Type 2 Diabetes
Conditions
Brief summary
Primary Objective: To compare the insulin glargine/lixisenatide fixed ratio combination to lixisenatide alone and to insulin glargine alone (on top of metformin treatment) in glycated hemoglobin (HbA1c) change from baseline to Week 30. Secondary Objective: To compare the overall efficacy and safety of insulin glargine/lixisenatide fixed ratio combination (FRC) to insulin glargine alone and to lixisenatide alone (on top of metformin treatment) over a 30 week treatment period in participants with type 2 diabetes.
Detailed description
Approximately 37 weeks including up to 6 weeks of screening, 30-week treatment period, and a 3 days follow-up period.
Interventions
Insulin glargine/Lixisenatide FRC was self-administered by subcutaneous (SC) injection in the morning within one hour before breakfast using one of the 2 prefilled disposable SoloStar® pen-injectors: Pen A containing 100 U/mL insulin glargine (Lantus, 100 U/mL) and 50 mcg/mL lixisenatide in a ratio of 2 U:1 mcg, used for administration of doses from 10 U to 40 U (10 U/5mcg to 40 U/20mcg). Pen B containing 100 U/mL insulin glargine (Lantus, 100 U/mL) and 33 mcg/mL lixisenatide in a ratio of 3 U:1 mcg, used to administer doses from 41 U to 60 U (41 U/13 mcg to 60 U/20 mcg). The starting dose was 10 U/5 mcg. Dose was then adjusted individually 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) while avoiding hypoglycemia.
Insulin glargine (100 U/mL) was self-administered by SC injection at approximately the same time every day. Dose was adjusted individually to reach and maintain fasting SMPG of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L) while avoiding hypoglycemia.
DRUGLixisenatide (AVE0010)
Lixisenatide was self-administered by SC injection within 0 to 60 minutes before breakfast or evening meal. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.
DRUGMetformin
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
* Participants with type 2 diabetes mellitus diagnosed for at least 1 year before the screening visit, treated for at least 3 months prior to visit 1 with metformin alone or metformin and a second oral anti-diabetic treatment that could be a sulfonylurea, a glinide, a sodium glucose co-transporter-2 inhibitor or a di-peptidyl peptidase 4 (DPP-4) inhibitors, and who were not adequately controlled with this treatment. * Signed written informed consent.
Exclusion criteria
* HbA1c at screening visit: * less than 7.5% or more than 10% for participants previously treated with metformin alone, * less than 7.0% or more than 9% for participants previously treated with metformin and a second oral anti-diabetic treatment. * Pregnancy or lactation, women of childbearing potential with no effective contraceptive method. * Use of oral glucose-lowering agents other than those stated in the inclusion criteria or any injectable glucose-lowering agents during the 3 months before screening. * Previous Treatment with insulin (except for short-term treatment due to intercurrent illness including gestational diabetes, at the discretion of the trial physician). * History of discontinuation of a previous treatment with a glucagon-like peptide (GLP-1) receptor agonist (GLP-1 RA) due to safety/tolerability issue or lack of efficacy. * Participant who previously participated in any clinical trial with lixisenatide or the insulin glargine/lixisenatide fixed ratio combination or had previously received lixisenatide. * Any contraindication to metformin use, according to local labeling. * 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 (e.g, 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline to Week 30 | Baseline, Week 30 | Primary outcome was to test superiority of FRC versus Lixisenatide and non-inferiority versus Insulin glargine. Change in HbA1c was calculated by subtracting baseline value from Week 30 value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma Glucose Excursion From Baseline to Week 30 | Baseline, Week 30 | Plasma glucose excursion = 2-hour postprandial plasma glucose (PPG) value minus plasma glucose value obtained 30 minutes prior to the start of meal and before investigational medicinal product (IMP) administration if IMP was injected before breakfast. Change in plasma glucose excursions were calculated by subtracting baseline value from Week 30 value. Missing data was imputed using last observation carried forward (LOCF). |
