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LixiLan-O: Efficacy and Safety of Insulin Glargine/ Lixisenatide Fixed Ratio Combination Compared to Insulin Glargine Alone and Lixisenatide Alone on Top of Metformin in Patients With T2DM

Sponsor
Sanofi (Industry)
Overall Status
Completed
CT.gov ID
NCT02058147
Collaborator
(none)
1,170
Enrollment
273
Locations
3
Arms
15.9
Duration (Months)
4.3
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Insulin glargine/lixisenatide Fixed Ratio Combination
  • Drug: Insulin glargine (HOE901)
  • Drug: Lixisenatide (AVE0010)
  • Drug: Metformin
 Phase 3

Detailed Description

Approximately 37 weeks including up to 6 weeks of screening, 30-week treatment period, and a 3 days follow-up period.

Study Design

Study Type:
Interventional
Actual Enrollment :
1170 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized, 30 Week, Active-controlled, Open-label, 3-treatment Arm, Parallel-group Multicenter Study Comparing the Efficacy and Safety of Insulin Glargine/ Lixisenatide Fixed Ratio Combination to Insulin Glargine Alone and to Lixisenatide Alone on Top of Metformin in Patients With Type 2 Diabetes Mellitus (T2DM)
Study Start Date :
Feb 1, 2014
Actual Primary Completion Date :
Jun 1, 2015
Actual Study Completion Date :
Jun 1, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)

FRC once daily (QD) for 30 weeks. Dose individually adjusted.

Drug: Insulin glargine/lixisenatide Fixed Ratio Combination
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.
Other Names:
  • (HOE901/AVE0010)

    • Drug: Metformin
    Pharmaceutical form: Tablet; Route of administration: Oral administration.
    Active Comparator: Insulin Glargine

    Insulin glargine QD for 30 weeks. Dose individually adjusted.

    Drug: Insulin glargine (HOE901)
    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.
    Other Names:
  • Lantus

    • Drug: Metformin
    Pharmaceutical form: Tablet; Route of administration: Oral administration.
    Active Comparator: Lixisenatide

    Lixisenatide 10 mcg QD for 2 weeks, then 20 mcg QD (maintenance dose).

    Drug: Lixisenatide (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.
    Other Names:
  • Lyxumia

    • Drug: Metformin
    Pharmaceutical form: Tablet; Route of administration: Oral administration.

    Outcome Measures

    Primary Outcome Measures

    1. 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 Outcome Measures

    1. 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.

    2. 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).

    3. 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.

    4. 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.

    5. 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.

    6. Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 [Week 30]

    7. 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).

    8. 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.

    9. 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.

    10. 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.

    11. 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%.

    12. 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).

    13. 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).

    14. 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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts 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).

    Exclusion Criteria for randomization at the end of the screening period:

    • HbA1c less than 7% or above 10%;

    • Fasting Plasma glucose above 250 mg/dL (13.9 mmol/L);

    • Metformin maximal tolerated dose less than 1500 mg/day;

    • Amylase and/or lipase more than 3 ULN.

    The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Investigational Site Number 840027 Phoenix Arizona United States 85028
    2 Investigational Site Number 840122 Phoenix Arizona United States 85032
    3 Investigational Site Number 840062 Tempe Arizona United States 85282
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    223 Investigational Site Number 642004 Timisoara Romania 300133
    224 Investigational Site Number 642003 Timisoara Romania 300456
    225 Investigational Site Number 643006 Moscow Russian Federation 119991
    226 Investigational Site Number 643008 Penza Russian Federation 440026
    227 Investigational Site Number 643012 Petrozavodsk Russian Federation 185019
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    229 Investigational Site Number 643014 Samara Russian Federation 443067
    230 Investigational Site Number 643009 Saratov Russian Federation 410026
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    232 Investigational Site Number 643005 St-Petersburg Russian Federation 190068
    233 Investigational Site Number 643007 St-Petersburg Russian Federation 194354
    234 Investigational Site Number 643002 St-Petersburg Russian Federation 195257
    235 Investigational Site Number 643003 St. Petersburg Russian Federation 194358
    236 Investigational Site Number 643016 Tomsk Russian Federation 634050
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    238 Investigational Site Number 710002 Cap Town South Africa 7530
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    263 Investigational Site Number 804010 Kyiv Ukraine 03049
    264 Investigational Site Number 804007 Kyiv Ukraine 04050
    265 Investigational Site Number 804006 Kyiv Ukraine
    266 Investigational Site Number 804012 Lviv Ukraine 79010
    267 Investigational Site Number 804011 Vinnytsya Ukraine 21001
    268 Investigational Site Number 804008 Vinnytsya Ukraine 21010
    269 Investigational Site Number 826001 Coventry United Kingdom CV2 2DX
    270 Investigational Site Number 826002 Dundee United Kingdom DD1 9SI
    271 Investigational Site Number 826006 Guildford United Kingdom GU2 7XX
    272 Investigational Site Number 826007 Leicester United Kingdom LE5 4PW
    273 Investigational Site Number 826003 Norwich United Kingdom NR1 3SR

