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    Clinical Trial Results:
    A Phase 3, Parallel-Design, Open-Label, Randomized Controlled Study to Evaluate the Efficacy and Safety of LY3209590 as a Weekly Basal Insulin Compared to Insulin Glargine in Adults with Type 2 Diabetes on Multiple Daily Injections

    Summary
    EudraCT number
    		 2021-005878-25
    Trial protocol
    		 DE   ES   IT  
    Global end of trial date
    27 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2025
    First version publication date
    15 Mar 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    I8H-MC-BDCV
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05462756
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 18260
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Feb 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The reason for this study is to evaluate if the once-weekly study drug insulin efsitora alfa (LY3209590) is safe and effective compared with daily insulin glargine in participants with Type 2 diabetes (T2D) that have already been treated with basal insulin and at least 2 injections per day of prandial insulin. The study consists of a 3-week screening/lead-in period, a 26-week treatment period and a 5-week safety follow-up period. The study will last up to 34 weeks.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Aug 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 166
    Country: Number of subjects enrolled
    Germany: 51
    Country: Number of subjects enrolled
    India: 100
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Mexico: 169
    Country: Number of subjects enrolled
    Spain: 70
    Country: Number of subjects enrolled
    United States: 148
    Worldwide total number of subjects
    730
    EEA total number of subjects
    147
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    508
    From 65 to 84 years
    220
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants underwent a 26-week treatment period, followed by a 5-week safety follow-up period.

    Pre-assignment
    Screening details
    		 Not Applicable

    Period 1
    Period 1 title
    Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 500 U/mL - Insulin Efsitora
    Arm description
    		 Participants received 500 units per milliliter (U/mL) Insulin Efsitora Alfa (insulin efsitora) administered subcutaneously (SC) once weekly (QW) along with 100 U/mL insulin lispro given SC.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin Efsitora
    Investigational medicinal product code
    Other name
    LY3209590
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously.

    Arm title
    		 100 U/mL - Insulin Glargine
    Arm description
    		 Participants received 100 U/mL insulin glargine administered SC once daily (QD) along with 100 U/mL insulin lispro given SC.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin Glargine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously.

    Number of subjects in period 1
    		500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Started
    365
    365
    Received At Least 1 Dose of Study Drug
    365
    365
    Completed
    348
    344
    Not completed
    17
    21
         Physician decision
    2
    -
         Consent withdrawn by subject
    5
    12
         Non-Compliance with Study Drug
    1
    3
         Adverse event, non-fatal
    3
    -
         Death
    -
    1
         Lost to follow-up
    2
    1
         Assigned Treatment by Mistake
    4
    3
         Protocol deviation
    -
    1
    Period 2
    Period 2 title
    Follow-Up Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 500 U/mL - Insulin Efsitora
    Arm description
    		 Participants who received 500 U/mL insulin efsitora administered SC QW along with 100 U/mL insulin lispro given SC in the treatment period were required to complete a safety follow-up period and participants who discontinued the study treatment prematurely were encouraged to remain in the study for safety monitoring.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin Efsitora
    Investigational medicinal product code
    Other name
    LY3209590
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously.

    Arm title
    		 100 U/mL - Insulin Glargine
    Arm description
    		 Participants who received 100 U/mL insulin glargine administered SC once daily (QD) along with 100 U/mL insulin lispro given SC in the treatment period were required to complete a safety follow-up period and participants who discontinued the study treatment prematurely were encouraged to remain in the study for safety monitoring.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin Glargine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously.

    Number of subjects in period 2
    		500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Started
    357
    354
    Completed
    352
    349
    Not completed
    5
    5
         Consent withdrawn by subject
    -
    4
         Adverse event, non-fatal
    1
    -
         Death
    1
    -
         Lost to follow-up
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    500 U/mL - Insulin Efsitora
    Reporting group description
    		 Participants received 500 units per milliliter (U/mL) Insulin Efsitora Alfa (insulin efsitora) administered subcutaneously (SC) once weekly (QW) along with 100 U/mL insulin lispro given SC.

