A Trial Comparing the Efficacy and Safety of Liraglutide 1.8 mg/Day to Liraglutide 0.9 mg/Day in Japanese Subjects With Type 2 Diabetes Mellitus.

Study Overview
=================
Brief Summary
-----------------
This trial is conducted in Asia. The aim of the trial is to compare the efficacy and safety of liraglutide 1.8 mg/day to liraglutide 0.9 mg/day in Japanese subjects with type 2 diabetes mellitus.

Official Title
-----------------
A Trial Comparing the Efficacy and Safety of Liraglutide 1.8 mg/Day to Liraglutide 0.9 mg/Day in Japanese Subjects With Type 2 Diabetes Mellitus

Conditions
-----------------
Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Drug: liraglutide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female Japanese subjects at least 20 years of age at the time of informed consent Type 2 diabetes subjects (diagnosed clinically) for at least 6 months prior to screening HbA1c 7.5-10.0% [58 mmol/mol-86 mmol/mol] (both inclusive) Subjects on stable therapy with one OAD (oral antidiabetic drug) (stable therapy is defined as unchanged medication and unchanged dose) for for at least 60 days before screening according to approved Japanese labelling Exclusion Criteria: Treatment with insulin within 12 weeks prior to screening Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 60 days before screening 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 Within the past 180 days any of the following: myocardial infarction, stroke or hospitalisation for unstable angina and/or transient ischemic attack Diagnosis of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer, polyps and in-situ carcinomas) Any condition which, in the opinion of the investigator might jeopardise subject's safety or compliance with the protocol

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liraglutide 1.8 mg<br>The total trial duration for the 1.8 mg/day treatment arm will be approximately 67 weeks, consisting of 2 weeks screening period, a 12 weeks run-in period, a 26-week main treatment period, a safety extension period of 26 weeks and a follow-up visit. | Drug: liraglutide<br>* Injected subcutaneously s.c. (under the skin) once daily.<br>|
| Active Comparator: Liraglutide 0.9 mg<br>The total trial duration for the 0.9 mg/day treatment arm will be approximately 41 weeks, consisting of 2 weeks screening period, a 12 weeks run-in period, a 26-week treatment period, and a follow-up visit. | Drug: liraglutide<br>* Injected subcutaneously s.c. (under the skin) once daily.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glycosylated Haemoglobin (HbA1c) (Week 26) | Change from baseline (week 0) in glycosylated haemoglobin (HbA1c) was evaluated after 26 weeks of treatment. The change from baseline in the response after 26 weeks of treatment is analysed using an analysis of covariance (ANCOVA) model with treatment as a fixed effect and baseline response as a covariate. | Week 0, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c (Week 52) | Change from baseline (week 0) in HbA1c was evaluated after 52 weeks of treatment. | Week 0, Week 52 | 
| Responder for HbA1c Below 7.0% (53 mmol/Mol) | Reported results are number of subjects who achieved HbA1c target below 7.0% after 26 weeks and 52 weeks of treatment, respectively. | Week 26 and Week 52 | 
| Responder for HbA1c Below or Equal to 6.5% (48 mmol/Mol) | Reported results are number of subjects who achieved HbA1c target below or equal to 6.5% after 26 weeks and 52 weeks of treatment, respectively. | Week 26 and Week 52 | 
| Responder for HbA1c Below 7.0% Without Weight Gain | Reported results are number of subjects who achieved HbA1c target below 7.0% without weight gain after 26 weeks and 52 weeks of treatment, respectively. | Week 26 and Week 52 | 
| Responder for HbA1c Below 7.0% Without Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | Reported results are subjects with HbA1c <7.0% after 26 weeks and 52 weeks of treatment, respectively without treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes. Severe or BG confirmed symptomatic hypoglycaemia: severe as per ADA classification or BG confirmed by plasma glucose (PG) value <3.1 mmol/L with symptoms consistent with hypoglycaemia. Severe hypoglycaemia as per ADA: episode requiring assistance of another person to actively administer carbohydrate/glucagon, or take other corrective actions. PG levels may not be available during an event, but neurological recovery following the return of PG to normal is considered sufficient evidence that the event was induced by a low PG level. Treatment emergent: episode with onset date on or after randomisation (from week (wk)0) and no later than 7 days after the last day on liraglutide (maximum till wk26+7days and wk52+7days). Hence, the following shown 'Time Frame' should be read as 'Wk26+7days and Wk52+7days' | Week 26 and Week 52 | 
| Change in Self-Measured Blood Glucose (SMBG) 7-point Profile: 7-point Profile (Individual Points in the Profile) | Reported results are 7-point SMBG values at week 0, week 26 and week 52. The 7-point profile blood glucose levels were measured at the following time points always starting with the first: 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. | Week 0 and Week 26 and Week 52 | 
