Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia. The aim of this trial is to compare the efficacy and safety of insulin degludec/liraglutide, insulin degludec and liraglutide in Japanese subjects with type 2 diabetes mellitus.
Interventions
DRUGinsulin degludec/liraglutide
Injected s.c. / subcutaneously (under the skin) once daily (OD) , in combination with pre-trial OAD (oral antidiabetic drug)kept in unchanged dose.
DRUGinsulin degludec
Injected s.c. / subcutaneously (under the skin) once daily (OD) , in combination with pre-trial OAD (oral antidiabetic drug)kept in unchanged dose.
DRUGliraglutide
Injected s.c. / subcutaneously (under the skin) once daily (OD) , in combination with pre-trial OAD (oral antidiabetic drug)kept in unchanged dose.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female Japanese subjects, age at least 20 years at the time of signing informed consent * Type 2 diabetes subjects (diagnosed clinically) at least 6 months prior to screening * HbA1c (glycosylated haemoglobin) 7.0-11.0 % (both inclusive) by central laboratory analysis, with the aim of a median of 8.3%. When approximately 50% of the randomised subjects have a HbA1c above 8.3%, the remaining subjects randomised must have a HbA1c below or equal to 8.3%; or when approximately 50% of the randomised subjects have a HbA1c below or equal to 8.3%, the remaining subjects randomised must have a HbA1c above 8.3% * Body-mass index (BMI) above or equal to 20 kg/m\^2 * Subjects on stable therapy with one OAD (defined as unchanged medication and unchanged dose) for at least 60 days (metformin, a-GI, TZD, SU, SGLT2i or glinide) prior to screening according to approved Japanese labelling
Exclusion criteria
* Previous treatment with insulin (except for short-term treatment in connection with intercurrent illness including gestational diabetes) * Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 60 days before screening * Anticipated initiation or change in concomitant medications in excess of 14 days known to affect weight or glucose metabolism * Impaired liver function, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) equal to or above 2.5 times upper limit of normal * Renal impairment estimated Glomerular Filtration Rate (eGFR) below 60mL/min/1.73m\^2 as per Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) * Screening calcitonin equal to 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 From Baseline in HbA1c (Glycosylated Haemoglobin) Tested for Non-inferiority of IDegLira vs IDeg and Superiority of IDegLira vs Lira | Week 0, Week 52 | Change from baseline (week 0) in HbA1c after 52 weeks of treatment was measured. Statistical analyses were performed to test the hypotheses: non-inferiority of IDegLira vs. IDeg and superiority of IDegLira vs. Liraglutide (Lira). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes | Weeks 0-52 | 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. |
| Change From Baseline in HbA1c (Glycosylated Haemoglobin) Tested for Superiority of IDegLira vs IDeg | Week 0, Week 52 | Change from baseline (week 0) in HbA1c after 52 weeks of treatment was measured. Statistical analysis was performed to test the hypothesis: superiority of IDegLira vs. IDeg. |
| Change From Baseline in Fasting Plasma Glucose (FPG) | Week 0, Week 52 | Change from baseline (week 0) in FPG after 52 weeks |
| Insulin Dose | After 52 weeks of treatment | Actual daily total insulin dose after 52 weeks of treatment. |
| Responder (Yes/no): HbA1c Less Than 7.0% | After 52 weeks of treatment | Number of subjects with HbA1c less than 7.0% after 52 weeks of treatment. |
| Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero | After 52 weeks of treatment | Number of subjects with HbA1c less than 7.0% and without weight gain after 52 weeks of treatment. |
| 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 52 weeks of treatment | Number of subjects with HbA1c less than 7.0% after 52 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 Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | After 52 weeks of treatment | Number of subjects with HbA1c less than 7.0% and without weight gain, 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 6.5% | After 52 weeks of treatment | Number of subjects with HbA1c less than 6.5% after 52 weeks of treatment. |
| Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero | After 52 weeks of treatment | Number of subjects with HbA1c less than 6.5% and without weight gain after 52 weeks of treatment. |
| Responder (Yes/no): HbA1c Less Than 6.5% Without Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment. | After 52 weeks of treatment | Number of subjects with HbA1c less than 6.5% after 52 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 6.5% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | After 52 weeks of treatment | Number of subjects with HbA1c less than 6.5% with no weight gain, 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 52 | Change from baseline (week 0) in waist circumference after 52 weeks of treatment. |
| Change in Blood Pressure (Systolic and Diastolic) | Week 0, Week 52 | Change from baseline in blood pressure (systolic and diastolic) after 52 weeks of treatment. |
| Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | After 52 weeks of the treatment | 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. |
| Change in SMBG 9-point Profile - Mean of the 9-point Profile | Week 0, week 52 | 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 Increments (From Before Meal to 90 Min After for Breakfast, Lunch and Dinner) | Week 0, week 52 | 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. |
| Total Cholesterol as a Ratio to Baseline at 52 Weeks | After 52 weeks of treatment | Total cholesterol after 52 weeks of treatment was represented as ratio to baseline (week 0) values. |
| Low Density Lipoprotein (LDL) Cholesterol as a Ratio to Baseline at 52 Weeks | After 52 weeks of treatment | Low density lipoprotein (LDL) cholesterol after 52 weeks of treatment was represented as ratio to baseline (week 0) values. |
| Change From Baseline in Body Weight (kg) | Week 0, Week 52 | Change from baseline (week 0) in body weight after 52 weeks of treatment. |
| Very Low Density Lipoprotein (VLDL) Cholesterol as a Ratio to Baseline at 52 Weeks | After 52 weeks of treatment | Very low density lipoprotein (VLDL) cholesterol after 52 weeks of treatment was represented as ratio to baseline (week 0) values. |
| Triglycerides as a Ratio to Baseline at 52 Weeks | After 52 weeks of treatment | Triglycerides after 52 weeks of treatment was represented as ratio to baseline (week 0) values. |
| Free Fatty Acids as a Ratio to Baseline at 52 Weeks | After 52 weeks of treatment | Free fatty acids after 52 weeks of treatment was represented as ratio to baseline (week 0) values. |
| Fasting C-peptide as a Ratio to Baseline at 52 Weeks | After 52 weeks of treatment | Fasting C-peptide after 52 weeks of treatment was represented as ratio to baseline (week 0) values. |
| Fasting Human Insulin as a Ratio to Baseline at 52 Weeks | After 52 weeks of treatment | Fasting human insulin after 52 weeks of treatment was represented as ratio to baseline (week 0) values. |
| Fasting Glucagon as a Ratio to Baseline at 52 Weeks | After 52 weeks of treatment | Fasting glucagon after 52 weeks of treatment was represented as ratio to baseline (week 0) values. |