    Reporting group title
    100 U/mL - Insulin Glargine
    Reporting group description
    		 Participants received 100 U/mL insulin glargine administered SC once daily (QD) along with 100 U/mL insulin lispro given SC.

    Reporting group values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine Total
    Number of subjects
    		 365 365 730
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 265 243 508
        From 65-84 years
    		 99 121 220
        85 years and over
    		 1 1 2
    Gender categorical
    Units: Subjects
        Female
    		 193 176 369
        Male
    		 172 189 361
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 201 203 404
        Not Hispanic or Latino
    		 163 161 324
        Unknown or Not Reported
    		 1 1 2
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 46 45 91
        Asian
    		 54 51 105
        Black or African American
    		 20 11 31
        White
    		 245 258 503
    Region of Enrollment
    Units: Subjects
        Argentina
    		 83 83 166
        Germany
    		 27 24 51
        India
    		 50 50 100
        Italy
    		 11 15 26
        Mexico
    		 85 84 169
        Spain
    		 35 35 70
        United States
    		 74 74 148

    End points

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    End points reporting groups
    Reporting group title
    500 U/mL - Insulin Efsitora
    Reporting group description
    		 Participants received 500 units per milliliter (U/mL) Insulin Efsitora Alfa (insulin efsitora) administered subcutaneously (SC) once weekly (QW) along with 100 U/mL insulin lispro given SC.

    Reporting group title
    100 U/mL - Insulin Glargine
    Reporting group description
    		 Participants received 100 U/mL insulin glargine administered SC once daily (QD) along with 100 U/mL insulin lispro given SC.
    Reporting group title
    500 U/mL - Insulin Efsitora
    Reporting group description
    		 Participants who received 500 U/mL insulin efsitora administered SC QW along with 100 U/mL insulin lispro given SC in the treatment period were required to complete a safety follow-up period and participants who discontinued the study treatment prematurely were encouraged to remain in the study for safety monitoring.

    Reporting group title
    100 U/mL - Insulin Glargine
    Reporting group description
    		 Participants who received 100 U/mL insulin glargine administered SC once daily (QD) along with 100 U/mL insulin lispro given SC in the treatment period were required to complete a safety follow-up period and participants who discontinued the study treatment prematurely were encouraged to remain in the study for safety monitoring.

    Primary: Change From Baseline in Hemoglobin A1c (HbA1c) [Noninferiority]

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    End point title
    		 Change From Baseline in Hemoglobin A1c (HbA1c) [Noninferiority]
    End point description
    HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Analysis Population Description (APD): All participants who received at least one dose of study drug and had at least one post-baseline HbA1c data.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    361
    362
    Units: millimoles per mole (mmol/mol)
        least squares mean (standard error)
    -11.09 ( 0.506 )
    -10.95 ( 0.506 )
    Statistical analysis title
    		 Outcome Measure No. 1
    Statistical analysis description
    Least Squares (LS) Mean was determined using ANCOVA model with Baseline + Country + Personal Use of CGM or FGM at Randomization + Treatment (Type III sum of squares) as variables. Missing data at Week 26 were imputed by return-to-baseline multiple imputations approach. A total of 100 datasets were imputed. The NIM of 0.4% is equivalent to a NIM of 4.372 mmol/mol.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    723
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.534
         upper limit
    		 1.272
    Notes
    [1] - The sample size provided >99% statistical power to show noninferiority assuming a 0.4% noninferiority margin (NIM), in insulin efsitora doses compared to insulin glargine, in a 1:1 randomization, a standard deviation (SD) of 1.1%, and a dropout rate of 15%.

    Secondary: Change From Baseline in HbA1c [Superiority]

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    End point title
    		 Change From Baseline in HbA1c [Superiority]
    End point description
    HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. APD: All participants who received at least one dose of study drug and had at least one post-baseline HbA1c data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    361
    362
    Units: millimoles per mole
        least squares mean (standard error)
    -11.09 ( 0.506 )
    -10.95 ( 0.506 )
    Statistical analysis title
    		 Outcome Measure No. 2
    Statistical analysis description
    Least Squares (LS) Mean was determined using ANCOVA model with Baseline + Country + Personal Use of CGM or FGM at Randomization + Treatment (Type III sum of squares) as variables. Missing data at Week 26 were imputed by return-to-baseline multiple imputations approach. A total of 100 datasets were imputed.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    723
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.855
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.534
         upper limit
    		 1.272

