Type 2 Diabetes Mellitus
Conditions
Brief summary
Primary Objective: To demonstrate the superiority of the insulin glargine/lixisenatide fixed ratio combination (FRC) versus GLP-1 receptor agonist (GLP-1 RA) in hemoglobin A1c (HbA1c) change. Secondary Objectives: To compare the overall efficacy and safety of the insulin glargine/lixisenatide FRC to GLP-1 RA on top of metformin (with or without pioglitazone, with or without sodium-glucose co-transporter 2 \[SGLT2\] inhibitor) in participants with type 2 diabetes. To evaluate safety, efficacy and other endpoints of FRC up to the end of the extension period.
Detailed description
The maximum duration for GLP1-RA participants was approximately 29 weeks: up to 2 week screening period, a 26 week treatment period (either randomized or uncontrolled), and a 3 or 9 day post-treatment safety follow-up period. Maximum duration for FRC participants was approximately 55 weeks: up to 2-week screening period, a 26-week randomized treatment period, a 26-week extension period and a 3-day post-treatment safety follow-up period. All primary and secondary efficacy, safety and other outcome measures were assessed at the end of the extension period.
Interventions
Pharmaceutical form: solution for injection Route of administration: subcutaneous
DRUGliraglutide
Pharmaceutical form: solution for injection Route of administration: subcutaneous
DRUGexenatide
Pharmaceutical form: solution for injection Route of administration: subcutaneous
Pharmaceutical form: solution for injection Route of administration: subcutaneous
DRUGalbiglutide
Pharmaceutical form: solution for injection Route of administration: subcutaneous
DRUGdulaglutide
Pharmaceutical form: solution for injection Route of administration: subcutaneous
DRUGBackground therapy: Oral Anti-diabetic Drug (Metformin, Pioglitazone, SGLT2 inhibitor)
Pharmaceutical form: tablet Route of administration: oral If previously taken, doses to remain stable through the study.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
: * Participants with type 2 diabetes mellitus diagnosed at least 1 year prior to screening visit. * Participants who were treated with one of the following GLP-1 receptor agonists for at least 4 months prior to screening visit 1 (V1), and with stable dose for at least 3 months prior to screening visit (V1): * Liraglutide (Victoza®) 1.8 milligram (mg) QD or 1.2 mg QD, if the 1.8 mg QD dose was not well tolerated according to the Investigator's judgment or * Exenatide (Byetta®) 10 microgram (µg) BID or of 5 µg BID, if 10 µg BID dose was not well tolerated according to the Investigator's judgment in combination with metformin (daily dose greater than equal to \[\>=\] 1500 mg/day or maximum tolerated dose \[MTD\]), with or without pioglitazone, with or without SGLT2 inhibitor, all at stable dose for at least 3 months prior to screening. or Participants who were treated with stable dose of one of the following GLP-1 receptor agonists for at least 6 months prior to screening visit (V1): * Exenatide extended-release (Bydureon®) 2 mg once weekly (QW), if well tolerated according to Investigator's judgment, * Albiglutide (Tanzeum®) 50 mg QW or 30 mg QW, if 50 mg QW was not well tolerated according to Investigator's judgment, * Dulaglutide (Trulicity®) 1.5 mg QW or 0.75 mg QW, if 1.5 mg QW was not well tolerated according to Investigator's judgment in combination with metformin (daily dose ≥1500 mg/day or MTD), with or without pioglitazone, with or without SGLT2 inhibitor, all at stable dose for at least 3 months prior to screening; -Signed written informed consent.