| 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. |
| Change in Fasting Plasma Glucose (FPG) From Baseline to Week 30 | Baseline, Week 30 | Change in FPG 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 | — |
| 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 | Participants without Week 30 value for HbA1c were counted as non-responders. |
| Change in 2-Hour Postprandial Plasma Glucose (PPG) From Baseline to Week 30 | Baseline, Week 30 | The 2-hour PPG test measured blood glucose 2 hours after eating a liquid standardized breakfast meal. Change in PPG was calculated by subtracting baseline value from Week 30 value. Missing data was imputed using LOCF. |
| Percentage of Participants Reaching HbA1c <7.0% at Week 30 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). The analysis included all HbA1c measurements at Week 30, including those obtained after the IMP discontinuation or the introduction of rescue medication. |
| 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) was 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) | Documented symptomatic hypoglycemia was an event during which 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) | Documented symptomatic hypoglycemia was an event during which 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) | 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 have 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 of injury to themselves or others. |
| Average Daily Insulin Glargine Dose at Week 30 | Week 30 | The analysis included scheduled measurements obtained up to the date of last injection of the IMP, including those obtained after introduction of rescue therapy. |
Countries
Australia, Belgium, Canada, Chile, Czechia, Denmark, Estonia, France, Germany, Hungary, Italy, Latvia, Lithuania, Mexico, Poland, Romania, Russia, South Africa, Spain, Sweden, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 240 centers in 23 countries. A total of 2457 participants were screened between February 12, 2014 and September 16, 2014. 978 participants were not eligible for run-in mainly due to glycosylated hemoglobin (HbA1c) value at screening visit being out of the protocol defined range.
Pre-assignment details
After 2 weeks screening period, 1479 participants underwent 4-week run-in period. 309 participants were run-in failures. A total of 1170 participants were randomized in 2:2:1 to insulin glargine/lixisenatide, insulin glargine and lixisenatide arms respectively in open-label treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | 469 |
| Insulin Glargine Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. | 467 |
| Lixisenatide Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose). | 234 |
| Total | 1,170 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 12 | 9 | 21 |
| Overall Study | Lack of Efficacy | 1 | 0 | 3 |
| Overall Study | Other than specified | 8 | 9 | 0 |
| Overall Study | Poor compliance to protocol | 8 | 9 | 4 |
| Overall Study | Randomized but not treated | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Total | Lixisenatide | Insulin Glargine |
|---|---|---|---|---|
| Age, Continuous | 58.2 years STANDARD_DEVIATION 9.5 | 58.4 years STANDARD_DEVIATION 9.3 | 58.7 years STANDARD_DEVIATION 8.7 | 58.3 years STANDARD_DEVIATION 9.4 |
| Body Mass Index (BMI) | 31.64 kg/m^2 STANDARD_DEVIATION 4.4 | 31.72 kg/m^2 STANDARD_DEVIATION 4.44 | 31.99 kg/m^2 STANDARD_DEVIATION 4.39 | 31.66 kg/m^2 STANDARD_DEVIATION 4.51 |
| Daily Dose of Metformin | 2246.1 mg STANDARD_DEVIATION 456.8 | 2249.8 mg STANDARD_DEVIATION 445.9 | 2267.3 mg STANDARD_DEVIATION 427.4 | 2244.7 mg STANDARD_DEVIATION 444.7 |
| Duration of Diabetes | 8.89 years STANDARD_DEVIATION 5.51 | 8.80 years STANDARD_DEVIATION 5.69 | 8.89 years STANDARD_DEVIATION 6.26 | 8.66 years STANDARD_DEVIATION 5.59 |
| Ethnicity Hispanic | 85 Participants | 223 Participants | 51 Participants | 87 Participants |
| Ethnicity Not Hispanic | 384 Participants | 947 Participants | 183 Participants | 380 Participants |
| Fasting Plasma Glucose (FPG) | 9.87 mmol/L STANDARD_DEVIATION 2.35 | 9.80 mmol/L STANDARD_DEVIATION 2.31 | 9.75 mmol/L STANDARD_DEVIATION 2.19 | 9.75 mmol/L STANDARD_DEVIATION 2.32 |
| HbA1c | 8.08 percentage of HbA1c STANDARD_DEVIATION 0.71 | 8.09 percentage of HbA1c STANDARD_DEVIATION 0.7 | 8.13 percentage of HbA1c STANDARD_DEVIATION 0.72 | 8.08 percentage of HbA1c STANDARD_DEVIATION 0.69 |
| Race Asian/Oriental | 8 Participants | 18 Participants | 3 Participants | 7 Participants |