| Proinsulin as a Ratio to Baseline at 52 Weeks | After 52 weeks of treatment | Proinsulin after 52 weeks of treatment was represented as ratio to baseline (week 0) values. |
| Number of Treatment Emergent Adverse Events (TEAEs) | 0-52 weeks | 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 Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | 0-52 weeks | 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 Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | 0-52 weeks | 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. |
| Number of Treatment Emergent Hypoglycaemic Episodes According to American Diabetes Association (ADA) Definition | 0-52 weeks | 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. |
| Anti-drug Antibodies: Anti-insulin Degludec Antibodies | at week 52 | Insulin degludec (IDeg)-specific antibodies were measured at week 52, as %B/T (percentage of bound & precipitated radioactive drug/total added drug to the sample). A sample is measured in 2 different series. In series 1, the radioactive IDeg (tracer) and surplus unlabeled IDeg are added to the sample. In series 2, the tracer and surplus unlabeled human insulin are added to the sample. Series 1 represents unspecific background binding. Series 2 represents IDeg specific antibodies including unspecific background binding. The reported %B/T is calculated by subtracting the background %B/T in series 1 from the %B/T result in series 2. If the background result has higher values than the %B/T in series 2, the resulting value is negative %B/T. Here, a negative %B/T value means that the test samples do not have IDeg-specific antibodies. The reason for getting a negative value for %B/T is due to variation in the analytical background. Thus, the results presented are not a change from baseline. |
| Anti-drug Antibodies: Number of Participants Positive or Negative for Anti-liraglutide Antibodies | at week 52 | Anti-liraglutide antibodies were measured at week 52. Number of participants positive or negative for anti-liraglutide antibodies at week 52 were reported. |
| Change in Clinical Evaluation: Fundoscopy or Fundus Photography | at screening (week -2 to week 0), at week 52 | 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 52. |
| Change in Clinical Evaluation: Electrocardiogram (ECG) | at screening (week -2 to week 0), at week 52 | 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 52. |
| Change in Clinical Evaluation: Pulse | Week 0, week 52 | Change in pulse after 52 weeks of treatment. |
| Serum Concentrations of Insulin Degludec | Weeks 2, 8, 16, 26, 44, 52 | Samples from the IDegLira and IDeg arms were analysed for serum concentrations of insulin degludec using validated ELISA assays. |
| Plasma Concentrations of Liraglutide | Weeks 2, 8, 16, 26, 44, 52 | Samples from the IDegLira and liraglutide arms were assayed for plasma concentrations of liraglutide using validated ELISA assays. |
| High Density Lipoprotein (HDL) Cholesterol as a Ratio to Baseline at 52 Weeks | After 52 weeks of treatment | High density lipoprotein (HDL) cholesterol after 52 weeks of treatment was represented as ratio to baseline (week 0) values. |
Countries
Japan
Participant flow
Recruitment details
The trial was conducted at 71 sites in Japan. 71 sites screened and randomised subjects.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Degludec/Liraglutide Eligible subjects were treated with insulin degludec/liraglutide (IDegLira) once daily (OD) in combination with pre-trial oral anti diabetic drugs (at stable dose level and dosing frequency; dose reduction was allowed in case of safety concern). The recommended starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36 mg liraglutide). 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). One follow-up visit was scheduled 7 days after end of treatment. IDegLira was injected subcutaneously in the thigh, upper arm (deltoid region) or abdomen. The injection area chosen remained unchanged throughout the trial, although rotation within the area was recommended. | 275 |
| Insulin Degludec Eligible subjects were treated with insulin degludec (IDeg) once daily (OD) in combination with pre-trial oral anti diabetic drugs (at stable dose level and dosing frequency unless there were safety concerns, in which case dose reduction was allowed). The recommended starting dose of IDeg was 10 units. IDeg was titrated twice weekly according to a predefined titration algorithm, aiming to reach a fasting plasma glucose target between 72 mg/dL (4.0 mmol/L) and 90 mg/dL (5.0 mmol/L). There was no maximum dose decided for IDeg. One follow-up visit was scheduled 7 days after end of treatment. IDeg was injected subcutaneously in the thigh, upper arm (deltoid region) or abdomen. The injection area chosen remained unchanged throughout the trial, although rotation within the area was recommended. | 271 |
| Liraglutide Eligible subjects were treated with liraglutide once daily (OD) in combination with pre-trial oral anti diabetic drugs (at stable dose level and dosing frequency unless there were safety concerns, in which case dose reduction was allowed). For liraglutide the starting dose of liraglutide was 0.3 mg/day and subsequent weekly dose escalation by 0.3 mg weekly to a fixed maximum dose of 1.8 mg/day. One follow-up visit was scheduled 7 days after end of treatment. Liraglutide was injected subcutaneously in the thigh, upper arm (deltoid region) or abdomen. The injection area chosen remained unchanged throughout the trial, although rotation within the area was recommended. | 273 |
| Total | 819 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 6 | 6 |
| Overall Study | Lack of Efficacy | 0 | 1 | 1 |
| Overall Study | Protocol Violation | 4 | 2 | 1 |
| Overall Study | Unclassified | 1 | 4 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 10 | 2 |
Baseline characteristics
| Characteristic | Insulin Degludec/Liraglutide | Insulin Degludec | Liraglutide | Total |
|---|---|---|---|---|
| Age, Continuous | 56.9 Years STANDARD_DEVIATION 10.2 | 57.8 Years STANDARD_DEVIATION 9.9 | 56.8 Years STANDARD_DEVIATION 10.1 | 57.2 Years STANDARD_DEVIATION 10.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 275 Participants | 271 Participants | 273 Participants | 819 Participants |
| Glycosylated Haemoglobin (HbA1c) | 8.52 Percentage of HbA1c STANDARD_DEVIATION 1.12 | 8.53 Percentage of HbA1c STANDARD_DEVIATION 1.05 | 8.32 Percentage of HbA1c STANDARD_DEVIATION 0.99 | 8.45 Percentage of HbA1c STANDARD_DEVIATION 1.06 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 275 Participants | 271 Participants | 273 Participants | 819 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 81 Participants | 76 Participants | 81 Participants | 238 Participants |
| Sex: Female, Male Male | 194 Participants | 195 Participants | 192 Participants | 581 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 275 | 0 / 271 | 0 / 273 |
| other Total, other adverse events | 153 / 275 | 137 / 271 | 158 / 273 |
| serious Total, serious adverse events | 17 / 275 | 13 / 271 | 14 / 273 |
Outcome results
Primary
Change From Baseline in HbA1c (Glycosylated Haemoglobin) Tested for Non-inferiority of IDegLira vs IDeg and Superiority of IDegLira vs Lira
Change from baseline (week 0) in HbA1c after 52 weeks of treatment was measured. Statistical analyses were performed to test the hypotheses: non-inferiority of IDegLira vs. IDeg and superiority of IDegLira vs. Liraglutide (Lira).
