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 (DUAL™ II Japan)

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Diabetes
• Intervention / Treatment: Drug: Insulin degludec/liraglutide; Drug: Insulin degludec

• Study Type: Interventional
• Enrollment (Actual): 210
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Asahikawa-shi, Hokkaido, Japan, 078-8211
    • Novo Nordisk Investigational Site
  • Chigasaki-shi, Kanagawa, Japan, 253-0044
    • Novo Nordisk Investigational Site
  • Chitose, Hokkaido, Japan, 066-0032
    • Novo Nordisk Investigational Site
  • Chiyoda-ku, Tokyo, Japan, 101-0024
    • Novo Nordisk Investigational Site
  • Fujisawa-shi, Kanagawa, Japan, 251-0041
    • Novo Nordisk Investigational Site
  • Fukui-shi, Fukui, Japan, 918-8503
    • Novo Nordisk Investigational Site
  • Fukuoka, Japan, 830 8522
    • Novo Nordisk Investigational Site
  • Fukuoka-shi, Fukuoka, Japan, 819-0006
    • Novo Nordisk Investigational Site
  • Fukuoka-shi, Fukuoka, Japan, 810-0001
    • Novo Nordisk Investigational Site
  • Fukushima, Japan, 963-8851
    • Novo Nordisk Investigational Site
  • Hokkaido, Japan, 060-0062
    • Novo Nordisk Investigational Site
  • Ibaraki, Japan, 311-0113
    • Novo Nordisk Investigational Site
  • Kanagawa, Japan, 235-0045
    • Novo Nordisk Investigational Site
  • Kashiwara-shi, Osaka, Japan, 582-0005
    • Novo Nordisk Investigational Site
  • Kawagoe-shi, Saitama, Japan, 350-0851
    • Novo Nordisk Investigational Site
  • Kawaguchi-shi, Saitama, Japan, 332-0012
    • Novo Nordisk Investigational Site
  • Kumamoto, Japan, 862-0976
    • Novo Nordisk Investigational Site
  • Kumamoto-shi, Kumamoto, Japan, 862-0965
    • Novo Nordisk Investigational Site
  • Mitaka-shi, Tokyo, Japan, 181-0013
    • Novo Nordisk Investigational Site
  • Miyazaki, Japan, 880-0034
    • Novo Nordisk Investigational Site
  • Nagano, Japan, 390-8621
    • Novo Nordisk Investigational Site
  • Nakagami, Okinawa, Japan, 901-2393
    • Novo Nordisk Investigational Site
  • Neyagawa-shi, Osaka, Japan
    • Novo Nordisk Investigational Site
  • Niigata-shi, Niigata, Japan, 950 1104
    • Novo Nordisk Investigational Site
  • Okawa-shi, Fukuoka, Japan, 831-0016
    • Novo Nordisk Investigational Site
  • Osaka, Japan, 569-1045
    • Novo Nordisk Investigational Site
  • Osaka-shi, Osaka, Japan, 536-0001
    • Novo Nordisk Investigational Site
  • Ota-ku, Tokyo, Japan, 1430015
    • Novo Nordisk Investigational Site
  • Saitama-shi, Saitama, Japan, 336-0967
    • Novo Nordisk Investigational Site
  • Sendai-shi, Miyagi, Japan, 980-0021
    • Novo Nordisk Investigational Site
  • Shimotsuke-shi, Tochigi, Japan, 329-0433
    • Novo Nordisk Investigational Site
  • Tochigi, Japan, 323-0022
    • Novo Nordisk Investigational Site
  • Tokyo, Japan, 103-0027
    • Novo Nordisk Investigational Site
  • Tokyo, Japan, 103-0028
    • Novo Nordisk Investigational Site
  • Tokyo, Japan, 113-8431
    • Novo Nordisk Investigational Site
  • Tomigusuku-shi, Okinawa, Japan, 901-0244
    • Novo Nordisk Investigational Site
  • Tomigusuku-shi, Okinawa, Japan, 901-0243
    • Novo Nordisk Investigational Site
  • Yamaguchi-shi, Yamaguchi, Japan, 754-0002
    • Novo Nordisk Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Insulin degludec/liraglutide	Drug: Insulin degludec/liraglutide; Injected s.c. / subcutaneously (under the skin) once daily
ACTIVE_COMPARATOR: Insulin degludec	Drug: Insulin degludec; Injected s.c. / subcutaneously (under the skin) once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Glycosylated Haemoglobin (HbA1c)	Change from baseline (week 0) in HbA1c after 26 weeks of treatment.	week 0, week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Body Weight	Change from baseline (week 0) in body weight after 26 weeks of treatment.	week 0, week 26
Change in Fasting Plasma Glucose (FPG)	Change from baseline (week 0) in FPG after 26 weeks of treatment.	week 0, week 26
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.	During 26 weeks of treatment
Daily Insulin Dose	Actual daily total insulin dose after 26 weeks.	After 26 weeks
Responder (Yes/no): HbA1c Less Than 7.0%	Number of subjects with HbA1c less than 7.0% after 26 weeks.	After 26 weeks
Responder (Yes/no): HbA1c Less Than 7.0% and Without Weight Gain	Number of subjects with HbA1c less than 7.0% and without weight gain after 26 weeks.	After 26 weeks
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 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.	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	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.	After 26 weeks
Responder (Yes/no): HbA1c Less Than or Equal to 6.5%	Number of subjects with HbA1c less than or equal to 6.5% after 26 weeks.	After 26 weeks
Responder (Yes/no): HbA1c Less Than or Equal to 6.5% and Without Weight Gain	Number of subjects with HbA1c less than or equal to 6.5% and without weight gain	After 26 weeks
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	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.	After 26 weeks
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	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.	After 26 weeks
Change in Waist Circumference	Change from baseline (week 0) in waist circumference after 26 weeks of treatment.	week 0, week 26
Change in Blood Pressure (Systolic and Diastolic)	Change from baseline in blood pressure (systolic and diastolic) after 26 weeks of treatment.	week 0, week 26
Self-measured Blood Glucose (SMBG) 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 26 weeks
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 26
Change in SMBG 9-point Profile: Mean of Postprandial Plasma Glucose Increments (From Before Meal to 90 Minutes After 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 26
Fasting Lipid Profile	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.	Week 0, week 26
Number of Treatment Emergent Adverse Events (TEAE)	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.	During 26 weeks of treatment
Number of Treatment Emergent 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. 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.	During 26 weeks of treatment
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.	During 26 weeks of treatment
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.	During 26 weeks of treatment
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 26.	Screening (week -2 to week 0), week 26
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 26.	Screening (week -2 to week 0), week 26
Change in Pulse	Change in pulse after 26 weeks of treatment.	Week 0, week 26
Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire	For the DTR-QOL questionnaire, change from baseline in the 'Total score' and the following four 'Domain scores' were analysed: Burden on social activities and daily activities; Anxiety and dissatisfaction with treatment; Hypoglycaemia; 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).	week 0, week 26
Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: EuroQol-5D (EQ-5D-5L) Questionnaire	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).	week 0, week 26

