Type 2 Diabetes Mellitus
Conditions
Brief summary
The purpose of this study is to evaluate benefits and risks of lixisenatide (AVE0010), in comparison to sitagliptin, as an add-on treatment to metformin, in obese (body mass index \[BMI\] greater than or equal to 30 kilogram per square meter \[kg/m\^2\]) type 2 diabetic patients less than 50 years of age, over a period of 24 weeks of treatment. The primary objective of this study is to assess the efficacy of lixisenatide, in comparison to sitagliptin, as an add-on treatment to metformin on a composite endpoint of glycemic control in terms of glycosylated hemoglobin (HbA1c) and body weight, at Week 24. Secondary objectives are to assess the effects of lixisenatide, in comparison to sitagliptin, as an add-on treatment to metformin on absolute changes in HbA1c values and body weight; fasting plasma glucose (FPG); plasma glucose, insulin, C-peptide, glucagon, and proinsulin during a 2-hour standardized meal test; insulin resistance assessed by homeostatic model assessment of insulin resistance (HOMA-IR); beta cell function assessed by homeostatic model assessment of beta-cell function (HOMA-beta); to evaluate safety, tolerability, and anti-lixisenatide antibody development.
Interventions
DRUGLixisenatide Placebo
Self-administered by subcutaneous injections once daily within the hour preceding breakfast.
DEVICEPen auto-injector
DRUGSitagliptin
Administered orally once a day in the morning with or without food at approximately the same time each day.
DRUGLixisenatide (AVE0010)
Self-administered by subcutaneous injections once daily within the hour preceding breakfast.
Administered orally once a day in the morning with or without food at approximately the same time each day.
DRUGMetformin
Metformin to be continued at stable dose (at least 1.5 gram per day) up to Week 24.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 49 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes mellitus, diagnosed for at least 1 year at the time of screening visit, insufficiently controlled with metformin at a stable dose of at least 1.5 gram/day (g/day) for at least 3 months prior to the screening visit * Patients with obesity (BMI greater than equal to \[\>=\] 30 kg/m\^2) and aged from 18 years to less than 50 years
Exclusion criteria
* HbA1c less than (\<) 7.0 percent (%) or HbA1c greater than (\>) 10% at screening * Type 1 diabetes mellitus * Pregnant or breastfeeding women or women of childbearing potential with no effective contraceptive method * FPG at screening \>250 milligram/deciliter (mg/dL) (\>13.9 millimole/ liter \[mmol/L\]) * Weight change of more than 5 kg during the 3 months preceding the screening visit * History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, inflammatory bowel disease, personal or family history of medullary thyroid cancer (MTC) or genetic conditions that predispose to MTC (for example, multiple endocrine neoplasia syndromes) * History of metabolic acidosis, including diabetic ketoacidosis within 1 year prior to screening * Hemoglobinopathy or hemolytic anemia or receipt of blood or plasma products within 3 months prior to the time of screening * Within the last 6 months prior to screening: history of myocardial infarction, stroke, or heart failure requiring hospitalization * Known history of drug or alcohol abuse within 6 months prior to the time of screening * Any clinically significant abnormality identified on physical examination, laboratory tests, electrocardiogram (ECG) or vital signs at the time of screening that in the judgment of the investigator or any sub-investigator could have precludes safe completion of the study or constrains efficacy assessment such as major systemic diseases, presence of clinically significant diabetic retinopathy or presence of macular edema likely to require laser treatment within the study period * Uncontrolled or inadequately controlled hypertension at the time of screening with a resting systolic or diastolic blood pressure \>180 millimeter of mercury (mmHg) or \>110 mmHg, respectively * Laboratory findings at the time of screening : Amylase and/or lipase \>3 times the upper limit of normal (ULN) laboratory range; alanine aminotransferase (ALT): \>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 (HBsAg) and/or Hepatitis C antibody (HCAb), positive serum pregnancy test in females of childbearing potential, and calcitonin \>=20 picogram per milliliter (pg/mL) (5.9 picomole per liter) * Patients who are considered by the investigator or any sub-investigator as inappropriate for the study for any reason (for example, impossibility to meet specific protocol requirements \[such as scheduled visits, being able to do self-injections\], likelihood of requiring treatment during the screening phase and treatment phase with drugs not permitted by the clinical study protocol, investigator or any sub-investigator, pharmacist, study coordinator, other study staff or relative thereof directly involved in the conduct of the protocol) * Use of other oral or injectable antidiabetic or hypoglycemic agents than metformin (for example, sulfonylurea, alpha glucosidase inhibitor, thiazolidinedione, exenatide, dipeptidyl peptidase IV (DPP-IV) inhibitors, insulin) within 3 months prior to the time of screening * History of bariatric surgery, anti-obesity treatment, or unstable diet within 3 months prior to the time of screening * Use of systemic glucocorticoids (excluding topical application or inhaled forms) for one week or more within 3 months prior to the time