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

Diabetes Mellitus, Type 2 Clinical Trial

— DUAL™ II Japan  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02911948
• Other study ID #: NN9068-4184
• Secondary ID: U1111-1178-3453J
• Status: Completed
• Phase: Phase 3
• Start date: September 21, 2016
• Est. completion date: November 22, 2017

Study information

• Verified date: March 2021
• Source: Novo Nordisk A/S
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 210
• Est. completion date: November 22, 2017
• Est. primary completion date: November 17, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

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, a-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

Related Conditions & MeSH terms

• Diabetes
• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• Insulin degludec/liraglutide
Injected s.c. / subcutaneously (under the skin) once daily
• Insulin degludec
Injected s.c. / subcutaneously (under the skin) once daily

Locations

Country	Name	City	State
Japan	Novo Nordisk Investigational Site	Asahikawa-shi, Hokkaido
Japan	Novo Nordisk Investigational Site	Chigasaki-shi, Kanagawa
Japan	Novo Nordisk Investigational Site	Chitose, Hokkaido
Japan	Novo Nordisk Investigational Site	Chiyoda-ku, Tokyo
Japan	Novo Nordisk Investigational Site	Fujisawa-shi, Kanagawa
Japan	Novo Nordisk Investigational Site	Fukui-shi, Fukui
Japan	Novo Nordisk Investigational Site	Fukuoka
Japan	Novo Nordisk Investigational Site	Fukuoka-shi, Fukuoka
Japan	Novo Nordisk Investigational Site	Fukuoka-shi, Fukuoka
Japan	Novo Nordisk Investigational Site	Fukushima
Japan	Novo Nordisk Investigational Site	Hokkaido
Japan	Novo Nordisk Investigational Site	Ibaraki
Japan	Novo Nordisk Investigational Site	Kanagawa
Japan	Novo Nordisk Investigational Site	Kashiwara-shi, Osaka
Japan	Novo Nordisk Investigational Site	Kawagoe-shi, Saitama
Japan	Novo Nordisk Investigational Site	Kawaguchi-shi, Saitama
Japan	Novo Nordisk Investigational Site	Kumamoto
Japan	Novo Nordisk Investigational Site	Kumamoto-shi, Kumamoto
Japan	Novo Nordisk Investigational Site	Mitaka-shi, Tokyo
Japan	Novo Nordisk Investigational Site	Miyazaki
Japan	Novo Nordisk Investigational Site	Nagano
Japan	Novo Nordisk Investigational Site	Nakagami, Okinawa
Japan	Novo Nordisk Investigational Site	Neyagawa-shi, Osaka
Japan	Novo Nordisk Investigational Site	Niigata-shi, Niigata
Japan	Novo Nordisk Investigational Site	Okawa-shi, Fukuoka
Japan	Novo Nordisk Investigational Site	Osaka
Japan	Novo Nordisk Investigational Site	Osaka-shi, Osaka
Japan	Novo Nordisk Investigational Site	Ota-ku, Tokyo
Japan	Novo Nordisk Investigational Site	Saitama-shi, Saitama
Japan	Novo Nordisk Investigational Site	Sendai-shi, Miyagi
Japan	Novo Nordisk Investigational Site	Shimotsuke-shi, Tochigi
Japan	Novo Nordisk Investigational Site	Tochigi
Japan	Novo Nordisk Investigational Site	Tokyo
Japan	Novo Nordisk Investigational Site	Tokyo
Japan	Novo Nordisk Investigational Site	Tokyo
Japan	Novo Nordisk Investigational Site	Tomigusuku-shi, Okinawa
Japan	Novo Nordisk Investigational Site	Tomigusuku-shi, Okinawa
Japan	Novo Nordisk Investigational Site	Yamaguchi-shi, Yamaguchi

Sponsors (1)

Lead Sponsor	Collaborator
Novo Nordisk A/S

Country where clinical trial is conducted

Japan, 

References & Publications (2)

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: — View Citation

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 indiv — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Glycosylated Haemoglobin (HbA1c)	Change from baseline (week 0) in HbA1c after 26 weeks of treatment.	week 0, week 26
Secondary	Change in Body Weight	Change from baseline (week 0) in body weight after 26 weeks of treatment.	week 0, week 26
Secondary	Change in Fasting Plasma Glucose (FPG)	Change from baseline (week 0) in FPG after 26 weeks of treatment.	week 0, week 26
Secondary	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
Secondary	Daily Insulin Dose	Actual daily total insulin dose after 26 weeks.	After 26 weeks
Secondary	Responder (Yes/no): HbA1c Less Than 7.0%	Number of subjects with HbA1c less than 7.0% after 26 weeks.	After 26 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in Waist Circumference	Change from baseline (week 0) in waist circumference after 26 weeks of treatment.	week 0, week 26
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in Pulse	Change in pulse after 26 weeks of treatment.	Week 0, week 26
Secondary	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
Secondary	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