Type 2 Diabetes Mellitus
Conditions
Brief summary
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
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.
Interventions
DRUGLixisenatide (AVE0010)
Self administered by subcutaneous injections once daily 30 minutes before breakfast.
DEVICEPen auto-injector
DRUGLiraglutide
Self administered by subcutaneous injections once daily 30 minutes before breakfast.
DEVICEPre-filled pen injector
DRUGMetformin
Metformin to be continued at stable dose (1.5 gram per day) up to Week 4.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pro-insulin AUC(0:30-4:30h) at Day 28 | 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 | 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. |
| Change From Baseline in Insulin AUC(0:30-4:30h) at Day 28 | 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 | 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. |
| Change From Baseline in C-Peptide AUC(0:30-4:30h) at Day 28 | 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 | 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. |
| Change From Baseline in Glucagon AUC(0:30-4:30h) at Day 28 | 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 | 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. |
| Change From Baseline in Postprandial Plasma Glucose (PPG) Excursion at Day 28 | 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 | 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. |
| Change From Time-matched Baseline in Peptide YY3-36 (PYY3-36) Concentration at Day 28 | 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 was calculated by subtracting time-matched baseline value from Day 28 value. Baseline value was the Day -1 time-matched PYY-36 assessment. |
| Change From Time-matched Baseline in Obestatin Concentration at Day 28 | 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 was calculated by subtracting time-matched baseline value from Day 28 value. Baseline value was the Day -1 time-matched obestatin assessment. |
| Percentages of Patients by Ranges of Oxyntomodulin Levels | 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 | 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. |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Day 29 | Pre-dose (Hour 0) on Day 1 and 29 (that is, 24 hours post-dose on Day 28) | 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). |
Countries
Germany
Participant flow
Recruitment details
The study was conducted at 7 centers in Germany between August 03, 2010 and November 18, 2010.
Pre-assignment details
A total of 259 patients were screened of which 111 (42.9%) were screen failures. A total of 148 patients were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Lixisenatide 1-step initiation regimen of lixisenatide: 10 mcg QD subcutaneously for 2 weeks, followed by 20 mcg QD up to Week 4. | 77 |
| Liraglutide 2-step initiation regimen of liraglutide: 0.6 mg QD subcutaneously for 1 week, followed by 1.2 mg QD for 1 week, then 1.8 mg QD up to Week 4. | 71 |
| Total | 148 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
Baseline characteristics
| Characteristic | Lixisenatide | Liraglutide | Total |
|---|---|---|---|
| Age, Continuous | 60.5 years STANDARD_DEVIATION 7.5 | 59.7 years STANDARD_DEVIATION 8.5 | 60.1 years STANDARD_DEVIATION 8 |
| Area Under Plasma Glucose Concentration Curve From Time 0.5 Hours to 4.5 Hours (GLU-AUC0:30-4:30h) | 169.41 hour*milligram per deciliter (h*mg/dL) STANDARD_DEVIATION 84.03 | 183.86 hour*milligram per deciliter (h*mg/dL) STANDARD_DEVIATION 100.89 | 176.28 hour*milligram per deciliter (h*mg/dL) STANDARD_DEVIATION 92.39 |
| C-Peptide AUC(0:30-4:30h) | 10.61 hour*nanogram per milliliter (h*ng/mL) STANDARD_DEVIATION 4.44 | 9.99 hour*nanogram per milliliter (h*ng/mL) STANDARD_DEVIATION 4.89 | 10.31 hour*nanogram per milliliter (h*ng/mL) STANDARD_DEVIATION 4.65 |
| Glucagon AUC(0:30-4:30h) | 27.10 hour*picogram per milliliter (h*pg/mL) STANDARD_DEVIATION 60.54 | 16.47 hour*picogram per milliliter (h*pg/mL) STANDARD_DEVIATION 78.98 | 22.05 hour*picogram per milliliter (h*pg/mL) STANDARD_DEVIATION 69.87 |
