Diabetes Mellitus, Type 2
Conditions
Keywords
hyperglycemia, GLP-1
Brief summary
The purpose of this study is to evaluate the benefits and risks of lixisenatide (AVE0010), in comparison to placebo, as an add-on treatment to sulfonylurea without or with metformin, over a period of 24 weeks of treatment, followed by an extension. The primary objective is to assess the effects of lixisenatide when added to sulfonylurea with or without metformin on glycemic control in terms of glycosylated hemoglobin (HbA1c) reduction (absolute change) at Week 24. The secondary objectives are to assess the effects of lixisenatide on percentage of patients reaching HbA1c less than (\<) 7 percent (%); percentage of patients reaching HbA1c less than or equal to (\<=) 6.5%; body weight; fasting plasma glucose (FPG); beta-cell function assessed by homeostasis model assessment (HOMA) beta; 2-hour postprandial plasma glucose (PPG), glucagon, insulin, proinsulin, and C-peptide after a standardized meal challenge test in a sub-study in all patients in selected centers; to evaluate safety, tolerability, pharmacokinetics (PK) and anti-lixisenatide antibody development.
Detailed description
Patients who complete the 24-week main double-blind treatment would undergo a variable double-blind extension treatment, which ends for all patients at approximately the scheduled date of Week 76 visit (Visit 25) for the last randomized patient.
Interventions
DRUGLixisenatide (AVE0010)
Self administered by subcutaneous injections once daily within the hour preceding breakfast.
DRUGPlacebo
Self administered by subcutaneous injections once daily within the hour preceding breakfast.
DEVICEPen auto-injector
DRUGSulfonylurea
Sulfonylurea to be continued at maximum effective dose according to local labeling up to end of treatment.
DRUGMetformin
Metformin if given to be continued at stable dose (at least 1.5 gram per day \[except at least 0.75 gram per day in Japan and 1.0 gram per day in South Korea\]) up to the end of treatment.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes mellitus, diagnosed for at least 1 year before screening visit, insufficiently controlled with a sulfonylurea alone or a sulfonylurea in association with metformin
Exclusion criteria
* HbA1c less than (\<) 7% or greater than (\>) 10% at screening * At the time of screening age less than legal age of majority * Pregnant or breastfeeding women or women of childbearing potential with no effective contraceptive method * Type 1 diabetes mellitus * Sulfonylurea less than the maximum effective dose according to local labeling * Sulfonylurea not at a stable (unchanged) dose for at least 3 months prior to screening * In case of treatment with metformin in association with sulfonylurea, no stable (unchanged) treatment with metformin of at least 1.5 gram per day (except at least 0.75 gram per day in Japan and at least 1.0 gram per day in South Korea), for at least 3 months prior to screening visit * FPG at screening \>250 milligram per deciliter (mg/dL) (\>13.9 millimole per liter \[mmol/L\]) * History of hypoglycemia unawareness * Body mass index less than or equal to (\<=) 20 kilogram per square meter (kg/m\^2) * Weight change of \>5 kg during the 3 months preceding the screening visit * History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, inflammatory bowel disease * History of metabolic acidosis, including diabetic ketoacidosis within 1 year prior to screening * Hemoglobinopathy or hemolytic anemia, 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 * Cardiovascular, hepatic, neurological, 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, history or presence of clinically significant diabetic retinopathy, history 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 blood pressure (SBP) or diastolic blood pressure (DBP) \>180 millimeter of mercury (mmHg) or \>95 mmHg, respectively * Laboratory findings at the time of screening: aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase: \>2 times upper limit of the normal (ULN) laboratory range; amylase and/or 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 * 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 or constrains efficacy assessment * Patients who are considered by the Investigator or any sub investigator as inappropriate for this 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) * Patients with condition/concomitant diseases making them non-evaluable for the efficacy assessment * Use of oral or injectable antidiabetic or hypoglycemic agents other than sulfonylurea and metformin (for example, alpha glucosidase inhibitor, thiazolidinedione, rimonabant, exenatide, dipeptidyl-peptidase 4 (DPP-4) inhibitors, insulin) 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 * Use of any investigational drug within 3 months prior to study * Any previous treatment with lixisenatide (for example, participation in a previous study with lixisenatide) * Renal impairment defined with serum creatinine \>1.4 mg/dL in women and serum creatinine \>1.5 mg/dL in men (applicable only for patients with