Diabetes Mellitus, Type 2
Conditions
Keywords
hyperglycemia, GLP-1, metformin, insulin
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 basal insulin with or without 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 basal insulin on glycemic control in terms of glycosylated hemoglobin (HbA1c) reduction at Week 24. The secondary objectives are to assess the effects of lixisenatide when added to basal insulin on body weight, 2-hour postprandial plasma glucose (PPG) after standardized meal challenge test, percentage of patients reaching HbA1c less than 7 percent (%), percentage of patients reaching HbA1c less than or equal to 6.5%, fasting plasma glucose (FPG), change in 7-point self-monitored plasma glucose (SMPG) profiles, change in basal insulin and total insulin doses; 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 patients.
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.
DRUGBasal Insulin
Dose to be kept stable.
DRUGMetformin
Metformin if given to be continued at stable dose (1.5 gram per day) up to the end of treatment.
DEVICEPen auto-injector
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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 basal insulin with or without metformin
Exclusion criteria
* HbA1c less than (\<) 7 % or greater than (\>) 10% at screening * At the time of screening age \< legal age of majority * Pregnant or breastfeeding women or women of childbearing potential with no effective contraceptive method * Type 1 diabetes mellitus * Treatment with basal insulin for less than 3 months prior to screening or insulin regimen changed during the last 3 months prior to screening * Basal insulin dose at screening \<30 units/day and/or not at a stable dose (+/- 20 percent \[%\]) during the last 2 months * If treatment with metformin, no stable dose of at least 1.5 gram/day (except for South Korea: at least 1.0 gram/day) 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, or 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 and positive serum pregnancy test in females of childbearing potential * Any clinically significant abnormality identified on physical examination, laboratory tests, electrocardiogram, 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 attending 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 other than metformin or basal insulin (for example, sulfonylurea, alpha-glucosidase inhibitor, thiazolidinedione, rimonabant, exenatide, dipeptidyl-peptidase-4 inhibitors, fast-acting insulin for 1 week or more) 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 * Any previous treatment with lixisenatide or participation in any previous study with lixisenatide * Use of any investigational drug within 3 months prior to study * Renal impairment defined with creatinine \>1.4 mg/dL in women and creatinine \>1.5 mg/dL in men (applicable only for patients with metformin treatment) * End-stage renal disease as defined by a calculated serum creatinine clearance of \<15 milliliter/minute 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 the previous 6 months * History of 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 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 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. |
| 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 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 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 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 Average 7-Point Self Monitored Plasma Glucose (SMPG) Profiles at Week 24 | Baseline, Week 24 | Patients recorded a 7-point plasma glucose profile measured before and 2 hours after each meal and at bedtime once in a week and the average value for the 7-time points was calculated. 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 Total Insulin Dose at Week 24 | Baseline, Week 24 | Change was calculated for total insulin dose by subtracting the 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 |
|---|---|---|
| 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 125 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. |
| 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. |
| 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 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
Brazil, Canada, Chile, Egypt, France, Germany, India, Italy, Mexico, Puerto Rico, Russia, South Korea, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 111 centers in 15 countries between July 29, 2008 and February 8, 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 879 patients were screened of which 383 (43.6%) 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 496 patients 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. | 167 |
| 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. | 328 |
| Total | 495 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 37 |
| Overall Study | Familial and personal reasons | 10 | 22 |
| Overall Study | Incorrect randomization (not treated) | 0 | 1 |
| Overall Study | Lack of Efficacy | 11 | 11 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Poor compliance | 6 | 13 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Sponsor decision | 0 | 4 |
| Overall Study | Withdrawal by Subject | 11 | 25 |
Baseline characteristics
| Characteristic | Placebo | Lixisenatide | Total |
|---|---|---|---|
| 2-Hour Postprandial Plasma Glucose (PPG) | 16.11 mmol/L STANDARD_DEVIATION 3.86 | 16.47 mmol/L STANDARD_DEVIATION 4.3 | 16.35 mmol/L STANDARD_DEVIATION 4.15 |
| Age, Continuous | 56.9 years STANDARD_DEVIATION 9.8 | 57.4 years STANDARD_DEVIATION 9.5 | 57.2 years STANDARD_DEVIATION 9.6 |
| Average 7-Point Self Monitored Plasma Glucose (SMPG) | 10.58 mmol/L STANDARD_DEVIATION 2.69 | 10.76 mmol/L STANDARD_DEVIATION 2.61 | 10.70 mmol/L STANDARD_DEVIATION 2.64 |
| Basal Insulin Treatment Duration | 3.20 years STANDARD_DEVIATION 3.96 | 3.06 years STANDARD_DEVIATION 3.37 | 3.11 years STANDARD_DEVIATION 3.57 |
| Body Mass Index (BMI) | 32.56 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.32 | 31.91 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.17 | 32.13 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.22 |
| Body Weight | 88.94 kilogram (kg) STANDARD_DEVIATION 20.84 | 87.10 kilogram (kg) STANDARD_DEVIATION 20.01 | 87.72 kilogram (kg) STANDARD_DEVIATION 20.29 |
| Duration of Diabetes | 12.43 years STANDARD_DEVIATION 6.33 | 12.48 years STANDARD_DEVIATION 7.04 | 12.46 years STANDARD_DEVIATION 6.8 |
| Fasting Plasma Glucose (FPG) | 8.05 millimole per liter (mmol/L) STANDARD_DEVIATION 2.65 | 8.13 millimole per liter (mmol/L) STANDARD_DEVIATION 2.83 | 8.10 millimole per liter (mmol/L) STANDARD_DEVIATION 2.76 |
