Type 2 Diabetes Mellitus
Conditions
Brief summary
Primary Objective: * The purpose of this study was to compare insulin glargine/ lixisenatide fixed ratio combination (FRC) versus insulin glargine on glycemic control over 24 weeks, as evaluated by glycosylated hemoglobin (HbA1c) reduction in type 2 diabetic participants treated with metformin. Secondary Objectives: * To compare insulin glargine/lixisenatide FRC versus insulin glargine over 24 weeks on: * Glycemic control in relation to a meal as evaluated by post-prandial plasma glucose and glucose excursions during a standardized meal test; * Percentage of participants reaching HbA1c \<7% or ≤6.5%; * 7-point Self-Monitored Plasma Glucose (SMPG) profile; * Body weight; * Insulin glargine dose * Fasting Plasma Glucose (FPG); * Percentage of participants requiring rescue therapy during the 24-week open label treatment period; * To assess safety and tolerability of insulin glargine/lixisenatide FRC.
Detailed description
Approximately 27 weeks including a 24-week treatment period.
Interventions
FRC was self-administered by subcutaneous (SC) injection within 1 hour before breakfast using pen-type injector (Tactipen®): 100 U/ml insulin glargine and 50 mcg Lixisenatide (ratio of 2 U/1 mcg). The initial dose was 10 U/5 mcg and then dose was adjusted weekly to reach and maintain fasting self-monitored plasma glucose (SMPG) of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L.
DRUGInsulin glargine
Insulin glargine (100 U/ml) was self-administered by SC injection before breakfast using pen-type injector (Lantus® Solostar®). The initial daily dose of insulin glargine was 10 U and then dose was adjusted weekly to reach and maintain fasting SMPG of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L).
Pharmaceutical form: Tablet; Route of administration: oral administration. To be kept 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 for at least 1 year. * Metformin treatment at a stable dose of at least 1.5 g/day for at least 3 months prior to screening.
Exclusion criteria
* Age \< legal age of adulthood (18 years). * Screening HbA1c \<7% or \>10%. * Screening FPG \>250 mg/dL (\>13.9 mmol/L). * Pregnancy or lactation, women of childbearing potential with no effective contraceptive method. * Type 1 diabetes mellitus. * Treatment with glucose-lowering agent(s) other than metformin in a period of 3 months prior to screening. * Use of insulin within the last 6 months. * Previous use of insulin, except for episode(s) of short-term treatment (≤15 consecutive days) due to intercurrent illness. * Amylase and/or lipase \>3 times the upper limit of the normal laboratory range (ULN) at screening. * Calcitonin ≥20 pg/ml (5.9 pmol/l) at screening. * Alanine Transferase (ALT) \>3 ULN at screening. * History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy. * Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predisposes to MTC (e.g. multiple endocrine neoplasia syndromes). * Uncontrolled or inadequately controlled hypertension at the time of screening with a resting supine systolic or diastolic blood pressure \>180 mmHg or \>110 mmHg, respectively. * Within the last 6 months prior to screening: history of heart failure requiring hospitalization, myocardial infarction, or stroke. Planned coronary, carotid or peripheral artery revascularisation procedures. * Body Mass Index (BMI) ≤20 or \>40 kg/m\^2. * Any previous treatment with lixisenatide The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline to Week 24 | Baseline, Week 24 | Change in HbA1c was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using last observation carried forward (LOCF). On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of investigational medicinal product (IMP). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in 2-hour Plasma Glucose Excursion From Baseline to Week 24 | Baseline, Week 24 | 2-hour plasma glucose excursion = 2-hour PPG minus plasma glucose value obtained 30 minutes prior to the start of the meal and before IMP administration. Change in plasma glucose excursion was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP. |