Exclusion criteria
* At screening visit, age \<18. * Screening HbA1c \<7% and \>9%. * Pregnancy or lactation, women of childbearing potential with no effective contraceptive method. * Any use of antidiabetic drugs within 3 months prior to the screening visit other than those described in the inclusion criteria. * Previous treatment with insulin in the year prior to screening visit (note: short-term treatment with insulin \[\<=10 days\] due to intercurrent illness including gestational diabetes was allowed at the discretion of the study physician). * Laboratory findings at the time of screening, including: * Fasting plasma glucose (FPG) \>250 mg/dL (13.9 millimoles per litre \[mmol/L\]), * Amylase and/or lipase \>3 times the upper limit of the normal laboratory range (ULN), * Alanine transaminase or aspartate transaminase \>3 ULN, * Calcitonin \>=20 pg/mL (5.9 pmol/L), * Positive pregnancy test. * Participant who had renal function impairment with estimated glomerular filtration rate \<30mL/min/1.73m\^2 (using the Modification of Diet in Renal Disease formula) or end-stage renal disease. * Contraindication to use of insulin glargine, or lixisenatide or GLP-1 receptor agonist (Victoza®, Byetta®, Bydureon®, Tanzeum® or Trulicity®) according to local labeling. * Any contraindication to metformin or pioglitazone or SGLT2 inhibitor use, according to local labeling. * History of hypersensitivity to insulin glargine, or to any of the excipients. * History of allergic reaction to any GLP-1 receptor agonist or to meta-cresol. * Personal or immediate family history of medullary thyroid cancer (MTC) or genetic condition that predisposes to MTC (eg, multiple endocrine neoplasia type 2 syndromes). * 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. * Body mass index \<=20 or \>40 kg/m\^2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period | Baseline, Week 26 | Change in HbA1c was calculated by subtracting baseline value from Week 26 value. Adjusted least squares (LS) mean and standard error (SE) were obtained from Mixed-effect model with repeated measures (MMRM) to account for missing data using all available post baseline data during the 26 week treatment period. |
| Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 52: Single Arm Extension Period | Baseline, Week 52 | Change in HbA1c was calculated by subtracting baseline value from Week 52 value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26: Core Period | Baseline, Week 26 | Change in FPG was calculated by subtracting baseline value from Week 26 value. Adjusted LS means and SE were obtained from MMRM to account for missing data using all available post baseline data during the 26 week treatment period. |
| Change From Baseline in Fasting Plasma Glucose (FPG) to Week 52: Single Arm Extension Period | Baseline, Week 52 | Change in FPG was calculated by subtracting baseline value from Week 52 value. |
| Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 26: Core Period | Baseline, Week 26 | The 7-point SMPG profile was measured at the following 7 points: pre-prandial and 2 hours postprandial for breakfast, lunch, dinner and at bedtime. Two hours postprandial (breakfast, lunch and dinner) was defined as 2 hours after the start of the meal. Adjusted LS means and SE were obtained from MMRM to account for missing data using all available post baseline data during the 26 week treatment period. |
| Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 52: Single Arm Extension Period | Baseline, Week 52 | The 7-point SMPG profile was measured at the following 7 points: pre-prandial and 2 hours postprandial for breakfast, lunch, dinner and at bedtime. Two hours postprandial (breakfast, lunch and dinner) was defined as 2 hours after the start of the meal. |
| Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 26: Core Period | Baseline, Week 26 | 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 26 value. Missing data was imputed using last observation carried forward (LOCF). |
| Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 52: Single Arm Extension Period | Baseline, Week 52 | 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 52 value. Missing data was imputed using LOCF. |
| Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 26: Core Period | Baseline, Week 26 | 2-hour plasma glucose excursion = 2-hour 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 26 value. Missing data was imputed using LOCF. |