    Secondary: Percentage of Participants Achieving HbA1c <7% Without Nocturnal Hypoglycemia

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    End point title
    		 Percentage of Participants Achieving HbA1c <7% Without Nocturnal Hypoglycemia
    End point description
    Percentage of participants achieving HbA1c <7% without nocturnal hypoglycemia [<54 milligram/deciliter (mg/dL) 3.0 millimole/Liter (mmol/L)] or severe during treatment phase up to week 26. Nocturnal hypoglycemia is a hypoglycemia event, including severe hypoglycemia, that occurs at night and presumably during sleep between midnight and 6:00 am. APD: All participants who received at least one dose of study drug and had evaluable data for this outcome.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    361
    362
    Units: Percentage of participants
        number (not applicable)
    38.6
    35.9
    Statistical analysis title
    		 Outcome Measure No. 3
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    723
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.504
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.52

    Secondary: Nocturnal Hypoglycemia Event Rate

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    End point title
    		 Nocturnal Hypoglycemia Event Rate
    End point description
    The event rate of participant-reported clinically significant nocturnal hypoglycemia, (where glucose <54 mg/dL (3.0 mmol/L) or severe and occurs at night and presumably during sleep between midnight and 6:00 am), measured during treatment phase up to week 26. APD: All participants who received at least one dose of study drug and had evaluable data for this outcome.
    End point type
    Secondary
    End point timeframe
    Baseline Up To Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    365
    365
    Units: Events per year
        arithmetic mean (standard error)
    0.67 ( 0.112 )
    1.00 ( 0.151 )
    Statistical analysis title
    		 Outcome Measure No. 4
    Statistical analysis description
    Group mean is determined by Negative Binomial Model using Number of episodes = Baseline hypoglycemia rate + Hemoglobin A1c at Baseline (%) + Treatment, with log (exposure in days/365.25) as an offset variable.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    730
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.058
    Method
    		 Negative binomial model
    Parameter type
    		 Relative Rate
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 1.01

    Secondary: Change From Baseline in Fasting Glucose

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    End point title
    		 Change From Baseline in Fasting Glucose
    End point description
    Change from baseline in fasting glucose measured by self-monitoring blood glucose (SMBG). APD: All participants who received at least one dose of study drug and had evaluable data for this outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    361
    361
    Units: millimoles per liter
        least squares mean (standard error)
    -1.71 ( 0.104 )
    -1.48 ( 0.104 )
    Statistical analysis title
    		 Outcome Measure No. 5
    Statistical analysis description
    LS Mean was determined using ANCOVA model using Baseline + Country + Personal Use of CGM or FGM at Randomization + Hemoglobin A1c Stratum at Baseline + Treatment (Type III sum of squares) as variables. Missing data at Baseline were imputed with multiple imputation with assumption of missing at random. Missing data at Week 26 were imputed by return-to-baseline multiple imputations approach. A total of 100 datasets were imputed with one for each of the 100 datasets imputed at Baseline.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.104
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.525
         upper limit
    		 0.049

    Secondary: Percentage of Time in Glucose Range

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    End point title
    		 Percentage of Time in Glucose Range
    End point description
    Percentage of Time in glucose range between 70 and 180 mg/dL (3.9 and 10.0 mmol/L), inclusive measured during the continuous glucose monitoring (CGM) session. APD: All participants who received at least one dose of the study drug and had evaluable data for this outcome.
    End point type
    Secondary
    End point timeframe
    Week 22 to Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    359
    360
    Units: Percentage of time
        least squares mean (standard error)
    58.39 ( 0.993 )
    57.05 ( 0.990 )
    Statistical analysis title
    		 Outcome Measure No. 6
    Statistical analysis description
    LS Mean was determined using ANCOVA model using Baseline + Country + Personal Use of CGM or FGM at Randomization + Hemoglobin A1c Stratum at Baseline + Treatment (Type III sum of squares) as variables. Missing data at Baseline were imputed with multiple imputation with assumption of missing at random. Missing data at Week 22-Week 26 were imputed by return-to-baseline multiple imputations approach. A total of 100 datasets were imputed with one for each of the 100 datasets imputed at Baseline.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.337
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.404
         upper limit
    		 4.101