Time frame: Week 0, Week 52
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 From Baseline in HbA1c (Glycosylated Haemoglobin) Tested for Non-inferiority of IDegLira vs IDeg and Superiority of IDegLira vs Lira | -2.42 Percentage of HbA1c | Standard Deviation 1.04 |
| Insulin Degludec | Change From Baseline in HbA1c (Glycosylated Haemoglobin) Tested for Non-inferiority of IDegLira vs IDeg and Superiority of IDegLira vs Lira | -1.80 Percentage of HbA1c | Standard Deviation 1.02 |
| Liraglutide | Change From Baseline in HbA1c (Glycosylated Haemoglobin) Tested for Non-inferiority of IDegLira vs IDeg and Superiority of IDegLira vs Lira | -1.80 Percentage of HbA1c | Standard Deviation 0.92 |
Comparison: The change from baseline in response after 52 weeks are analysed using an ANCOVA model with treatment and pre-trial OAD as fixed factors and baseline HbA1c value as covariate.p-value: <0.000195% CI: [-0.75, -0.52]ANCOVA
Comparison: The change from baseline in response after 52 weeks are analysed using an ANCOVA model with treatment and pre-trial OAD as fixed factors and baseline HbA1c value as covariate.p-value: <0.000195% CI: [-0.6, -0.37]ANCOVA
Secondary
Anti-drug Antibodies: Anti-insulin Degludec Antibodies
Insulin degludec (IDeg)-specific antibodies were measured at week 52, as %B/T (percentage of bound & precipitated radioactive drug/total added drug to the sample). A sample is measured in 2 different series. In series 1, the radioactive IDeg (tracer) and surplus unlabeled IDeg are added to the sample. In series 2, the tracer and surplus unlabeled human insulin are added to the sample. Series 1 represents unspecific background binding. Series 2 represents IDeg specific antibodies including unspecific background binding. The reported %B/T is calculated by subtracting the background %B/T in series 1 from the %B/T result in series 2. If the background result has higher values than the %B/T in series 2, the resulting value is negative %B/T. Here, a negative %B/T value means that the test samples do not have IDeg-specific antibodies. The reason for getting a negative value for %B/T is due to variation in the analytical background. Thus, the results presented are not a change from baseline.
Time frame: at week 52
Population: Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (819 subjects). Subjects in the safety set contributed to the evaluation as treated. Missing data were imputed using LOCF method. This endpoint is only applicable for subjects in IDegLira and IDeg arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Anti-drug Antibodies: Anti-insulin Degludec Antibodies | 0.12 Percentage B/T | Standard Deviation 3.34 |
| Insulin Degludec | Anti-drug Antibodies: Anti-insulin Degludec Antibodies | -0.11 Percentage B/T | Standard Deviation 0.42 |
Secondary
Anti-drug Antibodies: Number of Participants Positive or Negative for Anti-liraglutide Antibodies
Anti-liraglutide antibodies were measured at week 52. Number of participants positive or negative for anti-liraglutide antibodies at week 52 were reported.
Time frame: at week 52
Population: Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (819 subjects). Subjects in the safety set contributed to the evaluation as treated. Missing data were imputed using LOCF method.This endpoint is only applicable for subjects in IDegLira and Lira arm.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Anti-drug Antibodies: Number of Participants Positive or Negative for Anti-liraglutide Antibodies | Negative | 247 Participants |
| Insulin Degludec/Liraglutide | Anti-drug Antibodies: Number of Participants Positive or Negative for Anti-liraglutide Antibodies | Positive | 28 Participants |
| Insulin Degludec | Anti-drug Antibodies: Number of Participants Positive or Negative for Anti-liraglutide Antibodies | Negative | 224 Participants |
| Insulin Degludec | Anti-drug Antibodies: Number of Participants Positive or Negative for Anti-liraglutide Antibodies | Positive | 49 Participants |
Secondary
Change From Baseline in Body Weight (kg)
Change from baseline (week 0) in body weight after 52 weeks of treatment.
Time frame: Week 0, Week 52
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 From Baseline in Body Weight (kg) | 2.9 Kg | Standard Deviation 3.2 |
| Insulin Degludec | Change From Baseline in Body Weight (kg) | 4.1 Kg | Standard Deviation 4.3 |
| Liraglutide | Change From Baseline in Body Weight (kg) | -1.0 Kg | Standard Deviation 3.4 |
Comparison: The change from baseline in response after 52 weeks were analysed using an ANCOVA method with treatment and pre-trial OAD treatment as fixed factors and baseline body weight as covariate.p-value: 0.000195% CI: [-1.8, -0.59]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
Change from baseline (week 0) in FPG after 52 weeks
Time frame: Week 0, Week 52
Population: Full Analysis Set (FAS) included all randomised subjects (819 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. Number Analyzed = subjects with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Change From Baseline in Fasting Plasma Glucose (FPG) | -4.08 mmol/L | Standard Deviation 2.47 |
| Insulin Degludec | Change From Baseline in Fasting Plasma Glucose (FPG) | -3.97 mmol/L | Standard Deviation 2.56 |
| Liraglutide | Change From Baseline in Fasting Plasma Glucose (FPG) | -2.62 mmol/L | Standard Deviation 1.95 |
Secondary
Change From Baseline in HbA1c (Glycosylated Haemoglobin) Tested for Superiority of IDegLira vs IDeg
Change from baseline (week 0) in HbA1c after 52 weeks of treatment was measured. Statistical analysis was performed to test the hypothesis: superiority of IDegLira vs. IDeg.