| Percentage of Participants Reaching HbA1c <7% or <=6.5% at Week 26: Core Period | Week 26 | Participants without any available HbA1c assessment at Week 26 were considered as non-responders. |
| Percentage of Participants Requiring Rescue Therapy During the 26 Week Treatment Period: Core Period | From Baseline to Week 26 | Routine HbA1c value was used to determine the requirement of rescue medication. Threshold values at Week 12 or later on Week 12: HbA1c \>8%. |
| Percentage of Participants Requiring Rescue Therapy During the 52 Week Treatment Period: Single Arm Extension Period | From Week 26 to Week 52 | Routine HbA1c value was used to determine the requirement of rescue medication. Threshold values at Week 12 or later on Week 12: HbA1c \>8%. |
| Change From Baseline in Body Weight at Week 26: Core Period | Baseline, Week 26 | Change in body weight was calculated by subtracting baseline value from Week 26 value. |
| Change From Baseline in Body Weight to Week 52: Single Arm Extension Period | Baseline, Week 52 | Change in body weight was calculated by subtracting baseline value from Week 52 value. |
| Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Core Period | From Baseline to Week 26 | Documented symptomatic hypoglycemia was an event during which symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of \<=3.9 mmol/L (70 mg/dL). Hypoglycemic episodes with plasma glucose of \<3.0 mmol/L (54 mg/dL) were also analyzed. |
| Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Single Arm Extension Period | From Baseline to Week 52 | Documented symptomatic hypoglycemia was an event during which symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of \<=3.9 mmol/L (70 mg/dL). Hypoglycemic episodes with plasma glucose of \<3.0 mmol/L (54 mg/dL) were also analyzed. |
| Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 52: Single Arm Extension Period | Baseline, Week 52 | 2-hour plasma glucose excursion = 2-hour PPG value minus plasma glucose value obtained 30 minutes prior to the start of meal and before IMP administration if IMP was injected before breakfast. Change in plasma glucose excursions were calculated by subtracting baseline value from Week 52 value. Missing data was imputed using LOCF. |
| Percentage of Participants Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period | Week 52 | Participants without any available HbA1c assessment at Week 52 were considered as non-responders. |
Countries
Canada, Estonia, Germany, Israel, Italy, Romania, Slovakia, Spain, United States
Participant flow
Recruitment details
The study was conducted at 112 sites in 9 countries. A total of 840 participants were screened between 06 July 2016 and 01 November 2017, of which 326 were screen failures. Screen failures were mainly due to glycated hemoglobin (HbA1c) level lesser than (\<)7% or more than (\>)9% at screening visit.
Pre-assignment details
A total of 514 participants were randomized in 1:1 (Insulin Glargine/Lixisenatide fixed ratio combination \[FRC\] or glucagon-like peptide-1 receptor agonist \[GLP-1 RA\]) ratio. Randomization was stratified by values of HbA1c at screening (\<8%, \>=8%) & GLP-1 RA subtype at screening (once/twice daily \[QD/BID\], once weekly \[QW\] formulations).
Participants by arm
| Arm | Count |
|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted. | 257 |
| GLP-1 Receptor Agonist GLP-1 RA receptor agonist (liraglutide QD, exenatide BID, exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization. | 257 |
| Total | 514 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Core Period: 26 Weeks | Adverse Event | 10 | 0 |
| Core Period: 26 Weeks | Lack of Efficacy | 1 | 0 |
| Core Period: 26 Weeks | Other than specified | 3 | 1 |
| Core Period: 26 Weeks | Poor compliance to protocol | 2 | 0 |
| Core Period: 26 Weeks | Randomized but not treated | 2 | 1 |
| Core Period: 26 Weeks | Withdrawal by Subject | 9 | 9 |
| Extension Period:26 Weeks(Upto 52 Weeks) | Adverse Event | 1 | 0 |
| Extension Period:26 Weeks(Upto 52 Weeks) | Other than specified | 5 | 0 |
| Extension Period:26 Weeks(Upto 52 Weeks) | Poor compliance to protocol | 3 | 0 |
Baseline characteristics
| Characteristic | GLP-1 Receptor Agonist | Total | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) |
|---|---|---|---|
