A Trial Comparing Insulin Degludec/Liraglutide and Insulin Degludec in Combination With Metformin in Chinese Subjects With Type 2 Diabetes Mellitus Inadequately Controlled With Basal Insulin Therapy and Metformin With or Without One Other Oral Antidiabetic Drug (OAD)

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 confirm the superiority of insulin degludec/liraglutide versus insulin degludec in controlling glycaemia in Chinese subjects with type 2 diabetes mellitus after 26 weeks of treatment

Official Title
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A Trial Comparing the Efficacy and Safety of Insulin Degludec/Liraglutide and Insulin Degludec in Combination With Metformin in Chinese Subjects With Type 2 Diabetes Mellitus Inadequately Controlled With Basal Insulin Therapy and Metformin With or Without One Other OAD

Conditions
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Diabetes, Diabetes Mellitus, Type 2

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including procedures to determine suitability for the trial - Male or female, age at least 18 years at the time of signing inform consent - Type 2 diabetes mellitus (clinically diagnosed) - HbA1c (glycosylated haemoglobin) above or equal to 7.5% by central laboratory analysis, with the aim of a median of 8.5%. When approximately 50% of the randomised subjects have an HbA1c above 8.5%, the remaining subjects randomised must have an HbA1c below or equal to 8.5% or when approximately 50% of the subjects randomised have an HbA1c below or equal to 8.5%, the remaining subjects randomised must have an HbA1c above 8.5% - Current treatment for at least 90 calendar days prior to screening with basal insulin plus metformin plus/minus α-glucosidase inhibitors, sulphonylureas, glinides or thiazolidinediones. Subjects should be on a stable dose for at least 60 calendar days prior to screening of: Basal insulin 20-50 units (U)/day (both inclusive) ( Individual fluctuations of plus/minus 5U during the 60 day period prior to the day of screening are acceptable.) on the day of screening in combination with: - Metformin (above or equal to 1500 mg or max tolerated dose) or - Metformin (above or equal to 1500 mg or max tolerated dose) and sulphonylureas (above or equal to half of the max approved dose according to local label) or - Metformin (above or equal to 1500 mg or max tolerated dose) and glinide (at least half of the max approved dose according to local label) or - Metformin (above or equal to 1500 mg or max tolerated dose) and α-glucosidase inhibitors (AGI) (at least half of the max approved dose according to local label) or - Metformin (above or equal to 1500 mg or max tolerated dose) and thiazolidinediones (at least half of the max approved dose according to local label) - Body mass index (BMI) above or equal to 24 kg/m^2 Exclusion Criteria: Current use of any antidiabetic drug (except for basal insulin, metformin, α-glucosidase inhibitors, sulphonylureas, glinides or thiazolidinediones) or anticipated change in concomitant medication, that in the investigator´s opinion could interfere with glucose level (e.g. systemic corticosteroids) - Treatment with glucagon like peptide -1 receptor agonists, or dipeptidyl-peptidase-4 inhibitors or insulin (except for basal insulin) within 90 days prior to Visit 1 - Impaired liver function defined as alanine aminotransferase above or equal to 2.5 times upper normal range - Impaired renal function defined as serum-creatinine above or equal to 133 μmol/L for males and above or equal to 125 μmol/L for females, or as defined according to local contraindications for metformin Screening calcitonin above or equal to 50 ng/L - Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN2) - Cardiac disorder defined as: congestive heart failure (NYHA class III-IV), diagnosis of unstable angina pectoris, cerebral stroke and/or myocardial infarction within the last 12 months prior to screening and/or planned coronary, carotid or peripheral artery revascularisation procedures - Severe uncontrolled treated or untreated hypertension (systolic blood pressure above or equal to 180 mm Hg or diastolic blood pressure above or equal to 100 mm Hg) - Proliferative retinopathy or maculopathy (macular oedema) requiring acute treatment - History of pancreatitis (acute or chronic)

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin degludec/liraglutide<br> | Drug: Insulin degludec/liraglutide<br>* Administered subcutaneously (s.c., under the skin) once daily in combination with metformin for the treatment duration of 26 weeks.<br>|
| Active Comparator: Insulin degludec<br> | Drug: Insulin degludec<br>* Administered subcutaneously (s.c., under the skin) once daily in combination with metformin for the treatment duration of 26 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c | Change in glycosylated haemoglobin (HbA1c) from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight | Change in body weight from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Number of Treatment-emergent Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes | Severe or BG confirmed hypoglycaemic episodes were defined as episodes that were severe according to the American Diabetes Association (ADA) classification (requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value < 3.1 millimoles per liter (mmol/L) with or without symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Number of treatment-emergent severe or BG confirmed hypoglycaemic episodes during 26 weeks of treatment is presented. | Up to 26 weeks | 