| Change in Average 7-Point Self-Monitored Plasma Glucose (SMPG) Profiles From Baseline to Week 24 | Baseline, Week 24 | Participants recorded a 7-point plasma glucose profile measured before and 2-hours after each meal and at bedtime, over a single day, once in a week before baseline, before visit Week 12 and before visit Week 24 and the average value across the profiles performed in the week before a visit for the 7-time points was calculated. Change in average 7-point SMPG was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP. |
| Change in Body Weight From Baseline to Week 24 | Baseline, Week 24 | Change in body weight was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to 3 days after the last injection of IMP. |
| Average Daily Insulin Glargine Dose at Week 24 | Week 24 | 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 till before the introduction of rescue medication and up to the date of last injection of IMP. |
| Change in FPG From Baseline to Week 24 | Baseline, Week 24 | Change in FPG was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to 1 day after the last injection of IMP. |
| Percentage of Participants Requiring Rescue Therapy During 24-week Treatment 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 exceed the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after Week 12) were performed. Threshold values from Week 8 to Week 12: fasting SMPG/FPG \>240 mg/dL (13.3 mmol/L), and from Week 12 to Week 30: fasting SMPG/FPG \>200 mg/dL (11.1 mmol/L) or HbA1c \>8%. |
| Change in 2-hour Postprandial Plasma Glucose (PPG) From Baseline to Week 24 | Baseline, Week 24 | 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 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP. |
| Change in 30-minute and 1-hour PPG From Baseline to Week 24 | Baseline, Week 24 | The 30 minute and 1-hour PPG test measured blood glucose 30 minutes and 1-hour after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP. |
| Change in 30 Minute and 1-hour Plasma Glucose Excursion From Baseline to Week 24 | Baseline, Week 24 | 30-minute and 1-hour plasma glucose excursion = 30-minute and 1-hour PPG minus plasma glucose value obtained 30 minutes prior to the start of the meal and before IMP administration. Change in plasma glucose excursion was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP. |
| Percentage of Participants Reaching HbA1c <7% at Week 24 With no Documented Symptomatic Hypoglycemia During 24-week Treatment Period | Baseline up to Week 24 | Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of ≤70 mg/dL (3.9 mmol/L). Participants without any post-baseline on-treatment value for HbA1c were counted as non-responders if they experienced at least one documented symptomatic hypoglycemia before the introduction of rescue medication and up to 1 day after the last injection of IMP. Otherwise, they were counted as missing data. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of IMP. |
| Percentage of Participants Reaching HbA1c <7% With no Body Weight Gain at Week 24 | Week 24 | Participants without any 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 (for HbA1c and body weight) was available and showed non-response. Otherwise, they were counted as missing data. |
| 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 219 days) | Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of ≤70 mg/dL (3.9 mmol/L).Severe symptomatic hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes were associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. All episodes in which neurological impairment was severe enough to prevent self-treatment and which were thought to place participants at risk for injury to themselves or others. |
| Percentage of Participants With HbA1c ≤6.5 % or <7.0 % at Week 24 | Week 24 | On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of IMP. |
Countries
Chile, Czechia, Denmark, France, Germany, Hungary, Lithuania, Mexico, Poland, Romania, Slovakia, Sweden, United States
Participant flow
Recruitment details
The study was conducted at 70 centers in 13 countries. A total of 520 participants were screened between November 21, 2011 and June 08, 2012. Out of 520 participants, 197 were screen failure; main reason for screen failure was that glycosylated hemoglobin (HbA1c) values were out of the protocol defined range.
Pre-assignment details
A total of 323 participants were randomized in 1:1 ratio to insulin glargine/lixisenatide fixed ratio combination (FRC) and insulin glargine arms, stratified by screening HbA1c values (\<8% or ≥8%) and screening body mass index (BMI) values (\<30 kg/m\^2, ≥30 kg/m\^2).
