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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Parallel-Design, Open-Label Study to Evaluate the Efficacy and Safety of LY3209590 as a Weekly Basal Insulin Compared with Insulin Degludec in Participants with Type 1 Diabetes Treated with Multiple Daily Injection Therapy

    Summary
    EudraCT number
    		 2021-005892-38
    Trial protocol
    		 SK   PL  
    Global end of trial date
    07 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 May 2025
    First version publication date
    22 May 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    I8H-MC-BDCY
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05463744
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 18263
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, 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
    07 May 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    A Study of Insulin Efsitora Alfa (LY3209590) Compared with Insulin Degludec in Participants with Type 1 Diabetes Treated with Multiple Daily Injection Therapy
    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
    12 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
    Poland: 132
    Country: Number of subjects enrolled
    Slovakia: 32
    Country: Number of subjects enrolled
    Argentina: 197
    Country: Number of subjects enrolled
    Japan: 101
    Country: Number of subjects enrolled
    Taiwan: 32
    Country: Number of subjects enrolled
    United States: 198
    Worldwide total number of subjects
    692
    EEA total number of subjects
    164
    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)
    631
    From 65 to 84 years
    61
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    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 Alfa
    Arm description
    		 Participants who were treated with prestudy basal insulin and prandial insulin therapy (100 units per milliliter (U/mL) Insulin Lispro) received 500 U/mL of insulin efsitora alfa administered once weekly (QW) for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin Efsitora Alfa
    Investigational medicinal product code
    LY3209590
    Other name
    Basal Insulin-FC
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who were treated with prestudy basal insulin and prandial insulin therapy (100 U/mL Insulin Lispro) received 500 U/mL of insulin efsitora alfa administered QW for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.

    Arm title
    		 100 U/mL Insulin Degludec
    Arm description
    		 Participants who were treated with prestudy basal insulin and prandial insulin therapy (100 U/mL Insulin Lispro) received 100 U/mL of Insulin Degludec administered once daily (QD) for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin Degludec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who were treated with prestudy basal insulin and prandial insulin therapy (100 U/mL Insulin Lispro) received 100 U/mL of Insulin Degludec administered QD for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.

    Number of subjects in period 1
    		500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Started
    343
    349
    Received at Least one Dose of Study Drug
    343
    349
    Completed
    316
    319
    Not completed
    27
    30
         Non-compliance with Study Drug
    1
    -
         Consent withdrawn by subject
    19
    16
         Physician decision
    -
    1
         Adverse event, non-fatal
    4
    4
         Death
    -
    1
         Pregnancy
    -
    3
         Inadvertent enrollment
    2
    1
         Lost to follow-up
    1
    3
         Subject Terminated by Sponsor
    -
    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 Alfa
    Arm description
    		 Participants who were treated with prestudy basal insulin and prandial insulin therapy (100U/mL Insulin Lispro) received 500 U/mL of insulin efsitora alfa administered QW for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin Efsitora Alfa
    Investigational medicinal product code
    LY3209590
    Other name
    Basal Insulin-FC
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who were treated with prestudy basal insulin and prandial insulin therapy (100 U/mL Insulin Lispro) received 500 U/mL of insulin efsitora alfa administered QW for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.

    Arm title
    		 100 U/mL Insulin Degludec
    Arm description
    		 Participants who were treated with prestudy basal insulin and prandial insulin therapy (100 U/mL Insulin Lispro) received 100 U/mL of Insulin Degludec administered QD for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin Degludec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants who were treated with prestudy basal insulin and prandial insulin therapy (100 U/mL Insulin Lispro) received 100 U/mL of Insulin Degludec administered QD for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.

    Number of subjects in period 2
    		500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Started
    332
    326
    Completed
    328
    324
    Not completed
    4
    2
         Consent withdrawn by subject
    3
    1
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    500 U/mL Insulin Efsitora Alfa
    Reporting group description
    		 Participants who were treated with prestudy basal insulin and prandial insulin therapy (100 units per milliliter (U/mL) Insulin Lispro) received 500 U/mL of insulin efsitora alfa administered once weekly (QW) for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.

    Reporting group title
    100 U/mL Insulin Degludec
    Reporting group description
    		 Participants who were treated with prestudy basal insulin and prandial insulin therapy (100 U/mL Insulin Lispro) received 100 U/mL of Insulin Degludec administered once daily (QD) for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.

