Type 2 Diabetes
Conditions
Brief summary
Primary Objective: To demonstrate the superiority of the insulin glargine/lixisenatide fixed ratio combination (FRC) to insulin glargine in glycated hemoglobin (HbA1c) change from baseline to Week 30. Secondary Objective: To compare the overall efficacy and safety of insulin glargine/lixisenatide FRC to insulin glargine (with or without metformin) over a 30 week treatment period in participants with type 2 diabetes.
Detailed description
Maximum duration of approximately 39 weeks: an up to 8-week screening period, a 30-week randomized treatment period and 3 days post-treatment safety follow up period.
Interventions
Insulin glargine/lixisenatide FRC was self-administered by subcutaneous (SC) injection within 1 hour before breakfast using one of 2 SoloStar® pen-injectors: Pen A (ratio of 2 Units (U) of insulin glargine U 100:1 mcg of lixisenatide) or Pen B (ratio of 3 U of insulin glargine U 100:1 mcg of lixisenatide). After run-in, the FRC was initiated at a dose of either 20 U/10 mcg with Pen A or 30 U/10 mcg with Pen B, depending on participant's dose of Insulin glargine on the day prior to randomization. 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). Pen A was used for administration of doses up to 40 U/20 mcg and Pen B for administration of doses from 30 U/10 mcg up to 60 U/20 mcg.
Insulin glargine was self-administered QD by SC injection at approximately the same time every day. After screening, eligible participants entered 6 week run-in phase during which they were switched (if necessary) to insulin glargine and dose was stabilized. The first dose after randomization was same as the one administered on the day prior to randomization 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
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
: * Type 2 diabetes mellitus diagnosed at least 1 year before the screening visit. * Treatment with basal insulin for at least 6 months before the screening visit. * Stable basal insulin regimen (i.e. type of insulin and time/frequency of the injection) for at least 3 months before the screening visit. * Stable (plus/minus 20 percent) total daily basal insulin dose between 15 and 40 Units/day for at least 2 months prior to the screening visit. * For participants receiving basal insulin and 1 or 2 oral anti-diabetic drugs (OADs): the OAD dose(s) must be stable during the 3 months before the screening visit. The OADs could be 1 to 2 out of: * metformin (more than or equal to 1500 mg/day or maximal tolerated dose), * a sulfonylurea, * a glinide, * a dipeptidyl-peptidase-4 inhibitor, * a sodium glucose co-transporter 2 inhibitor, * Fasting Plasma Glucose (FPG) less than or equal to 180 mg/dL(10.0 mmol/L) at screening visit for participants receiving basal insulin in combination with 2 OADs or with 1 OAD other than metformin; FPG less than or equal to 200 mg/dL (11.1 mmol/L) at screening visit for participants on basal insulin only or basal insulin plus metformin at screening visit. * Signed written informed consent.