Participants by arm
| Arm | Count |
|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination FRC injected subcutaneously QD for 24 weeks. Dose individually adjusted. | 161 |
| Insulin Glargine Insulin glargine injected subcutaneously QD for 24 weeks. Dose individually adjusted. | 162 |
| Total | 323 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 0 |
| Overall Study | Other reasons | 4 | 2 |
| Overall Study | Poor compliance to protocol | 1 | 1 |
Baseline characteristics
| Characteristic | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine | Total |
|---|---|---|---|
| Age, Continuous | 56.9 years STANDARD_DEVIATION 9.5 | 56.6 years STANDARD_DEVIATION 9.4 | 56.7 years STANDARD_DEVIATION 9.4 |
| Baseline BMI | 32.24 kg/m^2 STANDARD_DEVIATION 4.75 | 32.02 kg/m^2 STANDARD_DEVIATION 4.35 | 32.13 kg/m^2 STANDARD_DEVIATION 4.55 |
| Daily Dose of Metformin | 2075.8 mg STANDARD_DEVIATION 440.7 | 2093.7 mg STANDARD_DEVIATION 415.5 | 2084.8 mg STANDARD_DEVIATION 427.7 |
| Duration of Diabetes | 6.29 years STANDARD_DEVIATION 4.29 | 7.10 years STANDARD_DEVIATION 5.27 | 6.69 years STANDARD_DEVIATION 4.82 |
| Ethnicity Hispanic | 35 participants | 30 participants | 65 participants |
| Ethnicity Non Hispanic | 126 participants | 132 participants | 258 participants |
| Fasting Plasma Glucose (FPG) | 9.76 mmol/L STANDARD_DEVIATION 2.19 | 9.46 mmol/L STANDARD_DEVIATION 2.16 | 9.61 mmol/L STANDARD_DEVIATION 2.18 |
| Gender Female | 81 Participants | 77 Participants | 158 Participants |
| Gender Male | 80 Participants | 85 Participants | 165 Participants |
| Race Asian/Oriental | 1 participants | 1 participants | 2 participants |
| Race Black | 2 participants | 1 participants | 3 participants |
| Race Caucasian/White | 158 participants | 160 participants | 318 participants |
| Screening HbA1c | 8.12 percentage of haemoglobin STANDARD_DEVIATION 0.8 | 8.08 percentage of haemoglobin STANDARD_DEVIATION 0.77 | 8.10 percentage of haemoglobin STANDARD_DEVIATION 0.78 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 26 / 161 | 21 / 162 |
| serious Total, serious adverse events | 9 / 161 | 6 / 162 |
Outcome results
Primary
Change in HbA1c From Baseline to Week 24
Change in HbA1c was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using last observation carried forward (LOCF). On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of investigational medicinal product (IMP).
Time frame: Baseline, Week 24
Population: Modified intent-to-treat (mITT) population consisted of all randomized participants received at least 1 dose of IMP and had both baseline and at least 1 post-baseline efficacy assessment. Number of participants analyzed = participants with both baseline and at least one post-baseline HbA1c assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in HbA1c From Baseline to Week 24 | -1.82 percentage of hemoglobin | Standard Error 0.058 |
| Insulin Glargine | Change in HbA1c From Baseline to Week 24 | -1.64 percentage of hemoglobin | Standard Error 0.057 |
Comparison: Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, randomization strata of screening HbA1c (\<8.0, ≥8.0%), randomization strata of screening BMI (\<30 kg/m\^2, ≥30 kg/m\^2), and country as fixed effects and baseline HbA1c value as covariates. A step-down testing procedure described by Hochberg and Tamhane was used to control type-1 error.95% CI: [-0.312, -0.037]ANCOVA
Comparison: Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c (\<8.0, ≥8.0%), randomization strata of screening BMI (\<30 kg/m\^2, ≥30 kg/m\^2), and country as fixed effects and baseline HbA1c value as covariates. If non-inferiority was established, then a test of superiority of insulin glargine/lixisenatide FRC over insulin glargine would be performed, at alpha level of 0.05 (2-sided).p-value: 0.01395% CI: [-0.312, -0.037]ANCOVA
Secondary
Average Daily Insulin Glargine Dose at Week 24
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 till before the introduction of rescue medication and up to the date of last injection of IMP.