| Race Black | 33 Participants | 78 Participants | 12 Participants | 33 Participants |
| Race Caucasian | 417 Participants | 1054 Participants | 216 Participants | 421 Participants |
| Race Other | 11 Participants | 20 Participants | 3 Participants | 6 Participants |
| Second OAD Use at Screening by Class Dipeptidyl peptidase-4 inhibitor | 12 Participants | 28 Participants | 5 Participants | 11 Participants |
| Second OAD Use at Screening by Class Glinide | 3 Participants | 18 Participants | 5 Participants | 10 Participants |
| Second OAD Use at Screening by Class None | 193 Participants | 489 Participants | 101 Participants | 195 Participants |
| Second OAD Use at Screening by Class Sodium-glucose co-transporter-2 inhibitor | 2 Participants | 4 Participants | 0 Participants | 2 Participants |
| Second OAD Use at Screening by Class Sulfonylurea | 259 Participants | 631 Participants | 123 Participants | 249 Participants |
| Second Oral Anti-diabetic Drug (OAD) Use No | 195 Participants | 493 Participants | 101 Participants | 197 Participants |
| Second Oral Anti-diabetic Drug (OAD) Use Yes | 274 Participants | 677 Participants | 133 Participants | 270 Participants |
| Sex: Female, Male Female | 247 Participants | 578 Participants | 101 Participants | 230 Participants |
| Sex: Female, Male Male | 222 Participants | 592 Participants | 133 Participants | 237 Participants |
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 | 138 / 469 | 85 / 467 | 98 / 233 |
| serious Total, serious adverse events | 18 / 469 | 19 / 467 | 9 / 233 |
Outcome results
Primary
Change in HbA1c From Baseline to Week 30
Primary outcome was to test superiority of FRC versus Lixisenatide and non-inferiority versus Insulin glargine. 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 HbA1c From Baseline to Week 30 | -1.63 percentage of hemoglobin | Standard Error 0.038 |
| Insulin Glargine | Change in HbA1c From Baseline to Week 30 | -1.34 percentage of hemoglobin | Standard Error 0.039 |
| Lixisenatide | Change in HbA1c From Baseline to Week 30 | -0.85 percentage of hemoglobin | Standard Error 0.052 |
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 second OAD use at screening, visits, treatment-by-visit interaction, and country as fixed effects and baseline HbA1c value-by-visit interaction as a covariate.p-value: <0.000195% CI: [-0.898, -0.665]Mixed Models Analysis
Comparison: Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (\<8.0, ≥8.0%), randomization strata of second OAD use at screening, visits, treatment-by-visit interaction, and country as fixed effects and baseline HbA1c value-by-visit interaction as a covariate.95% CI: [-0.384, -0.194]Mixed Models Analysis
Comparison: Test of superiority was also performed as a secondary endpoint according to hierarchical testing procedure. Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (\<8.0, ≥8.0%), randomization strata of second OAD use at screening, visits, treatment-by-visit interaction, and country as fixed effects and baseline HbA1c value-by-visit interaction, as a covariate.p-value: <0.000195% CI: [-0.384, -0.194]Mixed Models Analysis
Secondary
Average Daily Insulin Glargine Dose at Week 30
The analysis included scheduled measurements obtained up to the date of last injection of the IMP, including those obtained after introduction of rescue therapy.
Time frame: Week 30
Population: mITT population. Here, number of participants analyzed = participants with insulin glargine dose assessment during study period. Data of this endpoint was planned to be analyzed for Insulin Glargine/Lixisenatide FRC and Insulin glargine arms only, not for lixisenatide arm.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Average Daily Insulin Glargine Dose at Week 30 | 39.77 Units (U) | Standard Error 0.699 |
| Insulin Glargine | Average Daily Insulin Glargine Dose at Week 30 | 40.46 Units (U) | Standard Error 0.701 |
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 second OAD use at screening, visits, treatment-by-visit interaction, and country as fixed effects.p-value: 0.485795% CI: [-2.632, 1.252]Mixed Models Analysis
Secondary
Change in 2-Hour Postprandial Plasma Glucose (PPG) From Baseline to Week 30
The 2-hour PPG test measured blood glucose 2 hours after eating a liquid standardized breakfast meal. Change in PPG was calculated by subtracting baseline value from Week 30 value. Missing data was imputed using LOCF.
