Type 2 Diabetes
Conditions
Brief summary
Primary Objective: \- To compare lixisenatide versus insulin glulisine in terms of glycosylated hemoglobin (HbA1c) reduction and body weight change at Week 26 in type 2 diabetic participants not adequately controlled on insulin glargine ± metformin. Secondary Objectives: \- To compare the treatments/regimens on: * The percentage of participants reaching the target of HbA1c \<7% or ≤6.5%, * Body weight, * Self-Monitored Glucose profiles, * Fasting Plasma Glucose (FPG), * Post-prandial plasma glucose (PPG) /glucose excursions during a standardized meal test (subset of participants), * Daily doses of insulins, * Safety and tolerability.
Detailed description
Approximately 41 weeks including a 26 week treatment period.
Interventions
DRUGLixisenatide (AVE0010)
Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection 30 to 60 minutes before breakfast or dinner.
DRUGInsulin glulisine QD
Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection within 15 minutes before breakfast or dinner. The initial dose was 3-5 units and then individually titrated to obtain the SMPG value \>5.6 mmol/L (100 mg/dL) and ≤7.8 mmol/L (140 mg/dL) before lunch (if administered at breakfast) or at bedtime (if administered at dinner).
DRUGInsulin glulisine TID
Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection within 15 minutes before each meal. The initial dose was 3-5 units for each meal and then individually titrated to obtain the SMPG value \>5.6 mmol/L (100 mg/dL) and ≤7.8 mmol/L (140 mg/dL) before the next meal or at bedtime (for injection at dinner).
DRUGInsulin Glargine (Mandatory background drug)
Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection at breakfast or dinner. Doses were adjusted to maintain a fasting self-monitored plasma glucose (SMPG) between 4.4 to 5.6 mmol/L (80 to 100 mg/dL).
Pharmaceutical form: Tablet; Route of administration: Oral administration. If previously taken, Metformin to be continued at stable dose (≥1.5 g/day) throughout the study.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
: * Participants with type 2 diabetes mellitus diagnosed at least 1 year before screening visit (V1). * Participants treated with basal insulin for at least 6 months. * Participants treated for at least 3 months prior to visit 1 with a stable basal insulin regimen (i.e. type of insulin and time/frequency of the injection). The insulin dose should be stable (± 20%) and ≥20 U/day for at least 2 months prior to visit 1. * Participants treated with basal insulin alone or in combination with 1 to 3 oral anti-diabetic drugs (OADs) that could be: metformin (≥1.5 g/day or maximal tolerated dose), a sulfonylurea (SU), a dipeptidyl-peptidase-4 (DPP-4) inhibitor, a glinide. The dose of OADs should be stable for at least 3 months prior to visit 1.
Exclusion criteria
* At screening: age \< legal age of majority. * At screening, HbA1c: \<7.5% and \>10.0% for participants treated with basal insulin alone or in combination with metformin only; \< 7.0% and \> 10.0% for participants treated with basal insulin and a combination of oral anti-diabetic drugs which included a SU and/or a DPP-4 inhibitor and/or a glinide. * Women of childbearing potential with no effective contraceptive method, pregnancy or lactation. * Type 1 diabetes mellitus. * Treatment with glucose-lowering agent(s) other than stated in the inclusion criteria within 3 months prior to screening. * Previous treatment with short or rapid acting insulin other than in relation to hospitalization or an acute illness. * Any previous treatment with lixisenatide, or any discontinuation from another glucagon-like peptide 1 (GLP-1) receptor agonist due to safety/tolerability issue or lack of efficacy. * At screening, Body Mass Index (BMI) ≤20 or \>40 kg/m\^2. * Weight change of more than 5 kg during the 3 months prior to the screening visit; use of weight loss drugs within 3 months prior to screening. * Within the last 6 months prior to screening: history of myocardial infarction, stroke, or heart failure requiring hospitalization. Planned coronary, carotid or peripheral artery revascularisation procedures. * History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery. * At screening resting systolic blood pressure \>180 mmHg or diastolic blood pressure \>95 mmHg. * Personal or immediate family history of medullary thyroid cancer (MTC) or genetic condition that predisposed to MTC (e.g. multiple endocrine neoplasia syndromes). * Contraindication related to metformin (for participant receiving this treatment), insulin glargine, insulin glulisine or lixisenatide. * Participants with severe renal impairment (creatinine clearance less than 30 ml/min) or end-stage renal disease. * At screening, amylase and/or lipase \>3 times the upper limit of the normal laboratory range (ULN). * At screening alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3 ULN. * At screening calcitonin ≥20 pg/ml (5.9 pmol/L).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline to Week 26 | Baseline, Week 26 | Change in HbA1C was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using last on-treatment observation carried forward (LOCF). On-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. Here, number of participants analyzed = participants with baseline and at least one post-baseline HbA1c assessment during on-treatment period. |