    Reporting group values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec Total
    Number of subjects
    		 343 349 692
    Age categorical
    Units: Subjects
    Age continuous
    Analysis Population Description (APD): All randomized participants who received at least one dose of the study drug.
    Units: years
        arithmetic mean (standard deviation)
    		 44.40 ( 14.22 ) 43.60 ( 14.01 ) -
    Gender categorical
    Units: Subjects
        Female
    		 150 158 308
        Male
    		 193 191 384
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 121 116 237
        Not Hispanic or Latino
    		 221 230 451
        Unknown or Not Reported
    		 1 3 4
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 69 73 142
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 11 13 24
        White
    		 259 262 521
        More than one race
    		 2 1 3
        Unknown or Not Reported
    		 0 0 0
    Region of Enrollment
    Units: Subjects
        Argentina
    		 98 99 197
        Japan
    		 48 53 101
        Poland
    		 66 66 132
        Slovakia
    		 15 17 32
        Taiwan
    		 15 17 32
        United States
    		 101 97 198
    HemoglobinA1c (HbA1c)
    HbA1c is the glycosylated fraction of hemoglobin A. It is measured primarily to identify the average plasma glucose concentration over prolonged periods of time.
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    		 7.88 ( 0.75 ) 7.94 ( 0.72 ) -

    End points

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    End points reporting groups
    Reporting group title
    500 U/mL Insulin Efsitora Alfa
    Reporting group description
    		 Participants who were treated with prestudy basal insulin and prandial insulin therapy (100 units per milliliter (U/mL) Insulin Lispro) received 500 U/mL of insulin efsitora alfa administered once weekly (QW) for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.

    Reporting group title
    100 U/mL Insulin Degludec
    Reporting group description
    		 Participants who were treated with prestudy basal insulin and prandial insulin therapy (100 U/mL Insulin Lispro) received 100 U/mL of Insulin Degludec administered once daily (QD) for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.
    Reporting group title
    500 U/mL Insulin Efsitora Alfa
    Reporting group description
    		 Participants who were treated with prestudy basal insulin and prandial insulin therapy (100U/mL Insulin Lispro) received 500 U/mL of insulin efsitora alfa administered QW for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.

    Reporting group title
    100 U/mL Insulin Degludec
    Reporting group description
    		 Participants who were treated with prestudy basal insulin and prandial insulin therapy (100 U/mL Insulin Lispro) received 100 U/mL of Insulin Degludec administered QD for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.

    Primary: Change from Baseline in Hemoglobin A1c (HbA1c) at Week 26 [Noninferiority Analysis]

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    End point title
    		 Change from Baseline in Hemoglobin A1c (HbA1c) at Week 26 [Noninferiority Analysis]
    End point description
    HbA1c is the glycosylated fraction of hemoglobin A. It is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined using Analysis of Covariance (ANCOVA) model treatment + country + CGM use prior to study entry [yes/no]+ carbohydrate counting for prandial insulin[yes/no] + baseline value of the dependent variable (Type III sum of squares) as variables. Missing data at Week 26 were imputed by return-to-baseline multiple imputations approach. APD: All randomized participants who received at least one dose of the study drug and had HbA1c measurement at baseline or Week 26. Participants who discontinued the study drug due to inadvertent enrollment were excluded.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    341
    348
    Units: millimoles per mole (mmol/mol)
        least squares mean (standard error)
    -5.53 ( 0.512 )
    -6.10 ( 0.506 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    689
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.85
         upper limit
    		 1.98
    Notes
    [1] - 0.4% noninferiority margin (NIM)

    Secondary: Change from Baseline in Hemoglobin A1c (HbA1c) at Week 26 [Superiority Analysis]

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    End point title
    		 Change from Baseline in Hemoglobin A1c (HbA1c) at Week 26 [Superiority Analysis]
    End point description
    HbA1c is the glycosylated fraction of hemoglobin A. It is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. LS mean was determined using ANCOVA model with treatment + country + CGM use prior to study entry [yes/no] + carbohydrate counting for prandial insulin[yes/no] + baseline value of the dependent variable (Type III sum of squares) as variables. Missing data at Week 26 were imputed by return-to-baseline multiple imputations approach. APD: All randomized participants who received at least one dose of the study drug and had HbA1c measurement at baseline or Week 26. Participants who discontinued the study drug due to inadvertent enrollment were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    341
    348
    Units: mmol/mol
        least squares mean (standard error)
    -5.53 ( 0.512 )
    -6.10 ( 0.506 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    689
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.432
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.85
         upper limit
    		 1.98

    Secondary: Percentage of Time-in-Glucose Range Between 70 and 180 mg/dL [3.9 and 10.0 mmol/L]

