Clinical trial NCT02911948: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes
Diabetes Mellitus, Type 2
Lead sponsor: Novo Nordisk A/S
Sponsor class: INDUSTRY
First posted: 2016-09-23
Enrollment: 210
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Change in Glycosylated Haemoglobin (HbA1c)
timeFrame: week 0, week 26
Secondary outcomes:
measure: Change in Body Weight
timeFrame: week 0, week 26
measure: Change in Fasting Plasma Glucose (FPG)
timeFrame: week 0, week 26
measure: Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Hypoglycaemic Episodes
timeFrame: During 26 weeks of treatment
measure: Daily Insulin Dose
timeFrame: After 26 weeks
measure: Responder (Yes/no): HbA1c Less Than 7.0%
timeFrame: After 26 weeks
measure: Responder (Yes/no): HbA1c Less Than 7.0% and Without Weight Gain
timeFrame: After 26 weeks
measure: 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
timeFrame: After 26 weeks
measure: 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
timeFrame: After 26 weeks
measure: Responder (Yes/no): HbA1c Less Than or Equal to 6.5%
timeFrame: After 26 weeks
measure: Responder (Yes/no): HbA1c Less Than or Equal to 6.5% and Without Weight Gain
timeFrame: After 26 weeks
measure: 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
timeFrame: After 26 weeks
measure: 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
timeFrame: After 26 weeks
measure: Change in Waist Circumference
timeFrame: week 0, week 26
measure: Change in Blood Pressure (Systolic and Diastolic)
timeFrame: week 0, week 26
measure: Self-measured Blood Glucose (SMBG) 9-point Profile (Individual Points in the Profile)
timeFrame: After 26 weeks
measure: Change in SMBG 9-point Profile: Mean of the 9-point Profile
timeFrame: Week 0, week 26
measure: Change in SMBG 9-point Profile: Mean of Postprandial Plasma Glucose Increments (From Before Meal to 90 Minutes After Breakfast, Lunch and Dinner)
timeFrame: Week 0, week 26
measure: Fasting Lipid Profile
timeFrame: Week 0, week 26
measure: Number of Treatment Emergent Adverse Events (TEAE)
timeFrame: During 26 weeks of treatment
measure: Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes
timeFrame: During 26 weeks of treatment
measure: Number of Treatment Emergent Hypoglycaemic Episodes According to American Diabetes Association (ADA) Definition
timeFrame: During 26 weeks of treatment
measure: Number of Treatment Emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes
timeFrame: During 26 weeks of treatment
measure: Change in Clinical Evaluation: Fundoscopy or Fundus Photography
timeFrame: Screening (week -2 to week 0), week 26
measure: Change in Clinical Evaluation: Electrocardiogram (ECG)
timeFrame: Screening (week -2 to week 0), week 26
measure: Change in Pulse
timeFrame: Week 0, week 26
measure: Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: Diabetes Therapy-Related Quality of Life (DTR-QOL)Questionnaire
timeFrame: week 0, week 26
measure: Change From Baseline in Patient Reported Outcomes (PROs) of Treatment: EuroQol-5D (EQ-5D-5L) Questionnaire
timeFrame: week 0, week 26
Other outcomes:
Locations:
city: Asahikawa-shi, Hokkaido
country: Japan
facility: Novo Nordisk Investigational Site
city: Chigasaki-shi, Kanagawa
country: Japan
facility: Novo Nordisk Investigational Site
city: Chitose, Hokkaido
country: Japan
facility: Novo Nordisk Investigational Site
city: Chiyoda-ku, Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Fujisawa-shi, Kanagawa
country: Japan
facility: Novo Nordisk Investigational Site
city: Fukui-shi, Fukui
country: Japan
facility: Novo Nordisk Investigational Site
city: Fukuoka-shi, Fukuoka
country: Japan
facility: Novo Nordisk Investigational Site
city: Fukuoka-shi, Fukuoka
country: Japan
facility: Novo Nordisk Investigational Site
city: Fukuoka
country: Japan
facility: Novo Nordisk Investigational Site
city: Fukushima
country: Japan
facility: Novo Nordisk Investigational Site
city: Hokkaido
country: Japan
facility: Novo Nordisk Investigational Site
city: Ibaraki
country: Japan
facility: Novo Nordisk Investigational Site
city: Kanagawa
country: Japan
facility: Novo Nordisk Investigational Site
city: Kashiwara-shi, Osaka
country: Japan
facility: Novo Nordisk Investigational Site
city: Kawagoe-shi, Saitama
country: Japan
facility: Novo Nordisk Investigational Site
city: Kawaguchi-shi, Saitama
country: Japan
facility: Novo Nordisk Investigational Site
city: Kumamoto-shi, Kumamoto
country: Japan
facility: Novo Nordisk Investigational Site
city: Kumamoto
country: Japan
facility: Novo Nordisk Investigational Site
city: Mitaka-shi, Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Miyazaki
country: Japan
facility: Novo Nordisk Investigational Site
city: Nagano
country: Japan
facility: Novo Nordisk Investigational Site
city: Nakagami, Okinawa
country: Japan
facility: Novo Nordisk Investigational Site
city: Neyagawa-shi, Osaka
country: Japan
facility: Novo Nordisk Investigational Site
city: Niigata-shi, Niigata
country: Japan
facility: Novo Nordisk Investigational Site
city: Okawa-shi, Fukuoka
country: Japan
facility: Novo Nordisk Investigational Site
city: Osaka-shi, Osaka
country: Japan
facility: Novo Nordisk Investigational Site
city: Osaka
country: Japan
facility: Novo Nordisk Investigational Site
city: Ota-ku, Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Saitama-shi, Saitama
country: Japan
facility: Novo Nordisk Investigational Site
city: Sendai-shi, Miyagi
country: Japan
facility: Novo Nordisk Investigational Site
city: Shimotsuke-shi, Tochigi
country: Japan
facility: Novo Nordisk Investigational Site
city: Tochigi
country: Japan
facility: Novo Nordisk Investigational Site
city: Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Tomigusuku-shi, Okinawa
country: Japan
facility: Novo Nordisk Investigational Site
city: Tomigusuku-shi, Okinawa
country: Japan
facility: Novo Nordisk Investigational Site
city: Yamaguchi-shi, Yamaguchi
country: Japan
facility: Novo Nordisk Investigational Site
Study officials:
affiliation: Novo Nordisk A/S
name: Global Clinical Registry (GCR, 1452)
role: STUDY_DIRECTOR
References:
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 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.
citation: 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.
citation: 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.