of screening * Use of any investigational drug within 3 months prior to screening * Clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting, including (but not limited to): gastroparesis, unstable (that is, worsening) and not controlled (that is, prolonged nausea and vomiting) gastroesophageal reflux disease requiring medical treatment, within 6 months prior to the time of screening * Any previous treatment with lixisenatide (for example, participation in a previous study with lixisenatide) * Allergic reaction to any glucagon like peptide-1 (GLP 1) agonist in the past (for example, exenatide, liraglutide) or to metacresol * History of a serious hypersensitivity reaction to sitagliptin * Moderate or severe renal impairment (creatinine clearance inferior to 50 milliliter/minute \[mL/min\]) * Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% and at Least 5% Weight Loss From Baseline at Week 24 | Week 24 | Percentage of patients who met both criteria (HbA1c \<7% at Week 24 and at least 5% weight loss from baseline at Week 24) is reported. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin (PPI) at Week 24 | Baseline, Week 24 | Change was calculated for fasting plasma insulin and 2-hour post prandial plasma insulin by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest. |
| Change From Baseline in Insulin Resistance Assessed by Homeostasis Model Assessment- Insulin Resistance (HOMA-IR) at Week 24 | Baseline, Week 24 | HOMA-IR was derived from FPG and FPI as: (FPI \[micro units per milliliter\]\*FPG \[mmol/L\]) divided by 22.5. Change was calculated for HOMA-IR by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. |
| Change From Baseline in Beta Cell Function Assessed by Homeostasis Model Assessment-Beta (HOMA-beta) at Week 24 | Baseline, Week 24 | HOMA-beta was derived from FPG and FPI as: (20\*FPI \[micro units/milliliter\]) divided by (FPG \[mmol/L\] minus 3.5). Change was calculated for HOMA-beta by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. |
| Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24 | Week 24 | The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. |
| Percentage of Patients Requiring Rescue Therapy During 24-Week Period | Baseline up to Week 24 | Routine fasting self-measured plasma glucose (SMPG) and central laboratory FPG (and HbA1c after week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after week 12) were performed. Threshold values - from baseline to Week 8: fasting SMPG/FPG \>270 milligram/deciliter (mg/dL) (15.0 mmol/L), from Week 8 to Week 12: fasting SMPG/FPG \>240 mg/dL (13.3 mmol/L), and from Week 12 to Week 24: fasting SMPG/FPG \>200 mg/dL (11.1 mmol/L) or HbA1c \>8.5%. |
| Absolute Change From Baseline in HbA1c at Week 24 | Baseline, Week 24 | Absolute change = HbA1c value at Week 24 minus HbA1c value at baseline. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. |
| Change From Baseline in Body Weight at Week 24 | Baseline, Week 24 | Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. |
| Change From Baseline in 2-hour Postprandial Plasma Glucose (PPG) at Week 24 | Baseline, Week 24 | The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest. |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Baseline, Week 24 | Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 1 day after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. |
| Change From Baseline in Glucose Excursion at Week 24 | Baseline, Week 24 | Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test, before study drug administration. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest. |
| Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24 | Baseline, Week 24 | Change was calculated for fasting C-peptide and 2-hour postprandial C-peptide by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. |
| Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24 | Baseline, Week 24 | Change was calculated for fasting glucagon and 2-hour postprandial glucagon by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. |
| Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24 | Baseline, Week 24 | Change was calculated for fasting proinsulin and 2-hour postprandial proinsulin by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of the study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Proinsulin-to-insulin Ratio and 2-hour Postprandial Proinsulin-to-insulin Ratio at Week 24 | Baseline, Week 24 | Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest. |
| Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | First dose of study drug up to 3 days after the last dose administration | Symptomatic hypoglycemia was an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose less than 60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose measurement was available. Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the patient required the assistance of another person and was associated with either a plasma glucose level below 36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available. |
| Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24 | Baseline, Week 24 | The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. |
| Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24 | Week 24 | The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. |
Countries
Australia, Brazil, Canada, Chile, Germany, Guatemala, Mexico, Peru, Poland, Romania, Russia, Ukraine, United States
Participant flow
Recruitment details
The study was conducted at 92 centers in 13 countries between August 31, 2009 and March 19, 2011.