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    End point title
    		 Percentage of Time-in-Glucose Range Between 70 and 180 mg/dL [3.9 and 10.0 mmol/L]
    End point description
    Time in glucose range between 70 and 180 milligram per deciliter (mg/dL) [3.9 and 10.0 millimole per liter (mmol/L)], measured by continued glucose monitoring (CGM) from week 23-26 inclusive over a 24-Hour Period. The time component of the time-in-range statistic was calculated using the display time recorded by the CGM device. LS mean was determined using ANCOVA model with treatment+country+CGM use prior to study entry [yes/no]+carbohydrate counting for prandial insulin dosing [yes/no]+Hemoglobin A1c Stratum at Baseline and baseline value of the dependent variable (Type III sum of squares) as variables.Missing data at Week 23-26 were imputed by return-to-baseline multiple imputations approach. APD:All randomized participants who took at least one dose of study drug and had evaluable data for this outcome at baseline or Week 23-26 were included. Participants who discontinued study drug due to inadvertent enrollment were excluded
    End point type
    Secondary
    End point timeframe
    Week 23 to Week 26
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    339
    347
    Units: Percentage of time
        least squares mean (standard error)
    52.54 ( 0.691 )
    52.85 ( 0.684 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    686
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.751
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.22
         upper limit
    		 1.6

    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 (defined as blood glucose level <54 mg/dL (3.0 mmol/L) or severe hypoglycemia and occurs at night and presumably during sleep between midnight and 6:00 AM), measured during treatment phase up to week 52. Group mean was reported and determined by Negative binomial model using Number of episodes = Baseline hypoglycemia rate + HbA1c at Baseline (%) + Treatment, with log (exposure in days/365.25) as an offset variable. APD: All randomized 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
    Baseline up to Week 52
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    343
    349
    Units: events per year
        arithmetic mean (standard error)
    1.99 ( 0.180 )
    1.96 ( 0.177 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 Negative binomial model
    Parameter type
    		 Relative Rate
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.31

    Secondary: Change from Baseline in HbA1c at Week 52 [Noninferiority Analysis]

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    End point title
    		 Change from Baseline in HbA1c at Week 52 [Noninferiority Analysis]
    End point description
    HbA1c is the glycosylated fraction of hemoglobin A. It is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. LS mean was determined using ANCOVA model with treatment + country + CGM use prior to study entry [yes/no]+ carbohydrate counting for prandial insulin[yes/no] + baseline value of the dependent variable (Type III sum of squares) as variables. Missing data at Week 52 were imputed by return-to-baseline multiple imputations approach. APD: All randomized participants who received at least one dose of the study drug and had HbA1c measurement at baseline or Week 52. Participants who discontinued the study drug due to inadvertent enrollment were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    341
    348
    Units: mmol/mol
        least squares mean (standard error)
    -4.10 ( 0.529 )
    -4.36 ( 0.524 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    689
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 1.72
    Notes
    [2] - 0.4% noninferiority margin (NIM)

    Secondary: Change from Baseline in Fasting Blood Glucose

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    End point title
    		 Change from Baseline in Fasting Blood Glucose
    End point description
    Change from baseline in fasting glucose measured by self-monitoring blood glucose (SMBG). LS mean was determined using ANCOVA model with treatment, country, CGM use prior to study entry [yes/no], carbohydrate counting for prandial insulin dosing [yes/no]) and baseline value of the dependent variable as variables. Missing data at Baseline were imputed with multiple imputation with assumption of missing at random. Missing data were imputed by return-to-baseline multiple imputations approach. APD: All randomized participants who received at least one dose of the study drug and had evaluable data for this outcome at Baseline, Week 26, or Week 52 were included in the analysis. For the Week 26 analysis, data from Baseline or Week 26 were considered, while for the Week 52 analysis, data from Baseline or Week 52 were included. Participants who discontinued the study drug due to inadvertent enrollment were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26, and Week 52
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    341
    348
    Units: millimoles per liter
    least squares mean (standard error)
        Week 26
    -1.48 ( 0.125 )
    -1.41 ( 0.123 )
        Week 52
    -1.38 ( 0.138 )
    -1.11 ( 0.136 )
    Statistical analysis title
    		 Statistical Analysis 1: Week 26
    Comparison groups
    100 U/mL Insulin Degludec v 500 U/mL Insulin Efsitora Alfa
    Number of subjects included in analysis
    689
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.697
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.41
         upper limit
    		 0.27
    Statistical analysis title
    		 Statistical Analysis 2: Week 52
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    689
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.163
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.65
         upper limit
    		 0.11

