A Double-blinded Trial Comparing the Efficacy and Safety of Insulin Degludec/Liraglutide and Insulin Degludec Both in Combination With Metformin in Japanese Subjects With Type 2 Diabetes Mellitus Inadequately Controlled With Basal or Pre-mix/Combination Insulin Therapy and Oral Anti-diabetic Drugs
- Conditions
- DiabetesDiabetes Mellitus, Type 2
- Interventions
- Registration Number
- NCT02911948
- Lead Sponsor
- Novo Nordisk A/S
- Brief Summary
This trial is conducted in Asia. The aim of this trial is to compare the efficacy and safety of insulin degludec/liraglutide and insulin degludec both in combination with metformin in Japanese subjects with type 2 diabetes mellitus inadequately controlled with basal or pre-mix/combination insulin therapy and oral anti-diabetic drugs.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 210
- Male or female Japanese subjects, age at least 20 years at the time of signing informed consent
- T2DM (type 2 diabetes mellitus) subjects (diagnosed clinically) for at least 6 months prior to screening
- HbA1c (glycosylated haemoglobin) 7.5-11.0 per cent [58 mmol/mol-97 mmol/mol] (both inclusive) by central laboratory analysis
- Subjects on stable daily insulin doses for at least 60 days prior to screening administered once or twice daily, either as basal insulin (e.g. IDeg, insulin glargine, insulin detemir, NPH insulin) or pre-mix/combination insulin (e.g. biphasic insulin aspart, insulin degludec/insulin aspart). Total daily insulin dose in the previous 60 days should be within 20-50 units, both inclusive, and on the day of screening, but fluctuations of plus/minus 20 per cent within the 60 days prior to screening are acceptable. The specified insulin treatment should be administered in combination with a stable daily dose of metformin within current approved Japanese label for at least 60 days prior to screening - additionally, the anti-diabetic treatment can be with or without a stable daily dose of one of the following other OADs (oral anti-diabetic drug): SU (sulfonylureas), glinides, alpha-glucosidase inhibitor, SGLT2i (sodium glucose co-transporter 2 inhibitor) or TZD (thiazolidinedione) within current approved Japanese label for at least 60 days prior to screening
- Body Mass Index (BMI) equal or above 23 kg/m^2
- Receipt of any investigational medicinal product (IMP) within 30 days before screening
- Use of any anti-diabetic drug in a period of 60 days before screening (except premix/ combination or basal insulin, metformin, SU, glinides, α-GI, SGLT2i, or TZD) or anticipated change in concomitant medication, which in the investigators opinion could interfere with glucose metabolism (e.g. systemic corticosteroids or bolus insulin)
- Treatment with glucagon-like peptide-1 (GLP-1) receptor agonist during the last 60 days prior to screening and furthermore, the discontinuation of GLP-1 receptor agonist at any point in time must not have been due to safety concerns, tolerability issues or lack of efficacy, as judged by the investigator
- Treatment with dipetidyl peptidase-4 (DPP-4) inhibitors during the last 60 days prior to screening - Impaired liver function, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) equal or above 2.5 times upper limit of normal
- Renal impairment estimated Glomerular Filtration Rate (eGFR) below 60 mL/min/1.73m^2 as per Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
- Screening calcitonin equal or above 50 ng/L
- History of pancreatitis (acute or chronic)
- Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN 2)
- Subjects presently classified as being in New York Heart Association (NYHA) Class IV
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Insulin degludec/liraglutide Insulin degludec/liraglutide - Insulin degludec Insulin degludec -
- Primary Outcome Measures
Name Time Method Change in Glycosylated Haemoglobin (HbA1c) week 0, week 26 Change from baseline (week 0) in HbA1c after 26 weeks of treatment.
- Secondary Outcome Measures
Name Time Method Change in Body Weight week 0, week 26 Change from baseline (week 0) in body weight after 26 weeks of treatment.