| Change in Body Weight From Baseline to Week 26 | Baseline, Week 26 | Primary outcome was the comparison between Lixisenatide versus Insulin Glulisine TID. Change in body weight was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Average 7-point SMPG Profiles From Baseline to Week 26 | Baseline, Week 26 | Participants recorded a 7-point plasma glucose profile measured before and 2 hours after each meal and at bedtime three times in a week before baseline, before visit Week 12 and before visit week 26 and the average value across the profiles performed in the week a visit for the 7-time points was calculated. Change in average 7-point SMPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to the day of last dose of study drug. |
| Change in FPG From Baseline to Week 26 | Baseline, Week 26 | Change in FPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to 1 day after the last dose of study drug. |
| Change in PPG From Baseline to Week 26 (in Participants Who Had an Injection of Investigational Medicinal Product [IMP] Before Breakfast) | Baseline, Week 26 | The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. |
| Change in Glucose Excursions From Baseline to Week 26 (in Participants Who Had an Injection of IMP Before Breakfast) | Baseline, Week 26 | Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test, before study drug administration. Change in glucose excursions was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. |
| Change in Insulin Glargine Dose From Baseline to Week 26 | Baseline, Week 26 | Change in Insulin glargine dose was calculated by subtracting the baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. |
| Percentage of Participants With HbA1c Level <7% and ≤6.5% at Week 26 | Week 26 | The on-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. Missing data was imputed using LOCF. |
| Total Insulin Dose at Week 26 | Week 26 | The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. Missing data was imputed using LOCF. The outcome is reporting results of total insulin (amounts of Insulin Glargine plus Insulin Glulisine ) only for the arms in which Insulin Glulisine was administered and is not applicable for the lixisenatide arm in which only Insulin Glargine is administered. Change in dose of the insulin used by patients in the Lixisenatide arm (i.e. Insulin Glargine) is reported in the secondary Outcome Measure 9. |
| Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia | First dose of study drug up to 3 days after the last dose administration (maximum of 185 days) | Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of \<60 mg/dL (3.3 mmol/L). Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the participant 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 Participants Who Reached the Target of HbA1c <7% at Week 26 and Did Not Experienced Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26 Week Treatment Period | Week 26 | The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for symptomatic hypoglycemia assessment was defined as the time from the first dose of study drug up to 1 day after the last dose of study drug. |
| Percentage of Participants Who Reached the Target of HbA1c <7% and Had no Weight Gain at Week 26 | Week 26 | The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for body weight assessment was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug. |
| Percentage of Participants Who Reached the Target of HbA1c <7%, Had no Weight Gain at Week 26, and Did Not Experience Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26-Week Treatment Period | Week 26 | The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for body weight assessment was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug. The on-treatment period for symptomatic hypoglycemia assessment was defined as the time from the first dose of study drug up to 1 day after the last dose of study drug. Participants without post-baseline on-treatment values (HbA1c and body weight) that were no more than 30 days apart were counted as non-responders if at least one of the components (HbA1c and/or body weight) was available and showed non-response, or if they experienced at least one documented symptomatic hypoglycemia during the on-treatment period. Otherwise, they were counted as missing data. |
| Insulin Glulisine Dose at Week 26 | Week 26 | The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. Missing data was imputed using LOCF. |
| Percentage of Participants With no Weight Gain at Week 26 | Week 26 | The on-treatment period for this efficacy variable was the time from the first dose of study drug up to 3 days after the last dose of study drug. |
Countries
Canada, Chile, Czechia, Estonia, France, Germany, Hungary, Italy, Latvia, Lithuania, Mexico, Poland, Romania, Russia, Spain, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 199 centers in 18 countries. A total of 2159 participants were screened between January 08, 2013 and April 10, 2014.