| Age, Continuous | 60.0 years STANDARD_DEVIATION 10.3 | 59.6 years STANDARD_DEVIATION 10 | 59.2 years STANDARD_DEVIATION 9.6 |
| Body Mass Index (BMI) <30 | 69 Participants | 140 Participants | 71 Participants |
| Body Mass Index (BMI) >=30 | 188 Participants | 374 Participants | 186 Participants |
| Daily dose of metformin at baseline | 2030.74 milligrams (mg) STANDARD_DEVIATION 497.15 | 1998.83 milligrams (mg) STANDARD_DEVIATION 467.54 | 1966.93 milligrams (mg) STANDARD_DEVIATION 434.56 |
| Daily dose of pioglitazone at baseline | 32.73 mg STANDARD_DEVIATION 8.83 | 32.21 mg STANDARD_DEVIATION 9.14 | 31.25 mg STANDARD_DEVIATION 10.03 |
| Daily dose of SGLT2 inhibitor at baseline Canagliflozin | 283.33 mg STANDARD_DEVIATION 57.74 | 257.89 mg STANDARD_DEVIATION 83.77 | 214.29 mg STANDARD_DEVIATION 106.9 |
| Daily dose of SGLT2 inhibitor at baseline Dapagliflozin | 9.00 mg STANDARD_DEVIATION 2.24 | 9.44 mg STANDARD_DEVIATION 3.38 | 9.62 mg STANDARD_DEVIATION 3.8 |
| Daily dose of SGLT2 inhibitor at baseline Empagliflozin | 16.67 mg STANDARD_DEVIATION 8.2 | 16.17 mg STANDARD_DEVIATION 7.67 | 15.42 mg STANDARD_DEVIATION 7.49 |
| Duration of diabetes | 10.95 years STANDARD_DEVIATION 6.08 | 11.09 years STANDARD_DEVIATION 6.78 | 11.23 years STANDARD_DEVIATION 7.42 |
| Duration of GLP-1 receptor agonist treatment | 1.92 years STANDARD_DEVIATION 1.85 | 1.90 years STANDARD_DEVIATION 1.81 | 1.89 years STANDARD_DEVIATION 1.76 |
| GLP-1 receptor agonist use by type at screening Once/twice daily formulation | 154 Participants | 307 Participants | 153 Participants |
| GLP-1 receptor agonist use by type at screening Once weekly formulation | 103 Participants | 207 Participants | 104 Participants |
| Hemoglobin A1C (HbA1C) | 7.80 percentage of HbA1c STANDARD_DEVIATION 0.56 | 7.79 percentage of HbA1c STANDARD_DEVIATION 0.59 | 7.78 percentage of HbA1c STANDARD_DEVIATION 0.62 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian/Oriental | 4 Participants | 7 Participants | 3 Participants |
| Race/Ethnicity, Customized Black | 7 Participants | 19 Participants | 12 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported' | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 244 Participants | 485 Participants | 241 Participants |
| Sex: Female, Male Female | 113 Participants | 244 Participants | 131 Participants |
| Sex: Female, Male Male | 144 Participants | 270 Participants | 126 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 255 | 0 / 256 | 1 / 206 |
| other Total, other adverse events | 69 / 255 | 48 / 256 | 75 / 206 |
| serious Total, serious adverse events | 10 / 255 | 9 / 256 | 21 / 206 |
Outcome results
Primary
Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period
Change in HbA1c was calculated by subtracting baseline value from Week 26 value. Adjusted least squares (LS) mean and standard error (SE) were obtained from Mixed-effect model with repeated measures (MMRM) to account for missing data using all available post baseline data during the 26 week treatment period.
Time frame: Baseline, Week 26
Population: Modified Intent-To-Treat (mITT) population:all randomized participants who had a baseline and at least 1 post-baseline assessment of any primary/secondary outcome measures, irrespective of compliance with study protocol and procedures.Overall number of participants analyzed=participants with baseline and at least 1 post-baseline HbA1c assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period | -1.02 percentage of HbA1c | Standard Error 0.048 |
| GLP-1 Receptor Agonist | Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period | -0.38 percentage of HbA1c | Standard Error 0.048 |
Comparison: Analysis was performed using Mixed-effect model with repeated measures (MMRM) with treatment groups, randomization strata of Week -2 HbA1c (\<8.0%, \>=8.0%), GLP-1 RA subtype at screening, visits, treatment-by-visit interaction, world region as fixed effects, baseline HbA1c value-by-visit interaction as a covariate. Analysis included all scheduled measurements obtained during 26-week randomized treatment period, including those obtained after IMP discontinuation/introduction of rescue medication.p-value: <0.000195% CI: [-0.77, -0.508]Mixed Models Analysis
Primary
Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 52: Single Arm Extension Period
Change in HbA1c was calculated by subtracting baseline value from Week 52 value.