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• Watada H, Kaneko S, Komatsu M, Agner BR, Nishida T, Ranthe M, Nakamura J. Superior HbA1c control with the fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with a maximum dose of 50 units of insulin degludec in Japanese individuals with type 2 diabetes in a phase 3, double-blind, randomized trial. Diabetes Obes Metab. 2019 Dec;21(12):2694-2703. doi: 10.1111/dom.13859. Epub 2019 Sep 17.
• Komatsu M, Watada H, Kaneko S, Ross Agner BF, Nishida T, Kaku K. Efficacy and safety of the fixed-ratio combination of insulin degludec and liraglutide by baseline glycated hemoglobin, body mass index and age in Japanese individuals with type 2 diabetes: A subgroup analysis of two phase III trials. J Diabetes Investig. 2021 Sep;12(9):1610-1618. doi: 10.1111/jdi.13525. Epub 2021 Mar 24.
• Watada H, Ross Agner BF, Doshi A, Bardtrum L, Ranthe MF, Billings LK. IDegLira Improves Glycemic Control in Japanese Patients with Uncontrolled Type 2 Diabetes on Premixed Insulin Therapy. Diabetes Ther. 2020 Jan;11(1):331-339. doi: 10.1007/s13300-019-00730-y. Epub 2019 Nov 23.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 21, 2016
• Primary Completion (ACTUAL): November 17, 2017
• Study Completion (ACTUAL): November 22, 2017

Study Registration Dates

• First Submitted: September 20, 2016
• First Submitted That Met QC Criteria: September 22, 2016
• First Posted (ESTIMATE): September 23, 2016

Study Record Updates

• Last Update Posted (ACTUAL): April 9, 2021
• Last Update Submitted That Met QC Criteria: March 10, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Insulin; Insulin, Globin Zinc; Insulin, Long-Acting; Liraglutide; Xultophy
• Other Study ID Numbers: NN9068-4184; U1111-1178-3453 (OTHER: WHO); JapicCTI-163385 (OTHER: JapicCTI)