| Change in Fasting Plasma Glucose (FPG) | Change in FPG from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Waist Circumference | Change in waist circumference from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Mean of the 9-point Self-measured Plasma Glucose (SMPG) Profile | Participants measured plasma glucose values using the blood glucose meter at 9 time points: before breakfast, 90 min after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 min after start of dinner, bedtime, at 4:00 am and before breakfast the following day. The mean of profile is defined as the area under the profile divided by measurement time and is calculated using the trapezoidal method. Change in mean of the 9-point SMPG profile from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in SMPG-mean Post Prandial Increments | Participants measured plasma glucose values using the blood glucose meter at 9 time points: before breakfast, 90 min after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 min after start of dinner, bedtime, at 4:00 am and before breakfast the following day. Change in SMPG-mean postprandial increment over all meals from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Insulin Dose | The mean of actual daily total insulin dose after 26 weeks of treatment is presented. | Week 26 | 
| SMPG-9-point Profile (Individual Points in the Profile) | Participants measured plasma glucose values using the blood glucose meter at 9 time points: before breakfast, 90 min after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 min after start of dinner, bedtime, at 4:00 am and before breakfast the following day. SMPG-9-point profile (individual points in the profile) at week 26 is presented. | Week 26 | 
| Change in Fasting High-density Lipoprotein (HDL) Cholesterol- Ratio to Baseline | Change in fasting HDL cholesterol (measured in mmol/L) from baseline (week 0) to week 26 is presented as ratio to baseline. | Week 0, week 26 | 
| Change in Fasting Low-density Lipoprotein (LDL) Cholesterol- Ratio to Baseline | Change in fasting LDL cholesterol (measured in mmol/L) from baseline (week 0) to week 26 is presented as ratio to baseline. | Week 0, week 26 | 
| Change in Fasting Very Low-density Lipoprotein (VLDL) Cholesterol- Ratio to Baseline | Change in fasting VLDL cholesterol (measured in mmol/L) from baseline (week 0) to week 26 is presented as ratio to baseline. | Week 0, week 26 | 
| Change in Fasting Total Cholesterol- Ratio to Baseline | Change in fasting total cholesterol (measured in mmol/L) from baseline (week 0) to week 26 is presented as ratio to baseline. | Week 0, week 26 | 
| Change in Fasting Triglycerides- Ratio to Baseline | Change in fasting triglycerides (measured in mmol/L) from baseline (week 0) to week 26 is presented as ratio to baseline. | Week 0, week 26 | 
| Change in Fasting Free Fatty Acids- Ratio to Baseline | Change in fasting free fatty acids (measured in mmol/L) from baseline (week 0) to week 26 is presented as ratio to baseline. | Week 0, week 26 | 
| Change in Fasting C-peptide- Ratio to Baseline | Change in fasting C-peptide (measured in nanomoles per liter (nmol/L)) from baseline (week 0) to week 26 is presented as ratio to baseline. | Week 0, week 26 | 
| Change in Fasting Insulin- Ratio to Baseline | Change in fasting insulin (measured in picomoles per liter (pmol/L)) from baseline (week 0) to week 26 is presented as ratio to baseline. | Week 0, week 26 | 
| Change in Fasting Glucagon- Ratio to Baseline | Change in fasting glucagon (measured in picograms per milliliter (pg/mL)) from baseline (week 0) to week 26 is presented as ratio to baseline. | Week 0, week 26 | 
| Change in HOMA-B (Beta-cell Function)- Ratio to Baseline | Change in HOMA-B from baseline (week 0) to week 26 is presented as ratio to baseline. | Week 0, week 26 | 
| Participants Who Achieved HbA1c < 7.0%, ADA Target (Yes/no) | Participants who achieved HbA1c < 7.0%, ADA target (yes/no) is presented. | Week 26 | 
| Participants Who Achieved HbA1c ≤ 6.5%, American Association of Clinical Endocrinologists (AACE) Target (Yes/no) | Participants who achieved HbA1c ≤ 6.5%, AACE target (yes/no) is presented. | Week 26 | 
| Participants Who Achieved HbA1c < 7.0% and Change From Baseline in Body Weight Below or Equal to Zero | Participants who achieved HbA1c < 7.0% and change from baseline in body weight below or equal to zero is presented. | Week 26 | 
| Participants Who Achieved HbA1c ≤ 6.5% and Change From Baseline in Body Weight Below or Equal to Zero | Participants who achieved HbA1c ≤ 6.5% and change from baseline in body weight below or equal to zero is presented. | Week 26 | 
