A Trial Comparing the Efficacy and Safety of Insulin Degludec/Liraglutide, Insulin Degludec and Liraglutide in Japanese Subjects With Type 2 Diabetes Mellitus.

Study Overview
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Brief Summary
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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.

Official Title
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A Trial Comparing the Efficacy and Safety of Insulin Degludec/Liraglutide, Insulin Degludec and Liraglutide in Japanese Subjects With Type 2 Diabetes Mellitus

Conditions
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Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: insulin degludec/liraglutide
* Drug: insulin degludec
* Drug: liraglutide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin degludec/liraglutide OD<br> | Drug: insulin degludec/liraglutide<br>* Injected s.c. / subcutaneously (under the skin) once daily (OD) , in combination with pre-trial OAD (oral antidiabetic drug)kept in unchanged dose.<br>|
| Active Comparator: Insulin degludec OD<br> | Drug: insulin degludec<br>* Injected s.c. / subcutaneously (under the skin) once daily (OD) , in combination with pre-trial OAD (oral antidiabetic drug)kept in unchanged dose.<br>|
| Active Comparator: Liraglutide OD<br> | Drug: liraglutide<br>* Injected s.c. / subcutaneously (under the skin) once daily (OD) , in combination with pre-trial OAD (oral antidiabetic drug)kept in unchanged dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Week 0, Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Body Weight (kg) | Change from baseline (week 0) in body weight after 52 weeks of treatment. | Week 0, Week 52 | 
| 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. | Weeks 0-52 | 
| 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. | Week 0, Week 52 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) | Change from baseline (week 0) in FPG after 52 weeks | Week 0, Week 52 | 
| Insulin Dose | Actual daily total insulin dose after 52 weeks of treatment. | After 52 weeks of treatment | 
| Responder (Yes/no): HbA1c Less Than 7.0% | Number of subjects with HbA1c less than 7.0% after 52 weeks of treatment. | 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 | Number of subjects with HbA1c less than 7.0% and without weight gain after 52 weeks of treatment. | 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. | 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. | 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 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. | After 52 weeks of treatment | 
| Responder (Yes/no): HbA1c Less Than 6.5% | Number of subjects with HbA1c less than 6.5% after 52 weeks of treatment. | 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 | Number of subjects with HbA1c less than 6.5% and without weight gain after 52 weeks of treatment. | 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. | 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. | 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 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. | After 52 weeks of treatment | 
| Change in Waist Circumference | Change from baseline (week 0) in waist circumference after 52 weeks of treatment. | Week 0, Week 52 | 
| Change in Blood Pressure (Systolic and Diastolic) | Change from baseline in blood pressure (systolic and diastolic) after 52 weeks of treatment. | Week 0, Week 52 | 
| 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. | After 52 weeks of the treatment | 
| 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. | Week 0, week 52 | 
| 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. | Week 0, week 52 | 
| 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. | After 52 weeks of treatment | 
| 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. | After 52 weeks of treatment | 
| 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. | After 52 weeks of treatment | 
| 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. | After 52 weeks of treatment | 
| Triglycerides as a Ratio to Baseline at 52 Weeks | Triglycerides after 52 weeks of treatment was represented as ratio to baseline (week 0) values. | After 52 weeks of treatment | 
| 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. | After 52 weeks of treatment | 
| 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. | After 52 weeks of treatment | 
| 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. | After 52 weeks of treatment | 
| 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. | After 52 weeks of treatment | 
| Proinsulin as a Ratio to Baseline at 52 Weeks | Proinsulin after 52 weeks of treatment was represented as ratio to baseline (week 0) values. | After 52 weeks of treatment | 
| 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. | 0-52 weeks | 
| 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. | 0-52 weeks | 
| 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. | 0-52 weeks | 
| 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: Severe hypoglycaemia Documented symptomatic hypoglycaemia Asymptomatic hypoglycaemia Probable symptomatic hypoglycaemia 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. | 0-52 weeks | 
| 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. | at week 52 | 
| 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. | at week 52 | 
| 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. | at screening (week -2 to week 0), at week 52 | 
| 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. | at screening (week -2 to week 0), at week 52 | 
| Change in Clinical Evaluation: Pulse | Change in pulse after 52 weeks of treatment. | Week 0, week 52 | 
| Serum Concentrations of Insulin Degludec | Samples from the IDegLira and IDeg arms were analysed for serum concentrations of insulin degludec using validated ELISA assays. | Weeks 2, 8, 16, 26, 44, 52 | 
| Plasma Concentrations of Liraglutide | Samples from the IDegLira and liraglutide arms were assayed for plasma concentrations of liraglutide using validated ELISA assays. | Weeks 2, 8, 16, 26, 44, 52 |