Pre-assignment details
A total of 620 patients were screened of which 301 (48.5%) were screen failures; main reason for screen failure was glycosylated hemoglobin (HbA1c) values being out of the defined protocol range (greater than or equal to 7% and less than or equal to 10%). A total of 319 patients were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Lixisenatide 2-step initiation regimen of lixisenatide along with sitagliptin placebo: lixisenatide 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to Week 24 along with placebo matching to sitagliptin 100 mg capsule orally QD up to Week 24. | 158 |
| Sitagliptin Sitagliptin along with 2-step initiation regimen of volume matching lixisenatide placebo: sitagliptin 100 mg capsule orally QD up to Week 24 along with volume matching lixisenatide placebo 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to Week 24. | 161 |
| Total | 319 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 5 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Personal and Familial Reason | 2 | 2 |
| Overall Study | Poor compliance to protocol | 3 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | Lixisenatide | Total | Sitagliptin |
|---|---|---|---|
| 2-hour Postprandial C-peptide | 2.79 mmol/L STANDARD_DEVIATION 1.28 | 2.86 mmol/L STANDARD_DEVIATION 1.32 | 2.92 mmol/L STANDARD_DEVIATION 1.35 |
| 2-hour Postprandial Glucagon | 66.36 ng/L STANDARD_DEVIATION 17.58 | 67.04 ng/L STANDARD_DEVIATION 22.05 | 67.72 ng/L STANDARD_DEVIATION 25.77 |
| 2-hour Postprandial Plasma Glucose (PPG) | 13.77 millimole per liter (mmol/L) STANDARD_DEVIATION 3.78 | 13.84 millimole per liter (mmol/L) STANDARD_DEVIATION 3.88 | 13.92 millimole per liter (mmol/L) STANDARD_DEVIATION 3.99 |
| 2-hour Postprandial Plasma Insulin | 424.67 pmol/L STANDARD_DEVIATION 350.96 | 422.56 pmol/L STANDARD_DEVIATION 327.02 | 420.45 pmol/L STANDARD_DEVIATION 302.17 |
| 2-hour Postprandial Proinsulin | 105.50 pmol/L STANDARD_DEVIATION 75.38 | 105.51 pmol/L STANDARD_DEVIATION 74.57 | 105.51 pmol/L STANDARD_DEVIATION 74 |
| 2-hour Postprandial Proinsulin-to-Insulin Ratio | 0.36 ratio STANDARD_DEVIATION 0.53 | 0.34 ratio STANDARD_DEVIATION 0.41 | 0.32 ratio STANDARD_DEVIATION 0.24 |
| Age, Continuous | 42.7 years STANDARD_DEVIATION 5.2 | 43.1 years STANDARD_DEVIATION 4.9 | 43.4 years STANDARD_DEVIATION 4.7 |
| Body Mass Index (BMI) | 36.76 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 7.25 | 36.76 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.8 | 36.76 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.34 |
| Body Weight | 98.51 kilogram STANDARD_DEVIATION 23.48 | 99.55 kilogram STANDARD_DEVIATION 23.61 | 100.56 kilogram STANDARD_DEVIATION 23.77 |
| Duration of Diabetes | 4.40 years STANDARD_DEVIATION 3.86 | 4.42 years STANDARD_DEVIATION 3.7 | 4.43 years STANDARD_DEVIATION 3.56 |
| Fasting C-Peptide | 1.19 mmol/L STANDARD_DEVIATION 0.51 | 1.20 mmol/L STANDARD_DEVIATION 0.52 | 1.20 mmol/L STANDARD_DEVIATION 0.52 |
| Fasting Glucagon | 59.12 nanogram/liter (ng/L) STANDARD_DEVIATION 15.81 | 59.28 nanogram/liter (ng/L) STANDARD_DEVIATION 18.32 | 59.43 nanogram/liter (ng/L) STANDARD_DEVIATION 20.53 |
| Fasting Plasma Glucose (FPG) | 9.09 mmol/L STANDARD_DEVIATION 2.6 | 9.03 mmol/L STANDARD_DEVIATION 2.59 | 8.96 mmol/L STANDARD_DEVIATION 2.59 |
| Fasting Plasma Insulin (FPI) | 108.56 picomole/liter (pmol/L) STANDARD_DEVIATION 82.03 | 107.76 picomole/liter (pmol/L) STANDARD_DEVIATION 82.23 | 106.99 picomole/liter (pmol/L) STANDARD_DEVIATION 82.69 |
| Fasting Proinsulin | 45.06 pmol/L STANDARD_DEVIATION 39.5 | 44.83 pmol/L STANDARD_DEVIATION 37.91 | 44.62 pmol/L STANDARD_DEVIATION 36.42 |
| Fasting Proinsulin-to-Insulin Ratio | 0.53 ratio STANDARD_DEVIATION 0.7 | 0.56 ratio STANDARD_DEVIATION 0.71 | 0.59 ratio STANDARD_DEVIATION 0.73 |
| Glucose Excursion | 4.37 mmol/L STANDARD_DEVIATION 2.64 | 4.42 mmol/L STANDARD_DEVIATION 2.61 | 4.48 mmol/L STANDARD_DEVIATION 2.59 |