    Sponsors and Collaborators

    • Sanofi

    Investigators

    • Study Director: Clinical Sciences & Operations, Sanofi

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Sanofi
    ClinicalTrials.gov Identifier:
    NCT02058147
    Other Study ID Numbers:
    • EFC12404
    • 2013-003131-30
    • U1111-1148-4334
    First Posted:
    Feb 7, 2014
    Last Update Posted:
    May 9, 2017
    Last Verified:
    Mar 1, 2017
    Additional relevant MeSH terms:
    Diabetes Mellitus, Type 2
    Insulin
    Insulin, Globin Zinc
    Metformin
    Insulin Glargine
    Lixisenatide

    Study Results

    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 Detail 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.
    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously once daily (QD) for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Period Title: Overall Study
    STARTED 469 467 234
    Treated 469 467 233
    COMPLETED 440 440 205
    NOT COMPLETED 29 27 29

    Baseline Characteristics

    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide Total
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose). Total of all reporting groups
    Overall Participants 469 467 234 1170
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    58.2
    (9.5)
    58.3
    (9.4)
    58.7
    (8.7)
    58.4
    (9.3)
    Sex: Female, Male (Count of Participants)
    Female
    247
    52.7%
    230
    49.3%
    101
    43.2%
    578
    49.4%
    Male
    222
    47.3%
    237
    50.7%
    133
    56.8%
    592
    50.6%
    Race (Count of Participants)
    Caucasian
    417
    88.9%
    421
    90.1%
    216
    92.3%
    1054
    90.1%
    Black
    33
    7%
    33
    7.1%
    12
    5.1%
    78
    6.7%
    Asian/Oriental
    8
    1.7%
    7
    1.5%
    3
    1.3%
    18
    1.5%
    Other
    11
    2.3%
    6
    1.3%
    3
    1.3%
    20
    1.7%
    Ethnicity (Count of Participants)
    Hispanic
    85
    18.1%
    87
    18.6%
    51
    21.8%
    223
    19.1%
    Not Hispanic
    384
    81.9%
    380
    81.4%
    183
    78.2%
    947
    80.9%
    Second Oral Anti-diabetic Drug (OAD) Use (Count of Participants)
    Yes
    274
    58.4%
    270
    57.8%
    133
    56.8%
    677
    57.9%
    No
    195
    41.6%
    197
    42.2%
    101
    43.2%
    493
    42.1%
    Second OAD Use at Screening by Class (Count of Participants)
    Sulfonylurea
    259
    55.2%
    249
    53.3%
    123
    52.6%
    631
    53.9%
    Glinide
    3
    0.6%
    10
    2.1%
    5
    2.1%
    18
    1.5%
    Sodium-glucose co-transporter-2 inhibitor
    2
    0.4%
    2
    0.4%
    0
    0%
    4
    0.3%
    Dipeptidyl peptidase-4 inhibitor
    12
    2.6%
    11
    2.4%
    5
    2.1%
    28
    2.4%
    None
    193
    41.2%
    195
    41.8%
    101
    43.2%
    489
    41.8%
    Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg/m^2]
    31.64
    (4.4)
    31.66
    (4.51)
    31.99
    (4.39)
    31.72
    (4.44)
    Duration of Diabetes (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    8.89
    (5.51)
    8.66
    (5.59)
    8.89
    (6.26)
    8.80
    (5.69)
    Daily Dose of Metformin (mg) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg]
    2246.1
    (456.8)
    2244.7
    (444.7)
    2267.3
    (427.4)
    2249.8
    (445.9)
    HbA1c (percentage of HbA1c) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [percentage of HbA1c]
    8.08
    (0.71)
    8.08
    (0.69)
    8.13
    (0.72)
    8.09
    (0.70)
    Fasting Plasma Glucose (FPG) (mmol/L) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mmol/L]
    9.87
    (2.35)
    9.75
    (2.32)
    9.75
    (2.19)
    9.80
    (2.31)