Exclusion criteria
* Age under legal age of adulthood at screening visit. * HbA1c at screening visit less than 7.5% or above 10%. * Pregnancy or lactation, women of childbearing potential with no effective contraceptive method. * Use of other oral or injectable glucose-lowering agents than stated in the inclusion criteria in a period of 3 months prior to screening. * Previous use of insulin other than basal insulin eg, prandial or pre-mixed insulin, in the year prior to screening. Note: Short term treatment (≤10 days) due to intercurrent illness is allowed. * History discontinuation of a previous treatment with Glucagon Like Peptide -1 Receptor Agonists for safety/tolerability or lack of efficacy. * Participant who had previously participated in any clinical trial with lixisenatide or the insulin glargine/lixisenatide FRC or had previously received lixisenatide. * Use of weight loss drugs within 3 months prior to screening visit. * Within the last 6 months prior to screening visit: history of stroke, myocardial infarction, unstable angina, or heart failure requiring hospitalization. Planned coronary, carotid or peripheral artery revascularisation procedures to be performed during the study period. * History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy was already performed), chronic pancreatitis, pancreatitis during a previous treatment with incretin therapies, pancreatectomy, stomach/gastric surgery. * Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predispose to MTC (eg, multiple endocrine neoplasia syndromes). * Uncontrolled or inadequately controlled hypertension (systolic blood pressure above 180 mmHg or diastolic blood pressure above 95 mmHg) at screening visit. * At screening visit, Body Mass Index (BMI) less than or equal to 20 or above 40 kg/m\^2. * At screening visit amylase and/or lipase more than 3 times the upper limit of the normal (ULN) laboratory range. * At screening visit alanine aminotransferase (ALT) or alkaline phosphatase (AST) more than 3 ULN. * At screening visit calcitonin above or equal to 20 pg/mL (5.9 pmol/L). * Any contraindication to metformin use, according to local labeling, if the participant was taking metformin. * Participant who had a renal function impairment with creatinine clearance less than 30 mL/min (using the Cockcroft and Gault formula) or end-stage renal disease for participants, not treated with metformin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycated Hemoglobin (HbA1c) From Baseline to Week 30 | Baseline, Week 30 | Change in HbA1c was calculated by subtracting baseline value from Week 30 value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in 2-hour Plasma Blood Glucose Excursion From Baseline to Week 30 | Baseline, Week 30 | Plasma glucose excursion = 2-hour postprandial glucose (PPG) minus plasma glucose value obtained 30 minutes prior to the start of the meal and before investigational medicinal product (IMP) administration, if IMP was injected before breakfast. Change in plasma glucose excursions was calculated by subtracting baseline value from Week 30 value. |
| Change in Body Weight From Baseline to Week 30 | Baseline, Week 30 | Change in body weight was calculated by subtracting baseline value from Week 30 value. |
| Mean Change in 7-point Self-monitored Plasma Glucose (SMPG) Profile From Baseline to Week 30 | Baseline, Week 30 | Participants recorded a 7-point plasma glucose profile measured before and 2-hours after each meal and at bedtime, two times in a week before baseline, before visit Week 12 and before visit Week 30 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 30 value. The analysis included all scheduled measurements obtained during the study. The missing data was handled by mixed effect model with repeated measures (MMRM) approach. |
| Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 | Week 30 | — |
| Change in Daily Insulin Glargine Dose From Baseline to Week 30 | Baseline, Week 30 | — |
| Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 and No Documented Symptomatic Hypoglycemia (Plasma Glucose [PG] ≤ 70 mg/dL [3.9 mmol/L]) During 30-Week Treatment Period | Baseline up to Week 30 | 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). |
| Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30 | Week 30 | — |
| Change in 2-hour PPG From Baseline to Week 30 | Baseline, Week 30 | Change in PPG was calculated by subtracting baseline value from Week 30 value. |
| Percentage of Participants Reaching HbA1c <7.0% With No Documented Symptomatic Hypoglycemia (PG ≤ 70 mg/dL [3.9 mmol/L]) During 30-Week Treatment Period | Baseline up to Week 30 | 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). |
| Percentage of Participants Requiring Rescue Therapy During 30-Week Treatment Period | Baseline up to Week 30 | Routine fasting SMPG and central laboratory FPG (and HbA1c after Week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after Week 12) were performed. Threshold values - from 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%. |
| Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year | First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine]) | 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). |
| Percentage of Participants With Documented Symptomatic Hypoglycemia | First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine]) | 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). |
| Percentage of Participants With Severe Symptomatic Hypoglycemia | First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine]) | Severe symptomatic hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Plasma glucose measurements might not had been available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal was considered sufficient evidence that the event had been induced by a low plasma glucose concentration. Severe symptomatic hypoglycemia included all episodes in which neurological impairment was severe enough to prevent self-treatment, and which were thus thought to place participants at risk for injury to themselves or others. |
| Change in FPG From Baseline to Week 30 | Baseline, Week 30 | Change in FPG was calculated by subtracting baseline value from Week 30 value. |
Countries
Australia, Canada, Chile, Czechia, Denmark, Estonia, Hungary, Lithuania, Mexico, Netherlands, Poland, Romania, Russia, Slovakia, Spain, Sweden, Ukraine, United States
Participant flow
Recruitment details
The study was conducted at 236 centers in 18 countries. A total of 1930 participants were screened between January 27, 2014 and October 15, 2014. 912 participants were not eligible for run-in-phase mainly due to glycated hemoglobin (HbA1c) value being out of the protocol defined range.