| Glucose Excursion | 7.32 mmol/L STANDARD_DEVIATION 3.43 | 7.59 mmol/L STANDARD_DEVIATION 3.6 | 7.50 mmol/L STANDARD_DEVIATION 3.54 |
| Glycosylated Hemoglobin (HbA1c) | 8.37 percentage of hemoglobin STANDARD_DEVIATION 0.84 | 8.42 percentage of hemoglobin STANDARD_DEVIATION 0.88 | 8.40 percentage of hemoglobin STANDARD_DEVIATION 0.87 |
| Metformin Daily Dose | 2008.02 milligram (mg) per day STANDARD_DEVIATION 441.88 | 1961.02 milligram (mg) per day STANDARD_DEVIATION 459.07 | 1976.72 milligram (mg) per day STANDARD_DEVIATION 453.38 |
| Number of Patients With Insulin Therapy at Baseline Detemir | 19 participants | 24 participants | 43 participants |
| Number of Patients With Insulin Therapy at Baseline Glargine | 83 participants | 165 participants | 248 participants |
| Number of Patients With Insulin Therapy at Baseline Neutral protamine hagedorn (NPH) | 64 participants | 134 participants | 198 participants |
| Number of Patients With Insulin Therapy at Baseline Premix (Mixed Insulin) | 3 participants | 5 participants | 8 participants |
| Number of Patients With Metformin use at Baseline No | 36 participants | 67 participants | 103 participants |
| Number of Patients With Metformin use at Baseline Yes | 131 participants | 261 participants | 392 participants |
| Race/Ethnicity, Customized Ethnicity: Hispanic | 40 participants | 94 participants | 134 participants |
| Race/Ethnicity, Customized Ethnicity: Non Hispanic | 127 participants | 234 participants | 361 participants |
| Race/Ethnicity, Customized Race: Asian/Oriental | 30 participants | 53 participants | 83 participants |
| Race/Ethnicity, Customized Race: Black | 6 participants | 14 participants | 20 participants |
| Race/Ethnicity, Customized Race: Caucasian/White | 130 participants | 254 participants | 384 participants |
| Race/Ethnicity, Customized Race: Other | 1 participants | 7 participants | 8 participants |
| Sex: Female, Male Female | 85 Participants | 182 Participants | 267 Participants |
| Sex: Female, Male Male | 82 Participants | 146 Participants | 228 Participants |
| Total Insulin Dose | 57.73 units per day STANDARD_DEVIATION 34.54 | 53.43 units per day STANDARD_DEVIATION 33.89 | 54.88 units per day STANDARD_DEVIATION 34.14 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 104 / 167 | 245 / 328 |
| serious Total, serious adverse events | 17 / 167 | 46 / 328 |
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 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. LOCF was 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 | -0.38 percentage of hemoglobin | Standard Error 0.107 |
| Lixisenatide | Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | -0.74 percentage of hemoglobin | Standard Error 0.09 |
Comparison: To detect a difference of 0.5% (or 0.4%) in change from baseline to Week 24 in HbA1c between lixisenatide and placebo, 300 patients in lixisenatide arm and 150 in placebo arm would provide a power of 96% (or 86%) assuming common standard deviation of 1.3% with a 2-sided test at 5% significance level.p-value: 0.000295% CI: [-0.55, -0.174]ANCOVA
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 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: 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 | -1.72 mmol/L | Standard Error 0.543 |
| Lixisenatide | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 24 | -5.54 mmol/L | Standard Error 0.468 |
Secondary
Change From Baseline in Average 7-Point Self Monitored Plasma Glucose (SMPG) Profiles at Week 24
Patients recorded a 7-point plasma glucose profile measured before and 2 hours after each meal and at bedtime once in a week and the average value for the 7-time points was calculated. 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: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline 7-point SMPG assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Average 7-Point Self Monitored Plasma Glucose (SMPG) Profiles at Week 24 | -0.61 mmol/L | Standard Error 0.238 |
| Lixisenatide | Change From Baseline in Average 7-Point Self Monitored Plasma Glucose (SMPG) Profiles at Week 24 | -1.49 mmol/L | Standard Error 0.201 |
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 | -0.52 kilogram | Standard Error 0.293 |
| Lixisenatide | Change From Baseline in Body Weight at Week 24 | -1.80 kilogram | Standard Error 0.246 |
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 | -0.55 mmol/L | Standard Error 0.281 |
| Lixisenatide | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -0.63 mmol/L | Standard Error 0.233 |
Secondary
Change From Baseline in Total Insulin Dose at Week 24
Change was calculated for total insulin dose by subtracting the 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: mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline total insulin dose assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Total Insulin Dose at Week 24 | -1.93 units per day | Standard Error 1.589 |
| Lixisenatide | Change From Baseline in Total Insulin Dose at Week 24 | -5.62 units per day | Standard Error 1.317 |
Secondary
Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period
Routine fasting 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 | 7.2 percentage of participants |
| Lixisenatide | Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period | 5.8 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 | 12.0 percentage of participants |
| Lixisenatide | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24 | 28.3 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 | 3.8 percentage of participants |
| Lixisenatide | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24 | 14.5 percentage of participants |
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, 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: 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 |
|---|---|---|---|
| Placebo | Change From Baseline in Glucose Excursion at Week 24 | -0.34 mmol/L | Standard Error 0.469 |
| Lixisenatide | Change From Baseline in Glucose Excursion at Week 24 | -4.14 mmol/L | Standard Error 0.408 |
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 125 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Symptomatic hypoglycemia | 65 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 | 138 participants |
| Lixisenatide | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Severe symptomatic hypoglycemia | 7 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 | 3.1 percentage of participants |
| Lixisenatide | Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24 | 13.2 percentage of participants |