| Participants Who Achieved HbA1c < 7.0% Without Treatment-emergent Severe or BG Confirmed Hypoglycaemic Episodes | Severe or BG confirmed hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification (required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value < 3.1 mmol/L with or without symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Participants who achieved HbA1c < 7.0% at week 26 without treatment-emergent severe or BG confirmed hypoglycaemic episodes during the last 12 weeks of treatment is presented. | Week 26 | 
| Participants Who Achieved HbA1c ≤ 6.5% Without Treatment-emergent Severe or BG Confirmed Hypoglycaemic Episodes | Severe or BG confirmed hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification (required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value < 3.1 mmol/L with or without symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Participants who achieved HbA1c ≤ 6.5% at week 26 without treatment-emergent severe or BG confirmed hypoglycaemic episodes during the last 12 weeks of treatment is presented. | Week 26 | 
| Participants Who Achieved HbA1c < 7.0% and Change From Baseline in Body Weight Below or Equal to Zero and Without Treatment-emergent Severe or BG Confirmed Hypoglycaemic Episodes | Severe or BG confirmed hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification (required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value < 3.1 mmol/L with or without symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Participants who achieved HbA1c < 7.0% and change from baseline in body weight below or equal to zero and without treatment-emergent severe or BG confirmed hypoglycaemic episodes during the last 12 weeks of treatment is presented. | Week 26 | 
| Participants Who Achieved HbA1c ≤ 6.5% and Change From Baseline in Body Weight Below or Equal to Zero and Without Treatment-emergent Severe or BG Confirmed Hypoglycaemic Episodes | Severe or BG confirmed hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification (required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value < 3.1 mmol/L with or without symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Participants who achieved HbA1c ≤ 6.5% and change from baseline in body weight below or equal to zero and without treatment-emergent severe or BG confirmed hypoglycaemic episodes during the last 12 weeks of treatment is presented. | Week 26 | 
| Number of Treatment-emergent Adverse Events (TEAEs) | A TEAE was defined as an adverse event with onset date on or after the first day of exposure to randomised treatment and no later than seven days after the last day of randomised treatment. 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. | Weeks 0-27 | 
| Number of Treatment-emergent Nocturnal Severe or BG Confirmed Hypoglycaemic Episodes | Severe or BG confirmed hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification (required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value < 3.1 mmol/L with or without symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Nocturnal hypoglycaemic episodes were episodes occurring between 00:01 and 05.59 a.m. both inclusive. Number of treatment-emergent nocturnal severe or BG confirmed hypoglycaemic episodes is presented. | Weeks 0-27 | 
| Number of Treatment-emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | Severe or BG confirmed hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification (required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value < 3.1 mmol/L with symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes is presented. | Weeks 0-27 | 
| Number of Treatment-emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | Severe or BG confirmed hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification (required assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a plasma glucose value < 3.1 mmol/L with symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Nocturnal hypoglycaemic episodes were episodes occurring between 00:01 and 05.59 a.m. both inclusive. Number of treatment-emergent nocturnal severe or BG confirmed symptomatic hypoglycaemic episodes is presented. | Weeks 0-27 | 
| Number of Treatment-emergent Hypoglycaemic Episodes According to ADA Definition | Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Number of treatment-emergent hypoglycaemic episodes according to ADA definition is presented. | Weeks 0-27 | 
| Change in Physical Examination | Physical examination parameters are categorised as cardiovascular system; central and peripheral nervous system; gastrointestinal system including mouth; general appearance; head, ears, eyes, nose, throat, neck; lymph node palpation; musculoskeletal system; respiratory system; skin and thyroid gland. The number of participants assessed as normal, abnormal not clinically significant (NCS) and abnormal clinically significant (CS) at week -2 and week 26 is presented. | Week -2, week 26 | 
| Eye Examination | Dilated fundoscopy or fundus photography was performed by the investigator at week -2 and week 26. The results of the examination were interpreted for each eye (left/right) are categorised as normal, abnormal NCS or abnormal CS. Number of participants in each category at week -2 and week 26 were presented. | Week -2, week 26 | 