Pre-assignment details
Participants underwent a 12-week run-in period with switch from other basal insulins to insulin glargine. A total of 1265 participants were screen failures/run-in failures; the most frequent reason for run-in failure was that glycosylated hemoglobin (HbA1c) criteria were not met at the end of run-in phase. 894 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Lixisenatide Lixisenatide 10 mcg QD SC for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin. | 298 |
| Insulin Glulisine QD Insulin glulisine QD SC up to Week 26 on top of insulin glargine with or without metformin. | 298 |
| Insulin Glulisine TID Insulin glulisine TID SC up to Week 26 on top of insulin glargine with or without metformin. | 298 |
| Total | 894 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 15 | 2 | 5 |
| Overall Study | Lack of Efficacy | 6 | 4 | 0 |
| Overall Study | Other than specified | 9 | 8 | 5 |
| Overall Study | Poor compliance to protocol | 0 | 3 | 2 |
| Overall Study | Randomized but not treated | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Lixisenatide | Total | Insulin Glulisine TID | Insulin Glulisine QD |
|---|---|---|---|---|
| 2-Hour Glucose Excursion | 7.31 mmol/L STANDARD_DEVIATION 3.19 | 7.33 mmol/L STANDARD_DEVIATION 3.37 | 7.35 mmol/L STANDARD_DEVIATION 3.34 | 7.31 mmol/L STANDARD_DEVIATION 3.63 |
| 2-Hour Postprandial Plasma Glucose (PPG) | 14.26 mmol/L STANDARD_DEVIATION 3.55 | 14.18 mmol/L STANDARD_DEVIATION 3.47 | 14.25 mmol/L STANDARD_DEVIATION 3.35 | 14.02 mmol/L STANDARD_DEVIATION 3.59 |
| Age, Continuous | 59.8 years STANDARD_DEVIATION 8.6 | 59.8 years STANDARD_DEVIATION 8.9 | 59.4 years STANDARD_DEVIATION 9.5 | 60.2 years STANDARD_DEVIATION 8.6 |
| Average 7-Point Self-monitored Plasma Glucose (SMPG) | 9.02 mmol/L STANDARD_DEVIATION 1.75 | 9.02 mmol/L STANDARD_DEVIATION 1.68 | 8.99 mmol/L STANDARD_DEVIATION 1.57 | 9.07 mmol/L STANDARD_DEVIATION 1.74 |
| BMI | 32.27 kg/m^2 STANDARD_DEVIATION 4.57 | 32.21 kg/m^2 STANDARD_DEVIATION 4.52 | 32.50 kg/m^2 STANDARD_DEVIATION 4.6 | 31.86 kg/m^2 STANDARD_DEVIATION 4.39 |
| Duration of Diabetes | 11.89 years STANDARD_DEVIATION 6.43 | 12.21 years STANDARD_DEVIATION 6.66 | 12.41 years STANDARD_DEVIATION 6.8 | 12.33 years STANDARD_DEVIATION 6.75 |
| Ethnicity Hispanic | 63 participants | 189 participants | 68 participants | 58 participants |
| Ethnicity Non-Hispanic | 235 participants | 705 participants | 230 participants | 240 participants |
| Fasting Plasma Glucose (FPG) | 6.58 mmol/L STANDARD_DEVIATION 1.82 | 6.69 mmol/L STANDARD_DEVIATION 1.9 | 6.65 mmol/L STANDARD_DEVIATION 1.89 | 6.84 mmol/L STANDARD_DEVIATION 1.98 |
| Gender Female | 160 Participants | 489 Participants | 166 Participants | 163 Participants |
| Gender Male | 138 Participants | 405 Participants | 132 Participants | 135 Participants |
| HbA1c | 7.77 percentage of hemoglobin STANDARD_DEVIATION 0.55 | 7.76 percentage of hemoglobin STANDARD_DEVIATION 0.58 | 7.79 percentage of hemoglobin STANDARD_DEVIATION 0.6 | 7.73 percentage of hemoglobin STANDARD_DEVIATION 0.59 |
