; Abnormal (Abn), Not Clinically significant (NCS); Abnormal, Clinically significant (CS). Reported results are number of subjects with 'normal'; 'Abn, NCS' and 'Abn, CS' fundoscopy/fundus photography results at screening (week -2 to week 0) and week 26.

Time frame: Screening (week -2 to week 0), week 26

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Left eye - at screening visit - normal	53 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Left eye - at screening visit - Abn, NCS	6 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Left eye - at screening visit - Abn, CS	46 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Left eye - week 26 - normal	54 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Left eye - week 26 - Abn, NCS	7 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Left eye - week 26 - Abn, CS	44 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Right eye - at screening visit - normal	55 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Right eye - at screening visit - Abn, NCS	7 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Right eye - at screening visit - Abn, CS	43 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Right eye - week 26 - normal	52 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Right eye - week 26 - Abn, NCS	8 Participants
Insulin Degludec/Liraglutide	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Right eye - week 26 - Abn, CS	45 Participants
Insulin Degludec	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Right eye - week 26 - Abn, NCS	6 Participants
Insulin Degludec	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Left eye - at screening visit - normal	70 Participants
Insulin Degludec	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Right eye - at screening visit - normal	72 Participants
Insulin Degludec	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Left eye - at screening visit - Abn, NCS	5 Participants
Insulin Degludec	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Right eye - week 26 - normal	69 Participants
Insulin Degludec	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Left eye - at screening visit - Abn, CS	30 Participants
Insulin Degludec	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Right eye - at screening visit - Abn, NCS	6 Participants
Insulin Degludec	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Left eye - week 26 - normal	64 Participants
Insulin Degludec	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Right eye - week 26 - Abn, CS	30 Participants
Insulin Degludec	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Left eye - week 26 - Abn, NCS	7 Participants
Insulin Degludec	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Right eye - at screening visit - Abn, CS	27 Participants
Insulin Degludec	Change in Clinical Evaluation: Fundoscopy or Fundus Photography	Left eye - week 26 - Abn, CS	34 Participants

Secondary

Change in Fasting Plasma Glucose (FPG)

Change from baseline (week 0) in FPG after 26 weeks of treatment.

Time frame: week 0, week 26

Arm	Measure	Value (MEAN)	Dispersion
Insulin Degludec/Liraglutide	Change in Fasting Plasma Glucose (FPG)	-2.81 mmol/L	Standard Deviation 3.17
Insulin Degludec	Change in Fasting Plasma Glucose (FPG)	-2.29 mmol/L	Standard Deviation 2.68

Secondary

Change in Pulse

Change in pulse after 26 weeks of treatment.

Time frame: Week 0, week 26

Population: Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (210 subjects). Missing data were imputed using last observation carried forward (LOCF) method.

Arm	Measure	Value (MEAN)	Dispersion
Insulin Degludec/Liraglutide	Change in Pulse	6.1 beats per minute	Standard Deviation 11
Insulin Degludec	Change in Pulse	-0.2 beats per minute	Standard Deviation 7.1

Secondary

Change in SMBG 9-point Profile: Mean of Postprandial Plasma Glucose Increments (From Before Meal to 90 Minutes After Breakfast, Lunch and Dinner)

Subjects were instructed to measure their plasma glucose at following timepoints: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, at bedtime, at 4:00 a.m. and before breakfast the following day. The mean increment over all meals was derived as the mean of all available meal increments.

Time frame: Week 0, week 26

Arm	Measure	Value (MEAN)	Dispersion
Insulin Degludec/Liraglutide	Change in SMBG 9-point Profile: Mean of Postprandial Plasma Glucose Increments (From Before Meal to 90 Minutes After Breakfast, Lunch and Dinner)	-0.76 mmol/L	Standard Deviation 3
Insulin Degludec	Change in SMBG 9-point Profile: Mean of Postprandial Plasma Glucose Increments (From Before Meal to 90 Minutes After Breakfast, Lunch and Dinner)	0.70 mmol/L	Standard Deviation 2.93

Secondary

Change in SMBG 9-point Profile: Mean of the 9-point Profile

Subjects were instructed to measure their plasma glucose at following timepoints: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, at bedtime, at 4:00 a.m. and before breakfast the following day. Mean of the 9-point profile was defined as the area under the profile (calculated using the trapezoidal method) divided by the measurement time.

