A Trial Comparing Insulin Degludec/Liraglutide, Insulin Degludec, and Liraglutide in Chinese Subjects With Type 2 Diabetes Inadequately Controlled on Oral Antidiabetic Drugs (OADs)

Phase 3

Completed

Conditions: Diabetes
Diabetes Mellitus, Type 2

Interventions: Drug: Insulin degludec/liraglutide
Drug: Insulin degludec
Drug: Liraglutide

Registration Number: NCT03172494

Lead Sponsor: Novo Nordisk A/S

Brief Summary: This trial is conducted in Asia. The aim of this trial is to confirm the efficacy of insulin degludec/liraglutide in controlling glycaemia in Chinese subjects with type 2 diabetes mellitus inadequately controlled on oral antidiabetic agents

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 720

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 activities to determine suitability for the trial
Type 2 diabetes mellitus (clinically diagnosed)
Male or female, age at least 18 years at the time of signing informed consent
HbA1c 7.0-10.0 % (both inclusive) by central laboratory analysis, with the aim of a median of8.3%. When approximately 50% of the randomised subjects have an HbA1c above 8.3%, the remaining subjects randomised must have an HbA1c below or equal to 8.3%; or when approximately 50% of the randomised subjects have an HbA1c below or equal to 8.3%, the remaining subjects randomised must have an HbA1c above 8.3%
Current treatment for at least 90 calendar days prior to screening with metformin plus/minus one other OAD: α-glucosidase inhibitors, sulphonylureas, glinides or thiazolidinediones. For above or equal to 60 calendar days prior to screening subjects should be on a stable dose of:
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 glinides (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 α-glucosidase inhibitors (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 thiazolidinediones (above or equal to half of the max approved dose according to local label)

Exclusion Criteria

Treatment with insulin (except for short-term treatment at the discretion of the investigator)
Treatment with glucagon-like-peptide-1 receptor agonists or dipeptidyl-peptidase-4 inhibitors within 90 days prior to screening
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 mmHg or diastolic blood pressure above or equal to 100 mmHg
Proliferative retinopathy or maculopathy (macular oedema), requiring acute treatment
History of pancreatitis (acute or chronic)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Insulin degludec/liraglutide	Insulin degludec/liraglutide	-
Insulin degludec	Insulin degludec	-
Liraglutide	Liraglutide	-

Primary Outcome Measures

Name	Time	Method
Change in HbA1c	Week 0, week 26	Change in HbA1c from baseline (week 0) after 26 weeks of treatment is presented.