    Secondary: Glucose Variability

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    End point title
    		 Glucose Variability
    End point description
    Glucose variability measured as coefficient of variation (CV) for blood glucose during the CGM session over a 24-hour period, between Week 23 to Week 26 and Week 49 to Week 52 was reported. LS mean was determined using mixed model repeated measures (MMRM) model with BASELINE + Country + Prior CGM use + Carbohydrate counting for Prandial Dose + Hemoglobin A1c Stratum at Baseline + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. Unstructured variance-covariance structure was used. APD: All randomized participants who took at least one dose of the study drug and had a baseline and at least one post- baseline value for this outcome. Participants who discontinued the study drug due to inadvertent enrollment were excluded.
    End point type
    Secondary
    End point timeframe
    Week 23 to Week 26 and Week 49 to Week 52
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    331
    332
    Units: percentage of CV
    least squares mean (standard error)
        Week 23 to Week 26
    33.72 ( 0.230 )
    33.69 ( 0.229 )
        Week 49 to Week 52
    33.69 ( 0.233 )
    33.18 ( 0.233 )
    Statistical analysis title
    		 Statistical Analysis 1: Week 23 to Week 26
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.939
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.61
         upper limit
    		 0.66
    Statistical analysis title
    		 Statistical Analysis 2: Week 49 to Week 52
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.116
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 1.17

    Secondary: Percentage of Time in the Blood Glucose Range Between 70 and 180 mg/dL [3.9 and 10.0 mmol/L]

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    End point title
    		 Percentage of Time in the Blood Glucose Range Between 70 and 180 mg/dL [3.9 and 10.0 mmol/L]
    End point description
    Percentage of time spent within the blood glucose range of 70 to 180 mg/dL [3.9 to 10.0 mmol/L], as measured during the CGM session over a 24-hour period, from Week 49 to Week 52. LS mean was determined using ANCOVA model with treatment, country, CGM use prior to study entry [yes/no], carbohydrate counting for prandial insulin dosing [yes/no]) and Hemoglobin A1c Stratum at baseline and baseline value of the dependent variable as variables. Missing data at Baseline were imputed with multiple imputation with assumption of missing at random. Missing data were imputed by return-to-baseline multiple imputations approach. APD: All randomized participants who received at least one dose of the study drug and had evaluable data for this outcome at baseline or Week 49-52 were included in the analysis. Participants who discontinued the study drug due to inadvertent enrollment were excluded.
    End point type
    Secondary
    End point timeframe
    Week 49 to Week 52
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    338
    347
    Units: percentage of time
        least squares mean (standard error)
    50.28 ( 0.755 )
    49.74 ( 0.744 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    685
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.61
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.54
         upper limit
    		 2.62

    Secondary: Basal Insulin Dose

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    End point title
    		 Basal Insulin Dose
    End point description
    The insulin dose was recorded daily or weekly in an electronic diary. The average weekly basal insulin dose at Week 26 and Week 52 was reported. LS mean was determined using MMRM model with BASELINE + Hemoglobin A1c Stratum at Baseline + Country + Prior CGM use + Carbohydrate counting for Prandial Dose + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. Variance-covariance structure was set as compound symmetry. APD: All randomized participants who received at least one dose of the study drug and had a baseline and at least one post-baseline value for this outcome. Participants who discontinued the study drug due to inadvertent enrollment were excluded.
    End point type
    Secondary
    End point timeframe
    Week 26 and Week 52
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    341
    347
    Units: Units per week (U/week)
    least squares mean (standard error)
        Week 26
    199.51 ( 4.47 )
    208.47 ( 4.43 )
        Week 52
    204.37 ( 4.50 )
    211.25 ( 4.46 )
    Statistical analysis title
    		 Statistical Analysis 1: Week 26
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    688
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.155
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -8.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.3
         upper limit
    		 3.38
    Statistical analysis title
    		 Statistical Analysis 2: Week 52
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    688
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.278
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -6.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.31
         upper limit
    		 5.55

    Secondary: Bolus Insulin Dose

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    End point title
    		 Bolus Insulin Dose
    End point description
    The insulin dose was recorded daily or weekly in an electronic diary. The average daily bolus insulin dose at Week 26 and Week 52 was reported. LS mean was determined using MMRM model with BASELINE + Hemoglobin A1c Stratum at Baseline + Country + Prior CGM use + Carbohydrate counting for Prandial Dose + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. Variance-covariance structure was set as compound symmetry. APD: All randomized participants who received at least one dose of the study drug and had a baseline and at least one post-baseline value for this outcome. Participants who discontinued the study drug due to inadvertent enrollment were excluded.
    End point type
    Secondary
    End point timeframe
    Week 26 and Week 52
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    307
    327
    Units: Units per day (U/day)
    least squares mean (standard error)
        Week 26
    21.48 ( 0.64 )
    25.25 ( 0.62 )
        Week 52
    22.62 ( 0.65 )
    26.10 ( 0.63 )
    Statistical analysis title
    		 Statistical Analysis 1: Week 26
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.52
         upper limit
    		 -2.03
    Statistical analysis title
    		 Statistical Analysis 2: Week 52
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.26
         upper limit
    		 -1.71