| Glycosylated Hemoglobin (HbA1c) | 7.20 percentage of hemoglobin STANDARD_DEVIATION 0.63 | 7.41 percentage of hemoglobin STANDARD_DEVIATION 0.81 | 7.30 percentage of hemoglobin STANDARD_DEVIATION 0.72 |
| Insulin AUC(0:30-4:30h) | 99.55 hour*micro international unit/milliliter STANDARD_DEVIATION 43.61 | 93.24 hour*micro international unit/milliliter STANDARD_DEVIATION 57.3 | 96.55 hour*micro international unit/milliliter STANDARD_DEVIATION 50.5 |
| Obestatin Concentration 0.5 h | 0.24 nanomole per liter (nmol/L) STANDARD_DEVIATION 0.12 | 0.29 nanomole per liter (nmol/L) STANDARD_DEVIATION 0.18 | 0.26 nanomole per liter (nmol/L) STANDARD_DEVIATION 0.15 |
| Obestatin Concentration 2.5 h | 0.22 nanomole per liter (nmol/L) STANDARD_DEVIATION 0.11 | 0.26 nanomole per liter (nmol/L) STANDARD_DEVIATION 0.15 | 0.24 nanomole per liter (nmol/L) STANDARD_DEVIATION 0.13 |
| Obestatin Concentration 4.5 h | 0.24 nanomole per liter (nmol/L) STANDARD_DEVIATION 0.12 | 0.27 nanomole per liter (nmol/L) STANDARD_DEVIATION 0.17 | 0.25 nanomole per liter (nmol/L) STANDARD_DEVIATION 0.15 |
| Peptide YY3-36 (PYY3-36) Concentration 0.5 h | 17.60 picomole per liter (pmol/L) STANDARD_DEVIATION 9.46 | 17.83 picomole per liter (pmol/L) STANDARD_DEVIATION 9.29 | 17.71 picomole per liter (pmol/L) STANDARD_DEVIATION 9.35 |
| Peptide YY3-36 (PYY3-36) Concentration 2.5 h | 21.73 picomole per liter (pmol/L) STANDARD_DEVIATION 11.83 | 21.02 picomole per liter (pmol/L) STANDARD_DEVIATION 9.19 | 21.40 picomole per liter (pmol/L) STANDARD_DEVIATION 10.62 |
| Peptide YY3-36 (PYY3-36) Concentration 4.5 h | 21.98 picomole per liter (pmol/L) STANDARD_DEVIATION 10.74 | 20.88 picomole per liter (pmol/L) STANDARD_DEVIATION 10.66 | 21.46 picomole per liter (pmol/L) STANDARD_DEVIATION 10.68 |
| Postprandial Plasma Glucose (PPG) Excursion | 88.06 milligram per deciliter (mg/dL) STANDARD_DEVIATION 29.31 | 88.06 milligram per deciliter (mg/dL) STANDARD_DEVIATION 35.86 | 88.06 milligram per deciliter (mg/dL) STANDARD_DEVIATION 32.47 |
| Pro-insulin AUC(0:30-4:30h) | 5.68 hour*micro international unit/milliliter STANDARD_DEVIATION 6.25 | 6.54 hour*micro international unit/milliliter STANDARD_DEVIATION 5.4 | 6.09 hour*micro international unit/milliliter STANDARD_DEVIATION 5.86 |
| Race/Ethnicity, Customized Black | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian/White | 76 participants | 71 participants | 147 participants |
| Sex: Female, Male Female | 28 Participants | 21 Participants | 49 Participants |
| Sex: Female, Male Male | 49 Participants | 50 Participants | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 36 / 77 | 47 / 71 |
| serious Total, serious adverse events | 0 / 77 | 0 / 71 |
Outcome results
Primary
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.
Time frame: 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
Population: Pharmacodynamic (PD) population (modified intent-to-treat \[mITT\] population) included all randomized patients, who received at least 1 dose of lixisenatide or liraglutide, and had both a baseline assessment and at least 1 post-baseline assessment of any pharmacodynamic variable, irrespective of compliance with the study protocol and procedures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | 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 | -227.25 h*mg/dL | 95% Confidence Interval 120.26 |
| Liraglutide | 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 | -72.83 h*mg/dL | 95% Confidence Interval 79.66 |
Comparison: To detect a difference of 100 or 150 h\*mg/dL in change from baseline to Day 28 in GLU-AUC(0:30-4:30h) between lixisenatide and liraglutide, 60 patients per group would provide a power of 90% assuming common standard deviation of 170 or 250 h\*mg/dL, respectively, with a 2-sided test at 5% significance level.p-value: <0.000195% CI: [-180.3, -128.54]Linear fixed effects model
Secondary
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.