Pre-assignment details
After screening phase, 1018 participants entered 6 week run-in phase during which participants were switched (if necessary) to insulin glargine and dose was titrated/stabilized, any oral anti-diabetic drugs (OAD) other than metformin were stopped. 282 participants were run-in failures and 736 were randomized in 1:1(FRC:insulin glargine arms) ratio.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | 367 |
| Insulin Glargine Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. | 369 |
| Total | 736 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 3 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other than specified above | 12 | 6 |
| Overall Study | Poor compliance to protocol | 4 | 1 |
| Overall Study | Randomized but not treated | 2 | 4 |
Baseline characteristics
| Characteristic | Insulin Glargine | Total | Insulin Glargine/Lixisenatide Fixed Ratio Combination |
|---|---|---|---|
| Age, Continuous | 60.3 years STANDARD_DEVIATION 8.7 | 60.0 years STANDARD_DEVIATION 9.1 | 59.6 years STANDARD_DEVIATION 9.4 |
| Baseline HbA1c | 8.08 percentage of HbA1c STANDARD_DEVIATION 0.73 | 8.08 percentage of HbA1c STANDARD_DEVIATION 0.71 | 8.07 percentage of HbA1c STANDARD_DEVIATION 0.68 |
| Body Mass Index (BMI) | 30.96 kg/m^2 STANDARD_DEVIATION 4.15 | 31.14 kg/m^2 STANDARD_DEVIATION 4.2 | 31.33 kg/m^2 STANDARD_DEVIATION 4.25 |
| Daily Dose of Metformin | 2042.0 mg STANDARD_DEVIATION 455.9 | 2062.4 mg STANDARD_DEVIATION 478.1 | 2082.8 mg STANDARD_DEVIATION 499.2 |
| Duration of Diabetes | 12.13 years STANDARD_DEVIATION 6.85 | 12.08 years STANDARD_DEVIATION 6.74 | 12.02 years STANDARD_DEVIATION 6.64 |
| Ethnicity Hispanic | 66 Participants | 132 Participants | 66 Participants |
| Ethnicity Not Hispanic | 303 Participants | 604 Participants | 301 Participants |
| Fasting Plasma Glucose (FPG) | 7.36 mmol/L STANDARD_DEVIATION 2.12 | 7.35 mmol/L STANDARD_DEVIATION 2.04 | 7.34 mmol/L STANDARD_DEVIATION 1.95 |
| OAD Use No | 19 Participants | 37 Participants | 18 Participants |
| OAD Use Yes | 350 Participants | 699 Participants | 349 Participants |
| OAD Use at Screening by Class Dipeptidyl-peptidase 4 (DPP-4) inhibitor | 4 Participants | 6 Participants | 2 Participants |
| OAD Use at Screening by Class Glinide | 1 Participants | 2 Participants | 1 Participants |
| OAD Use at Screening by Class Metfomrin + Glinide | 3 Participants | 5 Participants | 2 Participants |
| OAD Use at Screening by Class Metformin | 190 Participants | 360 Participants | 170 Participants |
| OAD Use at Screening by Class Metformin + DPP-4 inhibitor | 18 Participants | 38 Participants | 20 Participants |
| OAD Use at Screening by Class Metformin + Sulfonylurea | 118 Participants | 255 Participants | 137 Participants |
| OAD Use at Screening by Class None | 19 Participants | 37 Participants | 18 Participants |
| OAD Use at Screening by Class Sodium glucose co-transporter 2 (SGLT-2) inhibitor | 1 Participants | 1 Participants | 0 Participants |
| OAD Use at Screening by Class Sulfonylurea | 14 Participants | 30 Participants | 16 Participants |
| OAD Use at Screening by Class Sulfonylurea + DPP-4 inhibitor | 1 Participants | 2 Participants | 1 Participants |
| Race Asian/Oriental | 8 Participants | 20 Participants | 12 Participants |
| Race Black | 21 Participants | 38 Participants | 17 Participants |
| Race Caucasian | 338 Participants | 675 Participants | 337 Participants |
| Race Other | 2 Participants | 3 Participants | 1 Participants |
| Screening Glycated Hemoglobin (HbA1c) | 8.54 percentage of HbA1c STANDARD_DEVIATION 0.67 | 8.53 percentage of HbA1c STANDARD_DEVIATION 0.66 | 8.51 percentage of HbA1c STANDARD_DEVIATION 0.65 |