Time frame: Week 0, Week 52
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 From Baseline in HbA1c (Glycosylated Haemoglobin) Tested for Superiority of IDegLira vs IDeg | -2.42 Percentage of HbA1c | Standard Deviation 1.04 |
| Insulin Degludec | Change From Baseline in HbA1c (Glycosylated Haemoglobin) Tested for Superiority of IDegLira vs IDeg | -1.80 Percentage of HbA1c | Standard Deviation 1.02 |
| Liraglutide | Change From Baseline in HbA1c (Glycosylated Haemoglobin) Tested for Superiority of IDegLira vs IDeg | -1.80 Percentage of HbA1c | Standard Deviation 0.92 |
Comparison: The change from baseline in response after 52 weeks are analysed using an ANCOVA model with treatment, pre-trial OAD as fixed factors and corresponding baseline HbA1c value as covariate.p-value: <0.000195% CI: [-0.75, -0.52]ANCOVA
Secondary
Change in Blood Pressure (Systolic and Diastolic)
Change from baseline in blood pressure (systolic and diastolic) after 52 weeks of treatment.
Time frame: Week 0, Week 52
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Degludec/Liraglutide | Change in Blood Pressure (Systolic and Diastolic) | Systolic blood pressure | 1.7 mmHg | Standard Deviation 12 |
| Insulin Degludec/Liraglutide | Change in Blood Pressure (Systolic and Diastolic) | Diastolic blood pressure | 0.5 mmHg | Standard Deviation 7.9 |
| Insulin Degludec | Change in Blood Pressure (Systolic and Diastolic) | Systolic blood pressure | 3.4 mmHg | Standard Deviation 14.3 |
| Insulin Degludec | Change in Blood Pressure (Systolic and Diastolic) | Diastolic blood pressure | 0.6 mmHg | Standard Deviation 9.3 |
| Liraglutide | Change in Blood Pressure (Systolic and Diastolic) | Systolic blood pressure | -1.8 mmHg | Standard Deviation 13 |
| Liraglutide | Change in Blood Pressure (Systolic and Diastolic) | Diastolic blood pressure | -0.4 mmHg | Standard Deviation 8.3 |
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 52.
Time frame: at screening (week -2 to week 0), at week 52
Population: Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (819 subjects). Subjects in the safety set contributed to the evaluation as treated.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Electrocardiogram (ECG) | At screening visit - normal | 228 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Electrocardiogram (ECG) | At screening visit - Abn, NCS | 40 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Electrocardiogram (ECG) | At screening visit - Abn, CS | 7 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Electrocardiogram (ECG) | Week 52 - normal | 238 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Electrocardiogram (ECG) | Week 52 - Abn, NCS | 30 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Electrocardiogram (ECG) | Week 52 - Abn, CS | 7 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Electrocardiogram (ECG) | Week 52 - Abn, CS | 4 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Electrocardiogram (ECG) | At screening visit - normal | 230 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Electrocardiogram (ECG) | Week 52 - normal | 232 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Electrocardiogram (ECG) | Week 52 - Abn, NCS | 35 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Electrocardiogram (ECG) | At screening visit - Abn, NCS | 38 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Electrocardiogram (ECG) | At screening visit - Abn, CS | 3 Participants |
| Liraglutide | Change in Clinical Evaluation: Electrocardiogram (ECG) | At screening visit - Abn, NCS | 41 Participants |
| Liraglutide | Change in Clinical Evaluation: Electrocardiogram (ECG) | At screening visit - Abn, CS | 10 Participants |
| Liraglutide | Change in Clinical Evaluation: Electrocardiogram (ECG) | Week 52 - Abn, CS | 6 Participants |
| Liraglutide | Change in Clinical Evaluation: Electrocardiogram (ECG) | Week 52 - normal | 233 Participants |
| Liraglutide | Change in Clinical Evaluation: Electrocardiogram (ECG) | At screening visit - normal | 222 Participants |
| Liraglutide | Change in Clinical Evaluation: Electrocardiogram (ECG) | Week 52 - Abn, NCS | 34 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 52.
Time frame: at screening (week -2 to week 0), at week 52
Population: Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (819 subjects). Subjects in the safety set contributed to the evaluation as treated. Number Analyzed = subjects with available data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - at screening visit - normal | 225 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - at screening visit - Abn, NCS | 10 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - at screening visit - Abn, CS | 39 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - week 52 - normal | 217 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - week 52 - Abn, NCS | 17 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - week 52 - Abn, CS | 40 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - at screening visit - normal | 224 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - at screening visit - Abn, NCS | 10 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - at screening visit - Abn, CS | 41 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - week 52 - normal | 220 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - week 52 - Abn, NCS | 14 Participants |
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - week 52 - Abn, CS | 41 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - week 52 - Abn, CS | 40 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - at screening visit - normal | 213 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - at screening visit - normal | 212 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - at screening visit - Abn, CS | 45 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - at screening visit - Abn, NCS | 16 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - week 52 - Abn, CS | 41 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - week 52 - Abn, NCS | 14 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - at screening visit - Abn, CS | 42 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - at screening visit - Abn, NCS | 14 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - week 52 - Abn, NCS | 16 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - week 52 - normal | 214 Participants |
| Insulin Degludec | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - week 52 - normal | 217 Participants |
| Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - week 52 - normal | 212 Participants |
| Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - week 52 - Abn, NCS | 15 Participants |
| Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - week 52 - normal | 209 Participants |
| Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - week 52 - Abn, CS | 45 Participants |
| Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - at screening visit - normal | 207 Participants |
| Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - at screening visit - Abn, NCS | 12 Participants |
| Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - week 52 - Abn, NCS | 15 Participants |
| Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - at screening visit - normal | 211 Participants |
| Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - at screening visit - Abn, NCS | 14 Participants |
| Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - at screening visit - Abn, CS | 54 Participants |
| Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Left eye - at screening visit - Abn, CS | 47 Participants |
| Liraglutide | Change in Clinical Evaluation: Fundoscopy or Fundus Photography | Right eye - week 52 - Abn, CS | 49 Participants |
Secondary
Change in Clinical Evaluation: Pulse
Change in pulse after 52 weeks of treatment.