    Secondary: Total Insulin Dose

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    End point title
    		 Total Insulin Dose
    End point description
    The average weekly total insulin dose is the sum of the average weekly basal and bolus doses. LS mean was determined using MMRM model with BASELINE + Hemoglobin A1c Stratum at Baseline + Country + Prior CGM use + Carbohydrate counting for Prandial Dose + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. Variance-covariance structure was set as compound symmetry. APD: All randomized participants who received at least one dose of the study drug and had a baseline and at least one post-baseline value for this outcome. Participants who discontinued the study drug due to inadvertent enrollment were excluded.
    End point type
    Secondary
    End point timeframe
    Week 26 and Week 52
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    305
    327
    Units: Units per week (U/week)
    least squares mean (standard error)
        Week 26
    343.91 ( 6.72 )
    383.19 ( 6.47 )
        Week 52
    355.66 ( 6.81 )
    391.60 ( 6.53 )
    Statistical analysis title
    		 Statistical Analysis 1: Week 26
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    632
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -39.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.59
         upper limit
    		 -20.98
    Statistical analysis title
    		 Statistical Analysis 2: Week 52
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    632
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -35.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.44
         upper limit
    		 -17.43

    Secondary: Basal Insulin Dose to Total Insulin Dose Ratio

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    End point title
    		 Basal Insulin Dose to Total Insulin Dose Ratio
    End point description
    The basal/total insulin dose ratio is the average weekly basal dose divided by the average weekly total dose. LS mean was determined using MMRM model with BASELINE + Hemoglobin A1c Stratum at Baseline + Country + Prior CGM use + Carbohydrate counting for Prandial Dose + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. Variance-covariance structure was set as compound symmetry. APD: All randomized participants who received at least one dose of the study drug and had a baseline and at least one post-baseline value for this outcome. Participants who discontinued the study drug due to inadvertent enrollment were excluded.
    End point type
    Secondary
    End point timeframe
    Week 26 and Week 52
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    305
    327
    Units: Ratio
    least squares mean (standard error)
        Week 26
    56.4 ( 0.69 )
    53.2 ( 0.66 )
        Week 52
    55.4 ( 0.70 )
    52.6 ( 0.67 )
    Statistical analysis title
    		 Statistical Analysis 1: Week 26
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    632
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.32
         upper limit
    		 5.06
    Statistical analysis title
    		 Statistical Analysis 2: Week 52
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    632
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 4.7

    Secondary: Hypoglycemia Event Rate

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    End point title
    		 Hypoglycemia Event Rate
    End point description
    Rate of Composite Level 2 and 3 Hypoglycemia Events were reported. Hypoglycemia with glucose <54 mg/dL (Level 2) or Severe Hypoglycemia confirmed by the investigator to be an event that required assistance for treatment (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. Group mean was reported and determined by Negative binomial model using Number of episodes = Baseline hypoglycemia rate + HbA1c at Baseline (%) + Treatment, with log (exposure in days/365.25) as an offset variable. APD: All randomized participants who received at least one dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    343
    349
    Units: Events per year
        arithmetic mean (standard error)
    14.03 ( 0.816 )
    11.59 ( 0.681 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.016
    Method
    		 Negative binomial model
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.04
         upper limit
    		 1.41

    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. LS Mean was determined by MMRM model using Baseline + Treatment + Time + Treatment*Time (Type III sum of squares) as variables. Variance-covariance structure was set as compound symmetry. APD: All randomized participants who received at least one dose of the study drug and had baseline, at least one post-baseline evaluable data for this outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26, and Week 52
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    342
    348
    Units: kilograms (kg)
    least squares mean (standard error)
        Baseline, Week 26
    1.71 ( 0.159 )
    1.62 ( 0.158 )
        Baseline, Week 52
    1.96 ( 0.160 )
    1.85 ( 0.159 )
    Statistical analysis title
    		 Statistical Analysis 1: Week 26
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    690
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.702
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.086
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 0.53
    Statistical analysis title
    		 Statistical Analysis 2: Week 52
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    690
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.609
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0.56

    Secondary: Percentage of Time in Hypoglycemia Range With Blood Glucose <54 mg/dL (3.0 mmol/L)