| Sex: Female, Male Female | 190 Participants | 392 Participants | 202 Participants |
| Sex: Female, Male Male | 179 Participants | 344 Participants | 165 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 81 / 365 | 42 / 365 |
| serious Total, serious adverse events | 20 / 365 | 18 / 365 |
Outcome results
Primary
Change in Glycated Hemoglobin (HbA1c) From Baseline to Week 30
Change in HbA1c was calculated by subtracting baseline value from Week 30 value.
Time frame: Baseline, Week 30
Population: Modified intent-to-treat (mITT) population: all randomized participants who had both baseline and at least one post-baseline efficacy assessment. Here, number of participants analyzed = participants with baseline and at least one post-baseline HbA1c assessment during study period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in Glycated Hemoglobin (HbA1c) From Baseline to Week 30 | -1.13 percentage of HbA1c | Standard Error 0.057 |
| Insulin Glargine | Change in Glycated Hemoglobin (HbA1c) From Baseline to Week 30 | -0.62 percentage of HbA1c | Standard Error 0.055 |
Comparison: Analysis was performed using Mixed-effect model with repeated measures (MMRM) with treatment groups, randomization strata of Week -1 HbA1c (\<8.0, ≥8.0%), randomization strata of metformin use at screening, visits, treatment-by-visit interaction and country as fixed effects and baseline HbA1c value-by-visit interaction as covariates. A hierarchical testing procedure was used to control type I error and handle multiple endpoint analyses.p-value: <0.000195% CI: [-0.633, -0.397]Mixed Models Analysis
Secondary
Change in 2-hour Plasma Blood Glucose Excursion From Baseline to Week 30
Plasma glucose excursion = 2-hour postprandial glucose (PPG) minus plasma glucose value obtained 30 minutes prior to the start of the meal and before investigational medicinal product (IMP) administration, if IMP was injected before breakfast. Change in plasma glucose excursions was calculated by subtracting baseline value from Week 30 value.
Time frame: Baseline, Week 30
Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline plasma glucose excursion assessment during study period. Missing data was imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in 2-hour Plasma Blood Glucose Excursion From Baseline to Week 30 | -3.9 mmol/L | Standard Error 0.285 |
| Insulin Glargine | Change in 2-hour Plasma Blood Glucose Excursion From Baseline to Week 30 | -0.47 mmol/L | Standard Error 0.274 |
Comparison: Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, randomization strata of Week -1 HbA1c (\<8.0, ≥8.0%), randomization strata of metformin use at screening and country as fixed effects and baseline 2-hour plasma glucose excursion value as a covariate.p-value: <0.000195% CI: [-3.925, -2.939]ANCOVA
Secondary
Change in 2-hour PPG From Baseline to Week 30
Change in PPG was calculated by subtracting baseline value from Week 30 value.
Time frame: Baseline, Week 30
Population: mITT population. Here, number of participants analyzed= participants with baseline and at least one post-baseline PPG assessment during study period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in 2-hour PPG From Baseline to Week 30 | -4.72 mmol/L | Standard Error 0.322 |
| Insulin Glargine | Change in 2-hour PPG From Baseline to Week 30 | -1.39 mmol/L | Standard Error 0.31 |
Secondary
Change in Body Weight From Baseline to Week 30
Change in body weight was calculated by subtracting baseline value from Week 30 value.