Time frame: 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
Population: PD population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change From Baseline in C-Peptide AUC(0:30-4:30h) at Day 28 | -5.03 h*ng/mL | 95% Confidence Interval 5.97 |
| Liraglutide | Change From Baseline in C-Peptide AUC(0:30-4:30h) at Day 28 | 1.04 h*ng/mL | 95% Confidence Interval 4.71 |
Secondary
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.
Time frame: 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
Population: PD population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change From Baseline in Glucagon AUC(0:30-4:30h) at Day 28 | -46.71 h*pg/mL | 95% Confidence Interval 67.9 |
| Liraglutide | Change From Baseline in Glucagon AUC(0:30-4:30h) at Day 28 | -25.28 h*pg/mL | 95% Confidence Interval 68.07 |
Secondary
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).
Time frame: Pre-dose (Hour 0) on Day 1 and 29 (that is, 24 hours post-dose on Day 28)
Population: PD population. Here, number of patients analyzed = patients with post-baseline HbA1c assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Day 29 | -0.32 percentage of hemoglobin | 95% Confidence Interval 0.3 |
| Liraglutide | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Day 29 | -0.45 percentage of hemoglobin | 95% Confidence Interval 0.4 |
Secondary
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.
Time frame: 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
Population: PD population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change From Baseline in Insulin AUC(0:30-4:30h) at Day 28 | -64.22 hour*micro international unit/milliliter | 95% Confidence Interval 59.74 |
| Liraglutide | Change From Baseline in Insulin AUC(0:30-4:30h) at Day 28 | 5.34 hour*micro international unit/milliliter | 95% Confidence Interval 57.82 |
Secondary
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.
Time frame: 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
Population: PD population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change From Baseline in Postprandial Plasma Glucose (PPG) Excursion at Day 28 | -70.43 mg/dL | 95% Confidence Interval 42.04 |
| Liraglutide | Change From Baseline in Postprandial Plasma Glucose (PPG) Excursion at Day 28 | -24.93 mg/dL | 95% Confidence Interval 33.67 |
Secondary
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.
Time frame: 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
Population: PD population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change From Baseline in Pro-insulin AUC(0:30-4:30h) at Day 28 | -1.27 hour*micro international unit/milliliter | 95% Confidence Interval 6.18 |
| Liraglutide | Change From Baseline in Pro-insulin AUC(0:30-4:30h) at Day 28 | -2.47 hour*micro international unit/milliliter | 95% Confidence Interval 4.86 |
Secondary
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.
Time frame: 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
Population: PD population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lixisenatide | Change From Time-matched Baseline in Obestatin Concentration at Day 28 | Change at Day 28: 0.5 h | 0.04 nmol/L | Standard Deviation 0.09 |
| Lixisenatide | Change From Time-matched Baseline in Obestatin Concentration at Day 28 | Change at Day 28: 2.5 h | 0.03 nmol/L | Standard Deviation 0.09 |
| Lixisenatide | Change From Time-matched Baseline in Obestatin Concentration at Day 28 | Change at Day 28: 4.5 h | -0.01 nmol/L | Standard Deviation 0.08 |
| Liraglutide | Change From Time-matched Baseline in Obestatin Concentration at Day 28 | Change at Day 28: 0.5 h | 0.02 nmol/L | Standard Deviation 0.11 |
| Liraglutide | Change From Time-matched Baseline in Obestatin Concentration at Day 28 | Change at Day 28: 2.5 h | 0.01 nmol/L | Standard Deviation 0.11 |
| Liraglutide | Change From Time-matched Baseline in Obestatin Concentration at Day 28 | Change at Day 28: 4.5 h | -0.01 nmol/L | Standard Deviation 0.12 |
Secondary
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.