| Insulin Glargine Dose | 67.25 Units (U) STANDARD_DEVIATION 31.95 | 65.65 Units (U) STANDARD_DEVIATION 30.39 | 64.97 Units (U) STANDARD_DEVIATION 26.9 | 64.72 Units (U) STANDARD_DEVIATION 32.07 |
| Metformin Use at Screening No | 36 participants | 113 participants | 39 participants | 38 participants |
| Metformin Use at Screening Yes | 262 participants | 781 participants | 259 participants | 260 participants |
| Number of Participants with Categorical Body Mass Index (BMI) <30 kg/m^2 | 97 participants | 312 participants | 97 participants | 118 participants |
| Number of Participants with Categorical Body Mass Index (BMI) ≥30 kg/m^2 | 201 participants | 581 participants | 200 participants | 180 participants |
| Number of Participants with Categorical Body Mass Index (BMI) Participants not analyzed for BMI | 0 participants | 1 participants | 1 participants | 0 participants |
| Race Asian/Oriental | 9 participants | 29 participants | 13 participants | 7 participants |
| Race Black | 13 participants | 36 participants | 12 participants | 11 participants |
| Race Caucasian/White | 276 participants | 828 participants | 272 participants | 280 participants |
| Race Other | 0 participants | 1 participants | 1 participants | 0 participants |
| Weight | 90.06 kg STANDARD_DEVIATION 17.31 | 89.53 kg STANDARD_DEVIATION 16.79 | 90.08 kg STANDARD_DEVIATION 17.18 | 88.45 kg STANDARD_DEVIATION 15.84 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 183 / 298 | 186 / 301 | 195 / 294 |
| serious Total, serious adverse events | 11 / 298 | 11 / 301 | 14 / 294 |
Outcome results
Primary
Change in Body Weight From Baseline to Week 26
Primary outcome was the comparison between Lixisenatide versus Insulin Glulisine TID. Change in body weight was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug.
Time frame: Baseline, Week 26
Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline body weight assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change in Body Weight From Baseline to Week 26 | -0.63 kg | Standard Error 0.276 |
| Insulin Glulisine QD | Change in Body Weight From Baseline to Week 26 | 1.03 kg | Standard Error 0.276 |
| Insulin Glulisine TID | Change in Body Weight From Baseline to Week 26 | 1.37 kg | Standard Error 0.271 |
Comparison: Analysis was performed using ANCOVA model as described above. Hochberg procedure was used to control type 1 error at α = 0.025 (1-sided) for comparison between lixisenatide vs insulin glulisine TID in HbA1c and body weight. If both comparisons were met, then both would be declared significant. Otherwise, if only one was met, then the one met should be tested at α=0.0125 (1-sided).p-value: <0.000195% CI: [-2.593, -1.396]ANCOVA
Primary
Change in HbA1c From Baseline to Week 26
Change in HbA1C was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using last on-treatment observation carried forward (LOCF). On-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. Here, number of participants analyzed = participants with baseline and at least one post-baseline HbA1c assessment during on-treatment period.