Time frame: Baseline, Week 30
Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline body weight assessment during study period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in Body Weight From Baseline to Week 30 | -0.67 kg | Standard Error 0.181 |
| Insulin Glargine | Change in Body Weight From Baseline to Week 30 | 0.7 kg | Standard Error 0.178 |
Comparison: Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (\<8.0, ≥8.0%), randomization strata of metformin use at screening, scheduled visits, treatment-by-visit interaction and country as fixed effects and baseline body weight value-by-visit interaction as covariates.p-value: <0.000195% CI: [-1.808, -0.93]Mixed Models Analysis
Secondary
Change in Daily Insulin Glargine Dose From Baseline to Week 30
Time frame: Baseline, Week 30
Population: mITT population. The analysis included scheduled measurements obtained up to the date of last injection of IMP. Here, number of participants analyzed= participants with insulin glargine dose assessment during study period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in Daily Insulin Glargine Dose From Baseline to Week 30 | 10.64 Units (U) | Standard Error 0.601 |
| Insulin Glargine | Change in Daily Insulin Glargine Dose From Baseline to Week 30 | 10.89 Units (U) | Standard Error 0.587 |
Comparison: Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (\<8.0, ≥8.0%), randomization strata of metformin use at screening, scheduled visits, treatment-by-visit interaction and country as fixed effects and baseline daily insulin glargine dose-by-visit interaction as a covariate.p-value: 0.736295% CI: [-1.762, 1.246]Mixed Models Analysis
Secondary
Change in FPG From Baseline to Week 30
Change in FPG was calculated by subtracting baseline value from Week 30 value.
Time frame: Baseline, Week 30
Population: mITT population. Here, number of participants analyzed= participants with baseline and at least one post-baseline FPG assessment during study period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in FPG From Baseline to Week 30 | -0.35 mmol/L | Standard Error 0.142 |
| Insulin Glargine | Change in FPG From Baseline to Week 30 | -0.46 mmol/L | Standard Error 0.138 |
Secondary
Mean Change in 7-point Self-monitored Plasma Glucose (SMPG) Profile From Baseline to Week 30
Participants recorded a 7-point plasma glucose profile measured before and 2-hours after each meal and at bedtime, two times in a week before baseline, before visit Week 12 and before visit Week 30 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 30 value. The analysis included all scheduled measurements obtained during the study. The missing data was handled by mixed effect model with repeated measures (MMRM) approach.
Time frame: Baseline, Week 30
Population: mITT population. Here, number of participants analyzed= participants with baseline and at least one post-baseline 7-point SMPG assessment during study period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Mean Change in 7-point Self-monitored Plasma Glucose (SMPG) Profile From Baseline to Week 30 | -1.5 mmol/L | Standard Error 0.137 |
| Insulin Glargine | Mean Change in 7-point Self-monitored Plasma Glucose (SMPG) Profile From Baseline to Week 30 | -0.6 mmol/L | Standard Error 0.13 |
Comparison: Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (\<8.0, ≥8.0%), randomization strata of metformin use at screening, scheduled visits, treatment-by-visit interaction and country as fixed effects and baseline average SMPG value-by-visit interaction as covariates.p-value: <0.000195% CI: [-1.154, -0.64]Mixed Models Analysis
Secondary
Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year
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).
Time frame: First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine])
Population: Analysis was performed on safety population defined as all randomized participants who received at least one dose of IMP regardless of the amount of treatment administered.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year | 3.03 events per subject-year |
| Insulin Glargine | Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year | 4.22 events per subject-year |
Secondary
Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30
Time frame: Week 30
Population: mITT population. Participants without HbA1c and/or body weight value at Week 30 were counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 | 34.2 percentage of participants |
| Insulin Glargine | Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 | 13.4 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week -1 HbA1c (\<8.0%, ≥8.0%) and randomization strata of metformin use at screening.p-value: <0.000195% CI: [14.98, 26.66]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 and No Documented Symptomatic Hypoglycemia (Plasma Glucose [PG] ≤ 70 mg/dL [3.9 mmol/L]) During 30-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).