Time frame: Baseline, Week 30
Population: mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline 2-hour PPG assessment during study 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 30 | -5.68 mmol/L | Standard Error 0.176 |
| Insulin Glargine | Change in 2-Hour Postprandial Plasma Glucose (PPG) From Baseline to Week 30 | -3.31 mmol/L | Standard Error 0.178 |
| Lixisenatide | Change in 2-Hour Postprandial Plasma Glucose (PPG) From Baseline to Week 30 | -4.58 mmol/L | Standard Error 0.245 |
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 | -0.29 kg | Standard Error 0.182 |
| Insulin Glargine | Change in Body Weight From Baseline to Week 30 | 1.11 kg | Standard Error 0.183 |
| Lixisenatide | Change in Body Weight From Baseline to Week 30 | -2.3 kg | Standard Error 0.256 |
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 second OAD use at screening, visits, treatment-by-visit interaction, and country as fixed effects and baseline body weight value-by-visit interaction as a covariate.p-value: <0.000195% CI: [-1.891, -0.91]Mixed Models Analysis
Secondary
Change in Fasting Plasma Glucose (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 analysed = 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 Fasting Plasma Glucose (FPG) From Baseline to Week 30 | -3.46 mmol/L | Standard Error 0.09 |
| Insulin Glargine | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 30 | -3.27 mmol/L | Standard Error 0.091 |
| Lixisenatide | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 30 | -1.5 mmol/L | Standard Error 0.124 |
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 second OAD use at screening, visits, treatment-by-visit interaction, and country as fixed effects and baseline FPG value-by-visit interaction as a covariate.p-value: <0.000195% CI: [-2.246, -1.682]Mixed Models Analysis
Secondary
Change in Plasma Glucose Excursion From Baseline to Week 30
Plasma glucose excursion = 2-hour postprandial plasma glucose (PPG) value minus plasma glucose value obtained 30 minutes prior to the start of meal and before investigational medicinal product (IMP) administration if IMP was injected before breakfast. Change in plasma glucose excursions were calculated by subtracting baseline value from Week 30 value. Missing data was imputed using last observation carried forward (LOCF).
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Change in Plasma Glucose Excursion From Baseline to Week 30 | -2.31 mmol/L | Standard Error 0.154 |
| Insulin Glargine | Change in Plasma Glucose Excursion From Baseline to Week 30 | -0.18 mmol/L | Standard Error 0.157 |
| Lixisenatide | Change in Plasma Glucose Excursion From Baseline to Week 30 | -3.23 mmol/L | Standard Error 0.216 |
Comparison: 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 second OAD use at screening \& country as fixed effects \& baseline plasma glucose excursion value as a covariate. Hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially per pre-specified order.p-value: <0.000195% CI: [-2.498, -1.77]ANCOVA
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 | -3.35 mmol/L | Standard Deviation 0.081 |
| Insulin Glargine | Mean Change in 7-point Self-monitored Plasma Glucose (SMPG) Profile From Baseline to Week 30 | -2.66 mmol/L | Standard Deviation 0.084 |
| Lixisenatide | Mean Change in 7-point Self-monitored Plasma Glucose (SMPG) Profile From Baseline to Week 30 | -1.95 mmol/L | Standard Deviation 0.111 |
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 second OAD use at screening, visits, treatment-by-visit interaction, and country as fixed effects and baseline 7-point SMPG value-by-visit interaction as a covariate.p-value: <0.000195% CI: [-1.645, -1.158]Mixed Models Analysis
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 second OAD use at screening, visits, treatment-by-visit interaction, and country as fixed effects and baseline 7-point SMPG value-by-visit interaction, as a covariate.p-value: <0.000195% CI: [-0.892, -0.495]Mixed Models Analysis
Secondary
Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year
Documented symptomatic hypoglycemia was an event during which 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)
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 | 1.44 Events per subject-year |
| Insulin Glargine | Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year | 1.22 Events per subject-year |
| Lixisenatide | Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year | 0.34 Events per subject-year |
Secondary
Percentage of Participants Reaching HbA1c <7.0% at Week 30 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). The analysis included all HbA1c measurements at Week 30, including those obtained after the IMP discontinuation or the introduction of rescue medication.