| Glycosylated Hemoglobin (HbA1c) | 8.16 percentage of hemoglobin STANDARD_DEVIATION 0.89 | 8.12 percentage of hemoglobin STANDARD_DEVIATION 0.93 | 8.09 percentage of hemoglobin STANDARD_DEVIATION 0.96 |
| Homeostatic Model Assessment of Beta-cell Function (HOMA-beta) | 62.01 percentage of normal beta cells function STANDARD_DEVIATION 59.78 | 61.36 percentage of normal beta cells function STANDARD_DEVIATION 55.29 | 60.74 percentage of normal beta cells function STANDARD_DEVIATION 50.8 |
| Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | 6.30 milliunit * mmol /liter^2(mU * mmol/L^2) STANDARD_DEVIATION 5.08 | 6.28 milliunit * mmol /liter^2(mU * mmol/L^2) STANDARD_DEVIATION 5.2 | 6.26 milliunit * mmol /liter^2(mU * mmol/L^2) STANDARD_DEVIATION 5.32 |
| Race/Ethnicity, Customized Ethnicity: Hispanic | 73 participants | 145 participants | 72 participants |
| Race/Ethnicity, Customized Ethnicity: Non Hispanic | 85 participants | 174 participants | 89 participants |
| Race/Ethnicity, Customized Race: Asian/Oriental | 1 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized Race: Black | 8 participants | 19 participants | 11 participants |
| Race/Ethnicity, Customized Race: Caucasian/White | 132 participants | 259 participants | 127 participants |
| Race/Ethnicity, Customized Race: Other | 17 participants | 39 participants | 22 participants |
| Sex: Female, Male Female | 103 Participants | 191 Participants | 88 Participants |
| Sex: Female, Male Male | 55 Participants | 128 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 54 / 158 | 45 / 161 |
| serious Total, serious adverse events | 3 / 158 | 3 / 161 |
Outcome results
Primary
Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% and at Least 5% Weight Loss From Baseline at Week 24
Percentage of patients who met both criteria (HbA1c \<7% at Week 24 and at least 5% weight loss from baseline at Week 24) is reported. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Week 24
Population: mITT population included randomized patients who received at least 1 dose of study drug. Missing data was imputed using Last observation carried forward (LOCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lixisenatide | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% and at Least 5% Weight Loss From Baseline at Week 24 | 12.0 percentage of participants |
| Sitagliptin | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% and at Least 5% Weight Loss From Baseline at Week 24 | 7.5 percentage of participants |
Comparison: To demonstrate the superiority of lixisenatide over sitagliptin, 150 patients in each arm would provide a power of 90% with a 2-sided test at the 5% significance level, assuming the percentage of patients defined as responders on HbA1c (\<7%) and weight (at least 5% loss) is 25% with lixisenatide and 10% with sitagliptin.p-value: 0.169695% CI: [-1.84, 11]Cochran-Mantel-Haenszel
Secondary
Absolute Change From Baseline in HbA1c at Week 24
Absolute change = HbA1c value at Week 24 minus HbA1c value at baseline. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Baseline, Week 24
Population: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed=patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Absolute Change From Baseline in HbA1c at Week 24 | -0.66 percentage of hemoglobin | Standard Error 0.094 |
| Sitagliptin | Absolute Change From Baseline in HbA1c at Week 24 | -0.72 percentage of hemoglobin | Standard Error 0.097 |
Secondary
Change From Baseline in 2-hour Postprandial Plasma Glucose (PPG) at Week 24
The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Baseline, Week 24
Population: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline 2-hour PPG assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change From Baseline in 2-hour Postprandial Plasma Glucose (PPG) at Week 24 | -3.35 mmol/L | Standard Error 0.377 |
| Sitagliptin | Change From Baseline in 2-hour Postprandial Plasma Glucose (PPG) at Week 24 | -1.44 mmol/L | Standard Error 0.384 |
Secondary
Change From Baseline in Beta Cell Function Assessed by Homeostasis Model Assessment-Beta (HOMA-beta) at Week 24