Responder (Yes/no): HbA1c Less Than 7.0% and Without Weight Gain After 26 weeks Number of subjects with HbA1c less than 7.0% and without weight gain after 26 weeks.
Responder (Yes/no): HbA1c Less Than 7.0% and Without Weight Gain and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment After 26 weeks Number of subjects with HbA1c less than 7.0% and no weight gain after 26 weeks, who did not experience treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the last 12 weeks of treatment.
Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product.
Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification or BG confirmed by a plasma glucose value \< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.Responder (Yes/no): HbA1c Less Than 7.0% After 26 weeks Number of subjects with HbA1c less than 7.0% after 26 weeks.
Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes During 26 weeks of treatment Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product.
Severe or BG confirmed hypoglycaemic episodes were defined as episodes that were severe according to the American Diabetes Association (ADA) classification or BG confirmed by a plasma glucose value \< 3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia.
Severe hypoglycaemia according to the ADA definition: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration.Responder (Yes/no): HbA1c Less Than 7.0% Without Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment After 26 weeks Number of subjects with HbA1c less than 7.0% after 26 weeks, who did not experience treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the last 12 weeks of treatment.
Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product.
Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification or BG confirmed by a plasma glucose value \< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.Change in Pulse Week 0, week 26 Change in pulse after 26 weeks of treatment.
Responder (Yes/no): HbA1c Less Than or Equal to 6.5% After 26 weeks Number of subjects with HbA1c less than or equal to 6.5% after 26 weeks.
Change in Fasting Plasma Glucose (FPG) week 0, week 26 Change from baseline (week 0) in FPG after 26 weeks of treatment.
Daily Insulin Dose After 26 weeks Actual daily total insulin dose after 26 weeks.
Change in Waist Circumference week 0, week 26 Change from baseline (week 0) in waist circumference after 26 weeks of treatment.
Number of Treatment Emergent Adverse Events (TEAE) During 26 weeks of treatment Treatment emergent adverse event is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product. If the event had onset date before the first day of exposure on randomised treatment and increased in severity during the treatment period and until 7 days after the last drug date, then this event was considered as a TEAE.
Responder (Yes/no): HbA1c Less Than or Equal to 6.5% Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment After 26 weeks Number of subjects with HbA1c less than or equal to 6.5% after 26 weeks, who did not experience treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the last 12 weeks of treatment.
Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product.
Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification or BG confirmed by a plasma glucose value \< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.Change in SMBG 9-point Profile: Mean of the 9-point Profile Week 0, week 26 Subjects were instructed to measure their plasma glucose at following timepoints: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, at bedtime, at 4:00 a.m. and before breakfast the following day. Mean of the 9-point profile was defined as the area under the profile (calculated using the trapezoidal method) divided by the measurement time.
Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire week 0, week 26 For the DTR-QOL questionnaire, change from baseline in the 'Total score' and the following four 'Domain scores' were analysed:
1. Burden on social activities and daily activities
2. Anxiety and dissatisfaction with treatment
3. Hypoglycaemia
4. Satisfaction with treatment. The scoring range of 'Total score' was converted to 0-100 (best case response = 100; worst case response = 0).
The scoring range for each of four domains was converted to 0-100 (best case response = 100; worst case response = 0).Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: EuroQol-5D (EQ-5D-5L) Questionnaire week 0, week 26 Overall health state was rated by patients using the EQ-5D-5L visual analogue scale (VAS) and the EQ-5D-5L index score. The EQ-5D-5L VAS is a vertical scale where patients can rank their health from 0 (worst health imaginable) to 100 (best health imaginable).