Time frame: Baseline up to Week 30
Population: mITT population. Participants without Week 30 value for HbA1c were counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants Reaching HbA1c <7.0% at Week 30 With No Documented Symptomatic Hypoglycemia (PG ≤ 70 mg/dL [3.9 mmol/L]) During 30-Week Treatment Period | 53.6 percentage of participants |
| Insulin Glargine | Percentage of Participants Reaching HbA1c <7.0% at Week 30 With No Documented Symptomatic Hypoglycemia (PG ≤ 70 mg/dL [3.9 mmol/L]) During 30-Week Treatment Period | 44.4 percentage of participants |
| Lixisenatide | Percentage of Participants Reaching HbA1c <7.0% at Week 30 With No Documented Symptomatic Hypoglycemia (PG ≤ 70 mg/dL [3.9 mmol/L]) During 30-Week Treatment Period | 30.5 percentage of participants |
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 any 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 | 43.2 percentage of participants |
| Insulin Glargine | Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 | 25.1 percentage of participants |
| Lixisenatide | Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 | 27.9 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%, ≥8%) and randomization strata of second OAD use at screening.p-value: <0.000195% CI: [12.15, 24.01]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 any 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 | 31.8 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 | 18.9 percentage of participants |
| Lixisenatide | 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 | 26.2 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 second OAD use at screening.p-value: <0.000195% CI: [7.5, 18.45]Cochran-Mantel-Haenszel
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) was 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 | 3.6 percentage of participants |
| Insulin Glargine | Percentage of Participants Requiring Rescue Therapy During 30-Week Treatment Period | 3.4 percentage of participants |
| Lixisenatide | Percentage of Participants Requiring Rescue Therapy During 30-Week Treatment Period | 12.4 percentage of participants |
Secondary
Percentage of Participants With Documented Symptomatic Hypoglycemia
Documented symptomatic hypoglycemia was an event during which 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)
Population: Safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants With Documented Symptomatic Hypoglycemia | 25.6 percentage of participants |
| Insulin Glargine | Percentage of Participants With Documented Symptomatic Hypoglycemia | 23.6 percentage of participants |
| Lixisenatide | Percentage of Participants With Documented Symptomatic Hypoglycemia | 6.4 percentage of participants |
Secondary
Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30
Participants without Week 30 value for HbA1c were counted as non-responders.
Time frame: Week 30
Population: mITT population.
| 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% | 73.7 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% | 55.8 percentage of participants |
| Insulin Glargine | Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30 | HbA1c <7.0% | 59.4 percentage of participants |
| Insulin Glargine | Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30 | HbA1c ≤6.5% | 39.5 percentage of participants |
| Lixisenatide | Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30 | HbA1c <7.0% | 33 percentage of participants |
| Lixisenatide | Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30 | HbA1c ≤6.5% | 19.3 percentage of participants |
Comparison: HbA1c \<7.0%: Insulin Glargine/Lixisenatide FRC vs Lixisenatide.~Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week -1 HbA1c (\<8.0%, ≥8.0%) and randomization strata of second OAD use at screening. This analysis was out of testing order.p-value: <0.000195% CI: [33.63, 47.59]Cochran-Mantel-Haenszel
Comparison: HbA1c ≤6.5%: Insulin Glargine/Lixisenatide FRC vs Lixisenatide.~Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week -1 HbA1c (\<8.0%, ≥8.0%) and randomization strata of second OAD use at screening. This analysis was out of testing order.p-value: <0.000195% CI: [29.81, 42.95]Cochran-Mantel-Haenszel
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 second OAD use at screening. This analysis was out of testing order.p-value: <0.000195% CI: [8.37, 20.25]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 second OAD use at screening. This analysis was out of testing order.p-value: <0.000195% CI: [10.13, 22.58]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 have 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 of 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)
Population: Safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Percentage of Participants With Severe Symptomatic Hypoglycemia | 0 percentage of participants |
| Insulin Glargine | Percentage of Participants With Severe Symptomatic Hypoglycemia | 0.2 percentage of participants |
| Lixisenatide | Percentage of Participants With Severe Symptomatic Hypoglycemia | 0 percentage of participants |