Effects of Lixisenatide Compared to Liraglutide on the Postprandial Plasma Glucose in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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The purpose of the study is to compare the pharmacodynamic effects of lixisenatide (AVE0010), in comparison to liraglutide, as an add-on treatment to metformin, over a period of 4 weeks of treatment. The primary objective is to assess the effects of lixisenatide, in comparison to liraglutide, in reducing postprandial plasma glucose (PPG) assessed as area under the plasma glucose concentration curve (AUC) after a standardized breakfast at Week 4. The secondary objectives are to assess the effects of lixisenatide on the maximum PPG excursion, and on the changes in insulin, pro-insulin, C-peptide and glucagon plasma concentrations following a standardized breakfast, 24-hour profile of plasma glucose, glycosylated hemoglobin (HbA1c), satiety markers (obestatin, peptide YY [PYY3-36] and oxyntomodulin); and to assess the clinical and laboratory safety profile.

Detailed Description
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The duration of the study for each patient is up to 7 weeks including a screening period up to 2 weeks, a treatment period of 4 weeks (Day 1 to Day 28), and an end-of-study visit 7 +/- 2 days after last study drug administration.

Official Title
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An Open-label, Randomized Two-arm Parallel Group Study to Compare the Effects of 4-week QD Treatment With Lixisenatide or Liraglutide on the Postprandial Plasma Glucose in Patients With Type 2 Diabetes Not Adequately Controlled With Metformin

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Lixisenatide (AVE0010)
* Device: Pen auto-injector
* Drug: Liraglutide
* Device: Pre-filled pen injector
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Type 2 diabetes mellitus diagnosed for at least 1 year at the time of screening visit, not adequately controlled by metformin at a dose of at least 1.5 gram per day for at least 3 months prior to screening HbA1c greater than or equal to (>=) 6.5% (as recommended by the American Diabetes Association) and HbA1c less than or equal to (<=) 9% at screening Covered by Health Insurance System where applicable and/or in compliance with the recommendations of the National (German) Law in force relating to biomedical research Not under any administrative or legal supervision Exclusion criteria: At the time of screening age <18 years or >=75 years Body Mass Index (BMI): <=20 kilogram per square meter (kg/m^2) or >=37 kg/m^2 History of metabolic acidosis, including diabetic ketoacidosis within 1 year prior to screening Hemoglobinopathy or hemolytic anemia History of myocardial infarction, stroke, or heart failure requiring hospitalization within 6 months prior to the time of screening, history or presence of clinically significant diabetic retinopathy, history or presence of macular edema likely to require laser treatment within the study period Cardiovascular, hepatic, neurological, or endocrine disease, active malignant tumor or other major systemic disease or patients with short life expectancy making implementation of the protocol or interpretation of the study results difficult (euthyroid patients on replacement therapy are to be included if the dosage of thyroxin is stable for at least 3 months prior to the screening visit) Uncontrolled or inadequately controlled hypertension at the time of screening with a resting systolic or diastolic blood pressure >160 millimeter of mercury (mmHg) or >95 mmHg, respectively Any clinically significant abnormality identified on physical examination, laboratory tests, or vital signs at the time of screening that in the judgment of the investigator or any sub-investigator precludes safe completion of the study Receipt of blood or plasma products within 3 months prior to the time of screening Investigator or any sub-investigator, pharmacist, study coordinator, or their study staff or relative thereof directly involved in the conduct of the protocol Patients who are considered by the investigator or any sub-investigator as inappropriate for this study for any reason (for example, impossibility of meeting specific protocol requirements such as scheduled visits, being