metformin treatment) * End-stage renal disease as defined by a serum creatinine clearance of \<15 milliliter/minute (calculated by the Cockcroft and Gault formula) and/or patients on dialysis (if no treatment with metformin) * 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 * Allergic reaction to any glucagon like peptide-1 (GLP-1) agonist in the past (for example, exenatide, liraglutide) or to metacresol * Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Glycosylated Hemoglobin (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 time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in Modified Intent-to-Treat (mITT) population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24 | Baseline, Week 24 | The fasting glucagon and the 2-hour postprandial glucagon blood samples were drawn during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24 | Baseline, Week 24 | The fasting C-peptide and the 2-hour postprandial C-peptide blood samples were drawn during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy.For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| 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 time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| 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 time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period | Baseline up to Week 24 | Routine fasting self-monitored 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%. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 24 | Baseline, Week 24 | The 2-hour PPG blood sample was drawn 2 hours after start of a standardized meal (standardized meal challenge test performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| 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 time from the first dose of study drug and up to 1 day after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| 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 time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Change From Baseline in Beta-cell Function Assessed by HOMA-beta at Week 24 | Baseline, Week 24 | Beta cell function was assessed by HOMA-beta. HOMA-beta blood samples were drawn during a standardized meal challenge test (performed in selected sites). HOMA-beta (% of normal beta cells function) = (20 multiplied by fasting plasma insulin \[micro unit per milliliter\]) divided by (FPG \[mmol/L\] minus 3.5). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin at Week 24 | Baseline, Week 24 | The fasting plasma insulin and the 2-hour postprandial plasma insulin blood samples were drawn during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24 | Baseline, Week 24 | The fasting Proinsulin and the 2-hour postprandial Proinsulin blood samples were drawn during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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 time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | First dose of study drug up to 3 days after the last dose administration, for up to 120 weeks | 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. |
| 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 (performed in selected sites), before study drug administration. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
| Change From Baseline in Fasting Proinsulin-to-insulin Ratio and 2-hour Postprandial Proinsulin-to-insulin Ratio at Week 24 | Baseline, Week 24 | The fasting proinsulin-to-insulin ratio and 2-hour postprandial proinsulin-to-insulin ratio were measured during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. |
Countries
Bulgaria, Czechia, Egypt, Germany, India, Israel, Japan, Netherlands, Romania, Russia, South Korea, Taiwan, Thailand, Tunisia, Turkey (Türkiye), United States
Participant flow
Recruitment details
The study was conducted at 136 centers in 16 countries between July 08, 2008 and January 14, 2011. The overall duration of treatment was at least 76 weeks (24 weeks main double-blind treatment; variable double-blind extension treatment).
Pre-assignment details
A total of 1438 participants were screened of which 579 (40.3%) 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 859 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 2-step initiation regimen of volume matching placebo: 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment. | 285 |
| Lixisenatide 2-step initiation regimen of lixisenatide: 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment. | 574 |
| Total | 859 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 23 | 71 |
| Overall Study | Familial and Personal Reasons | 9 | 34 |
| Overall Study | Lack of Efficacy | 24 | 16 |
| Overall Study | Lost to Follow-up | 2 | 9 |
| Overall Study | Poor Compliance to Protocol | 7 | 14 |
| Overall Study | Sponsor Decision | 4 | 10 |
| Overall Study | Withdrawal by Subject | 13 | 23 |
Baseline characteristics
| Characteristic | Total | Placebo | Lixisenatide |
|---|---|---|---|
| 2-hour postprandial C-peptide | 2.03 mmol/L STANDARD_DEVIATION 0.95 | 2.12 mmol/L STANDARD_DEVIATION 1.05 | 1.99 mmol/L STANDARD_DEVIATION 0.9 |