Time frame: Week 0, week 52
Population: Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (819 subjects). Subjects in the safety set contributed to the evaluation as treated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Change in Clinical Evaluation: Pulse | 3.9 beats per minute | Standard Deviation 9.5 |
| Insulin Degludec | Change in Clinical Evaluation: Pulse | 0.8 beats per minute | Standard Deviation 8.9 |
| Liraglutide | Change in Clinical Evaluation: Pulse | 4.2 beats per minute | Standard Deviation 9.1 |
Secondary
Change in SMBG 9-point Profile - Mean of Postprandial Increments (From Before Meal to 90 Min After for 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 52
Population: Full Analysis Set (FAS) included all randomised subjects (819 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. Number Analyzed = subjects with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Change in SMBG 9-point Profile - Mean of Postprandial Increments (From Before Meal to 90 Min After for Breakfast, Lunch and Dinner) | -0.74 mmol/L | Standard Deviation 2.51 |
| Insulin Degludec | Change in SMBG 9-point Profile - Mean of Postprandial Increments (From Before Meal to 90 Min After for Breakfast, Lunch and Dinner) | -0.27 mmol/L | Standard Deviation 2.39 |
| Liraglutide | Change in SMBG 9-point Profile - Mean of Postprandial Increments (From Before Meal to 90 Min After for Breakfast, Lunch and Dinner) | -1.01 mmol/L | Standard Deviation 2.38 |
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 52
Population: Full Analysis Set (FAS) included all randomised subjects (819 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. Number Analyzed = subjects with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Change in SMBG 9-point Profile - Mean of the 9-point Profile | -4.60 mmol/L | Standard Deviation 2.65 |
| Insulin Degludec | Change in SMBG 9-point Profile - Mean of the 9-point Profile | -3.84 mmol/L | Standard Deviation 2.63 |
| Liraglutide | Change in SMBG 9-point Profile - Mean of the 9-point Profile | -3.46 mmol/L | Standard Deviation 2.37 |
Secondary
Change in Waist Circumference
Change from baseline (week 0) in waist circumference after 52 weeks of treatment.
Time frame: Week 0, Week 52
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 Waist Circumference | 2.5 Cm | Standard Deviation 4.5 |
| Insulin Degludec | Change in Waist Circumference | 3.4 Cm | Standard Deviation 5.2 |
| Liraglutide | Change in Waist Circumference | -1.1 Cm | Standard Deviation 4.4 |
Secondary
Fasting C-peptide as a Ratio to Baseline at 52 Weeks
Fasting C-peptide after 52 weeks of treatment was represented as ratio to baseline (week 0) values.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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. Number Analyzed = subjects with available data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Fasting C-peptide as a Ratio to Baseline at 52 Weeks | 0.61 Ratio | Geometric Coefficient of Variation 75.6 |
| Insulin Degludec | Fasting C-peptide as a Ratio to Baseline at 52 Weeks | 0.42 Ratio | Geometric Coefficient of Variation 82.6 |
| Liraglutide | Fasting C-peptide as a Ratio to Baseline at 52 Weeks | 1.12 Ratio | Geometric Coefficient of Variation 29.9 |
Secondary
Fasting Glucagon as a Ratio to Baseline at 52 Weeks
Fasting glucagon after 52 weeks of treatment was represented as ratio to baseline (week 0) values.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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. Number Analyzed = subjects with available data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Fasting Glucagon as a Ratio to Baseline at 52 Weeks | 0.95 Ratio | Geometric Coefficient of Variation 27.9 |
| Insulin Degludec | Fasting Glucagon as a Ratio to Baseline at 52 Weeks | 0.94 Ratio | Geometric Coefficient of Variation 27.6 |
| Liraglutide | Fasting Glucagon as a Ratio to Baseline at 52 Weeks | 0.96 Ratio | Geometric Coefficient of Variation 25.7 |
Secondary
Fasting Human Insulin as a Ratio to Baseline at 52 Weeks
Fasting human insulin after 52 weeks of treatment was represented as ratio to baseline (week 0) values.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Fasting Human Insulin as a Ratio to Baseline at 52 Weeks | 0.90 Ratio | Geometric Coefficient of Variation 89 |
| Insulin Degludec | Fasting Human Insulin as a Ratio to Baseline at 52 Weeks | 0.61 Ratio | Geometric Coefficient of Variation 81.1 |
| Liraglutide | Fasting Human Insulin as a Ratio to Baseline at 52 Weeks | 1.52 Ratio | Geometric Coefficient of Variation 66.6 |
Secondary
Free Fatty Acids as a Ratio to Baseline at 52 Weeks
Free fatty acids after 52 weeks of treatment was represented as ratio to baseline (week 0) values.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Free Fatty Acids as a Ratio to Baseline at 52 Weeks | 0.74 Ratio | Geometric Coefficient of Variation 60.8 |
| Insulin Degludec | Free Fatty Acids as a Ratio to Baseline at 52 Weeks | 0.70 Ratio | Geometric Coefficient of Variation 59.3 |
| Liraglutide | Free Fatty Acids as a Ratio to Baseline at 52 Weeks | 0.93 Ratio | Geometric Coefficient of Variation 49.5 |
Secondary
High Density Lipoprotein (HDL) Cholesterol as a Ratio to Baseline at 52 Weeks
High density lipoprotein (HDL) cholesterol after 52 weeks of treatment was represented as ratio to baseline (week 0) values.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | High Density Lipoprotein (HDL) Cholesterol as a Ratio to Baseline at 52 Weeks | 0.94 Ratio | Geometric Coefficient of Variation 16.4 |
| Insulin Degludec | High Density Lipoprotein (HDL) Cholesterol as a Ratio to Baseline at 52 Weeks | 0.94 Ratio | Geometric Coefficient of Variation 14.6 |
| Liraglutide | High Density Lipoprotein (HDL) Cholesterol as a Ratio to Baseline at 52 Weeks | 0.99 Ratio | Geometric Coefficient of Variation 14.5 |
Secondary
Insulin Dose
Actual daily total insulin dose after 52 weeks of treatment.