| Change in Electrocardiogram (ECG) | The ECG was assessed by the investigator at baseline (week -2) and week 26 and categorised as normal, abnormal NCS or abnormal CS. Number of participants in each ECG category at baseline and week 26 were presented. | Week -2, week 26 | 
| Change in Pulse | Change in pulse from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Blood Pressure (Systolic and Diastolic Blood Pressure) | Change in blood pressure (systolic and diastolic blood pressure) from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Biochemical Parameter- Amylase, Lipase, Creatinine Kinase, Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP) | Change in amylase, lipase, creatinine kinase, ALT, AST, ALP from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Biochemical Parameter-calcium (Total), Albumin Corrected Calcium, Potassium, Sodium, Urea | Change in calcium (total), albumin corrected calcium, potassium, sodium, urea from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Albumin | Change in albumin from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Total Bilirubin | Change in total bilirubin from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Creatinine | Change in creatinine from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Total Protein | Change in total protein from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Haematological Parameter- Haematocrit | Change in haematocrit from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Haematological Parameter- Haemoglobin | Change in haemoglobin from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Haematological Parameter- Leukocytes and Thrombocytes | Change in leukocytes and thrombocytes from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Haematological Parameter- Erythrocytes | Change in erythrocytes from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Haematological Parameter- Basophils | Change in basophils from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Haematological Parameter- Eosinophils | Change in eosinophils from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Haematological Parameter- Lymphocytes | Change in lymphocytes from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Haematological Parameter- Monocytes | Change in monocytes from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Haematological Parameter- Neutrophils | Change in neutrophils from baseline (week 0) to week 26 is presented. | Week 0, week 26 | 
| Change in Calcitonin | Calcitonin levels were measured and were categorised as low, normal or high. Number of participants in each category at week 0 and week 26 were presented. | Week 0, week 26 | 
| Urinalysis (Erythrocytes, Protein, Glucose and Ketones) | The urinalysis was the measurements of protein, glucose, erythrocytes and ketones at week 0 and week 26 and categorised as negative, trace, 1+, 2+ and 3+. Number of participants in each category at week 0 and week 26 are presented. | Week 0, week 26 | 
| Anti-insulin Degludec Specific Antibodies | Serum samples were analysed for the presence of anti-insulin degludec specific antibodies. Results are presented as percentage of bound radioactivity-labelled insulin/total added radioactivity-labelled insulin (%B/T). | Week 27 | 
| Antibodies Cross-reacting to Human Insulin | Serum samples were analysed for the presence of antibodies cross-reacting to human insulin. Results are presented as percentage of bound radioactivity-labelled insulin/total added radioactivity-labelled insulin (%B/T). | Week 27 | 
| Total Insulin Antibodies | Serum samples were analysed for the presence of total insulin antibodies. Results are presented as percentage of bound radioactivity-labelled insulin/total added radioactivity-labelled insulin (%B/T). | Week 27 | 
| Occurrence of Anti-liraglutide Antibodies (Yes/no) | This outcome measure is only applicable for the Insulin degludec/liraglutide treatment arm. Number of participants who measured with anti-liraglutide antibodies at week 27 are presented. | Week 27 | 
| Occurrence of Anti-liraglutide Antibodies Cross Reacting Native Glucagon-like Peptide-1 (GLP-1) | This outcome measure is only applicable for the Insulin degludec/liraglutide treatment arm. Number of participants who measured with anti-liraglutide antibodies cross reacting native GLP-1 at week 27 are presented. | Week 27 | 
| Occurrence of Neutralising Liraglutide Antibodies | This outcome measure is only applicable for the Insulin degludec/liraglutide treatment arm. Number of participants who measured with neutralising liraglutide antibodies at week 27 are presented. | Week 27 | 
| Occurrence of Neutralising Liraglutide Antibodies Cross Reacting Native GLP-1 | This outcome measure is only applicable for the Insulin degludec/liraglutide treatment arm. Number of participants who measured with neutralising liraglutide antibodies cross reacting native GLP-1 at week 27 are presented. | Week 27 |