Type 2 Diabetes Mellitus
Conditions
Brief summary
The purpose of the study is to evaluate the benefits and risks of lixisenatide (AVE0010), in comparison to placebo, as an add-on treatment to insulin glargine and metformin with or without thiazolidinediones (TZDs), over a period of 24 weeks of treatment. The primary objective is to assess the effects of lixisenatide in comparison to placebo, when added to insulin glargine and 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 the percentage of patients reaching HbA1c less than (\<) 7 percent (%) and less than or equal to (\<=) 6.5%, plasma glucose (fasting, postprandial during a standardized meal challenge test, 7-point self monitored profiles), body weight, insulin glargine doses, to evaluate safety and tolerability (including anti-lixisenatide antibody assessment), and to assess the impact on treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (state) (DTSQs) in the participating countries where it is validated.
Detailed description
The study comprises 3 periods: * An up to 14-week screening period, which includes an up to 2-week screening phase and a 12-week run-in phase with introduction and titration of insulin glargine on top of metformin +/-TZDs. * At the end of the run-in phase, patients whose HbA1c (centralized assay) is greater than or equal to (\>=) 7% and less than or equal to (\<=) 9% and whose mean fasting self-monitored plasma glucose (SMPG) calculated from the self measurements for the 7 days prior to Visit 12 (Week -1) is \<=140 milligram per deciliter (mg/dL) (7.8 millimole per liter \[mmol/L\]), would enter a 24-week double-blind randomized treatment period comparing lixisenatide to placebo (on top of insulin glargine + metformin +/- TZDs). * A 3-day safety follow up period. Maximum duration is of 39 weeks +/- 7 days.
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.
DRUGInsulin glargine
Dose to be adjusted to maintain a fasting SMPG between 100 and 80 mg/dL (5.6 and 4.4 mmol/L), inclusive.
DEVICEPen auto-injector
Lantus® SoloStar® OptiClik®
DRUGMetformin
Metformin to be continued at stable dose (at least 1.5 gram per day) up to Week 24.
TZD (either rosiglitazone or pioglitazone) if given, to be continued at stable dose up to Week 24.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
\- Type 2 diabetes mellitus, diagnosed for at least 1 year before screening visit, insufficiently controlled with insulin glargine and metformin
Exclusion criteria
* HbA1c \<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 * Metformin not at a stable dose of at least 1.5 gram per day for at least 3 months prior to the screening visit * Use of oral or injectable antidiabetic or hypoglycemic agents other than metformin, sulfonylurea (SU) and TZDs (for example, alpha glucosidase inhibitor, other glucagon like peptide-1 \[GLP-1\] receptor agonists, dipeptidyl peptidase-IV \[DPP-IV\] inhibitors, insulin etc.) within 3 months prior to the time of screening, use of weight loss drugs if not at a stable dose for at least 3 months prior to the screening visit * History of hypoglycemia unawareness * Body Mass Index (BMI) less than or equal to (\<=) 20 kilogram per square meter (kg/m\^2) * History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, inflammatory bowel disease, personal or family history of medullary thyroid cancer (MTC) or genetic conditions that predispose to MTC (for example, multiple endocrine neoplasia syndromes) * History of metabolic acidosis, including diabetic ketoacidosis within 1 year prior to screening * Hemoglobinopathy or hemolytic anemia, blood or plasma products transfusion within 3 months prior to the time of screening * Within the last 6 months prior to screening: history of myocardial infarction, stroke, or heart failure requiring hospitalization * Known history of drug or alcohol abuse within 6 months prior to the time of screening * Any clinically significant abnormality identified on physical examination, laboratory tests, electrocardiogram 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 such as active malignant tumor or other major systemic diseases, presence of clinically significant diabetic retinopathy or presence of macular edema likely to require laser treatment within the study period * Uncontrolled or inadequately controlled hypertension at the time of screening with a resting systolic or diastolic blood pressure \>180 millimeter of mercury (mmHg) or \>110 mmHg, respectively * Laboratory findings at the time of screening: amylase and/or lipase, alanine aminotransferase \>3 times upper limit of the normal (ULN) laboratory range; 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, positive serum pregnancy test in females of childbearing potential; and calcitonin \>=20 picogram per milliliter (pg/mL) (5.9 picomole per milliliter \[pmol/L\]) * 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, patient being investigator or any sub investigator, pharmacist, study coordinator, other study staff or relative thereof directly involved in the conduct of the protocol etc.) * Use of systemic glucocorticoids (excluding topical application or inhaled forms) for one week or more within 3 