| 2-hour postprandial glucagon | 99.31 ng/L STANDARD_DEVIATION 34.6 | 102.27 ng/L STANDARD_DEVIATION 39.37 | 97.83 ng/L STANDARD_DEVIATION 31.94 |
| 2-Hour Postprandial Plasma Glucose (PPG) | 16.60 millimole per liter (mmol/L) STANDARD_DEVIATION 3.92 | 16.44 millimole per liter (mmol/L) STANDARD_DEVIATION 3.74 | 16.69 millimole per liter (mmol/L) STANDARD_DEVIATION 4.02 |
| 2-hour postprandial plasma insulin | 266.76 pmol/L STANDARD_DEVIATION 205.09 | 281.26 pmol/L STANDARD_DEVIATION 243.56 | 259.44 pmol/L STANDARD_DEVIATION 182.64 |
| 2-hour postprandial proinsulin | 61.99 pmol/L STANDARD_DEVIATION 45.31 | 61.73 pmol/L STANDARD_DEVIATION 46.48 | 62.12 pmol/L STANDARD_DEVIATION 44.8 |
| 2-hour postprandial proinsulin-to-insulin ratio | 0.31 ratio STANDARD_DEVIATION 0.23 | 0.30 ratio STANDARD_DEVIATION 0.22 | 0.32 ratio STANDARD_DEVIATION 0.24 |
| Age, Continuous | 57.2 years STANDARD_DEVIATION 9.9 | 57.8 years STANDARD_DEVIATION 10.1 | 57.0 years STANDARD_DEVIATION 9.8 |
| Body Weight | 83.00 kilogram (kg) STANDARD_DEVIATION 22.13 | 84.42 kilogram (kg) STANDARD_DEVIATION 22.83 | 82.30 kilogram (kg) STANDARD_DEVIATION 21.76 |
| Fasting C-peptide | 0.85 mmol/L STANDARD_DEVIATION 0.47 | 0.89 mmol/L STANDARD_DEVIATION 0.55 | 0.83 mmol/L STANDARD_DEVIATION 0.43 |
| Fasting glucagon | 0.85 nanogram per liter (ng/L) STANDARD_DEVIATION 0.47 | 0.89 nanogram per liter (ng/L) STANDARD_DEVIATION 0.55 | 0.83 nanogram per liter (ng/L) STANDARD_DEVIATION 0.43 |
| Fasting Plasma Glucose (FPG) | 9.55 mmol/L STANDARD_DEVIATION 2.29 | 9.29 mmol/L STANDARD_DEVIATION 2.37 | 9.67 mmol/L STANDARD_DEVIATION 2.24 |
| Fasting plasma insulin (FPI) | 63.18 picomole per liter (pmol/L) STANDARD_DEVIATION 56.61 | 66.89 picomole per liter (pmol/L) STANDARD_DEVIATION 63.92 | 61.34 picomole per liter (pmol/L) STANDARD_DEVIATION 52.63 |
| Fasting proinsulin | 33.69 pmol/L STANDARD_DEVIATION 29.17 | 34.39 pmol/L STANDARD_DEVIATION 32.61 | 33.35 pmol/L STANDARD_DEVIATION 27.43 |
| Fasting proinsulin-to-insulin ratio | 0.67 ratio STANDARD_DEVIATION 0.51 | 0.62 ratio STANDARD_DEVIATION 0.36 | 0.70 ratio STANDARD_DEVIATION 0.57 |
| Glucose Excursion | 6.94 mmol/L STANDARD_DEVIATION 3.73 | 6.84 mmol/L STANDARD_DEVIATION 3.78 | 6.99 mmol/L STANDARD_DEVIATION 3.71 |
| Glycosylated Hemoglobin (HbA1c) | 8.25 percentage of hemoglobin STANDARD_DEVIATION 0.85 | 8.21 percentage of hemoglobin STANDARD_DEVIATION 0.84 | 8.28 percentage of hemoglobin STANDARD_DEVIATION 0.86 |
| Homeostasis Model Assessment for Beta-cell Function (HOMA-beta) | 34.99 percentage of normal beta cells function STANDARD_DEVIATION 61.39 | 36.43 percentage of normal beta cells function STANDARD_DEVIATION 39.43 | 34.28 percentage of normal beta cells function STANDARD_DEVIATION 69.82 |
| Race/Ethnicity, Customized Ethnicity: Hispanic | 23 participants | 5 participants | 18 participants |
| Race/Ethnicity, Customized Ethnicity: Non Hispanic | 836 participants | 280 participants | 556 participants |
| Race/Ethnicity, Customized Race: Asian/Oriental | 385 participants | 125 participants | 260 participants |
| Race/Ethnicity, Customized Race: Black | 26 participants | 9 participants | 17 participants |
| Race/Ethnicity, Customized Race: Caucasian/White | 448 participants | 151 participants | 297 participants |
| Sex: Female, Male Female | 425 Participants | 135 Participants | 290 Participants |
| Sex: Female, Male Male | 434 Participants | 150 Participants | 284 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 148 / 285 | 362 / 574 |
| serious Total, serious adverse events | 35 / 285 | 58 / 574 |
Outcome results
Primary
Absolute Change From Baseline in Glycosylated Hemoglobin (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 time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in Modified Intent-to-Treat (mITT) population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
Time frame: Baseline, Week 24
Population: mITT population:all randomized patients who received at least 1 dose;had baseline,at least 1 post-baseline efficacy assessment, irrespective of compliance with study protocol/procedures. Last observation carried forward used. 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 |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | -0.10 percentage of hemoglobin | Standard Error 0.071 |
| Lixisenatide | Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | -0.85 percentage of hemoglobin | Standard Error 0.061 |
Comparison: To detect a difference of 0.5% (or 0.4%) in change from baseline to Week 24 in HbA1c between lixisenatide and placebo, 570 patients in lixisenatide arm and 285 in placebo arm would provide a power of 99% (or 98%) assuming common standard deviation of 1.3% with a 2-sided test at 5% significance level.p-value: <0.000195% CI: [-0.867, -0.621]ANCOVA
Secondary
Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 24
The 2-hour PPG blood sample was drawn 2 hours after start of a standardized meal (standardized meal challenge test performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
Time frame: Baseline, Week 24