Secondary Outcome Measures

Name	Time	Method
Participants Who Achieved HbA1c < 7.0% Without Severe or BG Confirmed Episodes, and Change From Baseline in Body Weight Below or Equal to Zero.	Week 26	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 PG 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. Number of participants who achieved ADA HbA1c target (HbA1c \< 7.0%) (yes/no) after 26 weeks of treatment without severe or BG confirmed hypoglycaemic episodes during the last 12 weeks of treatment and with change from baseline in body weight below or equal to zero are presented. Missing values are imputed by LOCF.
Change in Waist Circumferance	Week 0, week 26	Change from baseline (week 0) in waist circumferance after 26 weeks of treatment is presented.
Change in Mean of 9-point SMPG Profile	Week 0, week 26	Participants measured their PG levels using blood glucose meters at 9 time points (before breakfast, 90 minutes after the start of breakfast, before lunch, 90 minutes after the start of lunch, before dinner, 90 minutes after the start of dinner, at bedtime, at 4 am, 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.
Change in Fasting High Density Lipoprotein (HDL) Cholesterol- Ratio to Baseline	Week 0, week 26	Change in fasting HDL cholesterol (measured in mmol/L) from baseline (week 0) to week 26 is presented as ratio to baseline
Change in Mean Post-prandial Plasma Glucose (PG) Increments	Week 0, week 26	Participants measured their PG levels using blood glucose meters at 9 time points (before breakfast, 90 minutes after the start of breakfast, before lunch, 90 minutes after the start of lunch, before dinner, 90 minutes after the start of dinner, at bedtime, at 4 am, before breakfast the following day). Post-prandial SMPG increments from before meal to 90 minutes after for breakfast, lunch and dinner were calculated. The mean increment over all meals was derived as the mean of all available meal increments. Change from baseline (week 0) in post-prandial SMPG increments for all meals after 26 weeks of treatment is presented.
Change in Fasting Total Cholesterol - Ratio to Baseline	Week 0, week 26	Change in fasting total cholesterol (measured in mmol/L) from baseline (week 0) to week 26 is presented as ratio to baseline.
Change in Fasting Very Low-density Lipoprotein (VLDL) Cholesterol- Ratio to Baseline	Week 0, week 26	Change in fasting VLDL cholesterol (measured in mmol/L) from baseline (week 0) to week 26 is presented as ratio to baseline
Change in Fasting Human Insulin - Ratio to Baseline	Week 0, week 26	Change in fasting human insulin (measured in picomoles per liter \[pmol/L\]) from baseline (week 0) to week 26 is presented as ratio to baseline.
Change in HOMA-B (Beta Cell Function)- Ratio to Baseline	Week 0, week 26	Change in HOMA-B (measured in %) from baseline (week 0) to week 26 is presented as ratio to baseline.
Change in Fasting Glucagon - Ratio to Baseline	Week 0, week 26	Change in fasting glucagon (measured in picograms per milliliter \[pg/mL\]) from baseline (week 0) to week 26 is presented as ratio to baseline.
Change in Fasting Triglycerides - Ratio to Baseline.	Week 0, week 26	Change in fasting triglycerides (measured in mmol/L) from baseline (week 0) to week 26 is presented as ratio to baseline.
Change in Fasting Free Fatty Acid - Ratio to Baseline	Week 0, week 26	Change in fasting free fatty acid (measured in mmol/L) from baseline (week 0) to week 26 is presented as ratio to baseline.
Change in Fasting Low Density Lipoprotein (LDL) Cholesterol- Ratio to Baseline	Week 0, week 26	Change in fasting LDL cholesterol (measured in mmol/L) from baseline (week 0) to week 26 is presented as ratio to baseline.
Number of Treatment-emergent Adverse Events (TEAE)	Weeks 0-26	A TEAE was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. The observed rates of adverse events (AEs) per patient years of exposure (PYE) (number of AEs divided by PYE multiplied by 100) after 26 weeks are presented.
Number of Treatment Emergent Nocturnal Severe or BG Confirmed Hypoglycaemic Episodes.	Weeks 0-26	Severe or BG confirmed hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification (requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a PG 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. Hypoglycaemic episodes were defined as nocturnal if the time of the onset was between 00:01 and 05.59 both inclusive. The number of episodes are represented as rates. The observed rates of episodes per PYE (number of episodes divided by PYE multiplied by 100) after 26 weeks of treatment are presented.
Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes.	Weeks 0-26	Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification (requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a PG 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. The number of episodes are represented as rates. The observed rates of episodes per PYE (number of episodes divided by PYE multiplied by 100) after 26 weeks of treatment are presented.
Number of Treatment Emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes	Weeks 0-26	Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification (requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a PG 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. Hypoglycaemic episodes were defined as nocturnal if the time of the onset was between 00:01 and 05.59 both inclusive. The number of episodes are represented as rates. The observed rates of episodes per PYE (number of episodes divided by PYE multiplied by 100) after 26 weeks of treatment are presented.
Number of Treatment Emergent Hypoglycaemic Episodes According to ADA Definition	Weeks 0-26	A hypoglycaemic episode was 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 days after the last day on trial product. The number of episodes are represented as rates. The observed rates of episodes (according to the ADA definition) per PYE (number of episodes divided by PYE multiplied by 100) after 26 weeks of treatment are presented.