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    End point title
    		 Percentage of Time in Hypoglycemia Range With Blood Glucose <54 mg/dL (3.0 mmol/L)
    End point description
    Percentage of time spent in the hypoglycemia range with blood glucose < 54 mg/dL (3.0 mmol/L), as measured during the CGM session over a 24-hour period from week 23 to week 26 and week 49 to week 52 was reported. LS Mean was determined by ANCOVA model using treatment + country + CGM use prior to study entry [yes/no] + carbohydrate counting for prandial insulin dosing [yes/no] + Hemoglobin A1c Stratum at Baseline and baseline value of the dependent variable (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 23-week 26 and week 49-week 52 were imputed by return-to-baseline multiple imputations approach. APD: For the Week 23-26 analysis, data from Baseline or Week 23-26 were considered, while for the Week 49-52 analysis, data from Baseline or Week 49-52 were included. Participants who discontinued the study drug due to inadvertent enrollment were excluded.
    End point type
    Secondary
    End point timeframe
    Week 23 to Week 26 and Week 49 to Week 52 APD: All randomized participants who received at least one dose of the study drug and had evaluable data for this outcome at Baseline, Week 23-26, or Week 49-52 were included in the analysis.
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    339
    347
    Units: percentage of time
    least squares mean (standard error)
        Week 23 to Week 26
    0.75 ( 0.058 )
    0.72 ( 0.057 )
        Week 49 to Week 52
    0.74 ( 0.053 )
    0.64 ( 0.052 )
    Statistical analysis title
    		 Statistical Analysis 1: Week 23 to Week 26
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    686
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.681
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.19
    Statistical analysis title
    		 Statistical Analysis 2: Week 49 to Week 52
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    686
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.182
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.24

    Secondary: Percentage of Time in Hyperglycemia Range With Blood Glucose >180 mg/dL (10.0 mmol/L) from Week 23 to Week 26

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    End point title
    		 Percentage of Time in Hyperglycemia Range With Blood Glucose >180 mg/dL (10.0 mmol/L) from Week 23 to Week 26
    End point description
    Percentage of time spent in the hyperglycemia range with blood glucose greater than (>) 180 mg/dL (10.0 mmol/L), as measured during the CGM session over a 24-hour period from Week 23 to Week 26 was reported. LS Mean was determined by ANCOVA model using treatment + country + CGM use prior to study entry [yes/no] + carbohydrate counting for prandial insulin dosing [yes/no] + Hemoglobin A1c Stratum at Baseline and baseline value of the dependent variable (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 23-week 26 were imputed by return-to-baseline multiple imputations approach. APD: All randomized participants who received at least one dose of the study drug and had evaluable data for this outcome at baseline or Week 23-26 were included in the analysis. Participants who discontinued the study drug due to inadvertent enrollment were excluded
    End point type
    Secondary
    End point timeframe
    Week 23 to Week 26
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    339
    347
    Units: percentage of time
        least squares mean (standard error)
    44.29 ( 0.743 )
    44.29 ( 0.735 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    686
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.999
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.06
         upper limit
    		 2.05

    Secondary: Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) at Week 26

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    End point title
    		 Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) at Week 26
    End point description
    The DTSQc score is used to assess relative change in participant satisfaction from baseline. The questionnaire consists of 8 items, 6 of which measure Treatment Satisfaction, dealing with: 1. satisfaction with current treatment; 2. convenience of the treatment; 3. flexibility; 4. satisfaction with own understanding of participant's diabetes; 5. how likely to recommend their present treatment; and 6. how satisfied to continue with their present treatment. Each item is rated on a 7-point Likert scale (which ranges from -3 (much less satisfied) to +3 (much more satisfied). The scores from the 6 treatment satisfaction items are summed to a Total Treatment Satisfaction Score, which ranges from -18 (much less satisfied) to +18 (much more satisfied). Higher the score the greater the improvement in satisfaction with treatment. The lower the score the greater the deterioration in satisfaction with treatment.
    End point type
    Secondary
    End point timeframe
    Week 26 APD: All randomized participants who received at least one dose of the study drug and had evaluable data for this outcome. Participants who discontinued the study drug due to inadvertent enrollment were excluded.
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    306
    314
    Units: score on a scale
        least squares mean (standard error)
    14.4 ( 4.53 )
    13.2 ( 5.20 )
    Statistical analysis title
    		 Statistical Analysis: Week 26
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.008
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) at Week 52