HOMA-beta was derived from FPG and FPI as: (20\*FPI \[micro units/milliliter\]) divided by (FPG \[mmol/L\] minus 3.5). Change was calculated for HOMA-beta by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Baseline, Week 24
Population: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HOMA-beta assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change From Baseline in Beta Cell Function Assessed by Homeostasis Model Assessment-Beta (HOMA-beta) at Week 24 | 17.66 percentage of normal beta cells function | Standard Error 9.652 |
| Sitagliptin | Change From Baseline in Beta Cell Function Assessed by Homeostasis Model Assessment-Beta (HOMA-beta) at Week 24 | 17.79 percentage of normal beta cells function | Standard Error 9.958 |
Secondary
Change From Baseline in Body Weight at Week 24
Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Baseline, Week 24
Population: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline body weight assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change From Baseline in Body Weight at Week 24 | -2.51 kilogram | Standard Error 0.294 |
| Sitagliptin | Change From Baseline in Body Weight at Week 24 | -1.17 kilogram | Standard Error 0.304 |
Secondary
Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24
Change was calculated for fasting C-peptide and 2-hour postprandial C-peptide by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Baseline, Week 24
Population: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline C-peptide assessment during on-treatment period and 'n' = patients with baseline and at least 1 post-baseline assessment for the specified category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Lixisenatide | Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24 | Fasting C-peptide (n= 123,139) | -0.02 nmol/L | Standard Error 0.039 |
| Lixisenatide | Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24 | 2-hour postprandial C-peptide (n=125, 139) | -0.15 nmol/L | Standard Error 0.1 |
| Sitagliptin | Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24 | Fasting C-peptide (n= 123,139) | -0.02 nmol/L | Standard Error 0.038 |
| Sitagliptin | Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24 | 2-hour postprandial C-peptide (n=125, 139) | 0.08 nmol/L | Standard Error 0.101 |
Secondary
Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24
Change was calculated for fasting glucagon and 2-hour postprandial glucagon by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Baseline, Week 24
Population: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline glucagon assessment during on-treatment period and 'n' = patients with baseline and at least 1 post-baseline assessment for the specified category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Lixisenatide | Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24 | Fasting Glucagon (n=124, 138) | 1.89 ng/L | Standard Error 1.667 |
| Lixisenatide | Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24 | 2-hour postprandial Glucagon (n=124, 134) | -8.16 ng/L | Standard Error 1.801 |
| Sitagliptin | Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24 | Fasting Glucagon (n=124, 138) | 3.52 ng/L | Standard Error 1.661 |
| Sitagliptin | Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24 | 2-hour postprandial Glucagon (n=124, 134) | -4.38 ng/L | Standard Error 1.824 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 1 day after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Baseline, Week 24
Population: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline FPG assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -0.45 mmol/L | Standard Error 0.193 |
| Sitagliptin | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -0.69 mmol/L | Standard Error 0.198 |
Secondary
Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin (PPI) at Week 24
Change was calculated for fasting plasma insulin and 2-hour post prandial plasma insulin by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Baseline, Week 24