months prior to the time of screening * Use of any investigational drug within 3 months prior to screening * Renal impairment defined with serum creatinine \> 1.4 mg/dL in women and \> 1.5 mg/dL in men * History of hypersensitivity to insulin glargine or to any of the excipients * Clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting, including (but not limited to): gastroparesis, unstable (that is, worsening) and not controlled (that is, prolonged nausea and vomiting) gastroesophageal reflux disease requiring medical treatment, within 6 months prior to the time of screening * Any previous treatment with lixisenatide (for example, participation in a previous study with lixisenatide) * Allergic reaction to any GLP-1 receptor 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 the time from the first dose of study drug up to 14 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 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. |
| 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 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 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 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 Average Insulin Glargine Daily Dose at Week 24 | Baseline, Week 24 | Change was calculated by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. 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 the Double-blind Period | Baseline up to Week 24 | Routine fasting SMPG, central laboratory FPG and HbA1c 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 were performed. Threshold values - from baseline to Week 8: fasting SMPG/FPG \>200 milligram/deciliter (mg/dL) (11.1 mmol/L) or HbA1c \>9%, from Week 8 to Week 24: fasting SMPG/FPG \>180 mg/dL (10.0 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 Treatment Satisfaction Score (Sum of Items 1, 4, 5, 6, 7 and 8 of DTSQ) at Week 24 | Baseline, Week 24 | Change was calculated by subtracting baseline value from Week 24 value. DTSQ: 8-item questionnaire to assess treatment satisfaction and patient perception of hyper and hypoglycemia. Each question (Q) scored on a Likert scale from 0 to 6. Six items (Q1 and 4-8; higher score = more satisfaction) measured treatment satisfaction and were summed to calculate treatment satisfaction score which ranged from 0 (very dissatisfied) to 36 (very satisfied). Two items (Q2 and 3), which were not included, measured perceived hyperglycemia and hypoglycemia, respectively and lower scores represented good perceived blood glucose control. 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. |
| 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 14 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 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 14 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. |
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 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. |
| Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | First dose of study drug up to 3 days after the last dose administration | Symptomatic hypoglycemia was an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose less than 60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose measurement was available. Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the patient required the assistance of another person and was associated with either a plasma glucose level below 36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available. |
Countries
Argentina, Brazil, Canada, Chile, Colombia, Czechia, Denmark, Estonia, France, Germany, Hungary, India, Israel, Italy, Malaysia, Mexico, Netherlands, Poland, Puerto Rico, Romania, Russia, South Africa, Sweden, Taiwan, Ukraine, United States
Participant flow
Recruitment details
The study was conducted at 140 centers in 25 countries between October 13, 2009 and August 01, 2011.
Pre-assignment details
A total of 1470 patients were screened of which 1024 were screen or run-in 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 9%). A total of 446 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. | 223 |
| 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. | 223 |
| Total | 446 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 19 |
| Overall Study | Familial and Personal Reasons | 2 | 2 |
| Overall Study | Poor Compliance to Protocol | 0 | 2 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Sponsor Decision | 0 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Total | Placebo | Lixisenatide |
|---|---|---|---|
| 2-Hour Postprandial Plasma Glucose (PPG) | 12.85 mmol/L STANDARD_DEVIATION 3.81 | 12.79 mmol/L STANDARD_DEVIATION 3.69 | 12.90 mmol/L STANDARD_DEVIATION 3.94 |
| Age, Continuous | 56.2 years STANDARD_DEVIATION 9.9 | 56.1 years STANDARD_DEVIATION 10.2 | 56.4 years STANDARD_DEVIATION 9.7 |
| Average 7-Point Self Monitored Plasma Glucose (SMPG) | 8.23 mmol/L STANDARD_DEVIATION 1.49 | 8.26 mmol/L STANDARD_DEVIATION 1.52 | 8.20 mmol/L STANDARD_DEVIATION 1.47 |
| Average Insulin Glargine Daily Dose | 43.84 units per day STANDARD_DEVIATION 19.34 | 44.24 units per day STANDARD_DEVIATION 19.86 | 43.44 units per day STANDARD_DEVIATION 18.84 |
