Diabetes Mellitus, Type 2
Conditions
Keywords
hyperglycemia, GLP-1, sulfonylurea, 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 sulfonylurea, over a period of 24 weeks of treatment. 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 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 daily basal insulin and total insulin doses; to evaluate safety, tolerability, pharmacokinetics (PK), and anti-lixisenatide antibody development.
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 if given, to be continued at a stable dose.
DRUGBasal Insulin
To be continued at a stable dose.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes mellitus, diagnosed for at least 1 year at the time of the screening visit, insufficiently controlled with basal insulin with or without sulfonylurea
Exclusion criteria
* HbA1c less than (\<) 7 percent (%) 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 \<10 units/day and/or during the last 2 months dose not stable (+/- 20%) * Sulfonylurea not at a stable (unchanged) dose for at least 3 months prior to screening * FPG at screening \>250 milligram/deciliter (mg/dL) (\>13.9 millimole/liter \[mmol/L\]) * History of hypoglycemia unawareness * Weight change of more than 5 kilogram (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 or diastolic blood pressure \>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 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) * Patient was an 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 sulfonylurea or basal insulin (for example, metformin, alpha glucosidase inhibitor, thiazolidinedione, rimonabant, exenatide, dipeptidyl peptidase 4 inhibitors, fast acting insulin for 1 week or more etc.) within 3 months prior to the time of screening * Use of systemic glucocorticoids (excluding topical application or inhaled forms) for 1 week or more within 3 months prior to the time of screening * Use of any investigational drug within 3 months prior to screening * Participation in any previous study with lixisenatide * End-stage renal disease defined by a serum creatinine clearance of \<15 milliliter/minute (mL/min) (calculated by the Cockcroft and Gault formula) and/or patients on dialysis * 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 | 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. 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 Average 7-Point Self Monitored Plasma Glucose (SMPG) Profile 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 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. 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 Screening in Total Insulin Dose at Week 24 | Screening, Week 24 | Change was calculated by subtracting screening 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. 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 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. 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 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 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. 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 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. 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 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. 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 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. 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 | 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 less than 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. 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 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. 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
Japan, Philippines, South Korea, Taiwan
Participant flow
Recruitment details
The study was conducted at 57 centers in 4 countries between March 10, 2009 and June 23, 2010.
Pre-assignment details
A total of 437 patients were screened of which 126 (28.8%) 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 311 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 Week 24. | 157 |
| 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 Week 24. | 154 |
| Total | 311 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 14 |
| Overall Study | Familial and Personal Reasons | 4 | 5 |
| Overall Study | Lack of Efficacy | 2 | 1 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Lixisenatide | Total |
|---|---|---|---|
| 2-Hour Postprandial Plasma Glucose (PPG) | 17.75 millimole per liter (mmol/L) STANDARD_DEVIATION 3.94 | 17.81 millimole per liter (mmol/L) STANDARD_DEVIATION 3.36 | 17.78 millimole per liter (mmol/L) STANDARD_DEVIATION 3.66 |
| Age, Continuous | 58.0 years STANDARD_DEVIATION 10.1 | 58.7 years STANDARD_DEVIATION 10.2 | 58.4 years STANDARD_DEVIATION 10.2 |
| Average 7-point Self-Monitored Plasma Glucose (SMPG) | 11.42 mmol/L STANDARD_DEVIATION 2.46 | 11.58 mmol/L STANDARD_DEVIATION 2.51 | 11.51 mmol/L STANDARD_DEVIATION 2.48 |
| Basal Insulin Treatment Duration | 3.01 years STANDARD_DEVIATION 4.27 | 2.94 years STANDARD_DEVIATION 3.67 | 2.97 years STANDARD_DEVIATION 3.97 |
| Body Mass Index (BMI) | 25.15 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.94 | 25.36 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.69 | 25.26 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.82 |
| Body Weight | 65.60 kilogram (kg) STANDARD_DEVIATION 12.47 | 65.93 kilogram (kg) STANDARD_DEVIATION 13 | 65.77 kilogram (kg) STANDARD_DEVIATION 12.72 |
| Duration of Diabetes | 14.13 years STANDARD_DEVIATION 7.72 | 13.71 years STANDARD_DEVIATION 7.73 | 13.92 years STANDARD_DEVIATION 7.71 |
| Fasting Plasma Glucose (FPG) | 7.75 mmol/L STANDARD_DEVIATION 2.25 | 7.67 mmol/L STANDARD_DEVIATION 2.32 | 7.71 mmol/L STANDARD_DEVIATION 2.28 |
| Glucose Excursion | 9.70 mmol/L STANDARD_DEVIATION 4.19 | 9.72 mmol/L STANDARD_DEVIATION 3.27 | 9.71 mmol/L STANDARD_DEVIATION 3.75 |
| Glycosylated Hemoglobin (HbA1c) | 8.52 percentage of hemoglobin STANDARD_DEVIATION 0.78 | 8.54 percentage of hemoglobin STANDARD_DEVIATION 0.73 | 8.53 percentage of hemoglobin STANDARD_DEVIATION 0.76 |
| Number of Patients With Insulin Therapy at Screening Detemir | 42 participants | 41 participants | 83 participants |
| Number of Patients With Insulin Therapy at Screening Glargine | 92 participants | 95 participants | 187 participants |