| Change in SMBG 7-point Profile: Mean of 7-point Profile | Change from baseline (week 0) in mean of the SMBG 7-point profile was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in SMBG 7-point Profile: Mean of Postprandial Increments (From Before Meal to 90 Minutes After for Breakfast, Lunch and Dinner) | Change from baseline (week 0) in mean of postprandial increments (from before meal to 90 minutes after for breakfast, lunch and dinner) of the SMBG 7-point profile was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Fasting Plasma Glucose (FPG) | Change from baseline (week 0) in FPG was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Waist Circumference | Change from baseline (week 0) in waist circumference was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Body Weight | Change from baseline (week 0) in body weight was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Body Mass Index (BMI) | Change from baseline (week 0) in BMI was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Blood Pressure (Systolic and Diastolic) | Change from baseline (week 0) in systolic blood pressure (SBP) and diastolic blood pressure (DBP) was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Fasting C-peptide | Fasting C-peptide was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 26 and Week 52 | 
| Fasting Insulin | Fasting insulin was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 26 and Week 52 | 
| Fasting Glucagon | Fasting glucagon was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 26 and Week 52 | 
| Proinsulin | Proinsulin was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 26 and Week 52 | 
| Proinsulin/Insulin | Proinsulin/insulin was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 26 and Week 52 | 
| Homeostasis Model Assessment of Beta-cell Function (HOMA-B) | HOMA-B was evaluated after 26 weeks and 52 weeks of treatment, respectively. HOMA-B is an index of beta-cell function and was calculated as: HOMA-B=[(20 x fasting insulin in µU/mL)/(FPG in mmol/L-3.5)]. | Week 26 and Week 52 | 
| Homeostasis Model Assessment as an Index of Insulin Resistance (HOMA-IR) | HOMA-IR was evaluated after 26 weeks and 52 weeks of treatment, respectively. HOMA-IR is an index of insulin resistance and was calculated as: HOMA-IR= fasting insulin (μU/mL) x FPG (mmol/L)/22.5. | Week 26 and Week 52 | 
| Total Cholesterol | Total cholesterol was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 26 and Week 52 | 
| Low Density Lipoprotein (LDL) Cholesterol | LDL was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 26 and Week 52 | 
| High Density Lipoprotein (HDL) Cholesterol | HDL was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 26 and Week 52 | 
| Very Low Density Lipoprotein (VLDL) Cholesterol | VLDL was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 26 and Week 52 | 
| Triglycerides | Triglycerides were evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 26 and Week 52 | 
| Free Fatty Acids | Free fatty acids were evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 26 and Week 52 | 
| Number of Treatment Emergent Adverse Events | Treatment emergent adverse events (TEAEs) were evaluated during the 26-week and 52-week treatment period, respectively. TEAE for weeks 0-26: Event that has onset date on or after randomisation (from week 0) and no later than seven days after the last day on liraglutide (maximum till week 26 + 7 days). TEAE for weeks 0-52: Event that has onset date on or after randomisation (from week 0) and no later than seven days after the last day on liraglutide (maximum till week 52 + 7 days). Hence, the following shown 'Time Frame' should be read as 'Weeks 0-26 + 7 days and Weeks 0-52 + 7 days'. | Weeks 0-26 and Weeks 0-52 | 
| Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were evaluated during the 26-week and 52-week treatment period, respectively. Severe or BG confirmed symptomatic hypoglycaemia (hypo):An episode that was severe according to the ADA classification or BG confirmed by a PG value <3.1 mmol/L with symptoms consistent with hypo. ADA definition of severe hypo:episode requiring assistance of another person to actively administer carbohydrate/glucagon, or take other corrective actions. PG levels may not be available during an event, but neurological recovery following the return of PG to normal is considered sufficient evidence that the event was induced by a low PG level. Treatment emergent: episode with onset date on or after randomisation (from week (wk) 0) and no later than 7 days after the last day on liraglutide (maximum till wk 26 and wk 52, respectively + 7 days). Hence, the following shown 'Time Frame' should be read as 'wk 0-26+7 days and wk 0-52+7 days'. | Weeks 0-26 and Weeks 0-52 | 
| Number of Treatment Emergent Nocturnal Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | Treatment emergent nocturnal severe or BG confirmed symptomatic hypoglycaemic episodes were evaluated during the26-week and 52-week treatment period, respectively. Nocturnal hypoglycaemic episodes: Those occurring between 00:01 and 05:59 hours, both inclusive. Severe or BG confirmed symptomatic hypoglycaemia: episode that was severe according to the ADA classification or BG confirmed by a PG value <3.1 mmol/L with symptoms consistent with hypoglycaemia. Treatment emergent: episode with onset date on or after randomisation (from week 0) and no later than 7 days after the last day on liraglutide (maximum till week 26 and week 52, respectively + 7 days). Hence, the following shown 'Time Frame' should be read as 'Week 0-26 + 7 days and Week 0-52 + 7 days'. | Weeks 0-26 and Weeks 0-52 | 
| Number of Treatment Emergent Hypoglycaemic Episodes According to ADA Definition | American Diabetes Association (ADA) classification of hypoglycaemia: Severe: Requiring assistance of another person to actively administer carbohydrate/glucagon/take other corrective actions. PG levels may not be available during an event, but neurological recovery following return of PG to normal is considered sufficient evidence that event was induced by a low PG level. Documented symptomatic: PG level ≤3.9 mmol/L with symptoms. Asymptomatic: PG level ≤3.9 mmol/L without symptoms. Probable symptomatic: No measurement with symptoms. Pseudo: PG level >3.9 mmol/L with symptoms. Treatment emergent hypoglycaemic episode: episode with onset date on or after randomisation (from week 0) and no later than 7 days after the last day on liraglutide (maximum till week 26 and week 52, respectively + 7 days). Hence, the following shown 'Time Frame' should be read as 'Week 0-26 + 7 days and Week 0-52 + 7 days'. | Weeks 0-26 and Weeks 0-52 | 