Time frame: Baseline, Week 26
Population: modified intent-to-treat (mITT) population: all randomized participants who received at least one dose of study drug; and had both baseline and at least one post-baseline efficacy assessment, irrespective of compliance with study protocol/procedures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change in HbA1c From Baseline to Week 26 | -0.63 percentage of hemoglobin | Standard Error 0.054 |
| Insulin Glulisine QD | Change in HbA1c From Baseline to Week 26 | -0.58 percentage of hemoglobin | Standard Error 0.054 |
| Insulin Glulisine TID | Change in HbA1c From Baseline to Week 26 | -0.84 percentage of hemoglobin | Standard Error 0.053 |
Comparison: Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, strata of Week -1 HbA1c (\<8.0, ≥8.0%), randomization strata of metformin use, and country as fixed effects and baseline HbA1c value as a covariate. The non-inferiority was assessed using upper bound of 2-sided 95% Confidence Interval (CI).95% CI: [-0.17, 0.064]ANCOVA
Comparison: Analysis was performed using ANCOVA model as described above. Hochberg procedure was used to control type 1 error at significance level = 0.025 (1-sided) for comparison between Lixisenatide vs Insulin glulisine TID in HbA1c and body weight. If both comparisons were met, then both would be declared significant. Otherwise, if only one was met, then the one met should be tested at α=0.0125 (1-sided).95% CI: [0.095, 0.328]ANCOVA
Secondary
Change in Average 7-point SMPG Profiles From Baseline to Week 26
Participants recorded a 7-point plasma glucose profile measured before and 2 hours after each meal and at bedtime three times in a week before baseline, before visit Week 12 and before visit week 26 and the average value across the profiles performed in the week a visit for the 7-time points was calculated. Change in average 7-point SMPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to the day of last dose of study drug.
Time frame: Baseline, Week 26
Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline 7-point SMPG assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change in Average 7-point SMPG Profiles From Baseline to Week 26 | -0.784 mmol/L | Standard Error 0.1141 |
| Insulin Glulisine QD | Change in Average 7-point SMPG Profiles From Baseline to Week 26 | -0.782 mmol/L | Standard Error 0.1133 |
| Insulin Glulisine TID | Change in Average 7-point SMPG Profiles From Baseline to Week 26 | -1.053 mmol/L | Standard Error 0.1105 |
Secondary
Change in FPG From Baseline to Week 26
Change in FPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to 1 day after the last dose of study drug.
Time frame: Baseline, Week 26
Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline FPG assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change in FPG From Baseline to Week 26 | -0.23 mmol/L | Standard Error 0.143 |
| Insulin Glulisine QD | Change in FPG From Baseline to Week 26 | -0.21 mmol/L | Standard Error 0.142 |
| Insulin Glulisine TID | Change in FPG From Baseline to Week 26 | -0.06 mmol/L | Standard Error 0.14 |
Secondary
Change in Glucose Excursions From Baseline to Week 26 (in Participants Who Had an Injection of IMP Before Breakfast)
Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test, before study drug administration. Change in glucose excursions was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug.
Time frame: Baseline, Week 26
Population: mITT population. Here, number of participants analyzed = participants with IMP injection before breakfast and baseline and at least one post-baseline glucose excursion assessment during on-treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change in Glucose Excursions From Baseline to Week 26 (in Participants Who Had an Injection of IMP Before Breakfast) | -3.42 mmol/L | Standard Deviation 4.13 |
| Insulin Glulisine QD | Change in Glucose Excursions From Baseline to Week 26 (in Participants Who Had an Injection of IMP Before Breakfast) | -1.59 mmol/L | Standard Deviation 3.42 |
| Insulin Glulisine TID | Change in Glucose Excursions From Baseline to Week 26 (in Participants Who Had an Injection of IMP Before Breakfast) | -1.56 mmol/L | Standard Deviation 2.52 |
Secondary
Change in Insulin Glargine Dose From Baseline to Week 26
Change in Insulin glargine dose was calculated by subtracting the baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug.
Time frame: Baseline, Week 26
Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline insulin glargine dose assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change in Insulin Glargine Dose From Baseline to Week 26 | 0.7 U | Standard Error 1.002 |
| Insulin Glulisine QD | Change in Insulin Glargine Dose From Baseline to Week 26 | -0.06 U | Standard Error 0.999 |
| Insulin Glulisine TID | Change in Insulin Glargine Dose From Baseline to Week 26 | -3.13 U | Standard Error 0.982 |
Secondary
Change in PPG From Baseline to Week 26 (in Participants Who Had an Injection of Investigational Medicinal Product [IMP] Before Breakfast)
The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug.