Time frame: Week 0, week 26

Arm	Measure	Value (MEAN)	Dispersion
Insulin Degludec/Liraglutide	Change in SMBG 9-point Profile: Mean of the 9-point Profile	-2.90 mmol/L	Standard Deviation 2.87
Insulin Degludec	Change in SMBG 9-point Profile: Mean of the 9-point Profile	-1.11 mmol/L	Standard Deviation 2.68

Secondary

Change in Waist Circumference

Change from baseline (week 0) in waist circumference after 26 weeks of treatment.

Time frame: week 0, week 26

Arm	Measure	Value (MEAN)	Dispersion
Insulin Degludec/Liraglutide	Change in Waist Circumference	-0.6 cm	Standard Deviation 3.8
Insulin Degludec	Change in Waist Circumference	0.1 cm	Standard Deviation 3.8

Secondary

Daily Insulin Dose

Actual daily total insulin dose after 26 weeks.

Time frame: After 26 weeks

Arm	Measure	Value (MEAN)	Dispersion
Insulin Degludec/Liraglutide	Daily Insulin Dose	37.6 Units	Standard Deviation 11.4
Insulin Degludec	Daily Insulin Dose	41.2 Units	Standard Deviation 11.5

Secondary

Fasting Lipid Profile

Lipid profile includes total cholesterol, low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein cholesterol (HDL cholesterol), very low density lipoprotein cholesterol (VLDL cholesterol), triglycerides and free fatty acids. Lipid profile parameters are represented as ratio to baseline values.

Time frame: Week 0, week 26

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Insulin Degludec/Liraglutide	Fasting Lipid Profile	Total cholesterol	0.90 Ratio	Geometric Coefficient of Variation 15.9
Insulin Degludec/Liraglutide	Fasting Lipid Profile	HDL cholesterol	0.90 Ratio	Geometric Coefficient of Variation 17.5
Insulin Degludec/Liraglutide	Fasting Lipid Profile	LDL cholesterol	0.86 Ratio	Geometric Coefficient of Variation 26.7
Insulin Degludec/Liraglutide	Fasting Lipid Profile	VLDL cholesterol	1.02 Ratio	Geometric Coefficient of Variation 50.5
Insulin Degludec/Liraglutide	Fasting Lipid Profile	Triglycerides	1.02 Ratio	Geometric Coefficient of Variation 58.5
Insulin Degludec/Liraglutide	Fasting Lipid Profile	Free fatty acids	0.86 Ratio	Geometric Coefficient of Variation 67.7
Insulin Degludec	Fasting Lipid Profile	Triglycerides	0.97 Ratio	Geometric Coefficient of Variation 39.3
Insulin Degludec	Fasting Lipid Profile	Total cholesterol	0.96 Ratio	Geometric Coefficient of Variation 13
Insulin Degludec	Fasting Lipid Profile	VLDL cholesterol	0.97 Ratio	Geometric Coefficient of Variation 38.2
Insulin Degludec	Fasting Lipid Profile	HDL cholesterol	0.95 Ratio	Geometric Coefficient of Variation 12.2
Insulin Degludec	Fasting Lipid Profile	Free fatty acids	0.77 Ratio	Geometric Coefficient of Variation 55.3
Insulin Degludec	Fasting Lipid Profile	LDL cholesterol	0.95 Ratio	Geometric Coefficient of Variation 21.5

Secondary

Number of Treatment Emergent Adverse Events (TEAE)

Treatment emergent adverse event is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product. If the event had onset date before the first day of exposure on randomised treatment and increased in severity during the treatment period and until 7 days after the last drug date, then this event was considered as a TEAE.