Change in Physical Examination	Week -2, week 26	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 screening (week -2) and week 26 per each category is presented.
Eye Examination	Week -2, Week 26	Dilated fundoscopy or fundus photography was performed by the investigator at screening (week -2) and week 26. The results of the examination were interpreted for each eye (left and right) and are categorised as normal, abnormal NCS or abnormal CS. Number of participants in each category at screening (week -2) and week 26 is presented.
Change in Electrocardiogram (ECG)	Week -2, week 26	Electrocardiogram was assessed by the investigator as normal, abnormal NCS and abnormal CS. Number of participants at screening (week -2) and at week 26 is presented.
Change in Pulse	Week 0, week 26	Change in pulse from baseline (week 0) after 26 weeks of treatment is presented
Change in Blood Pressure (Systolic and Diastolic Blood Pressure)	Week 0, week 26	Change in blood pressure (systolic and diastolic blood pressure) from baseline (week 0) after 26 weeks of treatment is presented
Change in Biochemistry Parameters: Alkaline Phosphatase, Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase, Amalyse, Lipase, Creatiine Kinase Serum	Week 0, week 26	Change in alkaline phosphatase, ALT, AST, creatine kinase, amylase, lipase, creatine kinase serum from baseline (week 0) after 26 weeks of treatment is presented.
Change in Biochemistry Parameters: Calcium Serum (Total), Calcium Corrected Serum, Potassium Serum, Sodium Serum, Urea Serum	Week 0, week 26	Change in calcium serum (total), calcium corrected serum, potassium serum, sodium serum, urea serum from baseline (week 0) after 26 weeks of treatment is presented.
Change in Biochemistry Parameters: Total Bilirubin Serum, Creatinine Serum	Week 0, week 26	Change in total bilirubin serum, creatinine serum from baseline (week 0) after 26 weeks of treatment is presented.
Change in Biochemistry Parameters (Albumin Serum, Total Protein)	Week 0, week 26	Change in total protein, albumin serum from baseline (week 0) after 26 weeks of treatment is presented.
Change in Haematological Parameter: Erythrocytes Blood	Week 0, week 26	Change in erythrocyte blood from baseline (week 0) after 26 weeks of treatment is presented.
Change in Haematological Parameter: Haematocrits	Week 0, week 26	Change in haematocrits from baseline (week 0) after 26 weeks of treatment is presented.
Change in Haemotological Parameter- Eosinophils	Week 0, week 26	Change in eosinophils from baseline after 26 weeks of treatment is presented.
Change in Haematological Parameter - Neutrophils	Week 0, week 26	Change in neutrophils from baseline (week 0) after 26 weeks of treatment is presented.
Change in Haematological Parameter: Basophils	Week 0, week 26	Change in basophils from baseline (week 0) after 26 weeks of treatment is presented.
Change in Haemotological Parameter- Monocytes	Week 0, week 26	Change in monocytes from baseline (week 0) after 26 weeks of treatment is presented
Change in Haematological Parameter - Lymphocytes	Week 0, week 26	Change in lymphocytes from baseline (week 0) after 26 weeks of treatment is presented
Change in Haematology: Haemoglobin Blood	Week 0, week 26	Change in haemoglobin from baseline (week 0) after 26 weeks of treatment is presented.
Change in Haematologcal Parameter: Leukocytes	Week 0, week 26	Change in leukocytes from baseline (week 0) after 26 weeks of treatment
Change in Haematological Parameter: Thrombocytes	Week 0, week 26	Change in thrombocytes from baseline (week 0) after 26 weeks of treatment
Change in Calcitonin	Week 0, week 26	Calcitonin levels were measured and were categorised as low, normal or high in relation to reference range (8.31- 14.3 picogram/milliliter \[pg/mL\]). Number of participants in each category at baseline (week 0) and week 26 are presented.
Urinalysis (Protein, Glucose, Erythrocytes and Ketones)	Week 0, week 26	The urinalysis assessment was the measurements of protein, glucose, erythrocytes and ketones in urine at baseline (week 0) and week 26 and categorised as negative, trace and positive. Number of participants in each category at week 0 and week 26 is presented.
Occurence of Anti-insulin Degludec Specific Antibodies	Week 27	This outcome measure is only applicable for the insulin degludec/liraglutide arm and insulin degludec arm. Serum samples were analysed for the presence of anti-insulin degludec specific antibodies. Results at week 27 are presented as percentage of bound radioactive-labelled insulin (B) /total radioactive-labelled insulin added to the samples (T).
Occurence of Antibodies Cross-reacting to Human Insulin	Week 27	This outcome measure is only applicable for the insulin degludec/liraglutide arm and insulin degludec arm. Serum samples were analysed for the presence of cross-reacting antibodies to human insulin. Results at week 27 are presented as percentage of bound radioactive-labelled insulin (B) /total radioactive-labelled insulin added to the samples (T).
Occurence of Total Insulin Antibodies	Week 27	This outcome measure is only applicable for the Insulin degludec/liraglutide arm and Insulin degludec arm. Serum samples were analysed for the presence of antobodies to human insulin. Results at week 27 are presented as percentage of bound radioactive-labelled insulin (B) /total radioactive-labelled insulin added to the samples (T).
Occurence of Anti-liraglutide Antibodies	Week 27	This outcome measure is applicable for the Insulin degludec/liraglutide arm and the liraglutide arm. Serum samples were analysed for the presence of anti-liraglutide antibodies. Number of participants who were assessed for anti-liraglutide antibodies at week 27 are presented.