Time frame: Baseline, Week 26
Population: mITT population. Here, number of participants analyzed = participants with IMP injection before breakfast and baseline and at least one post-baseline 2-hour PPG assessment during on-treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Change in PPG From Baseline to Week 26 (in Participants Who Had an Injection of Investigational Medicinal Product [IMP] Before Breakfast) | -3.93 mmol/L | Standard Deviation 4.29 |
| Insulin Glulisine QD | Change in PPG From Baseline to Week 26 (in Participants Who Had an Injection of Investigational Medicinal Product [IMP] Before Breakfast) | -1.62 mmol/L | Standard Deviation 4.01 |
| Insulin Glulisine TID | Change in PPG From Baseline to Week 26 (in Participants Who Had an Injection of Investigational Medicinal Product [IMP] Before Breakfast) | -1.87 mmol/L | Standard Deviation 3.18 |
Secondary
Insulin Glulisine Dose at Week 26
The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. Missing data was imputed using LOCF.
Time frame: Week 26
Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline insulin glulisine dose assessment during on-treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Insulin Glulisine Dose at Week 26 | 9.97 U | Standard Deviation 7.8 |
| Insulin Glulisine QD | Insulin Glulisine Dose at Week 26 | 20.24 U | Standard Deviation 13.04 |
Secondary
Percentage of Participants Who Reached the Target of HbA1c <7% and Had no Weight Gain at Week 26
The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for body weight assessment was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug.
Time frame: Week 26
Population: mITT population. Participants without post-baseline on-treatment values (for HbA1c and body weight) that were no more than 30 days apart were counted as non-responders if at least one of the components (HbA1c and/or body weight) was available and showed non-response. Otherwise, they were counted as missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lixisenatide | Percentage of Participants Who Reached the Target of HbA1c <7% and Had no Weight Gain at Week 26 | 31.2 percentage of participants |
| Insulin Glulisine QD | Percentage of Participants Who Reached the Target of HbA1c <7% and Had no Weight Gain at Week 26 | 16.7 percentage of participants |
| Insulin Glulisine TID | Percentage of Participants Who Reached the Target of HbA1c <7% and Had no Weight Gain at Week 26 | 17.6 percentage of participants |
Secondary
Percentage of Participants Who Reached the Target of HbA1c <7% at Week 26 and Did Not Experienced Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26 Week Treatment Period
The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for symptomatic hypoglycemia assessment was defined as the time from the first dose of study drug up to 1 day after the last dose of study drug.
Time frame: Week 26
Population: mITT population. Participants without any post-baseline on-treatment value for HbA1c were counted as non-responders if they experienced at least one symptomatic hypoglycemia. Otherwise, they were counted as missing.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lixisenatide | Percentage of Participants Who Reached the Target of HbA1c <7% at Week 26 and Did Not Experienced Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26 Week Treatment Period | 29.4 percentage of participants |
| Insulin Glulisine QD | Percentage of Participants Who Reached the Target of HbA1c <7% at Week 26 and Did Not Experienced Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26 Week Treatment Period | 24.2 percentage of participants |
| Insulin Glulisine TID | Percentage of Participants Who Reached the Target of HbA1c <7% at Week 26 and Did Not Experienced Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26 Week Treatment Period | 26.1 percentage of participants |
Secondary
Percentage of Participants Who Reached the Target of HbA1c <7%, Had no Weight Gain at Week 26, and Did Not Experience Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26-Week Treatment Period
The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for body weight assessment was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug. The on-treatment period for symptomatic hypoglycemia assessment was defined as the time from the first dose of study drug up to 1 day after the last dose of study drug. Participants without post-baseline on-treatment values (HbA1c and body weight) that were no more than 30 days apart were counted as non-responders if at least one of the components (HbA1c and/or body weight) was available and showed non-response, or if they experienced at least one documented symptomatic hypoglycemia during the on-treatment period. Otherwise, they were counted as missing data.