| Number of Patients With Insulin Therapy at Screening Neutral Protamine Hagedorn (NPH) | 21 participants | 18 participants | 39 participants |
| Number of Patients With Insulin Therapy at Screening Premix (Mixed Insulin) | 2 participants | 0 participants | 2 participants |
| Number of Patients With Screening HbA1c Greater Than or Equal to 8% | 121 participants | 119 participants | 240 participants |
| Number of Patients With Screening HbA1c Less Than 8% | 36 participants | 35 participants | 71 participants |
| Number of Patients With Sulfonylurea Use No | 46 participants | 46 participants | 92 participants |
| Number of Patients With Sulfonylurea Use Yes | 111 participants | 108 participants | 219 participants |
| Race/Ethnicity, Customized Ethnicity: Non Hispanic | 157 participants | 154 participants | 311 participants |
| Race/Ethnicity, Customized Race: Asian/Oriental | 157 participants | 154 participants | 311 participants |
| Sex: Female, Male Female | 77 Participants | 85 Participants | 162 Participants |
| Sex: Female, Male Male | 80 Participants | 69 Participants | 149 Participants |
| Sulfonylurea Treatment Duration | 6.80 years STANDARD_DEVIATION 5.24 | 5.33 years STANDARD_DEVIATION 4.83 | 6.07 years STANDARD_DEVIATION 5.08 |
| Total Insulin Dose | 24.11 units per day STANDARD_DEVIATION 14.18 | 24.85 units per day STANDARD_DEVIATION 13.96 | 24.48 units per day STANDARD_DEVIATION 14.05 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 71 / 157 | 125 / 154 |
| serious Total, serious adverse events | 9 / 157 | 10 / 154 |
Outcome results
Primary
Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) 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. 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. 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 | 0.11 percentage of hemoglobin | Standard Error 0.131 |
| Lixisenatide | Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | -0.77 percentage of hemoglobin | Standard Error 0.137 |
Comparison: To detect a difference of 0.5% in change from baseline to Week 24 in HbA1c between lixisenatide and placebo, 145 patients in each arm would provide a power of 90% assuming common standard deviation of 1.3% with a 2-sided t test at 5% significance level.p-value: <0.000195% CI: [-1.116, -0.65]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 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. 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 | -0.14 mmol/L | Standard Error 0.563 |
| Lixisenatide | Change From Baseline in 2-hour Postprandial Plasma Glucose (PPG) at Week 24 | -7.96 mmol/L | Standard Error 0.598 |
Secondary
Change From Baseline in Average 7-Point Self Monitored Plasma Glucose (SMPG) Profile 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 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. 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 average 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) Profile at Week 24 | -0.56 mmol/L | Standard Error 0.271 |
| Lixisenatide | Change From Baseline in Average 7-Point Self Monitored Plasma Glucose (SMPG) Profile at Week 24 | -1.91 mmol/L | Standard Error 0.272 |
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. 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 | 0.06 kilogram | Standard Error 0.271 |
| Lixisenatide | Change From Baseline in Body Weight at Week 24 | -0.38 kilogram | Standard Error 0.284 |
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. 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 | 0.25 mmol/L | Standard Error 0.302 |
| Lixisenatide | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -0.42 mmol/L | Standard Error 0.314 |
Secondary
Change From Screening in Total Insulin Dose at Week 24
Change was calculated by subtracting screening 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. 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: Screening, 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 insulin dose assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Screening in Total Insulin Dose at Week 24 | -0.11 units per day | Standard Error 0.442 |
| Lixisenatide | Change From Screening in Total Insulin Dose at Week 24 | -1.39 units per day | Standard Error 0.458 |
Secondary
Percentage of Patients Requiring Rescue Therapy During 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 24-Week Period | 3.2 percentage of participants |
| Lixisenatide | Percentage of Patients Requiring Rescue Therapy During 24-Week Period | 1.3 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 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. 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. 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 (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24 | 5.2 percentage of participants |
| Lixisenatide | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24 | 35.6 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. 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. 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 (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24 | 1.3 percentage of participants |
| Lixisenatide | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24 | 17.8 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 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. 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 | 0.14 mmol/L | Standard Error 0.542 |
| Lixisenatide | Change From Baseline in Glucose Excursion at Week 24 | -7.09 mmol/L | Standard Error 0.576 |
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 less than 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) |
|---|---|---|---|
| Placebo | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Symptomatic hypoglycemia | 37 participants |
| Placebo | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Severe symptomatic hypoglycemia | 0 participants |
| Lixisenatide | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Symptomatic hypoglycemia | 66 participants |
| Lixisenatide | 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. 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 (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24 | 4.5 percentage of participants |
| Lixisenatide | Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24 | 7.3 percentage of participants |