unable to do self-injections, etc.) Use of other oral or injectable antidiabetic or hypoglycemic agents other than metformin (for example, alpha glucosidase inhibitor, exenatide, dipeptidyl peptidase IV [DPP-IV] inhibitors, insulin, thiazolidinedione, sulfonylurea, etc.) within 3 months prior to the time of screening Use of systemic glucocorticoids (excluding topical application or inhaled forms) for 1 week or more within 3 months prior to the time of screening Likelihood of requiring treatment during the screening phase and treatment phase with drugs not permitted by the clinical study protocol Use of any investigational drug within 3 months prior to screening Pregnant or breastfeeding women or women of childbearing potential with no effective contraceptive method Clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting, including, but not limited to, gastroparesis and gastroesophageal reflux disease requiring medical treatment within 6 months prior to the time of screening Any previous treatment with lixisenatide or liraglutide Allergic reaction to any glucagon like peptide - 1 (GLP-1) agonist in the past (for example, exenatide) or to metacresol History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, inflammatory bowel disease Personal or family history of medullary thyroid cancer (MTC) or a genetic condition that predisposes to MTC Known history of drug or alcohol abuse within 6 months prior to the time of screening Laboratory findings at the time of screening: alanine aminotransferase: >3 times the upper limit of the normal (ULN) laboratory range; calcitonin >=20 picogram per milliliter (pg/mL); amylase and lipase >3 times ULN; total bilirubin >1.5 times ULN (except in case of Gilbert's syndrome); hemoglobin <11 gram/deciliter and/or neutrophils <1500 per cubic millimeter (mm^3) and/or platelets <100,000/mm^3; positive test for Hepatitis B surface antigen and/or Hepatitis C antibody and Positive reaction to tests for anti-human immunodeficiency virus (HIV) type 1 (HIV1) and anti-HIV2 antibodies Renal impairment defined by creatinine clearance <60 milliliter per minute (mL/min) using the Cockcroft-Gault formula

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lixisenatide<br>1-step initiation regimen of lixisenatide: 10 microgram (mcg) once daily (QD) for 2 weeks, followed by 20 mcg QD for up to Week 4. | Drug: Lixisenatide (AVE0010)<br>* Self administered by subcutaneous injections once daily 30 minutes before breakfast.<br>Device: Pen auto-injector<br> <br> * Other names: OptiClik®;Drug: Metformin<br>* Metformin to be continued at stable dose (1.5 gram per day) up to Week 4.<br>|
| Active Comparator: Liraglutide<br>2-step initiation regimen of liraglutide: 0.6 milligram (mg) QD subcutaneously for 1 week, followed by 1.2 mg QD for 1 week, then 1.8 mg QD up to Week 4. | Drug: Liraglutide<br>* Self administered by subcutaneous injections once daily 30 minutes before breakfast.<br>Device: Pre-filled pen injector<br> <br> * Other names: Victoza®;Drug: Metformin<br>* Metformin to be continued at stable dose (1.5 gram per day) up to Week 4.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Area Under the Plasma Glucose Concentration Curve From Time 0.5 Hours to 4.5 Hours (GLU-AUC0:30-4:30h) at Day 28 | The area under the plasma glucose concentration time curve (GLU-AUC0:30-4:30h) was calculated using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours] on Day 28) to 4 hours after breakfast start (time: 4.5 hours) and corrected by subtracting pre-breakfast plasma glucose concentration (time: 0.5 hours). GLU-AUC0:30-4:30h on Day -1 was the baseline. Change in GLU-AUC0:30-4:30h = GLU-AUC0:30-4:30h on Day 28 minus GLU-AUC0:30-4:30h on Day -1. | 0.5 (8:00 clock time; prior to standardized breakfast), 0.75, 1, 1.5, 2, 2.5, 3.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 0.75, 1, 1.5, 2, 2.5, 3.5, 4.5 hours post study drug administration on Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Postprandial Plasma Glucose (PPG) Excursion at Day 28 | PPG excursion was determined on Day -1 (Baseline) and 28 as the maximum change in PPG from time of breakfast start (time: 0.5 hours) until 4 hours later subtracted from pre-meal plasma concentration. | 0.5 (8:00 clock time; prior to standardized breakfast), 0.75, 1, 1.5, 2, 2.5, 3.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 0.75, 1, 1.5, 2, 2.5, 3.5, 4.5 hours post study drug administration on Day 28 | 