    Secondary: Percentage of Time in Hypoglycemia Range

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    End point title
    		 Percentage of Time in Hypoglycemia Range
    End point description
    Percentage of Time in hypoglycemia range with glucose <54 mg/dL (3.0 mmol/L), measured by CGM. APD: All participants who received at least one dose of study drug and had evaluable data for this outcome.
    End point type
    Secondary
    End point timeframe
    Week 22 to Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    359
    360
    Units: Percentage of time
        least squares mean (standard error)
    6.84 ( 0.700 )
    5.25 ( 0.680 )
    Statistical analysis title
    		 Outcome Measure No. 7
    Statistical analysis description
    LS Mean was determined by ANCOVA model using Baseline + Country + Personal Use of CGM or FGM at Randomization + Hemoglobin A1c Stratum at Baseline + Treatment (Type III sum of squares) as variables. Missing data at Baseline were imputed with multiple imputation with assumption of missing at random. Missing data at Week 22-Week 26 were imputed by return-to-baseline multiple imputations approach. A total of 100 datasets were imputed with one for each of the 100 datasets imputed at Baseline.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.104
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.327
         upper limit
    		 3.508

    Secondary: Percentatge of Time in Hyperglycemia Range

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    End point title
    		 Percentatge of Time in Hyperglycemia Range
    End point description
    Percentage of Time in hyperglycemia range with glucose >180 mg/dL (10.0 mmol/L), measured by CGM.
    End point type
    Secondary
    End point timeframe
    Week 22 to Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    359
    360
    Units: Percentage of time
        least squares mean (standard error)
    40.10 ( 1.024 )
    41.60 ( 1.024 )
    Statistical analysis title
    		 Outcome Measure No. 8
    Statistical analysis description
    LS Mean was determined by ANCOVA model using Baseline + Country + Personal Use of CGM or FGM at Randomization + Hemoglobin A1c Stratum at Baseline + Treatment (Type III sum of squares). Missing data at Baseline were imputed with multiple imputation with assumption of missing at random. Missing data at Week 22-Week 26 were imputed by return-to-baseline multiple imputations approach. A total of 100 datasets were imputed with one for each of the 100 datasets imputed at Baseline.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.304
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.358
         upper limit
    		 1.36

    Secondary: Glucose Variability Between Weeks 22 to 26

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    End point title
    		 Glucose Variability Between Weeks 22 to 26
    End point description
    Glucose variability measured as coefficient of variation for glucose within day for 24-hour period between Week 22 and 26 was reported. APD: All participants who received at least one dose of study drug and had evaluable data for this outcome.
    End point type
    Secondary
    End point timeframe
    Week 22 to Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    334
    341
    Units: Coefficient of Variation
        least squares mean (standard error)
    28.51 ( 0.259 )
    28.28 ( 0.254 )
    Statistical analysis title
    		 Outcome Measure No. 9
    Statistical analysis description
    LS Mean was determined by MMRM model with BASELINE + Hemoglobin A1c Stratum at Baseline + Country + Personal Use CGM or FGM at Randomization + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. Unstructured variance-covariance structure was used.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    675
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.523
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 0.95

    Secondary: Basal Insulin Dose at Week 26

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    End point title
    		 Basal Insulin Dose at Week 26
    End point description
    Average weekly basal Insulin Dose at Week 26 was reported. APD: All participants who received at least one dose of study drug and had evaluable data for this outcome.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    360
    362
    Units: Units per week of basal insulin
        least squares mean (standard error)
    391.59 ( 7.482 )
    426.62 ( 7.323 )
    Statistical analysis title
    		 Outcome Measure No. 10
    Statistical analysis description
    LS Mean was determined by Mixed Model Repeated Measures (MMRM) model using BASELINE + Hemoglobin A1c Stratum at Baseline + Country + Personal Use CGM or FGM at Randomization + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. Variance-covariance structure was set as compound symmetry.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -35.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -55.57
         upper limit
    		 -14.5