| Body Mass Index (BMI) | 31.82 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.32 | 31.65 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.01 | 31.99 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.63 |
| Body Weight | 87.03 kilogram (kg) STANDARD_DEVIATION 21.07 | 86.75 kilogram (kg) STANDARD_DEVIATION 20.41 | 87.31 kilogram (kg) STANDARD_DEVIATION 21.76 |
| Duration of Diabetes | 9.17 years STANDARD_DEVIATION 5.94 | 8.72 years STANDARD_DEVIATION 5.82 | 9.62 years STANDARD_DEVIATION 6.03 |
| Fasting Plasma Glucose (FPG) | 6.62 millimole per liter (mmol/L) STANDARD_DEVIATION 1.85 | 6.70 millimole per liter (mmol/L) STANDARD_DEVIATION 1.97 | 6.55 millimole per liter (mmol/L) STANDARD_DEVIATION 1.72 |
| Glucose Excursion | 6.29 mmol/L STANDARD_DEVIATION 3.96 | 6.33 mmol/L STANDARD_DEVIATION 3.54 | 6.24 mmol/L STANDARD_DEVIATION 4.35 |
| Glycosylated Hemoglobin (HbA1c) | 7.58 percentage of hemoglobin STANDARD_DEVIATION 0.54 | 7.60 percentage of hemoglobin STANDARD_DEVIATION 0.54 | 7.56 percentage of hemoglobin STANDARD_DEVIATION 0.55 |
| Metformin Daily Dose | 2048.7 milligram (mg) per day STANDARD_DEVIATION 417.8 | 2058.1 milligram (mg) per day STANDARD_DEVIATION 430.6 | 2039.2 milligram (mg) per day STANDARD_DEVIATION 405.3 |
| Number of Patients With Categorical BMI Greater than or equal to 30 | 240 participants | 120 participants | 120 participants |
| Number of Patients With Categorical BMI Less than 30 | 206 participants | 103 participants | 103 participants |
| Number of Patients With Thiazolidinedione (TZD) use at Baseline No | 392 participants | 196 participants | 196 participants |
| Number of Patients With Thiazolidinedione (TZD) use at Baseline Yes | 54 participants | 27 participants | 27 participants |
| Race/Ethnicity, Customized Ethnicity: Hispanic | 101 participants | 49 participants | 52 participants |
| Race/Ethnicity, Customized Ethnicity: Non Hispanic | 345 participants | 174 participants | 171 participants |
| Race/Ethnicity, Customized Race: Asian/Oriental | 87 participants | 43 participants | 44 participants |
| Race/Ethnicity, Customized Race: Black | 20 participants | 11 participants | 9 participants |
| Race/Ethnicity, Customized Race: Caucasian/White | 332 participants | 167 participants | 165 participants |
| Race/Ethnicity, Customized Race: Other | 7 participants | 2 participants | 5 participants |
| Sex: Female, Male Female | 224 Participants | 110 Participants | 114 Participants |
| Sex: Female, Male Male | 222 Participants | 113 Participants | 109 Participants |
| Treatment Satisfaction Score (Diabetes Treatment Satisfaction Questionnaire [DTSQ]) | 31.6 units on a scale STANDARD_DEVIATION 4.8 | 31.5 units on a scale STANDARD_DEVIATION 5.1 | 31.7 units on a scale STANDARD_DEVIATION 4.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 81 / 223 | 127 / 223 |
| serious Total, serious adverse events | 10 / 223 | 17 / 223 |
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 the time from the first dose of study drug up to 14 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. Number of patients analyzed=patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period. Last observation carried forward used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | -0.40 percentage of hemoglobin | Standard Error 0.092 |
| Lixisenatide | Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | -0.71 percentage of hemoglobin | Standard Error 0.091 |
Comparison: To detect a difference of 0.5% (or 0.4%) in change from baseline to Week 24 in HbA1c between lixisenatide and placebo, 225 patients in each arm would provide a power of 98% (or 90%) assuming common standard deviation of 1.3% with a 2-sided test at 5% significance level.p-value: <0.000195% CI: [-0.463, -0.171]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. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline 2-hour PPG assessment during on-treatment period. Missing data was imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 24 | 0.08 mmol/L | Standard Error 0.481 |
| Lixisenatide | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 24 | -3.09 mmol/L | Standard Error 0.482 |
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. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline average 7-point SMPG assessment during on-treatment period. Missing data was imputed using LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Average 7-Point Self Monitored Plasma Glucose (SMPG) Profile at Week 24 | -0.08 mmol/L | Standard Error 0.179 |
| Lixisenatide | Change From Baseline in Average 7-Point Self Monitored Plasma Glucose (SMPG) Profile at Week 24 | -0.47 mmol/L | Standard Error 0.178 |
Secondary
Change From Baseline in Average Insulin Glargine Daily Dose at Week 24
Change was calculated by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. 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 insulin glargine dose assessment during on-treatment period. Missing data was imputed using LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Average Insulin Glargine Daily Dose at Week 24 | 5.34 units per day | Standard Error 1.256 |
| Lixisenatide | Change From Baseline in Average Insulin Glargine Daily Dose at Week 24 | 3.10 units per day | Standard Error 1.26 |