Time frame: Week 24
Population: mITT population. Here, number of participants analyzed = participants with insulin glargine dose measured during on-treatment period
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Average Daily Insulin Glargine Dose at Week 24 | 36.08 Units (U) | Standard Error 1.415 |
| Insulin Glargine | Average Daily Insulin Glargine Dose at Week 24 | 39.32 Units (U) | Standard Error 1.384 |
Comparison: Testing according to the step-down testing procedure (continued only if previous endpoint was statistically significant). Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c (\<8.0, ≥8.0%), randomization strata of screening BMI (\<30 kg/m\^2, ≥30 kg/m\^2), and country as fixed effects.p-value: 0.058395% CI: [-6.592, 0.114]ANCOVA
Secondary
Change in 2-hour Plasma Glucose Excursion From Baseline to Week 24
2-hour plasma glucose excursion = 2-hour PPG minus plasma glucose value obtained 30 minutes prior to the start of the meal and before IMP administration. Change in plasma glucose excursion was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP.
Time frame: Baseline, Week 24
Population: mITT population. Here, number of participants analyzed = participants with both baseline and at least one post-baseline plasma glucose excursion assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in 2-hour Plasma Glucose Excursion From Baseline to Week 24 | -3.91 mmol/L | Standard Error 0.277 |
| Insulin Glargine | Change in 2-hour Plasma Glucose Excursion From Baseline to Week 24 | -0.67 mmol/L | Standard Error 0.269 |
Comparison: Testing according to the step-down testing procedure (continued only if previous endpoint was statistically significant). Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c (\<8.0, ≥8.0%), randomization strata of screening BMI (\<30 kg/m\^2, ≥30 kg/m\^2), and country as fixed effects and baseline 2-hour plasma glucose excursion value as covariates.p-value: <0.000195% CI: [-3.895, -2.592]ANCOVA
Secondary
Change in 2-hour Postprandial Plasma Glucose (PPG) From Baseline to Week 24
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 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP.
Time frame: Baseline, Week 24
Population: mITT population.Here, number of participants analyzed = participants with both baseline and at least one post-baseline 2-hour PPG assessment during on-treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in 2-hour Postprandial Plasma Glucose (PPG) From Baseline to Week 24 | -7.49 mmol/L | Standard Error 0.283 |
| Insulin Glargine | Change in 2-hour Postprandial Plasma Glucose (PPG) From Baseline to Week 24 | -4.33 mmol/L | Standard Error 0.274 |
Comparison: Analysis was performed using ANCOVA with treatment groups,randomization strata of screening HbA1c(\<8.0, ≥8.0%)\& screening BMI(\<30 kg/m\^2, ≥30 kg/m\^2),country as fixed effects and baseline 2-hour PPG value as covariates.A step-down testing procedure used to control type-1 error.If non-inferiority demonstrated for primary endpoint,superiority testing on secondary endpoints was performed sequentially in order endpoints are reported(continued only if previous endpoint was statistically significant).p-value: <0.000195% CI: [-3.832, -2.504]ANCOVA
Secondary
Change in 30 Minute and 1-hour Plasma Glucose Excursion From Baseline to Week 24
30-minute and 1-hour plasma glucose excursion = 30-minute and 1-hour PPG minus plasma glucose value obtained 30 minutes prior to the start of the meal and before IMP administration. Change in plasma glucose excursion was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP.
Time frame: Baseline, Week 24
Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline plasma glucose excursion assessment during on-treatment period.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in 30 Minute and 1-hour Plasma Glucose Excursion From Baseline to Week 24 | 1-hour plasma glucose excursion (n=150, 152) | -2.34 mmol/L | Standard Error 0.233 |
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in 30 Minute and 1-hour Plasma Glucose Excursion From Baseline to Week 24 | 30-minute plasma glucose excursion (n=151, 152) | -1.47 mmol/L | Standard Error 0.156 |
| Insulin Glargine | Change in 30 Minute and 1-hour Plasma Glucose Excursion From Baseline to Week 24 | 30-minute plasma glucose excursion (n=151, 152) | -0.05 mmol/L | Standard Error 0.151 |
| Insulin Glargine | Change in 30 Minute and 1-hour Plasma Glucose Excursion From Baseline to Week 24 | 1-hour plasma glucose excursion (n=150, 152) | -0.44 mmol/L | Standard Error 0.226 |
Secondary
Change in 30-minute and 1-hour PPG From Baseline to Week 24
The 30 minute and 1-hour PPG test measured blood glucose 30 minutes and 1-hour after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP.