Population: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline plasma insulin assessment during on-treatment period and 'n' = patients with baseline and at least 1 post-baseline assessment for the specified category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Lixisenatide | Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin (PPI) at Week 24 | FPI (n=119, 133) | -1.70 pmol/L | Standard Error 6.789 |
| Lixisenatide | Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin (PPI) at Week 24 | 2-hour PPI (n=123, 130) | -57.81 pmol/L | Standard Error 22.788 |
| Sitagliptin | Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin (PPI) at Week 24 | FPI (n=119, 133) | -0.88 pmol/L | Standard Error 7.02 |
| Sitagliptin | Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin (PPI) at Week 24 | 2-hour PPI (n=123, 130) | -2.85 pmol/L | Standard Error 23.309 |
Secondary
Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24
Change was calculated for fasting proinsulin and 2-hour postprandial proinsulin by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of the study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Baseline, Week 24
Population: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline proinsulin assessment during on-treatment period and 'n' = patients with baseline and at least 1 post-baseline assessment for the specified category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Lixisenatide | Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24 | Fasting Proinsulin (n=125, 140) | -2.18 pmol/L | Standard Error 3.172 |
| Lixisenatide | Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24 | 2-hour postprandial Proinsulin (n=125, 139) | 0.28 pmol/L | Standard Error 6.502 |
| Sitagliptin | Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24 | Fasting Proinsulin (n=125, 140) | -4.84 pmol/L | Standard Error 3.154 |
| Sitagliptin | Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24 | 2-hour postprandial Proinsulin (n=125, 139) | -3.95 pmol/L | Standard Error 6.477 |
Secondary
Change From Baseline in Glucose Excursion at Week 24
Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test, before study drug administration. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Baseline, Week 24
Population: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline glucose excursion assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change From Baseline in Glucose Excursion at Week 24 | -2.55 mmol/L | Standard Error 0.272 |
| Sitagliptin | Change From Baseline in Glucose Excursion at Week 24 | -0.42 mmol/L | Standard Error 0.275 |
Secondary
Change From Baseline in Insulin Resistance Assessed by Homeostasis Model Assessment- Insulin Resistance (HOMA-IR) at Week 24
HOMA-IR was derived from FPG and FPI as: (FPI \[micro units per milliliter\]\*FPG \[mmol/L\]) divided by 22.5. Change was calculated for HOMA-IR by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Baseline, Week 24
Population: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HOMA-IR assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change From Baseline in Insulin Resistance Assessed by Homeostasis Model Assessment- Insulin Resistance (HOMA-IR) at Week 24 | -0.52 mU * mmol/L^2 | Standard Error 0.366 |
| Sitagliptin | Change From Baseline in Insulin Resistance Assessed by Homeostasis Model Assessment- Insulin Resistance (HOMA-IR) at Week 24 | -0.57 mU * mmol/L^2 | Standard Error 0.378 |
Secondary
Percentage of Patients Requiring Rescue Therapy During 24-Week Period
Routine fasting self-measured plasma glucose (SMPG) and central laboratory FPG (and HbA1c after week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after week 12) were performed. Threshold values - from baseline to Week 8: fasting SMPG/FPG \>270 milligram/deciliter (mg/dL) (15.0 mmol/L), from Week 8 to Week 12: fasting SMPG/FPG \>240 mg/dL (13.3 mmol/L), and from Week 12 to Week 24: fasting SMPG/FPG \>200 mg/dL (11.1 mmol/L) or HbA1c \>8.5%.