Time frame: Baseline up to Week 30
Population: mITT population. Participants without HbA1c and/or body weight value at Week 30 were counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 and No Documented Symptomatic Hypoglycemia (Plasma Glucose [PG] ≤ 70 mg/dL [3.9 mmol/L]) During 30-Week Treatment Period | 19.9 percentage of participants |
| Insulin Glargine | Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 and No Documented Symptomatic Hypoglycemia (Plasma Glucose [PG] ≤ 70 mg/dL [3.9 mmol/L]) During 30-Week Treatment Period | 9.0 percentage of participants |
Secondary
Percentage of Participants Reaching HbA1c <7.0% With No Documented Symptomatic Hypoglycemia (PG ≤ 70 mg/dL [3.9 mmol/L]) During 30-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).
Time frame: Baseline up to Week 30
Population: mITT population. Participants with no value for HbA1c at Week 30 were counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants Reaching HbA1c <7.0% With No Documented Symptomatic Hypoglycemia (PG ≤ 70 mg/dL [3.9 mmol/L]) During 30-Week Treatment Period | 31.7 percentage of participants |
| Insulin Glargine | Percentage of Participants Reaching HbA1c <7.0% With No Documented Symptomatic Hypoglycemia (PG ≤ 70 mg/dL [3.9 mmol/L]) During 30-Week Treatment Period | 18.6 percentage of participants |
Secondary
Percentage of Participants Requiring Rescue Therapy During 30-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 exceeded 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 30
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants Requiring Rescue Therapy During 30-Week Treatment Period | 2.7 percentage of participants |
| Insulin Glargine | Percentage of Participants Requiring Rescue Therapy During 30-Week Treatment Period | 6 percentage of participants |
Secondary
Percentage of Participants With Documented 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).
Time frame: First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine])
Population: Analysis was performed on safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants With Documented Symptomatic Hypoglycemia | 40 percentage of participants |
| Insulin Glargine | Percentage of Participants With Documented Symptomatic Hypoglycemia | 42.5 percentage of participants |
Secondary
Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30
Time frame: Week 30
Population: mITT population. Participants with no value for HbA1c at Week 30 were counted as non-responders.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30 | HbA1c <7.0% | 54.9 percentage of participants |
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30 | HbA1c ≤ 6.5% | 33.9 percentage of participants |
| Insulin Glargine | Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30 | HbA1c <7.0% | 29.6 percentage of participants |
| Insulin Glargine | Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30 | HbA1c ≤ 6.5% | 14.2 percentage of participants |
Comparison: HbA1c \<7.0%: Insulin Glargine/Lixisenatide FRC vs Insulin Glargine.~Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week -1 HbA1c (\<8.0%, ≥8.0%) and randomization strata of metformin use at screening. This analysis was out of testing order.p-value: <0.000195% CI: [18.94, 32.1]Cochran-Mantel-Haenszel
Comparison: HbA1c ≤6.5%: Insulin Glargine/Lixisenatide FRC vs Insulin Glargine.~Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week -1 HbA1c (\<8.0%, ≥8.0%) and randomization strata of metformin use at screening. This analysis was out of testing order.p-value: <0.000195% CI: [13.9, 25.62]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Severe Symptomatic Hypoglycemia
Severe symptomatic hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Plasma glucose measurements might not had been available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal was considered sufficient evidence that the event had been induced by a low plasma glucose concentration. Severe symptomatic hypoglycemia included all episodes in which neurological impairment was severe enough to prevent self-treatment, and which were thus thought to place participants at risk for injury to themselves or others.
Time frame: First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine])
Population: Analysis was performed on safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants With Severe Symptomatic Hypoglycemia | 1.1 percentage of participants |
| Insulin Glargine | Percentage of Participants With Severe Symptomatic Hypoglycemia | 0.3 percentage of participants |