Time frame: After 52 weeks of treatment
Population: Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (819 subjects). Subjects in the safety set contributed to the evaluation as treated. Missing data were imputed using LOCF method. This endpoint evaluation is only applicable for subjects in IDegLira and IDeg arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Insulin Dose | 27.7 Insulin Units/Day | Standard Deviation 14.8 |
| Insulin Degludec | Insulin Dose | 34.8 Insulin Units/Day | Standard Deviation 26 |
Secondary
Low Density Lipoprotein (LDL) Cholesterol as a Ratio to Baseline at 52 Weeks
Low density lipoprotein (LDL) cholesterol after 52 weeks of treatment was represented as ratio to baseline (week 0) values.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Low Density Lipoprotein (LDL) Cholesterol as a Ratio to Baseline at 52 Weeks | 0.91 Ratio | Geometric Coefficient of Variation 23.4 |
| Insulin Degludec | Low Density Lipoprotein (LDL) Cholesterol as a Ratio to Baseline at 52 Weeks | 0.99 Ratio | Geometric Coefficient of Variation 18.2 |
| Liraglutide | Low Density Lipoprotein (LDL) Cholesterol as a Ratio to Baseline at 52 Weeks | 0.93 Ratio | Geometric Coefficient of Variation 24.2 |
Secondary
Number of Treatment Emergent Adverse Events (TEAEs)
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.
Time frame: 0-52 weeks
Population: Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (819 subjects). Subjects in the safety set contributed to the evaluation as treated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec/Liraglutide | Number of Treatment Emergent Adverse Events (TEAEs) | 873 Events |
| Insulin Degludec | Number of Treatment Emergent Adverse Events (TEAEs) | 829 Events |
| Liraglutide | Number of Treatment Emergent Adverse Events (TEAEs) | 885 Events |
Secondary
Number of Treatment Emergent Hypoglycaemic Episodes According to American Diabetes Association (ADA) Definition
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.
Time frame: 0-52 weeks
Population: Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (819 subjects). Subjects in the safety set contributed to the evaluation as treated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec/Liraglutide | Number of Treatment Emergent Hypoglycaemic Episodes According to American Diabetes Association (ADA) Definition | 4830 Episodes |
| Insulin Degludec | Number of Treatment Emergent Hypoglycaemic Episodes According to American Diabetes Association (ADA) Definition | 6340 Episodes |
| Liraglutide | Number of Treatment Emergent Hypoglycaemic Episodes According to American Diabetes Association (ADA) Definition | 162 Episodes |
Secondary
Number of Treatment Emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes
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.
Time frame: 0-52 weeks
Population: Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (819 subjects). Subjects in the safety set contributed to the evaluation as treated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec/Liraglutide | Number of Treatment Emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | 16 Episodes |
| Insulin Degludec | Number of Treatment Emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | 42 Episodes |
| Liraglutide | Number of Treatment Emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | 0 Episodes |
Secondary
Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes
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.
Time frame: Weeks 0-52
Population: Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (819 subjects). Subjects in the safety set contributed to the evaluation as treated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec/Liraglutide | Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes | 467 Episodes |
| Insulin Degludec | Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes | 869 Episodes |
| Liraglutide | Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes | 13 Episodes |
Comparison: The number of events is analysed using a negative binomial regression model (log link) with the logarithm of the treatment emergent exposure time (100 years) as offset. The model includes treatment and pre-trial OAD treatment as fixed factors.p-value: <0.000195% CI: [0.35, 0.68]Negative binomial regression
Secondary
Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes
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.
Time frame: 0-52 weeks
Population: Safety Analysis Set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (819 subjects). Subjects in the safety set contributed to the evaluation as treated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec/Liraglutide | Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | 135 Episodes |
| Insulin Degludec | Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | 362 Episodes |
| Liraglutide | Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | 136 Episodes |
Secondary
Plasma Concentrations of Liraglutide
Samples from the IDegLira and liraglutide arms were assayed for plasma concentrations of liraglutide using validated ELISA assays.
Time frame: Weeks 2, 8, 16, 26, 44, 52
Population: Full Analysis Set (FAS) included all randomised subjects (819 subjects). All subjects in FAS with at least one valid concentration value were included in the analysis. No imputations of missing concentration values were applied. Number Analyzed = subjects with available data. This endpoint is only applicable for subjects in IDegLira and Lira arm.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Degludec/Liraglutide | Plasma Concentrations of Liraglutide | At week 2 | 5681.3 pmol/L | Geometric Coefficient of Variation 49.4 |
| Insulin Degludec/Liraglutide | Plasma Concentrations of Liraglutide | At week 8 | 9107.8 pmol/L | Geometric Coefficient of Variation 61.4 |
| Insulin Degludec/Liraglutide | Plasma Concentrations of Liraglutide | At week 16 | 10038.1 pmol/L | Geometric Coefficient of Variation 69.5 |
| Insulin Degludec/Liraglutide | Plasma Concentrations of Liraglutide | At week 26 | 9995.3 pmol/L | Geometric Coefficient of Variation 77.5 |
| Insulin Degludec/Liraglutide | Plasma Concentrations of Liraglutide | At week 44 | 8791.7 pmol/L | Geometric Coefficient of Variation 81 |
| Insulin Degludec/Liraglutide | Plasma Concentrations of Liraglutide | At week 52 | 7426.2 pmol/L | Geometric Coefficient of Variation 103.5 |
| Insulin Degludec | Plasma Concentrations of Liraglutide | At week 44 | 12855.6 pmol/L | Geometric Coefficient of Variation 112.7 |
| Insulin Degludec | Plasma Concentrations of Liraglutide | At week 2 | 6081.6 pmol/L | Geometric Coefficient of Variation 65.4 |
| Insulin Degludec | Plasma Concentrations of Liraglutide | At week 26 | 13904.2 pmol/L | Geometric Coefficient of Variation 91.8 |
| Insulin Degludec | Plasma Concentrations of Liraglutide | At week 8 | 14539.5 pmol/L | Geometric Coefficient of Variation 71 |
| Insulin Degludec | Plasma Concentrations of Liraglutide | At week 52 | 12127.4 pmol/L | Geometric Coefficient of Variation 142.4 |
| Insulin Degludec | Plasma Concentrations of Liraglutide | At week 16 | 14046.5 pmol/L | Geometric Coefficient of Variation 73 |
Secondary
Proinsulin as a Ratio to Baseline at 52 Weeks
Proinsulin after 52 weeks of treatment was represented as ratio to baseline (week 0) values.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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. Number Analyzed = subjects with available data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Proinsulin as a Ratio to Baseline at 52 Weeks | 0.18 Ratio | Geometric Coefficient of Variation 231.5 |
| Insulin Degludec | Proinsulin as a Ratio to Baseline at 52 Weeks | 0.17 Ratio | Geometric Coefficient of Variation 188.8 |
| Liraglutide | Proinsulin as a Ratio to Baseline at 52 Weeks | 0.59 Ratio | Geometric Coefficient of Variation 85.9 |
Secondary
Responder (Yes/no): HbA1c Less Than 6.5%
Number of subjects with HbA1c less than 6.5% after 52 weeks of treatment.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% | Yes | 213 Participants |
| Insulin Degludec/Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% | No | 62 Participants |
| Insulin Degludec | Responder (Yes/no): HbA1c Less Than 6.5% | Yes | 134 Participants |
| Insulin Degludec | Responder (Yes/no): HbA1c Less Than 6.5% | No | 137 Participants |
| Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% | Yes | 171 Participants |
| Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% | No | 102 Participants |
Secondary
Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero
Number of subjects with HbA1c less than 6.5% and without weight gain after 52 weeks of treatment.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero | Yes | 41 Participants |
| Insulin Degludec/Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero | No | 234 Participants |
| Insulin Degludec | Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero | Yes | 17 Participants |
| Insulin Degludec | Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero | No | 254 Participants |
| Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero | Yes | 126 Participants |
| Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero | No | 147 Participants |
Secondary
Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment
Number of subjects with HbA1c less than 6.5% with no weight gain, 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.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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. Number Analyzed = subjects with available data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | Yes | 35 Participants |
| Insulin Degludec/Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | No | 235 Participants |
| Insulin Degludec | Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | Yes | 17 Participants |
| Insulin Degludec | Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | No | 248 Participants |
| Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | Yes | 125 Participants |
| Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | No | 146 Participants |
Secondary
Responder (Yes/no): HbA1c Less Than 6.5% Without Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment.