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population who entered the extension period. Here, Overall number of participants analyzed = participants with baseline and at least 1 post-baseline HbA1c assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 52: Single Arm Extension Period | -1.01 percentage of HbA1c | Standard Error 0.063 |
Secondary
Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 26: Core Period
2-hour plasma glucose excursion = 2-hour 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 26 value. Missing data was imputed using LOCF.
Time frame: Baseline, Week 26
Population: Analysis was performed using mITT population. Here, overall number of participants analyzed = participants with baseline and Week 26 assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 26: Core Period | -1.51 mmol/L | Standard Error 0.177 |
| GLP-1 Receptor Agonist | Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 26: Core Period | -0.52 mmol/L | Standard Error 0.173 |
Comparison: Analysis was performed using ANCOVA model with treatment groups, randomization strata of Week -2 HbA1c (\<8.0%, \>=8.0%), randomization strata of GLP-1 receptor agonist subtype (once/twice daily formulations, once weekly formulations) at screening, and world region as fixed effects and baseline 2-hour plasma glucose excursion value as a covariate. Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant).p-value: <0.000195% CI: [-1.468, -0.508]ANCOVA
Secondary
Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 52: Single Arm Extension Period
2-hour plasma glucose excursion = 2-hour PPG value minus plasma glucose value obtained 30 minutes prior to the start of meal and before IMP administration if IMP was injected before breakfast. Change in plasma glucose excursions were calculated by subtracting baseline value from Week 52 value. Missing data was imputed using LOCF.
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population who entered the extension period. Here, overall number of participants analyzed = participants with baseline and Week 52 assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 52: Single Arm Extension Period | -1.85 mmol/L | Standard Error 0.209 |
Secondary
Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 26: Core Period
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 26 value. Missing data was imputed using last observation carried forward (LOCF).
Time frame: Baseline, Week 26
Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants with baseline and at least one post-baseline plasma glucose assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 26: Core Period | -3.96 mmol/L | Standard Error 0.211 |
| GLP-1 Receptor Agonist | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 26: Core Period | -1.11 mmol/L | Standard Error 0.205 |
Comparison: Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, randomization strata of Week -2 HbA1c (\<8.0%, \>=8.0%), randomization strata of GLP-1 RA subtype (once/twice daily formulations, once weekly formulations) at screening, and world region as fixed effects and baseline 2-hour PPG value as a covariate. Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant).p-value: <0.000195% CI: [-3.42, -2.279]ANCOVA
Secondary
Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 52: Single Arm Extension Period
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 52 value. Missing data was imputed using LOCF.
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population who entered the extension period. Here, overall number of participants analyzed = participants with baseline and at least one post-baseline plasma glucose assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 52: Single Arm Extension Period | -4.30 mmol/L | Standard Error 0.284 |
Secondary
Change From Baseline in Body Weight at Week 26: Core Period
Change in body weight was calculated by subtracting baseline value from Week 26 value.
Time frame: Baseline, Week 26
Population: Analysis was performed using mITT population. Here, overall number of participants analyzed = participants with baseline and at least one post-baseline body weight assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Change From Baseline in Body Weight at Week 26: Core Period | 1.89 kilogram (kg) | Standard Error 0.222 |
| GLP-1 Receptor Agonist | Change From Baseline in Body Weight at Week 26: Core Period | -1.14 kilogram (kg) | Standard Error 0.22 |
Secondary
Change From Baseline in Body Weight to Week 52: Single Arm Extension Period
Change in body weight was calculated by subtracting baseline value from Week 52 value.