    Outcome Measures

    1. Primary Outcome
    Title Change in HbA1c From Baseline to Week 30
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Measure Participants 467 464 233
    Least Squares Mean (Standard Error) [percentage of hemoglobin]
    -1.63
    (0.038)
    -1.34
    (0.039)
    -0.85
    (0.052)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Lixisenatide
    Comments 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.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤0.05.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter Least Square (LS) Mean Difference
    Estimated Value -0.78
    Confidence Interval (2-Sided) 95%
    -0.898 to -0.665
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.059
    Estimation Comments Insulin Glargine/Lixisenatide FRC vs Lixisenatide
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine
    Comments 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.
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments Predefined non-inferiority margin of 0.3%.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.29
    Confidence Interval (2-Sided) 95%
    -0.384 to -0.194
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.048
    Estimation Comments Insulin Glargine/Lixisenatide FRC vs Insulin glargine
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine
    Comments 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.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.05.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.29
    Confidence Interval (2-Sided) 95%
    -0.384 to -0.194
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.048
    Estimation Comments Insulin Glargine/Lixisenatide FRC vs Insulin glargine
    2. Secondary Outcome
    Title Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30
    Description Participants without Week 30 value for HbA1c were counted as non-responders.
    Time Frame Week 30

    Outcome Measure Data

    Analysis Population Description
    mITT population.
    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Measure Participants 468 466 233
    HbA1c <7.0%
    73.7
    15.7%
    59.4
    12.7%
    33
    14.1%
    HbA1c ≤6.5%
    55.8
    11.9%
    39.5
    8.5%
    19.3
    8.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Lixisenatide
    Comments 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.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤0.05.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 40.61
    Confidence Interval (2-Sided) 95%
    33.63 to 47.59
    Parameter Dispersion Type:
    Value:
    Estimation Comments HbA1c <7.0%: Insulin Glargine/Lixisenatide FRC vs Lixisenatide.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Lixisenatide
    Comments 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.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.05.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 36.38
    Confidence Interval (2-Sided) 95%
    29.81 to 42.95
    Parameter Dispersion Type:
    Value:
    Estimation Comments HbA1c ≤6.5%: Insulin Glargine/Lixisenatide FRC vs Lixisenatide.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine
    Comments 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.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.05.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 14.31
    Confidence Interval (2-Sided) 95%
    8.37 to 20.25
    Parameter Dispersion Type:
    Value:
    Estimation Comments HbA1c <7.0%: Insulin Glargine/Lixisenatide FRC vs Insulin glargine.
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine
    Comments 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.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.05.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 16.35
    Confidence Interval (2-Sided) 95%
    10.13 to 22.58
    Parameter Dispersion Type:
    Value:
    Estimation Comments HbA1c ≤6.5%: Insulin Glargine/Lixisenatide FRC vs Insulin glargine.
    3. Secondary Outcome
    Title Change in Plasma Glucose Excursion From Baseline to Week 30
    Description 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

    Outcome Measure Data

    Analysis Population Description
    mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline plasma glucose excursion assessment during study period.
    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Measure Participants 428 425 192
    Least Squares Mean (Standard Error) [mmol/L]
    -2.31
    (0.154)
    -0.18
    (0.157)
    -3.23
    (0.216)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine
    Comments 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.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤0.05. The hierarchical testing continued only when primary hypotheses (superiority: FRC to lixisenatide; non-inferiority: FRC to insulin glargine for HbA1c) was statistically significant.
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -2.13
    Confidence Interval (2-Sided) 95%
    -2.498 to -1.77
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.185
    Estimation Comments Insulin Glargine/Lixisenatide FRC vs Insulin glargine.
    4. Secondary Outcome
    Title Change in Body Weight From Baseline to Week 30
    Description Change in body weight was calculated by subtracting baseline value from Week 30 value.
    Time Frame Baseline, Week 30