Number of subjects with HbA1c less than 6.5% after 52 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.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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. Number Analyzed = subjects with available data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% Without Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment. | Yes | 198 Participants |
| Insulin Degludec/Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% Without Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment. | No | 72 Participants |
| Insulin Degludec | Responder (Yes/no): HbA1c Less Than 6.5% Without Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment. | Yes | 123 Participants |
| Insulin Degludec | Responder (Yes/no): HbA1c Less Than 6.5% Without Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment. | No | 142 Participants |
| Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% Without Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment. | Yes | 170 Participants |
| Liraglutide | Responder (Yes/no): HbA1c Less Than 6.5% Without Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment. | No | 101 Participants |
Secondary
Responder (Yes/no): HbA1c Less Than 7.0%
Number of subjects with HbA1c less than 7.0% after 52 weeks of treatment.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Responder (Yes/no): HbA1c Less Than 7.0% | Yes | 245 Participants |
| Insulin Degludec/Liraglutide | Responder (Yes/no): HbA1c Less Than 7.0% | No | 30 Participants |
| Insulin Degludec | Responder (Yes/no): HbA1c Less Than 7.0% | Yes | 189 Participants |
| Insulin Degludec | Responder (Yes/no): HbA1c Less Than 7.0% | No | 82 Participants |
| Liraglutide | Responder (Yes/no): HbA1c Less Than 7.0% | Yes | 208 Participants |
| Liraglutide | Responder (Yes/no): HbA1c Less Than 7.0% | No | 65 Participants |
Secondary
Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero
Number of subjects with HbA1c less than 7.0% and without weight gain after 52 weeks of treatment.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero | Yes | 44 Participants |
| Insulin Degludec/Liraglutide | Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero | No | 231 Participants |
| Insulin Degludec | Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero | Yes | 22 Participants |
| Insulin Degludec | Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero | No | 249 Participants |
| Liraglutide | Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero | Yes | 142 Participants |
| Liraglutide | Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero | No | 131 Participants |
Secondary
Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment
Number of subjects with HbA1c less than 7.0% and without weight gain, 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.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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. Number Analyzed = subjects with available data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | Yes | 37 Participants |
| Insulin Degludec/Liraglutide | Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | No | 233 Participants |
| Insulin Degludec | Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | Yes | 22 Participants |
| Insulin Degludec | Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | No | 243 Participants |
| Liraglutide | Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | Yes | 141 Participants |
| Liraglutide | Responder (Yes/no): HbA1c Less Than 7.0% and Change in Body Weight From Baseline Below or Equal to Zero and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment | No | 130 Participants |
Secondary
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.
Number of subjects with HbA1c less than 7.0% after 52 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.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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. Number Analyzed = subjects with available data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Insulin Degludec/Liraglutide | 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. | Yes | 227 Participants |
| Insulin Degludec/Liraglutide | 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. | No | 43 Participants |
| Insulin Degludec | 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. | Yes | 169 Participants |
| Insulin Degludec | 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. | No | 96 Participants |
| Liraglutide | 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. | Yes | 206 Participants |
| Liraglutide | 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. | No | 65 Participants |
Secondary
Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the 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.