Time frame: Baseline, Week 52
Population: Analysis was performed using mITT population who entered the extension period. Here, overall number of participants analyzed = participants with baseline and at least one post-baseline body weight assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Change From Baseline in Body Weight to Week 52: Single Arm Extension Period | 2.78 kg | Standard Error 0.294 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26: Core Period
Change in FPG was calculated by subtracting baseline value from Week 26 value. Adjusted LS means and SE were obtained from MMRM to account for missing data using all available post baseline data during the 26 week treatment period.
Time frame: Baseline, Week 26
Population: Analysis was performed using mITT population. Here, overall number of participants analyzed = participants with baseline and at least one post-baseline FPG assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26: Core Period | -2.28 millimoles per litre (mmol/L) | Standard Error 0.12 |
| GLP-1 Receptor Agonist | Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26: Core Period | -0.60 millimoles per litre (mmol/L) | Standard Error 0.119 |
Comparison: Analysis was performed using MMRM with treatment groups, randomization strata of Week -2 HbA1c (\<8.0%, \>=8.0%), randomization strata of GLP-1 RA subtype at screening, scheduled visit, treatment-by-visit interaction, and world region as fixed effects, and and baseline FPG value-by visit interaction as a covariate. Testing according to the hierarchical testing procedure (continued only if previous outcome measures were statistically significant).p-value: <0.000195% CI: [-2.001, -1.341]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) to Week 52: Single Arm Extension Period
Change in FPG was calculated by subtracting baseline value from Week 52 value.
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population who entered the extension period. Here, overall number of participants analyzed = participants with baseline and at least one post-baseline FPG assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Change From Baseline in Fasting Plasma Glucose (FPG) to Week 52: Single Arm Extension Period | -2.27 mmol/L | Standard Error 0.173 |
Secondary
Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 26: Core Period
The 7-point SMPG profile was measured at the following 7 points: pre-prandial and 2 hours postprandial for breakfast, lunch, dinner and at bedtime. Two hours postprandial (breakfast, lunch and dinner) was defined as 2 hours after the start of the meal. Adjusted LS means and SE were obtained from MMRM to account for missing data using all available post baseline data during the 26 week treatment period.
Time frame: Baseline, Week 26
Population: Analysis was performed using mITT population. Here, overall number of participants analyzed = participants with baseline and at least one post-baseline 7-point SMPG assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 26: Core Period | -1.69 mmol/L | Standard Error 0.114 |
| GLP-1 Receptor Agonist | Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 26: Core Period | -0.67 mmol/L | Standard Error 0.112 |
Comparison: Analysis was performed using MMRM with treatment groups, randomization strata of Week -2 HbA1c (\<8.0%, \>=8.0%), randomization strata of GLP-1 RA subtype at screening, scheduled visit, treatment-by-visit interaction, and world region as fixed effects, and baseline average SMPG value-by-visit interaction as a covariate. Testing according to the hierarchical testing procedure (continued only if previous outcome measures were statistically significant).p-value: <0.000195% CI: [-1.325, -0.708]Mixed Models Analysis
Secondary
Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 52: Single Arm Extension Period
The 7-point SMPG profile was measured at the following 7 points: pre-prandial and 2 hours postprandial for breakfast, lunch, dinner and at bedtime. Two hours postprandial (breakfast, lunch and dinner) was defined as 2 hours after the start of the meal.
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population who entered the extension period. Here, overall number of participants analyzed = participants with baseline and at least one post-baseline 7-point SMPG assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 52: Single Arm Extension Period | -1.68 mmol/L | Standard Error 0.176 |
Secondary
Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Core Period
Documented symptomatic hypoglycemia was an event during which symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of \<=3.9 mmol/L (70 mg/dL). Hypoglycemic episodes with plasma glucose of \<3.0 mmol/L (54 mg/dL) were also analyzed.