    Outcome Measure Data

    Analysis Population Description
    mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline body weight assessment during study period.
    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Measure Participants 467 465 233
    Least Squares Mean (Standard Error) [kg]
    -0.29
    (0.182)
    1.11
    (0.183)
    -2.3
    (0.256)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine
    Comments 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.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.05.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.4
    Confidence Interval (2-Sided) 95%
    -1.891 to -0.91
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.25
    Estimation Comments Insulin Glargine/Lixisenatide FRC vs Insulin glargine
    5. Secondary Outcome
    Title Change in Fasting Plasma Glucose (FPG) From Baseline to Week 30
    Description Change in FPG was calculated by subtracting baseline value from Week 30 value.
    Time Frame Baseline, Week 30

    Outcome Measure Data

    Analysis Population Description
    mITT population. Here, number of participants analysed = participants with baseline and at least one post-baseline FPG assessment during study period.
    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Measure Participants 465 465 232
    Least Squares Mean (Standard Error) [mmol/L]
    -3.46
    (0.09)
    -3.27
    (0.091)
    -1.5
    (0.124)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Lixisenatide
    Comments 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.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.05.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.96
    Confidence Interval (2-Sided) 95%
    -2.246 to -1.682
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.144
    Estimation Comments Insulin Glargine/Lixisenatide FRC vs Lixisenatide
    6. Secondary Outcome
    Title Mean Change in 7-point Self-monitored Plasma Glucose (SMPG) Profile From Baseline to Week 30
    Description 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

    Outcome Measure Data

    Analysis Population Description
    mITT population. Here,number of participants analyzed = participants with baseline and at least one post baseline 7-point SMPG assessment during study period.
    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Measure Participants 421 411 204
    Least Squares Mean (Standard Deviation) [mmol/L]
    -3.35
    (0.081)
    -2.66
    (0.084)
    -1.95
    (0.111)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Lixisenatide
    Comments 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.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.05.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.4
    Confidence Interval (2-Sided) 95%
    -1.645 to -1.158
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.124
    Estimation Comments Insulin Glargine/Lixisenatide FRC vs Lixisenatide
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine
    Comments 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.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.05.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.69
    Confidence Interval (2-Sided) 95%
    -0.892 to -0.495
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.101
    Estimation Comments Insulin Glargine/Lixisenatide FRC vs Insulin Glargine
    7. Secondary Outcome
    Title Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30
    Description
    Time Frame Week 30

    Outcome Measure Data

    Analysis Population Description
    mITT population. Participants without any HbA1c and/or body weight value at Week 30 were counted as non-responders.
    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Measure Participants 468 466 233
    Number [percentage of participants]
    43.2
    9.2%
    25.1
    5.4%
    27.9
    11.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine
    Comments 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.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.05.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 18.08
    Confidence Interval (2-Sided) 95%
    12.15 to 24.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments Insulin Glargine/Lixisenatide FRC vs Insulin glargine
    8. Secondary Outcome
    Title 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
    Description 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

    Outcome Measure Data

    Analysis Population Description
    mITT population. Participants without any HbA1c and/or body weight value at Week 30 were counted as non-responders.
    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Measure Participants 468 466 233
    Number [percentage of participants]
    31.8
    6.8%
    18.9
    4%
    26.2
    11.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine
    Comments 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.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Threshold for significance ≤ 0.05.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Difference in percentage
    Estimated Value 12.98
    Confidence Interval (2-Sided) 95%
    7.5 to 18.45
    Parameter Dispersion Type:
    Value:
    Estimation Comments Insulin Glargine/Lixisenatide FRC vs Insulin Glargine
    9. Secondary Outcome
    Title Average Daily Insulin Glargine Dose at Week 30
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted.
    Measure Participants 467 463
    Least Squares Mean (Standard Error) [Units (U)]
    39.77
    (0.699)
    40.46
    (0.701)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine
    Comments 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.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.4857
    Comments Threshold for significance ≤ 0.05.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.69
    Confidence Interval (2-Sided) 95%
    -2.632 to 1.252
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.99
    Estimation Comments Insulin Glargine/Lixisenatide FRC vs Insulin Glargine
    10. Secondary Outcome
    Title Change in 2-Hour Postprandial Plasma Glucose (PPG) From Baseline to Week 30
    Description 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