| Change in Pulse | Change from baseline (week 0) in pulse was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Physical Examination | Reported results are physical examination outcomes at week (wk) 0, wk 26 and wk 52. Physical examination consisted of the following listed examinations and the outcome of each examination was evaluated as: 1) normal, 2) abnormal, not clinically significant (NCS) or 3) abnormal, clinically significant (CS). Cardiovascular system Central and peripheral nervous system (PNS) Gastrointestinal (GI) system including mouth General appearance Head, ears, eyes, nose, throat, neck Lymph node palpation Musculoskeletal system Respiratory system Skin Thyroid gland | Week 0 and Week 26 and Week 52 | 
| Change in Eye Examination | Reported results are eye examination (ophthalmoscopy) outcomes at week 0, week 26 and week 52. Ophthalmoscopy outcomes for both left and right eye were evaluated as: 1) normal, 2) abnormal, NCS or 3) abnormal, CS. | Week 0 and Week 26 and Week 52 | 
| Change in Electrocardiogram (ECG) | Reported results are ECG outcomes at week 0, week 26 and week 52. ECG outcomes were evaluated as: 1) normal, 2) abnormal, NCS or 3) abnormal, CS. | Week 0 and Week 26 and Week 52 | 
| Change in Biochemistry: Creatinine | Change from baseline (week 0) in creatinine was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Biochemistry: eGFR | Change from baseline (week 0) in estimated glomerular filtration rate (eGFR) was evaluated after 26 weeks and 52 weeks of treatment, respectively. eGFR was evaluated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, mL/min/1.73m^2. | Week 0, Week 26, Week 52 | 
| Change in Biochemistry: Alanine Aminotransferase | Change from baseline (week 0) in alanine aminotransferase was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Biochemistry: Aspartate Aminotransferase | Change from baseline (week 0) in aspartate aminotransferase was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Biochemistry: Alkaline Phosphatase | Change from baseline (week 0) in alkaline phosphatase was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Biochemistry: Sodium | Change from baseline (week 0) in sodium was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Biochemistry: Potassium | Change from baseline (week 0) in potassium was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Biochemistry: Albumin | Change from baseline (week 0) in albumin was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Biochemistry: Total Bilirubin | Change from baseline (week 0) in total bilirubin was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Biochemistry: Urea | Change from baseline (week 0) in urea was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Biochemistry: Creatine Kinase | Change from baseline (week 0) in creatine kinase was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Biochemistry: Calcium | Change from baseline (week 0) in calcium was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Biochemistry: Albumin Corrected Calcium | Change from baseline (week 0) in albumin corrected calcium was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Biochemistry: Amylase | Change from baseline (week 0) in amylase was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Biochemistry: Lipase | Change from baseline (week 0) in lipase was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Haematology: Haemoglobin | Change from baseline (week 0) in haemoglobin was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26, Week 52 | 
| Change in Haematology: Haematocrit | Change from baseline (week 0) in haematocrit was evaluated after 26 weeks and 52 weeks of treatment, respectively. Haematocrit is the ratio of the volume of red blood cells to the total volume of blood. | Week 0, Week 26, Week 52 | 
| Change in Haematology: Thrombocytes | Change from baseline (week 0) in thrombocytes (platelets) was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26 and Week 52 | 
| Change in Haematology: Erythrocytes | Change from baseline (week 0) in erythrocytes was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26 and Week 52 | 
| Change in Haematology: Leukocytes | Change from baseline (week 0) in leukocytes was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26 and Week 52 | 
| Change in Haematology: Eosinophils | Change from baseline (week 0) in eosinophils was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26 and Week 52 | 
| Change in Haematology: Neutrophils | Change from baseline (week 0) in neutrophils was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26 and Week 52 | 
| Change in Haematology: Basophils | Change from baseline (week 0) in basophils was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26 and Week 52 | 
| Change in Haematology: Monocytes | Change from baseline (week 0) in monocytes was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26 and Week 52 | 
| Change in Haematology: Lymphocytes | Change from baseline (week 0) in lymphocytes was evaluated after 26 weeks and 52 weeks of treatment, respectively. | Week 0, Week 26 and Week 52 | 
| Change in Calcitonin | Reported results are number of subjects with low, normal or high calcitonin values at week 0, week 26 and week 52. Number of subjects analyzed = number of subjects contributed to the analysis for individual time point. Calcitonin values were categorised as low, normal or high. | Week 0 and Week 26 and Week 52 |