| Change From Baseline in Pro-insulin AUC(0:30-4:30h) at Day 28 | The area under the pro-insulin concentration time curve (AUC0:30-4:30h) was calculated using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours] on Day 28) to 4 hours after breakfast start (time: 4.5 hours) and corrected by subtracting pre-breakfast pro-insulin concentration (time: 0.5 hours). Pro-insulin AUC0:30-4:30h on Day -1 was the baseline. Change in pro-insulin AUC0:30-4:30h = pro-insulin AUC0:30-4:30h on Day 28 minus pro-insulin AUC0:30-4:30h on Day -1. | 0.5 (8:00 clock time; prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours post study drug administration on Day 28 | 
| Change From Baseline in Insulin AUC(0:30-4:30h) at Day 28 | The area under the insulin concentration time curve (AUC0:30-4:30h) was calculated using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours] on Day 28) to 4 hours after breakfast start (time: 4.5 hours) and corrected by subtracting pre-breakfast insulin concentration (time: 0.5 hours). Insulin AUC0:30-4:30h on Day -1 was the baseline. Change in insulin AUC0:30-4:30h = insulin AUC0:30-4:30h on Day 28 minus insulin AUC0:30-4:30h on Day -1. | 0.5 (8:00 clock time; prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours post study drug administration on Day 28 | 
| Change From Baseline in C-Peptide AUC(0:30-4:30h) at Day 28 | The area under the C-peptide concentration time curve (AUC0:30-4:30h) was calculated using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours] on Day 28) to 4 hours after breakfast start (time: 4.5 hours) and corrected by subtracting pre-breakfast C-peptide concentration (time: 0.5 hours). C-peptide AUC0:30-4:30h on Day -1 was the baseline. Change in C-peptide AUC0:30-4:30h = C-peptide AUC0:30-4:30h on Day 28 minus C-peptide AUC0:30-4:30h on Day -1. | 0.5 (8:00 clock time; prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours post study drug administration on Day 28 | 
| Change From Baseline in Glucagon AUC(0:30-4:30h) at Day 28 | The area under the glucagon concentration time curve (AUC0:30-4:30h) was calculated using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours] on Day 28) to 4 hours after breakfast start (time: 4.5 hours) and corrected by subtracting pre-breakfast glucagon concentration (time: 0.5 hours). Glucagon AUC0:30-4:30h on Day -1 was the baseline. Change in glucagon AUC0:30-4:30h = glucagon AUC0:30-4:30h on Day 28 minus glucagon AUC0:30-4:30h on Day -1. | 0.5 (8:00 clock time; prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours post study drug administration on Day 28 | 
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Day 29 | Change = HbA1c value at Day 29 (24 hours post-dose on Day 28) minus HbA1c value at baseline (pre-dose [Hour 0] on Day 1). | Pre-dose (Hour 0) on Day 1 and 29 (that is, 24 hours post-dose on Day 28) | 
| Change From Time-matched Baseline in Peptide YY3-36 (PYY3-36) Concentration at Day 28 | Change was calculated by subtracting time-matched baseline value from Day 28 value. Baseline value was the Day -1 time-matched PYY-36 assessment. | 0.5 (8:00 clock time; prior to standardized breakfast), 2.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 2.5, 4.5 hours post study drug administration on Day 28 | 
| Change From Time-matched Baseline in Obestatin Concentration at Day 28 | Change was calculated by subtracting time-matched baseline value from Day 28 value. Baseline value was the Day -1 time-matched obestatin assessment. | 0.5 (8:00 clock time; prior to standardized breakfast), 2.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 2.5, 4.5 hours post study drug administration on Day 28 | 
| Percentages of Patients by Ranges of Oxyntomodulin Levels | Percentage of patients with oxyntomodulin level less than or equal to (<=) limit of detection (LOD), above limit of quantification (LOQ) and between LOD and LOQ were reported. The LOD and LOQ values for oxyntomodulin were 70 and 200 picogram per milliliter (pg/mL) respectively. | 0.5 (8:00 clock time; prior to standardized breakfast), 2.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 2.5, 4.5 hours post study drug administration on Day 28 |