    Outcome Measure Data

    Analysis Population Description
    mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline 2-hour PPG assessment during study period.
    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Measure Participants 430 430 196
    Least Squares Mean (Standard Error) [mmol/L]
    -5.68
    (0.176)
    -3.31
    (0.178)
    -4.58
    (0.245)
    11. Secondary Outcome
    Title 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
    Description 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

    Outcome Measure Data

    Analysis Population Description
    mITT population. Participants without Week 30 value for HbA1c were counted as non-responders.
    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Measure Participants 468 466 233
    Number [percentage of participants]
    53.6
    11.4%
    44.4
    9.5%
    30.5
    13%
    12. Secondary Outcome
    Title Percentage of Participants Requiring Rescue Therapy During 30-Week Treatment Period
    Description 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

    Outcome Measure Data

    Analysis Population Description
    mITT population.
    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Measure Participants 468 466 233
    Number [percentage of participants]
    3.6
    0.8%
    3.4
    0.7%
    12.4
    5.3%
    13. Secondary Outcome
    Title Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year
    Description 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)

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Measure Participants 469 467 233
    Number [Events per subject-year]
    1.44
    1.22
    0.34
    14. Secondary Outcome
    Title Percentage of Participants With Documented Symptomatic Hypoglycemia
    Description 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)

    Outcome Measure Data

    Analysis Population Description
    Safety population.
    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Measure Participants 469 467 233
    Number [percentage of participants]
    25.6
    5.5%
    23.6
    5.1%
    6.4
    2.7%
    15. Secondary Outcome
    Title Percentage of Participants With Severe Symptomatic Hypoglycemia
    Description 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)

    Outcome Measure Data

    Analysis Population Description
    Safety population.
    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted. Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose).
    Measure Participants 469 467 233
    Number [percentage of participants]
    0
    0%
    0.2
    0%
    0
    0%