Population: Subgroup for standardized meal test in mITT population. Missing data was imputed using last observation carried forward (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 |
|---|---|---|---|
| Placebo | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 24 | -0.21 mmol/L | Standard Error 0.489 |
| Lixisenatide | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 24 | -6.19 mmol/L | Standard Error 0.408 |
Secondary
Change From Baseline in Beta-cell Function Assessed by HOMA-beta at Week 24
Beta cell function was assessed by HOMA-beta. HOMA-beta blood samples were drawn during a standardized meal challenge test (performed in selected sites). HOMA-beta (% of normal beta cells function) = (20 multiplied by fasting plasma insulin \[micro unit per milliliter\]) divided by (FPG \[mmol/L\] minus 3.5). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
Time frame: Baseline, Week 24
Population: Subgroup for standardized meal test in 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 |
|---|---|---|---|
| Placebo | Change From Baseline in Beta-cell Function Assessed by HOMA-beta at Week 24 | 6.63 % of normal beta cells function | Standard Error 5.663 |
| Lixisenatide | Change From Baseline in Beta-cell Function Assessed by HOMA-beta at Week 24 | 4.83 % of normal beta cells function | Standard Error 4.686 |
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 time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
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 |
|---|---|---|---|
| Placebo | Change From Baseline in Body Weight at Week 24 | -0.93 kilogram | Standard Error 0.234 |
| Lixisenatide | Change From Baseline in Body Weight at Week 24 | -1.76 kilogram | Standard Error 0.202 |
Secondary
Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24
The fasting C-peptide and the 2-hour postprandial C-peptide blood samples were drawn during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy.For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
Time frame: Baseline, Week 24
Population: Subgroup for standardized meal test in 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 |
|---|---|---|---|---|
| Placebo | Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24 | Fasting C-peptide (n=117, 244) | -0.06 nmol/L | Standard Error 0.038 |
| Placebo | Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24 | 2-hour postprandial C-peptide (n=119, 248) | -0.14 nmol/L | Standard Error 0.087 |
| Lixisenatide | Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24 | Fasting C-peptide (n=117, 244) | -0.07 nmol/L | Standard Error 0.031 |
| Lixisenatide | Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24 | 2-hour postprandial C-peptide (n=119, 248) | -0.37 nmol/L | Standard Error 0.072 |
Secondary
Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24
The fasting glucagon and the 2-hour postprandial glucagon blood samples were drawn during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
Time frame: Baseline, Week 24
Population: Subgroup for standardized meal test in 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 |
|---|---|---|---|---|
| Placebo | Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24 | Fasting glucagon (n=111, 238) | 2.03 ng/L | Standard Error 2.566 |
| Placebo | Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24 | 2-hour postprandial glucagon (n=114, 234) | -1.19 ng/L | Standard Error 2.999 |
| Lixisenatide | Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24 | Fasting glucagon (n=111, 238) | -2.10 ng/L | Standard Error 2.081 |
| Lixisenatide | Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24 | 2-hour postprandial glucagon (n=114, 234) | -23.33 ng/L | Standard Error 2.5 |
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 time from the first dose of study drug and up to 1 day after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
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 |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -0.36 mmol/L | Standard Error 0.161 |
| Lixisenatide | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -0.99 mmol/L | Standard Error 0.139 |
Secondary
Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin at Week 24
The fasting plasma insulin and the 2-hour postprandial plasma insulin blood samples were drawn during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
Time frame: Baseline, Week 24
Population: Subgroup for standardized meal test in 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 |
|---|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin at Week 24 | FPI (n=117, 242) | 1.42 pmol/L | Standard Error 6.587 |
| Placebo | Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin at Week 24 | 2-hour postprandial plasma insulin (n=120, 244) | -2.22 pmol/L | Standard Error 18.754 |
| Lixisenatide | Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin at Week 24 | FPI (n=117, 242) | -4.03 pmol/L | Standard Error 5.445 |
| Lixisenatide | Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin at Week 24 | 2-hour postprandial plasma insulin (n=120, 244) | -67.67 pmol/L | Standard Error 15.944 |
Secondary
Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24
The fasting Proinsulin and the 2-hour postprandial Proinsulin blood samples were drawn during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
Time frame: Baseline, Week 24
Population: Subgroup for standardized meal test in 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 |
|---|---|---|---|---|
| Placebo | Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24 | Fasting proinsulin (n=97, 205) | -1.05 pmol/L | Standard Error 1.983 |
| Placebo | Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24 | 2-hour postprandial proinsulin (n=93, 193) | 3.55 pmol/L | Standard Error 4.2 |
| Lixisenatide | Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24 | Fasting proinsulin (n=97, 205) | -6.33 pmol/L | Standard Error 1.671 |
| Lixisenatide | Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24 | 2-hour postprandial proinsulin (n=93, 193) | -4.20 pmol/L | Standard Error 3.55 |
Secondary
Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period
Routine fasting self-monitored 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%. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
Time frame: Baseline up to Week 24
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period | 12.6 percentage of participants |
| Lixisenatide | Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period | 4.0 percentage of participants |
Secondary
Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24
The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
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) |
|---|---|---|
| Placebo | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24 | 13.5 percentage of participants |
| Lixisenatide | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24 | 36.4 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 time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
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) |
|---|---|---|
| Placebo | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24 | 4.7 percentage of participants |
| Lixisenatide | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24 | 19.3 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
The fasting proinsulin-to-insulin ratio and 2-hour postprandial proinsulin-to-insulin ratio were measured during a standardized meal challenge test (performed in selected sites). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
Time frame: Baseline, Week 24
Population: Subgroup for standardized meal test in mITT population. Missing data imputed using LOCF. 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 specific category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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=95, 199) | -0.04 ratio | Standard Error 0.049 |
| Placebo | Change From Baseline in Fasting Proinsulin-to-insulin Ratio and 2-hour Postprandial Proinsulin-to-insulin Ratio at Week 24 | 2-hour postprandial ratio (n=92, 190) | 0.01 ratio | Standard Error 0.06 |
| Lixisenatide | Change From Baseline in Fasting Proinsulin-to-insulin Ratio and 2-hour Postprandial Proinsulin-to-insulin Ratio at Week 24 | 2-hour postprandial ratio (n=92, 190) | 0.16 ratio | Standard Error 0.053 |
| 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=95, 199) | -0.13 ratio | Standard Error 0.043 |
Other Pre-specified
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 (performed in selected sites), before study drug administration. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to last dosing day of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
Time frame: Baseline, Week 24
Population: Subgroup for standardized meal test in mITT population. Missing data was imputed using last observation carried forward (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 |
|---|---|---|---|
| Placebo | Change From Baseline in Glucose Excursion at Week 24 | 0.35 mmol/L | Standard Error 0.432 |
| Lixisenatide | Change From Baseline in Glucose Excursion at Week 24 | -5.22 mmol/L | Standard Error 0.36 |
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, for up to 120 weeks
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.The one patient in the placebo group who received Lixisenatide was analyzed in the Lixisenatide group
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Symptomatic hypoglycemia | 51 participants |
| Placebo | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Severe symptomatic hypoglycemia | 1 participants |
| Lixisenatide | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Symptomatic hypoglycemia | 127 participants |
| Lixisenatide | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Severe symptomatic hypoglycemia | 2 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 time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.
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) |
|---|---|---|
| Placebo | Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24 | 7.2 percentage of participants |
| Lixisenatide | Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24 | 14.4 percentage of participants |