Time frame: Baseline, Week 24
Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline PPG assessment during on-treatment period. Here, 'n' signifies number of participants with available data for specified category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in 30-minute and 1-hour PPG From Baseline to Week 24 | 30-minute PPG (n=151, 153) | -5.01 mmol/L | Standard Error 0.194 |
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in 30-minute and 1-hour PPG From Baseline to Week 24 | 1-hour PPG (n=150, 153) | -5.94 mmol/L | Standard Error 0.246 |
| Insulin Glargine | Change in 30-minute and 1-hour PPG From Baseline to Week 24 | 1-hour PPG (n=150, 153) | -4.10 mmol/L | Standard Error 0.239 |
| Insulin Glargine | Change in 30-minute and 1-hour PPG From Baseline to Week 24 | 30-minute PPG (n=151, 153) | -3.76 mmol/L | Standard Error 0.187 |
Secondary
Change in Average 7-Point Self-Monitored Plasma Glucose (SMPG) Profiles From Baseline to Week 24
Participants recorded a 7-point plasma glucose profile measured before and 2-hours after each meal and at bedtime, over a single day, once in a week before baseline, before visit Week 12 and before visit Week 24 and the average value across the profiles performed in the week before a visit for the 7-time points was calculated. Change in average 7-point SMPG was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to the date of last injection of IMP.
Time frame: Baseline, Week 24
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 |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in Average 7-Point Self-Monitored Plasma Glucose (SMPG) Profiles From Baseline to Week 24 | -3.23 mmol/L | Standard Error 0.104 |
| Insulin Glargine | Change in Average 7-Point Self-Monitored Plasma Glucose (SMPG) Profiles From Baseline to Week 24 | -2.93 mmol/L | Standard Error 0.101 |
Comparison: Testing according to the step-down testing procedure (continued only if previous endpoint was statistically significant). Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c (\<8.0, ≥8.0%), randomization strata of screening BMI (\<30 kg/m\^2, ≥30 kg/m\^2), and country as fixed effects and baseline average 7-point SMPG value as covariates.p-value: 0.015495% CI: [-0.55, -0.058]ANCOVA
Secondary
Change in Body Weight From Baseline to Week 24
Change in body weight was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to 3 days after the last injection of IMP.
Time frame: Baseline, Week 24
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 |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in Body Weight From Baseline to Week 24 | -0.97 kg | Standard Error 0.289 |
| Insulin Glargine | Change in Body Weight From Baseline to Week 24 | 0.48 kg | Standard Error 0.282 |
Comparison: Testing according to the step-down testing procedure (continued only if previous endpoint was statistically significant). Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c (\<8.0, ≥8.0%), randomization strata of screening BMI (\<30 kg/m\^2, ≥30 kg/m\^2), and country as fixed effects and baseline body weight value as covariates.p-value: <0.000195% CI: [-2.11, -0.773]ANCOVA
Secondary
Change in FPG From Baseline to Week 24
Change in FPG was calculated by subtracting baseline value from Week 24 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 till before the introduction of rescue medication and up to 1 day after the last injection of IMP.
Time frame: Baseline, Week 24
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 |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in FPG From Baseline to Week 24 | -3.35 mmol/L | Standard Error 0.13 |
| Insulin Glargine | Change in FPG From Baseline to Week 24 | -3.51 mmol/L | Standard Error 0.128 |
Secondary
Percentage of Participants Reaching HbA1c <7% at Week 24 With no Documented Symptomatic Hypoglycemia During 24-week Treatment Period
Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of ≤70 mg/dL (3.9 mmol/L). Participants without any post-baseline on-treatment value for HbA1c were counted as non-responders if they experienced at least one documented symptomatic hypoglycemia before the introduction of rescue medication and up to 1 day after the last injection of IMP. Otherwise, they were counted as missing data. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of IMP.