Time frame: Week 26
Population: mITT population.Participants without post-baseline on-treatment values(HbA1c;body weight),no more than 30 days apart counted as non-responders if at least one of components(HbA1c;body weight) was available,showed non-response or experienced at least one symptomatic hypoglycemia during on-treatment period.Otherwise,they were counted as missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lixisenatide | Percentage of Participants Who Reached the Target of HbA1c <7%, Had no Weight Gain at Week 26, and Did Not Experience Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26-Week Treatment Period | 22.2 percentage of participants |
| Insulin Glulisine QD | Percentage of Participants Who Reached the Target of HbA1c <7%, Had no Weight Gain at Week 26, and Did Not Experience Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26-Week Treatment Period | 9.2 percentage of participants |
| Insulin Glulisine TID | Percentage of Participants Who Reached the Target of HbA1c <7%, Had no Weight Gain at Week 26, and Did Not Experience Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26-Week Treatment Period | 10.8 percentage of participants |
Secondary
Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia
Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of \<60 mg/dL (3.3 mmol/L). Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the participant 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 (maximum of 185 days)
Population: All randomized participants who were exposed to at least one dose of study drug, regardless of the amount of treatment administered.~The 4 participants in the TID group who received Insulin Glulisine QD were analyzed according to the QD dose.The 1 participant in the QD group who received Insulin Glulisine TID was analyzed according to the TID dose
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lixisenatide | Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia | Documented symptomatic hypoglycemia | 31.5 percentage of participants |
| Lixisenatide | Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia | Severe symptomatic hypoglycemia | 0 percentage of participants |
| Insulin Glulisine QD | Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia | Documented symptomatic hypoglycemia | 37.5 percentage of participants |
| Insulin Glulisine QD | Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia | Severe symptomatic hypoglycemia | 0.7 percentage of participants |
| Insulin Glulisine TID | Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia | Documented symptomatic hypoglycemia | 44.6 percentage of participants |
| Insulin Glulisine TID | Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia | Severe symptomatic hypoglycemia | 0 percentage of participants |
Secondary
Percentage of Participants With HbA1c Level <7% and ≤6.5% at Week 26
The on-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. Missing data was imputed using LOCF.
Time frame: Week 26
Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline HbA1c assessment during on-treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lixisenatide | Percentage of Participants With HbA1c Level <7% and ≤6.5% at Week 26 | HbA1c ≤6.5% | 20.5 percentage of participants |
| Lixisenatide | Percentage of Participants With HbA1c Level <7% and ≤6.5% at Week 26 | HbA1c <7.0% | 42.1 percentage of participants |
| Insulin Glulisine QD | Percentage of Participants With HbA1c Level <7% and ≤6.5% at Week 26 | HbA1c ≤6.5% | 17.8 percentage of participants |
| Insulin Glulisine QD | Percentage of Participants With HbA1c Level <7% and ≤6.5% at Week 26 | HbA1c <7.0% | 38.4 percentage of participants |
| Insulin Glulisine TID | Percentage of Participants With HbA1c Level <7% and ≤6.5% at Week 26 | HbA1c ≤6.5% | 30.8 percentage of participants |
| Insulin Glulisine TID | Percentage of Participants With HbA1c Level <7% and ≤6.5% at Week 26 | HbA1c <7.0% | 49.2 percentage of participants |
Secondary
Percentage of Participants With no Weight Gain at Week 26
The on-treatment period for this efficacy variable was the time from the first dose of study drug up to 3 days after the last dose of study drug.
Time frame: Week 26
Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline body weight assessment during on-treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lixisenatide | Percentage of Participants With no Weight Gain at Week 26 | 64.7 percentage of participants |
| Insulin Glulisine QD | Percentage of Participants With no Weight Gain at Week 26 | 36.6 percentage of participants |
| Insulin Glulisine TID | Percentage of Participants With no Weight Gain at Week 26 | 30.5 percentage of participants |
Secondary
Total Insulin Dose at Week 26
The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. Missing data was imputed using LOCF. The outcome is reporting results of total insulin (amounts of Insulin Glargine plus Insulin Glulisine ) only for the arms in which Insulin Glulisine was administered and is not applicable for the lixisenatide arm in which only Insulin Glargine is administered. Change in dose of the insulin used by patients in the Lixisenatide arm (i.e. Insulin Glargine) is reported in the secondary Outcome Measure 9.
Time frame: Week 26
Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline total insulin dose assessment during on-treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide | Total Insulin Dose at Week 26 | 73.61 U | Standard Deviation 39.13 |
| Insulin Glulisine QD | Total Insulin Dose at Week 26 | 81.05 U | Standard Deviation 33.55 |