    Adverse Events

    Time Frame All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 213) regardless of seriousness or relationship to investigational product.
    Adverse Event Reporting Description Reported AEs are treatment-emergent that is AEs that developed/worsened during 'on-treatment period' (time from first injection of open-label IMP up to 3 days after the last injection of IMP regardless of the introduction of rescue therapy). Analysis was done on safety population.
    Arm/Group Title Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Arm/Group Description FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted (median exposure: 211 days). Insulin glargine injected subcutaneously QD for 30 weeks. Dose individually adjusted (median exposure: 211 days). Lixisenatide 10 mcg injected subcutaneously QD for 2 weeks, then 20 mcg QD (maintenance dose) median exposure: 211 days).
    All Cause Mortality
    Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 18/469 (3.8%) 19/467 (4.1%) 9/233 (3.9%)
    Blood and lymphatic system disorders
    Pancytopenia 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Cardiac disorders
    Cardiac failure congestive 1/469 (0.2%) 1/467 (0.2%) 0/233 (0%)
    Palpitations 1/469 (0.2%) 0/467 (0%) 0/233 (0%)
    Acute myocardial infarction 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Cardiac failure acute 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Cardiac failure chronic 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Coronary artery disease 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Myocardial infarction 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Gastrointestinal disorders
    Oesophagitis 1/469 (0.2%) 0/467 (0%) 0/233 (0%)
    General disorders
    Death 0/469 (0%) 0/467 (0%) 1/233 (0.4%)
    Non-cardiac chest pain 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Hepatobiliary disorders
    Cholecystitis chronic 1/469 (0.2%) 0/467 (0%) 0/233 (0%)
    Immune system disorders
    Anaphylactic reaction 0/469 (0%) 0/467 (0%) 1/233 (0.4%)
    Infections and infestations
    Urinary tract infection 2/469 (0.4%) 0/467 (0%) 0/233 (0%)
    Erysipelas 1/469 (0.2%) 0/467 (0%) 1/233 (0.4%)
    Febrile infection 1/469 (0.2%) 0/467 (0%) 0/233 (0%)
    Bronchitis 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Meningitis staphylococcal 0/469 (0%) 0/467 (0%) 1/233 (0.4%)
    Pneumonia 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Pyelonephritis acute 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Urosepsis 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Injury, poisoning and procedural complications
    Tendon rupture 1/469 (0.2%) 0/467 (0%) 0/233 (0%)
    Comminuted fracture 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Toxicity to various agents 0/469 (0%) 0/467 (0%) 1/233 (0.4%)
    Investigations
    Electrocardiogram ST-T segment abnormal 1/469 (0.2%) 0/467 (0%) 0/233 (0%)
    Lipase increased 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control 0/469 (0%) 0/467 (0%) 1/233 (0.4%)
    Metabolic acidosis 0/469 (0%) 0/467 (0%) 1/233 (0.4%)
    Musculoskeletal and connective tissue disorders
    Costochondritis 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Spinal osteoarthritis 0/469 (0%) 0/467 (0%) 1/233 (0.4%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung cancer metastatic 1/469 (0.2%) 0/467 (0%) 0/233 (0%)
    Squamous cell carcinoma of skin 1/469 (0.2%) 0/467 (0%) 0/233 (0%)
    Lung neoplasm malignant 0/469 (0%) 0/467 (0%) 1/233 (0.4%)
    Metastases to liver 0/469 (0%) 0/467 (0%) 1/233 (0.4%)
    Pancreatic carcinoma 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Prostate cancer recurrent 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Squamous cell carcinoma of the oral cavity 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Thyroid adenoma 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Nervous system disorders
    Transient ischaemic attack 1/469 (0.2%) 0/467 (0%) 1/233 (0.4%)
    Lacunar infarction 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Radiculopathy 0/469 (0%) 0/467 (0%) 1/233 (0.4%)
    Renal and urinary disorders
    Renal colic 1/469 (0.2%) 0/467 (0%) 0/233 (0%)
    Acute kidney injury 0/469 (0%) 0/467 (0%) 1/233 (0.4%)
    Bladder prolapse 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Calculus urinary 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Hydronephrosis 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Reproductive system and breast disorders
    Acquired phimosis 1/469 (0.2%) 0/467 (0%) 0/233 (0%)
    Cervical dysplasia 1/469 (0.2%) 0/467 (0%) 0/233 (0%)
    Metrorrhagia 1/469 (0.2%) 0/467 (0%) 0/233 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Chronic obstructive pulmonary disease 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Dyspnoea 0/469 (0%) 1/467 (0.2%) 0/233 (0%)
    Respiratory failure 0/469 (0%) 0/467 (0%) 1/233 (0.4%)
    Skin and subcutaneous tissue disorders
    Angioedema 1/469 (0.2%) 0/467 (0%) 0/233 (0%)
    Urticaria 1/469 (0.2%) 0/467 (0%) 0/233 (0%)
    Vascular disorders
    Hypertension 1/469 (0.2%) 1/467 (0.2%) 0/233 (0%)
    Other (Not Including Serious) Adverse Events
    Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 138/469 (29.4%) 85/467 (18.2%) 98/233 (42.1%)
    Gastrointestinal disorders
    Nausea 45/469 (9.6%) 17/467 (3.6%) 56/233 (24%)
    Diarrhoea 42/469 (9%) 20/467 (4.3%) 21/233 (9%)
    Vomiting 15/469 (3.2%) 7/467 (1.5%) 15/233 (6.4%)
    Infections and infestations
    Upper respiratory tract infection 33/469 (7%) 23/467 (4.9%) 12/233 (5.2%)
    Nasopharyngitis 26/469 (5.5%) 25/467 (5.4%) 15/233 (6.4%)
    Nervous system disorders
    Headache 24/469 (5.1%) 15/467 (3.2%) 18/233 (7.7%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.

    Results Point of Contact

    Name/Title Trial Transparency Team
    Organization Sanofi
    Phone
    Email Contact-US@sanofi.com
    Responsible Party:
    Sanofi
    ClinicalTrials.gov Identifier:
    NCT02058147
    Other Study ID Numbers:
    • EFC12404
    • 2013-003131-30
    • U1111-1148-4334
    First Posted:
    Feb 7, 2014
    Last Update Posted:
    May 9, 2017
    Last Verified:
    Mar 1, 2017