Time frame: From Baseline to Week 26
Population: Analysis was performed on safety population which included all randomized participants who received at least one dose of open-label IMP, regardless of the amount of treatment administered. Participants were analyzed according to the treatment actually received (as treated).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Core Period | Documented symptomatic hypoglycemia(<=3.9 mmol/L) | 1.54 events per participant-year |
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Core Period | Documented symptomatic hypoglycemia (<3.0 mmol/L) | 0.25 events per participant-year |
| GLP-1 Receptor Agonist | Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Core Period | Documented symptomatic hypoglycemia(<=3.9 mmol/L) | 0.08 events per participant-year |
| GLP-1 Receptor Agonist | Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Core Period | Documented symptomatic hypoglycemia (<3.0 mmol/L) | 0.01 events per participant-year |
Secondary
Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Single Arm Extension Period
Documented symptomatic hypoglycemia was an event during which symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of \<=3.9 mmol/L (70 mg/dL). Hypoglycemic episodes with plasma glucose of \<3.0 mmol/L (54 mg/dL) were also analyzed.
Time frame: From Baseline to Week 52
Population: Analysis was performed on safety population who entered the extension period and their data for whole study duration was analyzed and reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Single Arm Extension Period | Documented symptomatic hypoglycemia(<=3.9 mmol/L) | 1.59 events per participant-year |
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Single Arm Extension Period | Documented symptomatic hypoglycemia (<3.0 mmol/L) | 0.24 events per participant-year |
Secondary
Percentage of Participants Reaching HbA1c <7% or <=6.5% at Week 26: Core Period
Participants without any available HbA1c assessment at Week 26 were considered as non-responders.
Time frame: Week 26
Population: Analysis was performed on mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Percentage of Participants Reaching HbA1c <7% or <=6.5% at Week 26: Core Period | HbA1c <7% | 61.9 percentage of participants |
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Percentage of Participants Reaching HbA1c <7% or <=6.5% at Week 26: Core Period | HbA1c <=6.5% | 40.5 percentage of participants |
| GLP-1 Receptor Agonist | Percentage of Participants Reaching HbA1c <7% or <=6.5% at Week 26: Core Period | HbA1c <=6.5% | 9.9 percentage of participants |
| GLP-1 Receptor Agonist | Percentage of Participants Reaching HbA1c <7% or <=6.5% at Week 26: Core Period | HbA1c <7% | 25.7 percentage of participants |
Comparison: HbA1c \<7.0%: Insulin Glargine/Lixisenatide FRC vs GLP-1 Receptor Agonist. Analysis was performed using Cochran-Mantel-Haenszel method method stratified on randomization strata of Week -2 HbA1c (\<8.0%, \>=8.0%), and randomization strata of GLP-1 receptor agonist subtype at screening. 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 (only HbA1c \< 7% was part of testing).p-value: <0.000195% CI: [28.11, 43.99]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period
Participants without any available HbA1c assessment at Week 52 were considered as non-responders.
Time frame: Week 52
Population: Analysis was performed on mITT population who entered the extension period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Percentage of Participants Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period | HbA1c <7% | 64.1 percentage of participants |
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Percentage of Participants Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period | HbA1c <=6.5% | 42.7 percentage of participants |
Secondary
Percentage of Participants Requiring Rescue Therapy During the 26 Week Treatment Period: Core Period
Routine HbA1c value was used to determine the requirement of rescue medication. Threshold values at Week 12 or later on Week 12: HbA1c \>8%.
Time frame: From Baseline to Week 26
Population: Analysis was performed using mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Percentage of Participants Requiring Rescue Therapy During the 26 Week Treatment Period: Core Period | 4.8 percentage of participants |
| GLP-1 Receptor Agonist | Percentage of Participants Requiring Rescue Therapy During the 26 Week Treatment Period: Core Period | 15.0 percentage of participants |
Secondary
Percentage of Participants Requiring Rescue Therapy During the 52 Week Treatment Period: Single Arm Extension Period
Routine HbA1c value was used to determine the requirement of rescue medication. Threshold values at Week 12 or later on Week 12: HbA1c \>8%.
Time frame: From Week 26 to Week 52
Population: Analysis was performed on mITT population who entered the extension period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Percentage of Participants Requiring Rescue Therapy During the 52 Week Treatment Period: Single Arm Extension Period | 1.5 percentage of participants |