Time frame: 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
Population: PD population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lixisenatide | Change From Time-matched Baseline in Peptide YY3-36 (PYY3-36) Concentration at Day 28 | Change at Day 28: 0.5 h | 0.02 pmol/L | Standard Deviation 5.32 |
| Lixisenatide | Change From Time-matched Baseline in Peptide YY3-36 (PYY3-36) Concentration at Day 28 | Change at Day 28: 2.5 h | -7.09 pmol/L | Standard Deviation 8.38 |
| Lixisenatide | Change From Time-matched Baseline in Peptide YY3-36 (PYY3-36) Concentration at Day 28 | Change at Day 28: 4.5 h | -8.33 pmol/L | Standard Deviation 6.73 |
| Liraglutide | Change From Time-matched Baseline in Peptide YY3-36 (PYY3-36) Concentration at Day 28 | Change at Day 28: 0.5 h | -0.79 pmol/L | Standard Deviation 6.77 |
| Liraglutide | Change From Time-matched Baseline in Peptide YY3-36 (PYY3-36) Concentration at Day 28 | Change at Day 28: 2.5 h | -3.14 pmol/L | Standard Deviation 6.67 |
| Liraglutide | Change From Time-matched Baseline in Peptide YY3-36 (PYY3-36) Concentration at Day 28 | Change at Day 28: 4.5 h | -2.47 pmol/L | Standard Deviation 7.66 |
Secondary
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.
Time frame: 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
Population: PD population. Here, 'n' signifies patients with oxyntomodulin assessment at the specified time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 0.5 h: <=LOD (n = 75, 68) | 33.3 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 0.5 h: LOD-LOQ (n = 75, 68) | 49.3 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 0.5 h: >LOQ (n = 75, 68) | 17.3 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 2.5 h: <=LOD (n = 75, 68) | 12.0 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 2.5 h: LOD-LOQ (n = 75, 68) | 25.3 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 2.5 h: >LOQ (n = 75, 68) | 62.7 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 4.5 h: <=LOD (n = 75, 68) | 17.3 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 4.5 h: LOD-LOQ (n = 75, 68) | 34.7 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 4.5 h: >LOQ (n = 75, 68) | 48.0 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 0.5 h: <=LOD (n = 75, 68) | 38.7 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 0.5 h: LOD-LOQ (n = 75, 68) | 40.0 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 0.5 h: >LOQ (n = 75, 68) | 21.3 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 2.5 h: <=LOD (n = 74, 68) | 52.7 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 2.5 h: LOD-LOQ (n = 74, 68) | 32.4 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 2.5 h: >LOQ (n = 74, 68) | 14.9 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 4.5 h: <=LOD (n = 75, 68) | 52.0 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 4.5 h: LOD-LOQ (n = 75, 68) | 33.3 percentage of participants |
| Lixisenatide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 4.5 h: >LOQ (n = 75, 68) | 14.7 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 2.5 h: LOD-LOQ (n = 74, 68) | 48.5 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 0.5 h: <=LOD (n = 75, 68) | 20.6 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 0.5 h: <=LOD (n = 75, 68) | 30.9 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 0.5 h: LOD-LOQ (n = 75, 68) | 55.9 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 4.5 h: >LOQ (n = 75, 68) | 26.5 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 0.5 h: >LOQ (n = 75, 68) | 23.5 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 0.5 h: LOD-LOQ (n = 75, 68) | 51.5 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 2.5 h: <=LOD (n = 75, 68) | 8.8 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 2.5 h: >LOQ (n = 74, 68) | 35.3 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 2.5 h: LOD-LOQ (n = 75, 68) | 23.5 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 0.5 h: >LOQ (n = 75, 68) | 17.6 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 2.5 h: >LOQ (n = 75, 68) | 67.6 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 4.5 h: LOD-LOQ (n = 75, 68) | 52.9 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 4.5 h: <=LOD (n = 75, 68) | 11.8 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 2.5 h: <=LOD (n = 74, 68) | 16.2 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 4.5 h: LOD-LOQ (n = 75, 68) | 39.7 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day 28, 4.5 h: <=LOD (n = 75, 68) | 20.6 percentage of participants |
| Liraglutide | Percentages of Patients by Ranges of Oxyntomodulin Levels | Day -1, 4.5 h: >LOQ (n = 75, 68) | 48.5 percentage of participants |