The EQ-5D-5L index score was calculated based on the 5 dimensions, i.e., mobility, self-care, usual activities (e.g., work, study), pain/discomfort and anxiety/depression with five response levels for each dimension, i.e., no problems, slight problems, moderate problems, severe problems and extreme problems. The scores from 5 dimensions are then converted to the EQ-5D-5L index score scale: 0 - 1 (full health/best-case response = 1; death/worst-case response = 0).Responder (Yes/no): HbA1c Less Than or Equal to 6.5% and Without Weight Gain After 26 weeks Number of subjects with HbA1c less than or equal to 6.5% and without weight gain
Responder (Yes/no): HbA1c Less Than or Equal to 6.5% and Without Weight Gain and Without Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During the Last 12 Weeks of Treatment After 26 weeks Number of subjects with HbA1c less than or equal to 6.5% and no weight gain after 26 weeks, who did not experience treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes during the last 12 weeks of treatment.
Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product.
Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the ADA classification or BG confirmed by a plasma glucose value \< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.Change in Blood Pressure (Systolic and Diastolic) week 0, week 26 Change from baseline in blood pressure (systolic and diastolic) after 26 weeks of treatment.
Self-measured Blood Glucose (SMBG) 9-point Profile (Individual Points in the Profile) After 26 weeks Subjects were instructed to measure their plasma glucose at following timepoints: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, at bedtime, at 4:00 a.m. and before breakfast the following day.
Change in SMBG 9-point Profile: Mean of Postprandial Plasma Glucose Increments (From Before Meal to 90 Minutes After Breakfast, Lunch and Dinner) Week 0, week 26 Subjects were instructed to measure their plasma glucose at following timepoints: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, at bedtime, at 4:00 a.m. and before breakfast the following day. The mean increment over all meals was derived as the mean of all available meal increments.
Fasting Lipid Profile Week 0, week 26 Lipid profile includes total cholesterol, low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein cholesterol (HDL cholesterol), very low density lipoprotein cholesterol (VLDL cholesterol), triglycerides and free fatty acids. Lipid profile parameters are represented as ratio to baseline values.
Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During 26 weeks of treatment Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product.
Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the American Diabetes Association (ADA) classification or BG confirmed by a plasma glucose value \< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
Severe hypoglycaemia according to the ADA definition: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration.Number of Treatment Emergent Hypoglycaemic Episodes According to American Diabetes Association (ADA) Definition During 26 weeks of treatment Results represent total number of treatment emergent hypoglycaemic episodes that fall under ADA's definition of hypoglycaemia. ADA's definition of hypoglycaemia includes following categories:
1. Severe hypoglycaemia
2. Documented symptomatic hypoglycaemia
3. Asymptomatic hypoglycaemia
4. Probable symptomatic hypoglycaemia
5. Pseudo-hypoglycaemia. Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product.Number of Treatment Emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes During 26 weeks of treatment Treatment emergent hypoglycaemic episode is defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last day on trial product. Nocturnal period: The period between 00:01 and 05:59 a.m. (both inclusive).
Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the American Diabetes Association (ADA) classification or BG confirmed by a plasma glucose value \< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
Severe hypoglycaemia according to the ADA definition: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration.Change in Clinical Evaluation: Fundoscopy or Fundus Photography Screening (week -2 to week 0), week 26 The result of the fundus photography/dilated fundoscopy was interpreted by the investigator into following categories: Normal; Abnormal (Abn), Not Clinically significant (NCS); Abnormal, Clinically significant (CS). Reported results are number of subjects with 'normal'; 'Abn, NCS' and 'Abn, CS' fundoscopy/fundus photography results at screening (week -2 to week 0) and week 26.
Change in Clinical Evaluation: Electrocardiogram (ECG) Screening (week -2 to week 0), week 26 The result of the ECG was interpreted by the investigator into following categories: Normal; Abnormal (Abn), Not Clinically significant (NCS); Abnormal, Clinically significant (CS). Reported results are number of subjects with 'normal'; 'Abn, NCS' and 'Abn, CS' ECG results at screening (week -2 to week 0) and week 26.
Trial Locations
- Locations (1)
Novo Nordisk Investigational Site
🇯🇵Yamaguchi-shi, Yamaguchi, Japan