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. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline body weight assessment during on-treatment period. Missing data was imputed using LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Body Weight at Week 24 | 1.16 kilogram | Standard Error 0.33 |
| Lixisenatide | Change From Baseline in Body Weight at Week 24 | 0.28 kilogram | Standard Error 0.331 |
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. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline FPG assessment during on-treatment period. Missing data was imputed using LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | 0.46 mmol/L | Standard Error 0.214 |
| Lixisenatide | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | 0.34 mmol/L | Standard Error 0.213 |
Secondary
Change From Baseline in Glucose Excursion at Week 24
Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test, before study drug administration. Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of 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. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline glucose excursion assessment during on-treatment period. Missing data was imputed using LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Glucose Excursion at Week 24 | -0.33 mmol/L | Standard Error 0.461 |
| Lixisenatide | Change From Baseline in Glucose Excursion at Week 24 | -3.42 mmol/L | Standard Error 0.462 |
Secondary
Change From Baseline in Treatment Satisfaction Score (Sum of Items 1, 4, 5, 6, 7 and 8 of DTSQ) at Week 24
Change was calculated by subtracting baseline value from Week 24 value. DTSQ: 8-item questionnaire to assess treatment satisfaction and patient perception of hyper and hypoglycemia. Each question (Q) scored on a Likert scale from 0 to 6. Six items (Q1 and 4-8; higher score = more satisfaction) measured treatment satisfaction and were summed to calculate treatment satisfaction score which ranged from 0 (very dissatisfied) to 36 (very satisfied). Two items (Q2 and 3), which were not included, measured perceived hyperglycemia and hypoglycemia, respectively and lower scores represented good perceived blood glucose control. 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. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline DTSQ assessment during on-treatment period. Missing data was imputed using LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Treatment Satisfaction Score (Sum of Items 1, 4, 5, 6, 7 and 8 of DTSQ) at Week 24 | 0.65 units on a scale | Standard Error 0.545 |
| Lixisenatide | Change From Baseline in Treatment Satisfaction Score (Sum of Items 1, 4, 5, 6, 7 and 8 of DTSQ) at Week 24 | 0.88 units on a scale | Standard Error 0.543 |
Secondary
Percentage of Patients Requiring Rescue Therapy During the Double-blind Period
Routine fasting SMPG, central laboratory FPG and HbA1c 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 were performed. Threshold values - from baseline to Week 8: fasting SMPG/FPG \>200 milligram/deciliter (mg/dL) (11.1 mmol/L) or HbA1c \>9%, from Week 8 to Week 24: fasting SMPG/FPG \>180 mg/dL (10.0 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 the Double-blind Period | 0.4 percentage of participants |
| Lixisenatide | Percentage of Patients Requiring Rescue Therapy During the Double-blind Period | 0.4 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 14 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. 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 | 38.5 percentage of participants |
| Lixisenatide | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24 | 56.3 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 the time from the first dose of study drug up to 14 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. 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 | 16.3 percentage of participants |
| Lixisenatide | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24 | 32.1 percentage of participants |
Other Pre-specified
Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia
Symptomatic hypoglycemia was an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose less than 60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose measurement was available. Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the patient required the assistance of another person and was associated with either a plasma glucose level below 36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available.
Time frame: First dose of study drug up to 3 days after the last dose administration
Population: Safety population included all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Symptomatic hypoglycemia | 30 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 | 50 participants |
| Lixisenatide | Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia | Severe symptomatic hypoglycemia | 1 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. 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 | 3.2 percentage of participants |
| Lixisenatide | Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24 | 5.1 percentage of participants |