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    End point title
    		 Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) at Week 52
    End point description
    The DTSQc score is used to assess relative change in participant satisfaction from baseline. The questionnaire consists of 8 items, 6 of which measure Treatment Satisfaction, dealing with: 1. satisfaction with current treatment; 2. convenience of the treatment; 3. flexibility; 4. satisfaction with own understanding of participant's diabetes; 5. how likely to recommend their present treatment; and 6. how satisfied to continue with their present treatment. Each item is rated on a 7-point Likert scale (which ranges from -3 (much less satisfied) to +3 (much more satisfied). The scores from the 6 treatment satisfaction items are summed to a Total Treatment Satisfaction Score, which ranges from -18 (much less satisfied) to +18 (much more satisfied). Higher the score the greater the improvement in satisfaction with treatment. The lower the score the greater the deterioration in satisfaction with treatment.
    End point type
    Secondary
    End point timeframe
    Week 52 APD: All randomized participants who received at least one dose of the study drug and had evaluable data for this outcome. Participants who discontinued the study drug due to inadvertent enrollment were excluded.
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    310
    312
    Units: score on a scale
        arithmetic mean (standard deviation)
    14.4 ( 5.31 )
    12.8 ( 5.67 )
    Statistical analysis title
    		 Statistical Analysis: Week 52
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    622
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change From Baseline in Short Form-36 Version 2 (SF-36 v2) Acute Form (Physical-Component and Mental-Component) Scores

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    End point title
    		 Change From Baseline in Short Form-36 Version 2 (SF-36 v2) Acute Form (Physical-Component and Mental-Component) Scores
    End point description
    The SF-36v2 is a participant-reported measure designed to assess health status using 36 items across 8 domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. The 8 health domains are aggregated into two summary scores known as the physical component summary (PCS) score and the mental component summary (MCS) score. Scoring of each domain and both summary scores are norm based and presented in the form of T-scores, with a mean of 50 and a standard deviation of 10. Higher scores indicate better levels of function and/or better health. Range cannot be specified in norm-based scores. LS Mean was determined by MMRM model with Baseline + Country + Carbohydrate counting for Prandial Dose + Prior CGM use + Hemoglobin A1c Stratum at Baseline + Treatment + Time + Treatment*Time (Type III sum of squares). as variables. Unstructured variance-covariance structure was used.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26, and Week 52 APD:All randomized participants who received at least one dose of study drug,had baseline and atleast one post-baseline value for this outcome.Participants discontinued study drug due to inadvertent enrollment were excluded
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    327
    330
    Units: score on a scale
    least squares mean (standard error)
        Physical Component Score: Baseline, Week 26
    0.19 ( 0.275 )
    -0.24 ( 0.272 )
        Physical Component Score: Baseline, Week 52
    0.48 ( 0.262 )
    -0.25 ( 0.260 )
        Mental Component Score: Baseline, Week 26
    0.58 ( 0.419 )
    0.36 ( 0.415 )
        Mental Component Score: Baseline, Week 52
    0.61 ( 0.419 )
    0.16 ( 0.417 )
    Statistical analysis title
    		 Statistical Analysis 1: PCS: Baseline, Week 26
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    657
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.27
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 1.19
    Statistical analysis title
    		 Statistical Analysis 2: PCS: Baseline, Week 52
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    657
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 1.45
    Statistical analysis title
    		 Statistical Analysis 3: MCS: Baseline, Week 26
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    657
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.71
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.94
         upper limit
    		 1.38
    Statistical analysis title
    		 Statistical Analysis 4: MCS: Baseline, Week 52
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    657
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.447
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.71
         upper limit
    		 1.61

    Secondary: Percentage of Time in Hyperglycemia Range With Blood Glucose >180 mg/dL (10.0 mmol/L) From Week 49 to Week 52

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    End point title
    		 Percentage of Time in Hyperglycemia Range With Blood Glucose >180 mg/dL (10.0 mmol/L) From Week 49 to Week 52
    End point description
    Percentage of time spent in the hyperglycemia range with blood glucose greater than (>) 180 mg/dL (10.0 mmol/L), as measured during the CGM session over a 24-hour period from Week 49 to Week 52 was reported. LS Mean was determined by ANCOVA model using treatment + country + CGM use prior to study entry [yes/no] + carbohydrate counting for prandial insulin dosing [yes/no] + Hemoglobin A1c Stratum at Baseline and baseline value of the dependent variable (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 49-week 52 were imputed by return-to-baseline multiple imputations approach. APD: All randomized participants who received at least one dose of the study drug and had evaluable data for this outcome at baseline or Week 49-52 were included in the analysis. Participants who discontinued the study drug due to inadvertent enrollment were excluded.
    End point type
    Secondary
    End point timeframe
    Week 49 to Week 52
    End point values
    		 500 U/mL Insulin Efsitora Alfa 100 U/mL Insulin Degludec
    Number of subjects analysed
    338
    347
    Units: percentage of time
        least squares mean (standard error)
    46.73 ( 0.811 )
    47.56 ( 0.797 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    500 U/mL Insulin Efsitora Alfa v 100 U/mL Insulin Degludec
    Number of subjects included in analysis
    685
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.468
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.06
         upper limit
    		 1.41