Time frame: After 52 weeks of the treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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. Number Analyzed = subjects with available data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Degludec/Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | 90 minutes after start of lunch | 9.85 mmol/L | Standard Deviation 3.16 |
| Insulin Degludec/Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Before breakfast the following day | 5.77 mmol/L | Standard Deviation 1.56 |
| Insulin Degludec/Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | 90 minutes after start of dinner | 9.67 mmol/L | Standard Deviation 3.01 |
| Insulin Degludec/Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Before dinner | 6.47 mmol/L | Standard Deviation 2.44 |
| Insulin Degludec/Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Before breakfast | 5.90 mmol/L | Standard Deviation 1.45 |
| Insulin Degludec/Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | At 4:00 a.m. | 6.12 mmol/L | Standard Deviation 1.7 |
| Insulin Degludec/Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Before lunch | 6.01 mmol/L | Standard Deviation 1.9 |
| Insulin Degludec/Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | 90 minutes after start of breakfast | 9.57 mmol/L | Standard Deviation 2.83 |
| Insulin Degludec/Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Bedtime | 8.27 mmol/L | Standard Deviation 2.79 |
| Insulin Degludec | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Before dinner | 6.90 mmol/L | Standard Deviation 2.57 |
| Insulin Degludec | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Before breakfast | 5.93 mmol/L | Standard Deviation 1.64 |
| Insulin Degludec | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | 90 minutes after start of breakfast | 10.43 mmol/L | Standard Deviation 3.16 |
| Insulin Degludec | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Before lunch | 6.72 mmol/L | Standard Deviation 2.59 |
| Insulin Degludec | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | 90 minutes after start of lunch | 11.12 mmol/L | Standard Deviation 3.04 |
| Insulin Degludec | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | 90 minutes after start of dinner | 10.89 mmol/L | Standard Deviation 3.25 |
| Insulin Degludec | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Bedtime | 9.49 mmol/L | Standard Deviation 3.28 |
| Insulin Degludec | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | At 4:00 a.m. | 6.41 mmol/L | Standard Deviation 2.18 |
| Insulin Degludec | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Before breakfast the following day | 5.71 mmol/L | Standard Deviation 1.68 |
| Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Before lunch | 6.87 mmol/L | Standard Deviation 2.07 |
| Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Before breakfast | 7.35 mmol/L | Standard Deviation 1.7 |
| Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Bedtime | 8.73 mmol/L | Standard Deviation 2.58 |
| Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | 90 minutes after start of breakfast | 10.59 mmol/L | Standard Deviation 3.25 |
| Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Before breakfast the following day | 7.13 mmol/L | Standard Deviation 1.68 |
| Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | Before dinner | 7.03 mmol/L | Standard Deviation 2.04 |
| Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | 90 minutes after start of lunch | 10.59 mmol/L | Standard Deviation 3.38 |
| Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | At 4:00 a.m. | 7.27 mmol/L | Standard Deviation 1.79 |
| Liraglutide | Self-Measured Blood Glucose (SMBG) 9-point Profile: 9-point Profile (Individual Points in the Profile) | 90 minutes after start of dinner | 10.14 mmol/L | Standard Deviation 3.03 |
Secondary
Serum Concentrations of Insulin Degludec
Samples from the IDegLira and IDeg arms were analysed for serum concentrations of insulin degludec using validated ELISA assays.
Time frame: Weeks 2, 8, 16, 26, 44, 52
Population: Full Analysis Set (FAS) included all randomised subjects (819 subjects). All subjects in FAS with at least one valid concentration value were included in the analysis. No imputations of missing concentration values were applied. Number Analyzed = subjects with available data. This endpoint is only applicable for subjects in IDegLira and IDeg arm.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Degludec/Liraglutide | Serum Concentrations of Insulin Degludec | At week 2 | 1468.7 pmol/L | Geometric Coefficient of Variation 55.9 |
| Insulin Degludec/Liraglutide | Serum Concentrations of Insulin Degludec | At week 8 | 2246.0 pmol/L | Geometric Coefficient of Variation 72.2 |
| Insulin Degludec/Liraglutide | Serum Concentrations of Insulin Degludec | At week 16 | 2511.0 pmol/L | Geometric Coefficient of Variation 83.6 |
| Insulin Degludec/Liraglutide | Serum Concentrations of Insulin Degludec | At week 26 | 2597.3 pmol/L | Geometric Coefficient of Variation 88.3 |
| Insulin Degludec/Liraglutide | Serum Concentrations of Insulin Degludec | At week 44 | 2766.6 pmol/L | Geometric Coefficient of Variation 85.8 |
| Insulin Degludec/Liraglutide | Serum Concentrations of Insulin Degludec | At week 52 | 2393.8 pmol/L | Geometric Coefficient of Variation 116.7 |
| Insulin Degludec | Serum Concentrations of Insulin Degludec | At week 44 | 3238.8 pmol/L | Geometric Coefficient of Variation 91.7 |
| Insulin Degludec | Serum Concentrations of Insulin Degludec | At week 2 | 1477.1 pmol/L | Geometric Coefficient of Variation 61.3 |
| Insulin Degludec | Serum Concentrations of Insulin Degludec | At week 26 | 2946.9 pmol/L | Geometric Coefficient of Variation 91.1 |
| Insulin Degludec | Serum Concentrations of Insulin Degludec | At week 8 | 2524.6 pmol/L | Geometric Coefficient of Variation 71.5 |
| Insulin Degludec | Serum Concentrations of Insulin Degludec | At week 52 | 3124.4 pmol/L | Geometric Coefficient of Variation 101.2 |
| Insulin Degludec | Serum Concentrations of Insulin Degludec | At week 16 | 2856.4 pmol/L | Geometric Coefficient of Variation 84.4 |
Secondary
Total Cholesterol as a Ratio to Baseline at 52 Weeks
Total cholesterol after 52 weeks of treatment was represented as ratio to baseline (week 0) values.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Total Cholesterol as a Ratio to Baseline at 52 Weeks | 0.92 Ratio | Geometric Coefficient of Variation 13.9 |
| Insulin Degludec | Total Cholesterol as a Ratio to Baseline at 52 Weeks | 0.97 Ratio | Geometric Coefficient of Variation 11.9 |
| Liraglutide | Total Cholesterol as a Ratio to Baseline at 52 Weeks | 0.94 Ratio | Geometric Coefficient of Variation 13 |
Secondary
Triglycerides as a Ratio to Baseline at 52 Weeks
Triglycerides after 52 weeks of treatment was represented as ratio to baseline (week 0) values.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Triglycerides as a Ratio to Baseline at 52 Weeks | 0.91 Ratio | Geometric Coefficient of Variation 48.3 |
| Insulin Degludec | Triglycerides as a Ratio to Baseline at 52 Weeks | 0.96 Ratio | Geometric Coefficient of Variation 44.2 |
| Liraglutide | Triglycerides as a Ratio to Baseline at 52 Weeks | 0.91 Ratio | Geometric Coefficient of Variation 44 |
Secondary
Very Low Density Lipoprotein (VLDL) Cholesterol as a Ratio to Baseline at 52 Weeks
Very low density lipoprotein (VLDL) cholesterol after 52 weeks of treatment was represented as ratio to baseline (week 0) values.
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) included all randomised subjects (819 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 (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide | Very Low Density Lipoprotein (VLDL) Cholesterol as a Ratio to Baseline at 52 Weeks | 0.92 Ratio | Geometric Coefficient of Variation 44.3 |
| Insulin Degludec | Very Low Density Lipoprotein (VLDL) Cholesterol as a Ratio to Baseline at 52 Weeks | 0.97 Ratio | Geometric Coefficient of Variation 42.1 |
| Liraglutide | Very Low Density Lipoprotein (VLDL) Cholesterol as a Ratio to Baseline at 52 Weeks | 0.91 Ratio | Geometric Coefficient of Variation 42.2 |