    Secondary: Bolus Insulin Dose at Week 26

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    End point title
    		 Bolus Insulin Dose at Week 26
    End point description
    Average daily bolus Insulin Dose at Week 26 was reported. APD: All participants who received at least one dose of the study drug and had evaluable data for this outcome.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    275
    285
    Units: Units per day of bolus insulin
        least squares mean (standard error)
    27.01 ( 1.182 )
    34.56 ( 1.156 )
    Statistical analysis title
    		 Outcome Measure No. 11
    Statistical analysis description
    LS Mean was determined by MMRM model using BASELINE + Hemoglobin A1c Stratum at Baseline + Country + Personal Use CGM or FGM at Randomization + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. Variance-covariance structure was set as compound symmetry.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    560
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -7.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.79
         upper limit
    		 -4.3

    Secondary: Total Insulin Dose at Week 26

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    End point title
    		 Total Insulin Dose at Week 26
    End point description
    Average total weekly insulin dose at Week 26 was reported. APD: All participants who received at least one dose of study drug and had evaluable data for this outcome.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    274
    285
    Units: Units per week of insulin
        least squares mean (standard error)
    592.92 ( 12.560 )
    666.43 ( 12.144 )
    Statistical analysis title
    		 Outcome Measure No. 12
    Statistical analysis description
    LS Mean was determined by MMRM model using BASELINE + Hemoglobin A1c Stratum at Baseline + Country + Personal Use CGM or FGM at Randomization + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. Variance-covariance structure was set as compound symmetry.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -73.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -107.81
         upper limit
    		 -39.2

    Secondary: Basal Insulin Dose to Total Insulin Dose Ratio at Week 26

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    End point title
    		 Basal Insulin Dose to Total Insulin Dose Ratio at Week 26
    End point description
    Basal insulin dose to total insulin dose ratio at Week 26 was reported. APD: All participants who received at least one dose of the study drug and had evaluable data for this outcome.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    274
    285
    Units: Ratio
        least squares mean (standard error)
    70.09 ( 0.749 )
    66.55 ( 0.722 )
    Statistical analysis title
    		 Outcome Measure No. 13
    Statistical analysis description
    LS Mean was determined by MMRM model using BASELINE + Hemoglobin A1c Stratum at Baseline + Country + Personal Use CGM or FGM at Randomization + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. Variance-covariance structure was set as compound symmetry.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.49
         upper limit
    		 5.58

    Secondary: Hypoglycemia Event Rate

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    End point title
    		 Hypoglycemia Event Rate
    End point description
    Hypoglycemia event rate was reported. Hypoglycemia with glucose <54 mg/dL (Level 2) or Severe Hypoglycemia (Level 3) was reported. A severe hypoglycemic event is characterized by altered mental or physical status requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions for the treatment of hypoglycemia. APD: All participants who received at least one dose of study drug and had evaluable data for this outcome.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    365
    365
    Units: Events per year
        arithmetic mean (standard error)
    6.58 ( 0.709 )
    5.94 ( 0.618 )
    Statistical analysis title
    		 Outcome Measure No. 14
    Statistical analysis description
    Group mean was reported and determined by Negative binomial method using Baseline hypoglycemia rate + Hemoglobin A1c at Baseline (%) + Treatment, with log (exposure in days/365.25) as variables.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    730
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.442
    Method
    		 Negative Binomial Model
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.44

    Secondary: Change From Baseline in Body Weight

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    End point title
    		 Change From Baseline in Body Weight
    End point description
    Change from baseline in body weight was reported. APD: All participants who received at least one dose of study drug and had evaluable data for this outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    365
    365
    Units: kilograms (kg)
        least squares mean (standard error)
    2.67 ( 0.165 )
    2.53 ( 0.165 )
    Statistical analysis title
    		 Outcome Measure No. 15
    Statistical analysis description
    LS Mean was determined by MMRM model using BASELINE + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    730
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.543
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.6

    Secondary: Treatment Experience for Diabetes Injection Device at Week 26 – Experience Questionnaire (DID-EQ)