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to end of safety follow-up (up to 57 weeks)
    Adverse event reporting additional description
    All randomized participants who received at least one dose of study drug. Gender specific events occurring only in male or female participants have had the number of participants at risk adjusted accordingly. Participants were analyzed based on the actual treatment they received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    100 U/mL Insulin Degludec
    Reporting group description
    		 Participants who were treated with prestudy basal insulin and prandial insulin therapy (100 U/mL Insulin Lispro) received 100 U/mL of Insulin Degludec administered once QW for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.

    Reporting group title
    500 U/mL Insulin Efsitora Alfa
    Reporting group description
    		 Participants who were treated with prestudy basal insulin and prandial insulin therapy (100 U/mL) Insulin Lispro) received 500 U/mL of insulin efsitora alfa administered QD for 52 weeks as subcutaneous injection, followed by a 5-week safety follow-up.

    Serious adverse events
    		 100 U/mL Insulin Degludec 500 U/mL Insulin Efsitora Alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 349 (6.88%)
    45 / 343 (13.12%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Vascular disorders
    aortic stenosis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    abortion spontaneous
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed [1]
    0 / 158 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    dyspnoea
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    completed suicide
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    ankle fracture
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    limb injury
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    meniscus injury
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    road traffic accident
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    chronic granulomatous disease
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    limb reduction defect
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    angina pectoris
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    angina unstable
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    coronary artery disease
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    acute myocardial infarction
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    aphasia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dizziness
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    seizure
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    epilepsy
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    generalised tonic-clonic seizure
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoglycaemic seizure
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoglycaemic unconsciousness
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    4 / 349 (1.15%)
    10 / 343 (2.92%)
         occurrences causally related to treatment / all
    3 / 5
    4 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    vertigo
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    gastritis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    costochondritis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 343 (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
    abscess limb
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    appendicitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bronchitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    osteomyelitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tooth infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sinusitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    diabetic ketoacidosis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 343 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoglycaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    7 / 349 (2.01%)
    27 / 343 (7.87%)
         occurrences causally related to treatment / all
    3 / 7
    16 / 33
         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 Degludec 500 U/mL Insulin Efsitora Alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    119 / 349 (34.10%)
    117 / 343 (34.11%)
    Skin and subcutaneous tissue disorders
    dermatitis contact
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    16 / 349 (4.58%)
    19 / 343 (5.54%)
         occurrences all number
    16
    20
    Infections and infestations
    covid-19
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    23 / 349 (6.59%)
    16 / 343 (4.66%)
         occurrences all number
    24
    16
    urinary tract infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    11 / 349 (3.15%)
    21 / 343 (6.12%)
         occurrences all number
    16
    24
    nasopharyngitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    42 / 349 (12.03%)
    40 / 343 (11.66%)
         occurrences all number
    54
    45
    upper respiratory tract infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    30 / 349 (8.60%)
    24 / 343 (7.00%)
         occurrences all number
    35
    29
    influenza
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    18 / 349 (5.16%)
    27 / 343 (7.87%)
         occurrences all number
    22
    30

    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
    - Objectives, Endpoints, and Estimands were modified. - Inclusion and Exclusion Criteria were modified. - Updated the analysis populations/sets. - Statistical Considerations: Made updates to endpoint word order throughout section and subsections for clarity - Primary Endpoint(s)/Estimand(s) Analysis: Replaced the stratification factor “prestudy basal insulin glargine U-300 or other basal insulin” with a new stratification factor “CGM use prior to study entry [yes/no]” in ANCOVA and MMRM models. - Safety Analyses: Removed inadvertently hidden text format applied to hypoglycemia time period definitions.
    21 Jun 2022
    - Schedule of Activities (SoA) have been updated. - Deleted text “Potential intrinsic and extrinsic factors” from tertiary endpoints for PK/PD of LY3209590. - Edited text to describe use of the unblinded Continuous glucose monitoring (CGM) system receive
    12 Oct 2022
    - SoA updated for clarity - Inclusion and Exclusion Criteria were modified - Added “if the participants can safely do this” for participants advised to check SMBG readings for suspected hypoglycemia for clarification. - Added a note for participants to not manually calibrate the study CGM with fingerstick blood glucose readings for clarification.

    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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