Time frame: Baseline up to Week 24
Population: mITT population. Here, number of participants analyzed = participants with at least one post-baseline HbA1c assessment during on-treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants Reaching HbA1c <7% at Week 24 With no Documented Symptomatic Hypoglycemia During 24-week Treatment Period | 67.5 percentage of participants |
| Insulin Glargine | Percentage of Participants Reaching HbA1c <7% at Week 24 With no Documented Symptomatic Hypoglycemia During 24-week Treatment Period | 59.0 percentage of participants |
Secondary
Percentage of Participants Reaching HbA1c <7% With no Body Weight Gain at Week 24
Participants without any 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 (for HbA1c and body weight) was available and showed non-response. Otherwise, they were counted as missing data.
Time frame: Week 24
Population: mITT population. Here, number of participants analyzed = participants with any post-baseline on-treatment values (for HbA1c and body weight) that were no more than 30 days apart or with one of the components (for HbA1c and body weight) showing non-response based on the last post-baseline on-treatment value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants Reaching HbA1c <7% With no Body Weight Gain at Week 24 | 56.3 percentage of participants |
| Insulin Glargine | Percentage of Participants Reaching HbA1c <7% With no Body Weight Gain at Week 24 | 37.3 percentage of participants |
Secondary
Percentage of Participants Requiring Rescue Therapy During 24-week Treatment 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 exceed the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after Week 12) were performed. Threshold values from Week 8 to Week 12: fasting SMPG/FPG \>240 mg/dL (13.3 mmol/L), and from Week 12 to Week 30: fasting SMPG/FPG \>200 mg/dL (11.1 mmol/L) or HbA1c \>8%.
Time frame: Baseline up to Week 24
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants Requiring Rescue Therapy During 24-week Treatment Period | 0 percentage of participants |
| Insulin Glargine | Percentage of Participants Requiring Rescue Therapy During 24-week Treatment Period | 0.6 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 ≤70 mg/dL (3.9 mmol/L).Severe symptomatic hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes were associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. All episodes in which neurological impairment was severe enough to prevent self-treatment and which were thought to place participants at risk for injury to themselves or others.
Time frame: First dose of study drug up to 3 days after the last dose administration (maximum of 219 days)
Population: Safety population that included all randomized participants who received at least 1 dose of study medication regardless of the amount of treatment administered.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia | Documented symptomatic hypoglycemia | 21.7 percentage of participants |
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia | Severe Symptomatic Hypoglycemia | 0.0 percentage of participants |
| Insulin Glargine | Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia | Documented symptomatic hypoglycemia | 22.8 percentage of participants |
| Insulin Glargine | Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia | Severe Symptomatic Hypoglycemia | 0.0 percentage of participants |
Secondary
Percentage of Participants With HbA1c ≤6.5 % or <7.0 % at Week 24
On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of IMP.
Time frame: Week 24
Population: mITT population. Here, number of participants analyzed = participants with at least one post-baseline HbA1c assessment during on-treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants With HbA1c ≤6.5 % or <7.0 % at Week 24 | HbA1c ≤6.5% | 71.9 percentage of participants |
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants With HbA1c ≤6.5 % or <7.0 % at Week 24 | HbA1c <7.0% | 84.4 percentage of participants |
| Insulin Glargine | Percentage of Participants With HbA1c ≤6.5 % or <7.0 % at Week 24 | HbA1c ≤6.5% | 64.6 percentage of participants |
| Insulin Glargine | Percentage of Participants With HbA1c ≤6.5 % or <7.0 % at Week 24 | HbA1c <7.0% | 78.3 percentage of participants |