Time frame: Baseline up to Week 24
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lixisenatide | Percentage of Patients Requiring Rescue Therapy During 24-Week Period | 9.5 percentage of participants |
| Sitagliptin | Percentage of Patients Requiring Rescue Therapy During 24-Week Period | 6.8 percentage of participants |
Secondary
Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24
The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Week 24
Population: mITT population. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lixisenatide | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24 | 24.0 percentage of participants |
| Sitagliptin | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24 | 26.3 percentage of participants |
Other Pre-specified
Change From Baseline in Fasting Proinsulin-to-insulin Ratio and 2-hour Postprandial Proinsulin-to-insulin Ratio at Week 24
Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Baseline, Week 24
Population: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline proinsulin-to-insulin ratio assessment during on-treatment period and 'n' = patients with baseline and at least 1 post-baseline assessment for the specified category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Lixisenatide | Change From Baseline in Fasting Proinsulin-to-insulin Ratio and 2-hour Postprandial Proinsulin-to-insulin Ratio at Week 24 | Fasting Proinsulin-to-insulin ratio (n=119, 133) | -0.08 ratio | Standard Error 0.035 |
| Lixisenatide | Change From Baseline in Fasting Proinsulin-to-insulin Ratio and 2-hour Postprandial Proinsulin-to-insulin Ratio at Week 24 | 2-hour PP Proinsulin-to-insulin ratio (n=123, 130) | -0.01 ratio | Standard Error 0.025 |
| Sitagliptin | Change From Baseline in Fasting Proinsulin-to-insulin Ratio and 2-hour Postprandial Proinsulin-to-insulin Ratio at Week 24 | Fasting Proinsulin-to-insulin ratio (n=119, 133) | -0.17 ratio | Standard Error 0.036 |
| Sitagliptin | Change From Baseline in Fasting Proinsulin-to-insulin Ratio and 2-hour Postprandial Proinsulin-to-insulin Ratio at Week 24 | 2-hour PP Proinsulin-to-insulin ratio (n=123, 130) | -0.05 ratio | Standard Error 0.026 |
Other Pre-specified
Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia
Symptomatic hypoglycemia was an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose less than 60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose measurement was available. Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the patient required the assistance of another person and was associated with either a plasma glucose level below 36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available.
Time frame: First dose of study drug up to 3 days after the last dose administration
Population: Safety population included all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lixisenatide | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Symptomatic hypoglycemia | 1 participants |
| Lixisenatide | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Severe symptomatic hypoglycemia | 0 participants |
| Sitagliptin | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Symptomatic hypoglycemia | 3 participants |
| Sitagliptin | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Severe symptomatic hypoglycemia | 0 participants |
Other Pre-specified
Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24
The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Baseline, Week 24
Population: mITT population. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline body weight assessment during on-treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lixisenatide | Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24 | 18.4 percentage of participants |
| Sitagliptin | Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24 | 11.9 percentage of participants |
Other Pre-specified
Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24
The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time frame: Week 24
Population: mITT population. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lixisenatide | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24 | 40.7 percentage of participants |
| Sitagliptin | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24 | 40.0 percentage of participants |