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    End point title
    		 Treatment Experience for Diabetes Injection Device at Week 26 – Experience Questionnaire (DID-EQ)
    End point description
    The DID-EQ is a self-administered, 10-item questionnaire designed to assess participants' perceptions of diabetes injection delivery systems for diabetes. The Device Characteristic Subscale is comprised of items 1 to 7 which focus on specific characteristics of injection devices. Each item is rated on a four-point Likert scale. Scores are transformed and range from 0 to 100. Higher scores indicate more positive perceptions of injection device characteristics APD: All participants who received at least one dose of study drug and had evaluable data for this outcome.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 500 U/mL - Insulin Efsitora 100 U/mL - Insulin Glargine
    Number of subjects analysed
    274
    286
    Units: Score on a scale
        least squares mean (standard error)
    88.1 ( 0.77 )
    86.3 ( 0.75 )
    Statistical analysis title
    		 Outcome Measure No. 16
    Statistical analysis description
    LS Mean was determined by ANCOVA model using Country + Personal Use CGM or FGM at Randomization + Hemoglobin A1c Stratum at Baseline + Treatment (Type III sum of squares) as variables.
    Comparison groups
    500 U/mL - Insulin Efsitora v 100 U/mL - Insulin Glargine
    Number of subjects included in analysis
    560
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.099
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline Through Safety Follow-Up (Up To 31 Weeks)
    Adverse event reporting additional description
    All participants who received at least one dose of the study drug. Gender specific events occurring only in male or female participants have had the number of participants at risk adjusted accordingly. Based on the planned safety analysis, adverse event analysis was planned as per the cohorts corresponding to the actual regimen received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    100 U/mL - Insulin Glargine
    Reporting group description
    		 Participants received 100 U/mL insulin glargine administered SC QD along with 100 U/mL insulin lispro given SC.

    Reporting group title
    500 U/mL - Insulin Efsitora
    Reporting group description
    		 Participants received 500 U/mL insulin efsitora administered SC QW along with 100 U/mL insulin lispro given SC.

    Serious adverse events
    		 100 U/mL - Insulin Glargine 500 U/mL - Insulin Efsitora
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 365 (6.58%)
    25 / 365 (6.85%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    cervix carcinoma
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed [1]
    0 / 176 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal cell carcinoma
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lung adenocarcinoma
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    aortic stenosis
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypotension
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypertensive emergency
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    chest pain
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    drug hypersensitivity
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    acute respiratory failure
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumothorax
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    respiratory distress
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    acute psychosis
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bipolar disorder
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    lower limb fracture
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rib fracture
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    arteriosclerosis coronary artery
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    angina pectoris
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiac arrest
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    acute myocardial infarction
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrioventricular block
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiac failure congestive
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    left ventricular failure
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    cerebrovascular accident
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    migraine
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    deafness neurosensory
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    abdominal hernia
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ascites
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abdominal pain
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemoperitoneum
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intestinal obstruction
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pancreatitis acute
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    cholelithiasis
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hepatic cirrhosis
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    postrenal failure
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nephrolithiasis
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary tract obstruction
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    spinal instability
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    appendicitis
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastroenteritis viral
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastroenteritis bacterial
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diabetic foot infection
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    osteomyelitis
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    soft tissue infection
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    hypoglycaemia
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    5 / 365 (1.37%)
    5 / 365 (1.37%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Gender specific events occurring only in male or female participants have had the number of participants at risk adjusted accordingly.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 100 U/mL - Insulin Glargine 500 U/mL - Insulin Efsitora
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 365 (10.96%)
    35 / 365 (9.59%)
    Infections and infestations
    nasopharyngitis
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    21 / 365 (5.75%)
    23 / 365 (6.30%)
         occurrences all number
    23
    25
    influenza
    alternative dictionary used: MedDRA 26.1
         subjects affected / exposed
    19 / 365 (5.21%)
    14 / 365 (3.84%)
         occurrences all number
    20
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 May 2022
    - Clarified terms and statements in the Objectives, Endpoints, and Estimands section; - Modified some inclusion and exclusion criteria for more clarity and to address regulator feedback.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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