Occurence of Antibodies Cross-reacting to Native Glucagon-like Peptide (GLP-1)	Week 27	This outcome measure is applicable to the Insulin degludec/liraglutide arm and the liraglutide arm. Serum samples were analysed for the presence of cross-reacting antibodies to native GLP-1. Number of participants who measured with anti-liraglutide antibodies cross reacting native GLP-1 at week 27 are presented.
Occurence of Neutralising Liraglutide Antibodies	Week 27	This outcome measure is only applicable for the Insulin degludec/liraglutide arm and liraglutide arm. Neutralising antibodies were assessed when the corresponding anti-Liraglutide antibody were positive at week 27. Number of participants who measured with neutralising liraglutide antibodies at week 27 are presented.
Occurence of Neutralising Antibodies Cross-reacting to Native GLP-1	Week 27	This outcome measure is only applicable for the Insulin degludec/liraglutide arm and liraglutide arm. Cross reacting antibodies were assessed when anti-liraglutide antibody was positive. Number of participants who measured with neutralising liraglutide antibodies cross-reacting to native GLP-1 at week 27 are presented.
Serum Concentrations of Insulin Degludec	Week 0, week 26	This outcome measure is applicable for Insulin degludec and Insulin degludec/liraglutide arms. Serum samples from the Insulin degludec/liraglutide and Insulin degludec arms were assayed using population PK analysis. The maximum serum concentrations (Cmax) are summarised for the two arms.
Plasma Concentration of Liraglutide	Week 0, week 26	This outcome measure is for Insulin degludec/liraglutide and liraglutide arms. Serum samples from the Insulin degludec/liraglutide and liraglutide arms were assayed using population PK analysis. The Cmax are summarised for the two arms.
Participants Who Achieved HbA1c < 7.0%, American Diabetes Association (ADA) Target (Yes/no)	Week 26	Number of participants who achieved ADA HbA1c target (HbA1c \< 7.0%) (yes/no) after 26 weeks of treatment are presented.
Participants Who Achieved HbA1c < 7.0% Without Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes	Week 26	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 PG 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. Number of participants who achieved ADA HbA1c target (HbA1c \<7.0%) (yes/no) after 26 weeks of treatment and without severe or BG confirmed hypoglycaemic episodes during the last 12 weeks of treatment are presented. Missing values are imputed by LOCF.
Participants Who Achieved HbA1c ≤ 6.5% Without Severe or BG Confirmed Episodes and Change From Baseline in Body Weight Below or Equal to Zero.	Week 26	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 PG 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. Number of participants who achieved IDF HbA1c target (HbA1c ≤ 6.5%) (yes/no) after 26 weeks of treatment without severe or BG confirmed hypoglycaemic episodes during the last 12 weeks of treatment and with change from baseline in body weight below or equal to zero are presented. Missing values are imputed by LOCF.
Change in Fasting Plasma Glucose (FPG)	Week 0, week 26	Change from baseline (week 0) in FPG after 26 weeks of treatment is presented.
Participants Who Achieved HbA1c ≤ 6.5%, International Diabetes Federation (IDF) Target (Yes/no)	Week 26	Number of participants who achieved IDF HbA1c target (HbA1c ≤ 6.5%) (yes/no) after 26 weeks of treatment are presented.
Participants Who Achieved HbA1c ≤ 6.5% and Change From Baseline in Body Weight Below or Equal to Zero	Week 26	Number of participants who achieved IDF HbA1c target (HbA1c ≤ 6.5%) (yes/no) and change from baseline in body weight below or equal to zero after 26 weeks are presented. Missing values are imputed by LOCF.
Change in Body Weight	Week 0, week 26	Change in body weight from baseline (week 0) after 26 weeks of treatment is presented.
Number of Treatment Emergent Severe or BG Confirmed Hypoglycaemic Episodes	Weeks 0-26	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 blood glucose (BG) confirmed by a plasma glucose (PG) 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. The number of episodes are represented as rates. The observed rates of treatment-emergent severe or BG confirmed hypoglycaemic episodes per patient years of exposure (PYE) (number of episodes divided by PYE multiplied by 100) during 26 weeks of treatment are presented.
Insulin Dose	Week 26	The actual daily total insulin dose after 26 weeks of treatment is presented. This outcome measure is only applicable for Insulin degludec/liraglutide and Insulin degludec treatment arms.
Participants Who Achieved HbA1c <7.0% and Change in Body Weight From Baseline Below or Equal to Zero	Week 26	Number of participants who achieved ADA HbA1c target (HbA1c \< 7.0%) (yes/no) and change from baseline in body weight below or equal to zero after 26 weeks are presented. Missing values are imputed by LOCF.
Participants Who Achieved HbA1c ≤ 6.5% Without Severe or BG Confirmed Hypoglycaemic Episodes	Week 26	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 PG 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. Number of participants who achieved IDF HbA1c target (HbA1c ≤ 6.5%) (yes/no) after 26 weeks of treatment and without severe or BG confirmed hypoglycaemic episodes during the last 12 weeks of treatment are presented. Missing values are imputed by LOCF.
9-point SMPG Profile	Week 26	Participants measured their PG levels using blood glucose meters at 9 time points (before breakfast, 90 minutes after the start of breakfast, before lunch, 90 minutes after the start of lunch, before dinner, 90 minutes after the start of dinner, at bedtime, at 4 am, before breakfast the following day). 9-point SMPG values at 26 weeks of treatment are presented.
Change in Fasting C-peptide - Ratio to Baseline	Week 0, week 26	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.